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Infections during extended circulatory support: University of Alabama at Birmingham experience 1989 to 1994
Infections During Extended Circulatory Support: University of Alabama at Birmingham Experience 1989 to 1994 William L. Holman, MD, C. Patrick Murrah, MD, Edward R. Ferguson, MD, Robert C. Bourge, MD, David C. McGiffin, MD, and James K. Kirklin, MD Departments of Cardiothoracic Surgery and Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama
Background. The University of Alabama at Birmingham experience with investigational ventricular assist devices (VADs) used as a bridge to transplantation has increased over the past several years; it now includes 27 VAD implantations with 13 VAD runs lasting for extended periods (ie, >30 days). A review of complications experienced by patients during extended VAD runs is warranted before the further development and testing of chronically implanted mechanical circulatory support devices. Methods. This study focuses on the infectious complications of extended VAD support; it includes 13 patients who were supported by either a Thoratec or HeartMate VAD for longer than 30 days pending cardiac transplantation. Infection was defined as any positive culture. The infections were classed according to site and severity as follows: class I were patient-related non-blood-borne infections, class II were blood-borne infections, class III were VAD percutaneous site infections, and class IV were infections of the blood-contacting surfaces or intracorporeal components of the VAD. Results. The 8 Thoratec and 5 HeartMate patients were supported for a total of 1,648 days with a range of 33 to 279 days per patient. Every patient had at least one infection; however, there were 6 patients who had no
class II or IV infections during the period of support. One of these 6 patients died of a stroke, whereas the other 5 patients survived VAD support. No trends were identified for a change in the incidence of bacterial compared with fungal infections during the course of VAD support, There was no trend for a greater number of infections in patients who died during VAD support compared with those who survived. Neither class II nor IV infections precluded transplantation. Three patients died during VAD support; I died as a direct consequence of fungal infection. Eight patients received transplants. One patient had an unanticipated recovery of cardiac function and the VAD was removed. Support in I patient is ongoing. Conclusions. Infection during VAD support pending cardiac transplantation is an important cause of morbidity and mortality in patients maintained for longer than 30 days by circulatory assist. Infectious complications will probably be a prominent component of the risk associated with the use of chronically implanted mechanical circulatory assist devices and will likely have an important effect on the quality of life experienced by these patients.
nfection, thromboembolism, and hemorrhage at the time of implantation are complications that may be associated with the use of mechanical circulatory support devices. The potential for infection in paracorporeal and intracorporeal blood pumps was noted early in the development of ventricular assist devices (VADs) and total artificial hearts (TAHs) [1]. Subsequent clinical experience with VADs and TAHs has demonstrated the accuracy of this prediction [2-9]. Several VADs have recently received Food and Drug Administration approval or are in the final stages of obtaining approval for use as a bridge to cardiac trans-
plantation. During this investigative clinical experience, some patients were maintained on mechanical circulatory support for extended periods of time. It is useful to examine the results of extended circulatory support as a predictor of problems that may occur when VADs and TAHs are used for permanent cardiac replacement. The purpose of this article is to summarize the clinical experience with infections in patients supported by two types of VADs pending cardiac transplantation at the University of Alabama at Birmingham (UAB). The study period extends from April 23, 1989, through September 20, 1994.
I
(Ann Thorac Surg 1996;61:366-71)
Material a n d M e t h o d s Presented at The Third International Conferenceon CirculatorySupport Devices for Severe Cardiac Failure, Pittsburgh, PA, Oct 28-30, 1994. Address reprint requests to Dr Holman, Department of Surgery,University of Alabama at Birmingham, University Station, Birmingham, AL 35294. © 1996 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
The ventricular assist device program at UAB received local institutional review board approval for the Thoratec (Thoratec Laboratories Inc, Berkeley, CA) VAD in September 1988. The first patient entered the Thoratec in0003-4975/96/$15.00 SSDI 0003-4975(95)01021-1
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vestigational device exemption protocol at UAB in April 1989. The Thermo Cardiosystems HeartMate (Thermo Cardiosystems, Inc, Woburn, MA) left VAD was approved by the local investigational review board in November 1990. The first patient supported by the HeartMate left VAD at UAB received his device in July 1991. Patients received the Thoratec device if they had any of the following: medically refractory ventricular arrhythmias, right ventricular failure requiring VAD support, or a condition that required left atrial cannulation for a left VAD (eg, acute anteroapical myocardial infarction). After the HeartMate device was approved at UAB, patients were randomized between the Thoratec and the HeartMate devices if they required only left ventricular support with a left ventricular apex to aorta VAD. All patients described in this study were accepted for cardiac transplantation before VAD placement. The patients met the device-specific criteria of the federal Food and Drug Administration investigational device exemption protocol for profound circulatory failure before implantation. For the purposes of this report, extended VAD support is defined as longer than 30 days in duration. Infection is defined as an antemortem positive culture result. Leukocyte counts and antibiotic administration were recorded, but did not determine the presence or absence of infection. Standard variables describing each infection were recorded for analysis. The first variable is the classification of infection. Class I infections include patient-related non-blood infections. Class I infections encompass infections of urine, wounds (exclusive of mediastinal infections), sputum, and catheter tips from intravascular or other indwelling lines. Class II infections include bloodborne organisms that were detected by blood culture. Class III infections were VAD-related infections at percutaneous insertion sites (ie, driveline and cannula insertion sites). Class IV infections were VAD-related infections that involved blood-contacting or intracorporeal VAD components. Mediastinitis is included in this group of infections. Infection time was calculated as the post-VAD insertion day (ie, infection date - VAD implant date) and the relative infection time (ie, post-VAD insertion day • total VAD duration-I). The infecting organism(s) were defined as bacterial or fungal and then defined by genus and species grouping. The site of infection was recorded. The outcome of infection was defined according to whether or not the infection led directly to the patient's death. Culture information was obtained retrospectively from hospital records. The data are complete in all patients as of September 20, 1994.
Results There have been 27 VAD implantations at UAB for the indication of profound circulatory failure pending cardiac transplantation. The duration of these implantations is displayed in Figure 1. Thirteen of the patients were
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Fig 1. Duration of ventricular assist device WAD) support for the 27 patients who have been managed with VADs at the University of Alabama at Birmingham is shown. This analysis of infection examines only the patients who were supportedfor longer than 30 days, as displayed by the dashed line.
supported for longer than 30 days. Eight of these 13 patients were supported by Thoratec devices and 5 patients were supported by the HeartMate left VAD. The total duration of support was 1,648 days in the 13 patients on a VAD for longer than 30 days. The 8 Thoratec patients accumulated 950 days of support with a range of 33 to 247 days per patient. The 5 HeartMate patients accumulated 698 days of support with a range of 71 to 279 days per patient. Subsequent comments are confined to the patients with VAD implantation durations of greater than 30 days. The VAD configuration was a left ventricular apical cannulation in all 5 HeartMate left VAD patients. Five Thoratec patients had left atrial cannulation for a left VAD. Two Thoratec patients had a left ventricular apical cannulation for a left VAD. One Thoratec patient had biventricular assist devices with left ventricular cannulation for the left-sided device. The infecting organisms according to the class of infection were as follows: Class I infections Mixed Yeast Staphylococcus aureus Staphylococcus epidermidis Others Class II infections Staphylococcus epidermidis Staphylococcus aureus Candida albicans
18 16 10 5 14 11 6 3
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The mixed class I infections were predominantly obtained from sputum samples (59 of 92 class I cultures), Nonspeciated class I yeast cultures were obtained predominantly from sputum samples (20 of 22 yeast cultures). Staphylococcus aureus was found in 21 class I and II infections, whereas Staphylococcus epidermidis occurred in 16 instances. There were three positive blood cultures w i t h Candida albicans. All of the Cand/da-positive blood cultures were obtained from 1 patient who died before transplantation. A wide variety of other gram-positive and gram-negative organisms were noted in class I and class II infections. These are listed as "Other". "'Yeast'" refers to nonspeciated yeast that were found in cutaneous, urine, and sputum cultures. "Mixed" refers to mixed organisms found in sputum. The mixed groupings are usually considered typical for normal respiratory flora and are not speciated. Staphylococcal organisms were responsible for the majority of the 16 percutaneous site infections (ie, class III infections). There were only two class IV infections. Both cultures were obtained from the mediastinum. One of these patients died before transplantation and the other underwent successful transplantation. Figure 2 illustrates the cumulative number of positive bacterial and fungal culture of all classes that occurred during VAD support in the 13 patients supported for
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Fig 3. Total number of injections of all classes for each patient is illustrated. The patients who died during ventricular assist device (VAD) support were placed on the left side of the graph to allow comparison with those who survived VAD support.
longer than 30 days. The occurrence of new bacterial and fungal cultures was spread across the entire duration of support. The total number of infections of all classes that occurred in each patient during VAD support is shown in Figure 3. The patients who died during VAD support were placed on the left side of the illustration. All patients had a least one positive culture, and there was no relationship between the total number of infections and death during VAD support. The more serious infections (ie, class II and class IV infections) for each patient are enumerated in Figure 4. One patient died without a class II or class IV infection, whereas 5 patients without similar infections survived. One patient with a total of 19 positive blood cultures underwent successful transplantation after 279 days of support. Positive sputum cultures for all patients and the subgroup of patients who survived until transplantation is shown in Figure 5. Patients who had successful transplantation had no positive sputum cultures reported after the initial 20% of the VAD run; patients in whom complications developed during VAD support and who did not have transplantation continued to suffer from pulmonary infections. In Figure 6, positive blood cultures that occurred during VAD support are illustrated for all patients and patients who survived VAD support. The initial positive blood cultures were obtained later in surviving patients, and these patients did not have any positive blood culture results during the final 20% of their period of VAD support. As noted in the figures, 3 patients died during VAD support. The first of these patients had a hemispheric
Ann Thorac Surg 1996;61:366-71
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Fig 6. Cumulative number of positive blood cultures is shown as a function of the relative infection time. (VAD = ventricular assist device.)
stroke. Thrombosis of the VAD inflow conduit then developed. Because of his severe fixed neurologic deficit, support was withdrawn. He ultimately died with cardiac failure and pneumonia. The second death occurred in a patient with a fungal class II infection. After the infection had been diagnosed, he had a stroke that produced a severe fixed neurologic deficit. This stroke was due to a septic embolus; this patient's death is considered to be
directly attributable to infection. At the family's request the VAD was removed and the patient subsequently died. The third patient who died during VAD support also had a stroke with a severe fixed neurologic deficit. He was subsequently found to have a class IV infection (ie, Staphylococcus aureus mediastinitis). At the family's request the VAD was removed and the patient died. There were 10 patients who survived VAD support. One patient had an unanticipated recovery of native cardiac function. His VAD was removed and he survived. Eight patients underwent cardiac transplantation, and support in 1 patient is ongoing.
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The potential for infection to adversely affect the risks of circulatory support and quality of life in patients with chronically implanted circulatory assist devices has long been recognized [1]. The use of investigational VADs for longer than 30 days in patients awaiting donor hearts affords us an opportunity to actually define the risks of infection in chronically implanted pumps. Previous reports of patients supported by VADs [2-4, 7-9] or TAHs [3, 6] unanimously include infection a m o n g the complications. In some instances device infection led to death; however, infections frequently were controlled by antibiotics, w o u n d debridement with irrigation, or VAD replacement. In one report of outcome after transplantation in VAD patients, the posttransplantation prevalence of infection was similar to the prevalence in transplant recipients who did not require VAD support [10]. However, in a larger multiinstitutional study, VAD support was a significant risk factor for posttransplantation infection [11].
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The present study included all positive cultures as infections. This broad definition resulted in a comparatively large number of reported events and a 100% prevalence of infection during VAD support of longer than 30 days. However, the chances for missing or not reporting an infection were minimized. Other investigators have required concomitant antibiotic treatment, fever, or leukocytosis for the definition of infection. In this retrospective analysis, the frequent use of antibiotics, high prevalence of fever, and persistent elevation of leukocyte counts rendered these variables useless as discriminators for infection. The classification scheme for infection attempts to place the data in perspective. If serious infection is defined as a class II or IV infection, there are 6 patients who did not experience serious infections during VAD support. Of these 6 patients, 1 died of a stroke with subsequent complications whereas 5 survived. Infection led directly to the death of 1 patient, and was an important source of morbidity in the patients who survived support on Thoratec or HeartMate VADs while awaiting transplantation. The cumulative number of bacterial and fungal infections was examined to determine if there was a change in the incidence of these types of infection during the period of circulatory support. It is possible that treatment with broad-spectrum antibiotics makes the patient more susceptible to fungal colonization and infection; however, there was no evidence for this effect in our patients. The genus and species grouping included nonspeciated yeast as a frequent inhabitant of the respiratory tract and percutaneous insertion site. Thus, prophylactic treatment with fluconazole during the initial period of VAD support and subsequent prophylactic treatment with nystatin seems prudent on an empirical basis. Staphylococcal species were noted frequently in all classes of infection. The high prevalence of staphylococcal infection in implanted biomaterials has been noted by others [4]. This finding may be related to the ability of Staphylococcus to adhere to a variety of surfaces and survive in the immediate vicinity of foreign materials [12-15], as well as their ability to generate a biofilm that insulates them from normal host defenses and antibiotics [16, 17]. A comparison of cumulative positive sputum cultures in transplant recipients and the entire group of VAD recipients showed that the transplant group had no positive cultures after the initial 20% of the VAD run. The patients who did not have transplantation all had strokes with major neurologic deficits. One patient required mechanical ventilation before death. Presumably, confinement to bed and the inability to mobilize pulmonary secretions resulted in the positive sputum cultures before death. Comparison of the positive blood cultures showed fewer positive cultures during the initial and late segments of VAD support in the patients who survived. Note that the majority of the blood cultures were obtained from 1 patient who had a left VAD for 279 days before transplantation. At the time of removal, there was no evidence of infection in this patient's p u m p or conduits.
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Subsequent to transplantation a Candida abscess of the chest wall developed. Mediastinitis occurred in 2 patients. In 1 patient, persistent leukocytosis and fevers followed a left VAD implantation. This implantation had been complicated by bleeding that led to reexploration of the chest; this was his second sternotomy. At a third operation, a large clot infected with Staphylococcus epidermidis was removed. Systemic vancomycin and chronic mediastinal irrigation with vancomycin in saline solution eradicated his infection and he received a transplant. The second patient had an aborted cardiac transplantation. He subsequently suffered a stroke. Before he died a spiking fever pattern developed and pus was aspirated from the mediastinum. This aspirate grew Staphylococcus aureus. These 2 cases suggest that repeat sternotomy may be an important risk factor for mediastinal infection in this group of debilitated patients with foreign material implanted in the mediastinum. Whether or not the amount of foreign material inside the mediastinum affects the prevalence of mediastinitis remains an open question that is relevant to the use of the TAH as a permanent replacement device [6]. Our current approach to the prevention of infection in VADs includes measures taken at the time of implantation, during the VAD run, and at explantation. At implantation, prophylactic antibiotics and antifungal agents are used. These drugs are vancomycin, ceftazidime, and fluconazole. They are given until the patient is extubated and lines are removed. Cutaneous decontamination is performed with Duraprep (3M Health Care, St. Paul, MN) and an Ioban drape (Surgical Products Division/3M, St. Paul, MN). Topical irrigation with vancomycin in saline solution is used. A cylinder-dilator assembly is used to gauge the size of the percutaneous insertion incision and protect the cannulas from contamination as they pass out of the body. During the VAD run, the percutaneous sites are washed daily with peroxide and saline solution, then dressed with either povidone-iodine or silver sulfadiazine. If granulation tissue develops, it is debrided to maintain the tightest possible contact between the cannula and skin. Nystatin therapy is continued throughout the duration of VAD support. At the time of explantation, prophylactic antibiotics include vancomycin and ceftazidime. The external VAD components are isolated with a separate application of Duraprep and a separate Ioban drape. In conclusion, infection during VAD support pending cardiac transplantation is an important cause of morbidity and mortality in patients maintained for longer than 30 days by circulatory assistance. Infectious complications will probably be a prominent component of the risk associated with the use of chronically implanted mechanical circulatory assist devices and will likely have an important effect on the quality of life experienced by these patients. Infection remains a problem despite the use of prophylactic antibiotic-antifungal therapy at the time of VAD insertion as well as the aggressive treatment of diagnosed infections during VAD support. However, infec-
Ann Thorac Surg 1996;61:366-71
tion d u r i n g VAD support does not preclude successful cardiac transplantation. The limitations of conventional antibiotic a n d antifungal therapies suggest that novel approaches to the prevention, treatment, a n d eradication of infection will improve the success of chronically i m p l a n t e d circulatory support devices. Novel methods currently u n d e r develo p m e n t for the prevention a n d treatment of infection in chronically i m p l a n t e d circulatory support devices include the following: the d e v e l o p m e n t of totally implantable circulatory support devices, the design of biomaterials that resist infection a n d a c c o m m o d a t e native i m m u n e responses [13, 14, 16], a n d the d e v e l o p m e n t of immunologically m e d i a t e d methods that prevent bacterial-biomaterial adhesion [12]. This work was performed during Dr Holman's tenure as an Established Investigator of the American Heart Association.
References 1. US Department of Health and Human Services. Artificial heart and assist devices: directions, needs, costs, societal and ethical issues. Bethesda: National Institutes of Health, 1985: 25-7. 2. Gray LA Jr, Ganzel BL, Mavroudis C, Slater AD. The PierceDonachy ventricular assist device as a bridge to cardiac transplantation. Ann Thorac Surg 1989;,48:222-7. 3. Gristina AG, Dobbins JJ, Giammara 13, Lewis JC, DeVries WC. Biomaterial-centered sepsis and the total artificial heart: microbial adhesion vs. tissue integration. JAMA 1988; 259:870-4. 4. Didisheim P, Oisen DB, Farrar DJ, et al. Infections and thromboembolism with implantable cardiovascular devices. Trans Am Soc Artif Intern Organs 1994;35:54-70.
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5. McBride LR, Ruzevich SA, Pennington DG, et al. Infectious complications associated with ventricular assist device support. Trans Am Soc Artif Intern Organs 1994;33: 201-2. 6. Kormos RL, Borovetz HS, Armitage JM, Hardesty RL, Marrone GC, Griffith BP. Evolving experience with mechanical circulatory support. Ann Surg 1991;214:471-7. 7. Burton NA, Lefrak EA, Macmanus Q, et al. A reliable bridge to cardiac transplantation: the TCI left ventricular assist device. Ann Thorac Surg 1993;55:1425-31. 8. Frazier OH, Rose EA, Macmanus Q, et al. Multicenter clinical evaluation of the HeartMate 1000 IP left ventricular assist device. Ann Thorac Surg 1992;53:1080-90. 9. Phillips WS, Burton NA, Macmanus Q, Lefrak EA. Surgical complications in bridging to transplantation: the Thermo Cardiosystems LVAD. Ann Thorac Surg 1992;53:482-6. 10. O'Connell JB, Renlund DG, Robinson JA, et al. Effect of preoperative hemodynamic support on survival after cardiac transplantation. Circulation 1988;78(Suppl 3):78-82. 11. Smart FH, Naftel DC, Costanzo MR, et al. Risk factors for early, cumulative, and fatal infections following cardiac transplantation: a multi-center study. J Heart Lung Transplant (in press). 12. Patti JM, Allen BL, McGavin MJ, Hook M. MSCRAMMMediated adherence of microorganisms to host tissues. Annu Rev Microbiol 1994;48:585-617. 13. Gristina AG. Biomaterial-centered infection: microbial adhesion versus tissue integration. Science 1987;237:1588-95. 14. Gristina AG, Giridhar G, Gabriel BL, Naylor PT, Myrvik QN. Cell biology and molecular mechanisms in artificial device infections. Int J Artif Organs 1993;16:755-64. 15. Tojo M, Yamashita N, Goldmann DA, Pier GB. Isolation and characterization of a capsular polysaccharide adhesin from Staphylococcus ep/derm/d/s. J Infect Dis 1988;157:713-22. 16. Gristina AG. Implant failure and the immuno-incompetent fibro-inflarnmatoryzone. Clin Orthop 1994;298:106-18. 17. Bergamini TM, Corpus RA Jr, Hoeg KL, Brittian KR, Peyton JC, Cheadle WG. Immune regulation of bacterial biofilm graft infection. ASAIO Trans 1994;40:219-26.
Background. The University of Alabama at Birmingham experience with investigational ventricular assist devices (VADs) used as a bridge to transplantation has increased over the past several years; it now includes 27 VAD implantations with 13 VAD runs lasting for extended periods (ie, >30 days). A review of complications experienced by patients during extended VAD runs is warranted before the further development and testing of chronically implanted mechanical circulatory support devices. Methods. This study focuses on the infectious complications of extended VAD support; it includes 13 patients who were supported by either a Thoratec or HeartMate VAD for longer than 30 days pending cardiac transplantation. Infection was defined as any positive culture. The infections were classed according to site and severity as follows: class I were patient-related non-blood-borne infections, class II were blood-borne infections, class III were VAD percutaneous site infections, and class IV were infections of the blood-contacting surfaces or intracorporeal components of the VAD. Results. The 8 Thoratec and 5 HeartMate patients were supported for a total of 1,648 days with a range of 33 to 279 days per patient. Every patient had at least one infection; however, there were 6 patients who had no
class II or IV infections during the period of support. One of these 6 patients died of a stroke, whereas the other 5 patients survived VAD support. No trends were identified for a change in the incidence of bacterial compared with fungal infections during the course of VAD support, There was no trend for a greater number of infections in patients who died during VAD support compared with those who survived. Neither class II nor IV infections precluded transplantation. Three patients died during VAD support; I died as a direct consequence of fungal infection. Eight patients received transplants. One patient had an unanticipated recovery of cardiac function and the VAD was removed. Support in I patient is ongoing. Conclusions. Infection during VAD support pending cardiac transplantation is an important cause of morbidity and mortality in patients maintained for longer than 30 days by circulatory assist. Infectious complications will probably be a prominent component of the risk associated with the use of chronically implanted mechanical circulatory assist devices and will likely have an important effect on the quality of life experienced by these patients.
nfection, thromboembolism, and hemorrhage at the time of implantation are complications that may be associated with the use of mechanical circulatory support devices. The potential for infection in paracorporeal and intracorporeal blood pumps was noted early in the development of ventricular assist devices (VADs) and total artificial hearts (TAHs) [1]. Subsequent clinical experience with VADs and TAHs has demonstrated the accuracy of this prediction [2-9]. Several VADs have recently received Food and Drug Administration approval or are in the final stages of obtaining approval for use as a bridge to cardiac trans-
plantation. During this investigative clinical experience, some patients were maintained on mechanical circulatory support for extended periods of time. It is useful to examine the results of extended circulatory support as a predictor of problems that may occur when VADs and TAHs are used for permanent cardiac replacement. The purpose of this article is to summarize the clinical experience with infections in patients supported by two types of VADs pending cardiac transplantation at the University of Alabama at Birmingham (UAB). The study period extends from April 23, 1989, through September 20, 1994.
I
(Ann Thorac Surg 1996;61:366-71)
Material a n d M e t h o d s Presented at The Third International Conferenceon CirculatorySupport Devices for Severe Cardiac Failure, Pittsburgh, PA, Oct 28-30, 1994. Address reprint requests to Dr Holman, Department of Surgery,University of Alabama at Birmingham, University Station, Birmingham, AL 35294. © 1996 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
The ventricular assist device program at UAB received local institutional review board approval for the Thoratec (Thoratec Laboratories Inc, Berkeley, CA) VAD in September 1988. The first patient entered the Thoratec in0003-4975/96/$15.00 SSDI 0003-4975(95)01021-1
Ann Thorac Surg 1996;61:366-71
vestigational device exemption protocol at UAB in April 1989. The Thermo Cardiosystems HeartMate (Thermo Cardiosystems, Inc, Woburn, MA) left VAD was approved by the local investigational review board in November 1990. The first patient supported by the HeartMate left VAD at UAB received his device in July 1991. Patients received the Thoratec device if they had any of the following: medically refractory ventricular arrhythmias, right ventricular failure requiring VAD support, or a condition that required left atrial cannulation for a left VAD (eg, acute anteroapical myocardial infarction). After the HeartMate device was approved at UAB, patients were randomized between the Thoratec and the HeartMate devices if they required only left ventricular support with a left ventricular apex to aorta VAD. All patients described in this study were accepted for cardiac transplantation before VAD placement. The patients met the device-specific criteria of the federal Food and Drug Administration investigational device exemption protocol for profound circulatory failure before implantation. For the purposes of this report, extended VAD support is defined as longer than 30 days in duration. Infection is defined as an antemortem positive culture result. Leukocyte counts and antibiotic administration were recorded, but did not determine the presence or absence of infection. Standard variables describing each infection were recorded for analysis. The first variable is the classification of infection. Class I infections include patient-related non-blood infections. Class I infections encompass infections of urine, wounds (exclusive of mediastinal infections), sputum, and catheter tips from intravascular or other indwelling lines. Class II infections include bloodborne organisms that were detected by blood culture. Class III infections were VAD-related infections at percutaneous insertion sites (ie, driveline and cannula insertion sites). Class IV infections were VAD-related infections that involved blood-contacting or intracorporeal VAD components. Mediastinitis is included in this group of infections. Infection time was calculated as the post-VAD insertion day (ie, infection date - VAD implant date) and the relative infection time (ie, post-VAD insertion day • total VAD duration-I). The infecting organism(s) were defined as bacterial or fungal and then defined by genus and species grouping. The site of infection was recorded. The outcome of infection was defined according to whether or not the infection led directly to the patient's death. Culture information was obtained retrospectively from hospital records. The data are complete in all patients as of September 20, 1994.
Results There have been 27 VAD implantations at UAB for the indication of profound circulatory failure pending cardiac transplantation. The duration of these implantations is displayed in Figure 1. Thirteen of the patients were
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Fig 1. Duration of ventricular assist device WAD) support for the 27 patients who have been managed with VADs at the University of Alabama at Birmingham is shown. This analysis of infection examines only the patients who were supportedfor longer than 30 days, as displayed by the dashed line.
supported for longer than 30 days. Eight of these 13 patients were supported by Thoratec devices and 5 patients were supported by the HeartMate left VAD. The total duration of support was 1,648 days in the 13 patients on a VAD for longer than 30 days. The 8 Thoratec patients accumulated 950 days of support with a range of 33 to 247 days per patient. The 5 HeartMate patients accumulated 698 days of support with a range of 71 to 279 days per patient. Subsequent comments are confined to the patients with VAD implantation durations of greater than 30 days. The VAD configuration was a left ventricular apical cannulation in all 5 HeartMate left VAD patients. Five Thoratec patients had left atrial cannulation for a left VAD. Two Thoratec patients had a left ventricular apical cannulation for a left VAD. One Thoratec patient had biventricular assist devices with left ventricular cannulation for the left-sided device. The infecting organisms according to the class of infection were as follows: Class I infections Mixed Yeast Staphylococcus aureus Staphylococcus epidermidis Others Class II infections Staphylococcus epidermidis Staphylococcus aureus Candida albicans
18 16 10 5 14 11 6 3
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Others Class III infections
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6
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The mixed class I infections were predominantly obtained from sputum samples (59 of 92 class I cultures), Nonspeciated class I yeast cultures were obtained predominantly from sputum samples (20 of 22 yeast cultures). Staphylococcus aureus was found in 21 class I and II infections, whereas Staphylococcus epidermidis occurred in 16 instances. There were three positive blood cultures w i t h Candida albicans. All of the Cand/da-positive blood cultures were obtained from 1 patient who died before transplantation. A wide variety of other gram-positive and gram-negative organisms were noted in class I and class II infections. These are listed as "Other". "'Yeast'" refers to nonspeciated yeast that were found in cutaneous, urine, and sputum cultures. "Mixed" refers to mixed organisms found in sputum. The mixed groupings are usually considered typical for normal respiratory flora and are not speciated. Staphylococcal organisms were responsible for the majority of the 16 percutaneous site infections (ie, class III infections). There were only two class IV infections. Both cultures were obtained from the mediastinum. One of these patients died before transplantation and the other underwent successful transplantation. Figure 2 illustrates the cumulative number of positive bacterial and fungal culture of all classes that occurred during VAD support in the 13 patients supported for
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longer than 30 days. The occurrence of new bacterial and fungal cultures was spread across the entire duration of support. The total number of infections of all classes that occurred in each patient during VAD support is shown in Figure 3. The patients who died during VAD support were placed on the left side of the illustration. All patients had a least one positive culture, and there was no relationship between the total number of infections and death during VAD support. The more serious infections (ie, class II and class IV infections) for each patient are enumerated in Figure 4. One patient died without a class II or class IV infection, whereas 5 patients without similar infections survived. One patient with a total of 19 positive blood cultures underwent successful transplantation after 279 days of support. Positive sputum cultures for all patients and the subgroup of patients who survived until transplantation is shown in Figure 5. Patients who had successful transplantation had no positive sputum cultures reported after the initial 20% of the VAD run; patients in whom complications developed during VAD support and who did not have transplantation continued to suffer from pulmonary infections. In Figure 6, positive blood cultures that occurred during VAD support are illustrated for all patients and patients who survived VAD support. The initial positive blood cultures were obtained later in surviving patients, and these patients did not have any positive blood culture results during the final 20% of their period of VAD support. As noted in the figures, 3 patients died during VAD support. The first of these patients had a hemispheric
Ann Thorac Surg 1996;61:366-71
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Fig 4. Class II and IV infections are considered serious infections in this analysis. The number of serious infections for each patient is displayed. (VAD = ventricular assist device.)
Fig 6. Cumulative number of positive blood cultures is shown as a function of the relative infection time. (VAD = ventricular assist device.)
stroke. Thrombosis of the VAD inflow conduit then developed. Because of his severe fixed neurologic deficit, support was withdrawn. He ultimately died with cardiac failure and pneumonia. The second death occurred in a patient with a fungal class II infection. After the infection had been diagnosed, he had a stroke that produced a severe fixed neurologic deficit. This stroke was due to a septic embolus; this patient's death is considered to be
directly attributable to infection. At the family's request the VAD was removed and the patient subsequently died. The third patient who died during VAD support also had a stroke with a severe fixed neurologic deficit. He was subsequently found to have a class IV infection (ie, Staphylococcus aureus mediastinitis). At the family's request the VAD was removed and the patient died. There were 10 patients who survived VAD support. One patient had an unanticipated recovery of native cardiac function. His VAD was removed and he survived. Eight patients underwent cardiac transplantation, and support in 1 patient is ongoing.
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The potential for infection to adversely affect the risks of circulatory support and quality of life in patients with chronically implanted circulatory assist devices has long been recognized [1]. The use of investigational VADs for longer than 30 days in patients awaiting donor hearts affords us an opportunity to actually define the risks of infection in chronically implanted pumps. Previous reports of patients supported by VADs [2-4, 7-9] or TAHs [3, 6] unanimously include infection a m o n g the complications. In some instances device infection led to death; however, infections frequently were controlled by antibiotics, w o u n d debridement with irrigation, or VAD replacement. In one report of outcome after transplantation in VAD patients, the posttransplantation prevalence of infection was similar to the prevalence in transplant recipients who did not require VAD support [10]. However, in a larger multiinstitutional study, VAD support was a significant risk factor for posttransplantation infection [11].
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The present study included all positive cultures as infections. This broad definition resulted in a comparatively large number of reported events and a 100% prevalence of infection during VAD support of longer than 30 days. However, the chances for missing or not reporting an infection were minimized. Other investigators have required concomitant antibiotic treatment, fever, or leukocytosis for the definition of infection. In this retrospective analysis, the frequent use of antibiotics, high prevalence of fever, and persistent elevation of leukocyte counts rendered these variables useless as discriminators for infection. The classification scheme for infection attempts to place the data in perspective. If serious infection is defined as a class II or IV infection, there are 6 patients who did not experience serious infections during VAD support. Of these 6 patients, 1 died of a stroke with subsequent complications whereas 5 survived. Infection led directly to the death of 1 patient, and was an important source of morbidity in the patients who survived support on Thoratec or HeartMate VADs while awaiting transplantation. The cumulative number of bacterial and fungal infections was examined to determine if there was a change in the incidence of these types of infection during the period of circulatory support. It is possible that treatment with broad-spectrum antibiotics makes the patient more susceptible to fungal colonization and infection; however, there was no evidence for this effect in our patients. The genus and species grouping included nonspeciated yeast as a frequent inhabitant of the respiratory tract and percutaneous insertion site. Thus, prophylactic treatment with fluconazole during the initial period of VAD support and subsequent prophylactic treatment with nystatin seems prudent on an empirical basis. Staphylococcal species were noted frequently in all classes of infection. The high prevalence of staphylococcal infection in implanted biomaterials has been noted by others [4]. This finding may be related to the ability of Staphylococcus to adhere to a variety of surfaces and survive in the immediate vicinity of foreign materials [12-15], as well as their ability to generate a biofilm that insulates them from normal host defenses and antibiotics [16, 17]. A comparison of cumulative positive sputum cultures in transplant recipients and the entire group of VAD recipients showed that the transplant group had no positive cultures after the initial 20% of the VAD run. The patients who did not have transplantation all had strokes with major neurologic deficits. One patient required mechanical ventilation before death. Presumably, confinement to bed and the inability to mobilize pulmonary secretions resulted in the positive sputum cultures before death. Comparison of the positive blood cultures showed fewer positive cultures during the initial and late segments of VAD support in the patients who survived. Note that the majority of the blood cultures were obtained from 1 patient who had a left VAD for 279 days before transplantation. At the time of removal, there was no evidence of infection in this patient's p u m p or conduits.
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Subsequent to transplantation a Candida abscess of the chest wall developed. Mediastinitis occurred in 2 patients. In 1 patient, persistent leukocytosis and fevers followed a left VAD implantation. This implantation had been complicated by bleeding that led to reexploration of the chest; this was his second sternotomy. At a third operation, a large clot infected with Staphylococcus epidermidis was removed. Systemic vancomycin and chronic mediastinal irrigation with vancomycin in saline solution eradicated his infection and he received a transplant. The second patient had an aborted cardiac transplantation. He subsequently suffered a stroke. Before he died a spiking fever pattern developed and pus was aspirated from the mediastinum. This aspirate grew Staphylococcus aureus. These 2 cases suggest that repeat sternotomy may be an important risk factor for mediastinal infection in this group of debilitated patients with foreign material implanted in the mediastinum. Whether or not the amount of foreign material inside the mediastinum affects the prevalence of mediastinitis remains an open question that is relevant to the use of the TAH as a permanent replacement device [6]. Our current approach to the prevention of infection in VADs includes measures taken at the time of implantation, during the VAD run, and at explantation. At implantation, prophylactic antibiotics and antifungal agents are used. These drugs are vancomycin, ceftazidime, and fluconazole. They are given until the patient is extubated and lines are removed. Cutaneous decontamination is performed with Duraprep (3M Health Care, St. Paul, MN) and an Ioban drape (Surgical Products Division/3M, St. Paul, MN). Topical irrigation with vancomycin in saline solution is used. A cylinder-dilator assembly is used to gauge the size of the percutaneous insertion incision and protect the cannulas from contamination as they pass out of the body. During the VAD run, the percutaneous sites are washed daily with peroxide and saline solution, then dressed with either povidone-iodine or silver sulfadiazine. If granulation tissue develops, it is debrided to maintain the tightest possible contact between the cannula and skin. Nystatin therapy is continued throughout the duration of VAD support. At the time of explantation, prophylactic antibiotics include vancomycin and ceftazidime. The external VAD components are isolated with a separate application of Duraprep and a separate Ioban drape. In conclusion, infection during VAD support pending cardiac transplantation is an important cause of morbidity and mortality in patients maintained for longer than 30 days by circulatory assistance. Infectious complications will probably be a prominent component of the risk associated with the use of chronically implanted mechanical circulatory assist devices and will likely have an important effect on the quality of life experienced by these patients. Infection remains a problem despite the use of prophylactic antibiotic-antifungal therapy at the time of VAD insertion as well as the aggressive treatment of diagnosed infections during VAD support. However, infec-
Ann Thorac Surg 1996;61:366-71
tion d u r i n g VAD support does not preclude successful cardiac transplantation. The limitations of conventional antibiotic a n d antifungal therapies suggest that novel approaches to the prevention, treatment, a n d eradication of infection will improve the success of chronically i m p l a n t e d circulatory support devices. Novel methods currently u n d e r develo p m e n t for the prevention a n d treatment of infection in chronically i m p l a n t e d circulatory support devices include the following: the d e v e l o p m e n t of totally implantable circulatory support devices, the design of biomaterials that resist infection a n d a c c o m m o d a t e native i m m u n e responses [13, 14, 16], a n d the d e v e l o p m e n t of immunologically m e d i a t e d methods that prevent bacterial-biomaterial adhesion [12]. This work was performed during Dr Holman's tenure as an Established Investigator of the American Heart Association.
References 1. US Department of Health and Human Services. Artificial heart and assist devices: directions, needs, costs, societal and ethical issues. Bethesda: National Institutes of Health, 1985: 25-7. 2. Gray LA Jr, Ganzel BL, Mavroudis C, Slater AD. The PierceDonachy ventricular assist device as a bridge to cardiac transplantation. Ann Thorac Surg 1989;,48:222-7. 3. Gristina AG, Dobbins JJ, Giammara 13, Lewis JC, DeVries WC. Biomaterial-centered sepsis and the total artificial heart: microbial adhesion vs. tissue integration. JAMA 1988; 259:870-4. 4. Didisheim P, Oisen DB, Farrar DJ, et al. Infections and thromboembolism with implantable cardiovascular devices. Trans Am Soc Artif Intern Organs 1994;35:54-70.
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5. McBride LR, Ruzevich SA, Pennington DG, et al. Infectious complications associated with ventricular assist device support. Trans Am Soc Artif Intern Organs 1994;33: 201-2. 6. Kormos RL, Borovetz HS, Armitage JM, Hardesty RL, Marrone GC, Griffith BP. Evolving experience with mechanical circulatory support. Ann Surg 1991;214:471-7. 7. Burton NA, Lefrak EA, Macmanus Q, et al. A reliable bridge to cardiac transplantation: the TCI left ventricular assist device. Ann Thorac Surg 1993;55:1425-31. 8. Frazier OH, Rose EA, Macmanus Q, et al. Multicenter clinical evaluation of the HeartMate 1000 IP left ventricular assist device. Ann Thorac Surg 1992;53:1080-90. 9. Phillips WS, Burton NA, Macmanus Q, Lefrak EA. Surgical complications in bridging to transplantation: the Thermo Cardiosystems LVAD. Ann Thorac Surg 1992;53:482-6. 10. O'Connell JB, Renlund DG, Robinson JA, et al. Effect of preoperative hemodynamic support on survival after cardiac transplantation. Circulation 1988;78(Suppl 3):78-82. 11. Smart FH, Naftel DC, Costanzo MR, et al. Risk factors for early, cumulative, and fatal infections following cardiac transplantation: a multi-center study. J Heart Lung Transplant (in press). 12. Patti JM, Allen BL, McGavin MJ, Hook M. MSCRAMMMediated adherence of microorganisms to host tissues. Annu Rev Microbiol 1994;48:585-617. 13. Gristina AG. Biomaterial-centered infection: microbial adhesion versus tissue integration. Science 1987;237:1588-95. 14. Gristina AG, Giridhar G, Gabriel BL, Naylor PT, Myrvik QN. Cell biology and molecular mechanisms in artificial device infections. Int J Artif Organs 1993;16:755-64. 15. Tojo M, Yamashita N, Goldmann DA, Pier GB. Isolation and characterization of a capsular polysaccharide adhesin from Staphylococcus ep/derm/d/s. J Infect Dis 1988;157:713-22. 16. Gristina AG. Implant failure and the immuno-incompetent fibro-inflarnmatoryzone. Clin Orthop 1994;298:106-18. 17. Bergamini TM, Corpus RA Jr, Hoeg KL, Brittian KR, Peyton JC, Cheadle WG. Immune regulation of bacterial biofilm graft infection. ASAIO Trans 1994;40:219-26.