Mechanical circulatory support with continuous-flow (CF) left ventricular assist devices (LVADs) is increasingly used as bridge-to-transplantation (BTT) or destination therapy (DT) in heart failure (HF) patients ineligible for heart transplantation.1 According to the most recent Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) report, more than 20,000 patients have received LVADs to date.2 The presence of hardware penetrating the skin along with a degree of acquired immune dysfunction makes these patients particularly vulnerable to infections.3 Rates of bloodstream infections (BSIs) and sepsis in prior studies were as high as 60%.4–6 Although mechanical design and durability have improved, along with timely identification of complications and better management strategies, infection while on LVAD support remains highly prevalent and is associated with significant morbidity and mortality.2,7,8
The BSIs are particularly difficult to treat in this population because of device seeding and persistent bacteremia, noted in up to 80% of cases.9 Moreover, due to the hemodynamic changes of CF-LVADs and nonphysiologic continuous cardiac output augmentation by the device, the clinical manifestations of BSIs are often unreliable and can lead to delayed detection of bacteremia.3,10 For instance, in one previous report, only 40% of LVAD recipients with endovascular infections met criteria for systemic inflammatory response syndrome (SIRS).3
In the current study, we sought to 1) investigate the clinical challenges of diagnosing BSIs, 2) identify risk factors for BSI, and 3) examine the impact of BSI on survival and heart transplantation in one of the largest contemporary cohorts of CF-LVAD recipients.
We reviewed the electronic medical records of patients implanted with CF-LVADs, either HeartMate II (Thoratec, Pleasanton, CA) or HeartWare (Framingham, MA), between January 1, 2006, and July 1, 2016, at Allegheny General Hospital, Pittsburgh, PA. We reviewed available microbiological data and hospitalizations to identify infections. Patients were excluded if they had history of pulsatile flow LVAD placement. Infections that were managed in the outpatient setting and were not associated with the LVAD (i.e., lower urinary tract infection, upper respiratory infection) were not captured. Data were collected independently by 2 physicians, and discrepancies were resolved with input from Cardiovascular and Infectious Diseases specialists. The study was approved by the institutional review board.
All patients at our institution receive perioperative antibiotic prophylaxis at the time of LVAD implantation. Until 2009 (20% of the study cohort), the combination of vancomycin–ciprofloxacin–fluconazole–rifampin was used for the first 24 hours post-sternal closure. Since 2010 (80% of the study cohort), we have used the combination of vancomycin–ceftriaxone–fluconazole–rifampin for the first 24 hours post-sternal closure. All patients are placed on continuous insulin infusion for postoperative glucose management. All patients are instructed to wear anchors (Centurion Foley, Centurion Medical Products, Williamston, MI) for the prevention of driveline trauma. For driveline care, all patients are instructed to perform clean dressing changes after applying topical chlorhexidine solution (ChloraPrep, Becton, Dickinson and Company, Franklin Lakes, NJ) and cover with a drain sponge and sterile 4 × 4 gauge. In the early postoperative period, patients are instructed to perform daily dressing changes, and as the driveline exit site heals, they perform dressing changes every 3 days. Patients with driveline infection (DLI) are instructed to perform daily dressing changes until the drainage from the exit site has stopped.
Blood cultures are examined based on individual clinical suspicion similar to non-LVAD patients. The majority of patients with LVAD BSI at our institution receive a varying duration of intravenous (IV) antibiotics based on the 1) offending organism, 2) presence of vegetation/endocarditis, and 3) deep-tissue involvement. The duration and choice of antibiotics are determined in collaboration with out Infectious Diseases colleagues. In general, patients who develop recurrent bacteremia with the same microorganism after appropriate treatment with IV antibiotics, and other potential source control (i.e., removal of implantable cardioverter-defibrillator/pacemaker if endocarditis is confirmed), are considered to have seeded their device. These patients are evaluated for device exchange, and if they are not candidates, they are placed on suppressive antibiotics and followed closely in concert with our Infectious Disease colleagues.
We used the International Society for Heart & Lung Transplantation definitions for LVAD-specific, LVAD-related, and nonrelated infections.11 DLI were characterized as superficial or deep, based on operative evidence of fascial involvement or radiographic evidence of a deep collection.11 We defined right HF according to the latest INTERMACS definition (Manual of Operations, version 5.0) as need for inhaled nitric oxide, inotrope support, IV vasodilators, or implantation of right ventricular assist device (RVAD) for duration of >7 days after LVAD implantation.12 We used the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions for SIRS, sepsis, severe sepsis, and septic shock.13 We defined BSI as positive blood cultures requiring hospitalization and antibiotic treatment. For blood cultures with skin flora bacteria (coagulase-negative Staphylococcus, Propionibacterium acnes, corynebacteria), we classified episodes as BSI only if 2 separate sets of blood cultures were positive.
Follow-up in the cohort began on the date of LVAD implantation and ended at the time of death, heart transplantation, or last follow-up, whichever occurred earlier. We present the incidence rates for BSIs as number of infections per 10,000 person-days of LVAD support. To determine risk factors for BSI, we first compared the characteristics of patients with and without BSI. Continuous variables were compared using the Wilcoxon rank sum test, and categorical variables were compared using the χ2 test or Fisher exact test, as appropriate. We included variables with p ≤ 0.20 from the univariate analyses in a multivariable logistic regression model and present the adjusted odds ratios (ORs) and their corresponding 95% confidence intervals (95% CI).
We plotted Kaplan–Meier curves to determine the probability of all-cause mortality according to presence or absence of any BSI and analyzed using the log-rank test. Patients were censored at date of transplantation or last follow-up. We chose logistic regression over Cox regression for mortality prediction as we included both DT and BTT LVAD recipients, which created a heterogeneous population in terms of expected survival. To accurately evaluate the impact of BSIs on the time-to-transplantation, we analyzed infection as a time-varying variable. To further reduce confounding from death as a competing event, we analyzed separately the impact of BSI on time-to-transplantation only among patients who received heart transplant in a sensitivity analysis. Statistical significance for all tests was set at a two-tailed α < 0.05. Data were analyzed with SPSS (v.22, IBM Corporation, Armonk, NY).
We identified 212 patients who received CF-LVAD during our study period. Patients were 80% male, 87% white, 58% with ischemic cardiomyopathy, 86% INTERMACS profile 1–3, 51% had diabetes, 36% had chronic kidney disease, and 27% had obstructive lung disease. The majority (80%) received HeartMate II device and 59% were BTT. Right HF requiring inotrope support for >7 days after implantation occurred in 34% of patients. Eleven patients (5%) required RVAD implantation. Median time on LVAD support was 257 days (range, 8–2202). A summary of baseline characteristics of all subjects is presented in Table 1.
We evaluated a total of 434 infection episodes, affecting 58% of all LVAD patients (Table 2). Almost one half (45%) of the patients experienced at least one LVAD-specific or LVAD-related infection. The DLI was documented in 31% of patients, with 40% of them being limited to the superficial layers and 60% having deep-tissue involvement. A total of 272 blood cultures in 122 patients with documented infection during LVAD support were reviewed; 66 patients (31%) suffered from a total of 135 BSIs over a total of 91,346 person-days of LVAD support. Incidence rate for developing at least one BSI was 7.2 (95% CI, 5.6–9.1) per 10,000 person-days of LVAD support for all patients, 6.0 (95% CI, 4.0–8.6) per 10,000 person-days of LVAD support for BTT-only patients, and 8.4 (95% CI, 6.1–11.4) per 10,000 person-days of LVAD support for DT-only patients. Patients who had LVAD implantation during the first half of our study (2006–2010) suffered from an incidence rate for BSI of 13.4 (95% CI, 9.3–18.6) per 10,000 person-days of LVAD support, whereas patients who were implanted during the second half of our study (2011–2016) suffered from an incidence rate of 5.1 (95% CI, 3.6–7.0) per 10,000 person-days of LVAD support (incidence rate ratio, 2.7; 95% CI, 1.6–4.3; p = 0.0002).
The majority of infections were caused by Gram-positive bacteria (56%); Staphylococcus aureus was the most common organism. Pseudomonas aeruginosa was the most common Gram-negative organism causing BSIs. We also documented 5 fungemias due to Candida species (three Candida parapsilosis, one Candida albicans, one Candida glabrata). In 36 (68%) of 53 BSIs with concurrent or recent culture data available from the driveline, the same organism was isolated. Median time to first BSI was 108 (range, 1–1965) days, and median length of hospital stay for BSIs was 12 (range, 3–74) days.
Risk Factors for BSIs
In univariate analysis, patients who experienced BSIs were more likely to have (Table 3) HeartMate II device (35% vs. 17% with HeartWare; p = 0.02), DT (45% vs. 21% as BTT; p < 0.001), ischemic cardiomyopathy (37% vs. 24% with nonischemic; p = 0.004), right HF at implantation (50% vs. 26%; p = 0.001), higher INTERMACS profile (p = 0.004), morbid obesity (17% vs. 8%; p = 0.04), history of any DLI (50% vs. 22%; p < 0.001), or history of deep-DLI (38% vs. 10%; p < 0.001).
In multivariate analysis, independent risk factors for BSIs included DT (OR, 2.3; 95% CI, 1.1–5.0; p = 0.04), right HF at implantation (OR, 2.2; 95% CI, 1.0–4.6; p = 0.04), INTERMACS 1 profile (OR, 5.2; 95% CI, 1.4–19.3; p = 0.007), morbid obesity (OR, 4.5; 95% CI, 1.4–14.3; p = 0.01), and deep-DLI (OR, 7.2; 95% CI, 3.1–16.8; p < 0.001).
SIRS, Hemodynamic Manifestations of BSI, and Mortality
At presentation of BSI, 47% of LVAD patients fulfilled SIRS criteria, 55% had evidence of end-organ dysfunction, and 24% had hemodynamic instability requiring vasopressor support. The SIRS criteria that were met on presentation in order of frequency were white cell count (50%), temperature (41%), elevated heart rate (38%), and elevated respiratory rate (22%). Lactic acidosis was evident in 13% and altered mentation in 18% of patients with BSIs. Overall, 51% of patients were admitted to the ICU for management of BSIs. For the ICU admitted patients, median Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score was 13 (range, 4–29) and median Sequential Organ Failure Assessment (SOFA) score was 5 (range, 0–15). Sixty-two (29%) patients died during our study period, including 18 (14%) BTT and 44 (51%) DT patients, at a median of 214 (range, 19–2202) days from LVAD implantation. Patients with SIRS at any BSI presentation had increased 30-day mortality compared with patients who did not have SIRS (27% vs. 11%; p = 0.02). Patients with SIRS at their first BSI presentation had significantly decreased survival after the BSI (Figure 1A; p = 0.006), regardless of BTT or DT status (Figure 1B; p = 0.008).
In univariate analysis, factors associated with increased mortality were as follows (Table 4): older age (median, 64 vs. 57 years; p < 0.001), HeartMate II device (34% vs. 10% with HeartWare; p = 0.002), DT (51% vs. 14% as BTT; p < 0.001), right HF at implantation (48% vs. 28%; p = 0.007), atrial fibrillation or atrial flutter (61% vs. 42%; p = 0.01), obstructive lung disease (37% vs. 23%; p = 0.03), deep-DLI (27% vs. 15%; p = 0.03), BSI (60% vs. 19%; p < 0.001), S. aureus or P. aeruginosa infection (55% vs. 22% for the rest; p < 0.001), pump thrombosis (24% vs. 9%; p = 0.002), and cerebrovascular accident (CVA; 31% vs. 7%; p < 0.001). In multivariate analysis, independent predictors of mortality were older age (OR, 1.05 for every year; 95% CI, 1.0–1.1; p = 0.03), DT (OR, 3.3; 95% CI, 1.3–8.4; p = 0.01), BSI (OR, 6.0; 95% CI, 2.3–15.6; p < 0.001), pump thrombosis (OR, 4.2; 95% CI, 1.2–14.8; p = 0.03), and cerebrovascular accident (OR, 4.9; 95% CI, 1.4–16.0; p = 0.01). Median time from first BSI to death was 88 (range, 1–1734) days.
On a separate multivariate model among patients who had BSI, albumin level at the time of BSI presentation was found to be an independent predictor of mortality (median [range], 2.8 [1.7–5.5] vs. 3.7 [2–4.3] g/dL for patients who survived; OR, 2.0; 95% CI, 1.0–4.0; p = 0.05), along with age. Factors included in the model were age, albumin level, gender, DT designation, INTERMACS profile, deep DLI, pump thrombosis, and CVA (data not shown).
In survival analysis, patients with BSIs had higher all-cause mortality (Figure 2A; p < 0.0001), regardless of BTT or DT status (Figure 2B; p < 0.0001). When analyzed as time-varying parameter, BSI was still associated with increased mortality (hazard ratio [HR], 8.5; 95% CI, 5.0–14.4; p < 0.001).
Impact of BSIs on Heart Transplantation
Overall, 104 (49%) patients underwent transplantation at a median of 190 days (range, 8–1,099 days) from LVAD implant. BTT patients were more likely to receive heart transplantation if they never developed a BSI compared with those who had at least one (75% vs. 56%; p = 0.05). In survival analysis, BSI had no impact on time-to-transplantation for all transplant recipients (p = 0.15) and for BTT-only transplant recipients (p = 0.28). However, when accounted as a time-varying parameter, BSI was associated with a shorter time-to-transplantation in all transplant recipients (HR, 2.0; 95% CI, 1.2–3.3; p = 0.009) and in BTT-only transplant recipients (HR, 2.2; 95% CI, 1.2–4.1; p = 0.01).
BSIs remain a challenging complication for LVAD patients with serious consequences for morbidity and mortality.14 Device-related infections, along with gastrointestinal bleeding and cerebrovascular accident, are the leading causes of hospital readmissions after LVAD implantation.15–18 Recognizing that infection remains an important complication and a major determinant of mortality in LVAD patients, the International Society for Heart and Lung Transplantation (ISHLT) recently released consensus recommendations for the management of infections in LVAD patients in collaboration with the International Consortium of Circulatory Assist Clinicians.19 These recommendations were formulated by a multidisciplinary panel of experts; however, the evidence support is limited by the inconsistency in management practices and definition of LVAD infections from older single-institution reports. In the current study, which is the largest series of BSIs in CF-LVADs to date, we found that more than 50% of patients suffered at least one infection and 31% developed BSI. The prolonged length of stay for BSIs (median of 12 days) highlights the complex management and course of these patients.
We found that less than half of LVAD patients with BSIs present with SIRS, in agreement with another study that showed that less than 40% of LVAD patients with BSIs met SIRS criteria.3 In contrast, prior studies in the general population revealed that SIRS is present in 72–95% of bacteremic patients.20,21 End-organ dysfunction was evident in many patients, regardless of SIRS at presentation. It is possible that some SIRS criteria, such as elevated respiratory rate and tachycardia, may not be evident as early manifestations of sepsis because of altered CF physiology and independent augmentation of cardiac output by the LVAD. This hypothesis is further supported by the finding that only 13% of the patients with BSI had lactic acidosis, a marker of poor tissue perfusion. Despite relatively low sensitivity and prevalence, SIRS was associated with increased mortality in our study and therefore maintained its prognostic value in the LVAD population. Future studies are needed to examine the utility of SIRS criteria in this unique patient population.
A variety of host and device factors have been associated with increased risk for BSIs.4,10 Driveline infections followed by BSI are the most common types of infection in LVAD recipients.3 Some studies have identified trauma involving the percutaneous driveline as the catalyst of infection; however, these studies were limited by the retrospective assessment of trauma in already infected patients.22,23 Various risk factors for infection have been previously reported in LVAD recipients, including age, male gender, diabetes, renal failure, obesity, and depression.24–28 In addition, some degree of immunodeficiency due to an acquired T-cell dysfunction is believed to inherently contribute to the susceptibility of LVAD recipients to infection and is likely more evident in frail patients.29–31 In our cohort, we focused on risk factors for BSIs and identified DT, INTERMACS profile, right HF at implantation, morbid obesity, and history of deep-DLI as independent risk factors for BSI. INTERMACS profile, DT status, and right HF likely represent a group of patients with overall poorer prognosis, greater illness severity and multiple comorbidities at time of implantation, and possibly higher inherent susceptibility to infection. While not specifically studied in our cohort, increased BSI in the right HF population may partly reflect associated risk of indwelling IV catheters for inotrope administration in the early post-LVAD period.
The driveline has been very well characterized as the Achilles’ heel as it is a portal of entry for pathogens, and in our study, deep DLI was the most significant risk factor for BSIs with an OR of 7.2.19,23 Unfortunately, it is often very difficult to distinguish superficial from deep DLIs despite being imperative in the choice of duration and route of antibiotic administration. Several institutions have implemented the use of positron emission tomography/computed tomography scanning to localize and detect the extent of infection and in certain cases to rule out infection as early as 3 weeks post-implantation.32 This appears to be a promising imaging modality in an attempt to risk stratify patients with DLI and may improve future treatment algorithms. Morbid obesity has been associated with increased risk for DLI,28 and possibly through the same mechanism or by immunomodulation,33 could increase the risk for BSI. Accordingly, it may be appropriate to adopt more stringent driveline care practices and have heightened infection surveillance in obese LVAD patients. The major risk factors identified by this study could be incorporated into future algorithms for infection management or risk stratification to promote improved screening and more aggressive management for the highest risk patients.
Similar to previous reports, we found a significant association of BSIs with mortality.6,18,25,34 Bloodstream infections and sepsis are associated with poor outcomes in this population because of a multitude of complications, such as device colonization, cerebral emboli, and multiorgan failure.4 The seventh INTERMACS report demonstrated that overall infection rates are decreasing over time.2 It is thought that as device design improves, with the advent of smaller, newer generation devices, and patient management is increasingly refined, contemporary infection rates will continue to improve.7,8 In our study, we noticed a significant decrease in the incidence rates of BSIs in the second half of our study when compared to the first half, possibly owing to improved clinical protocols over time. Our institution follows the contemporary ISHLT recommendations that likely reflect the improved rates. Nevertheless, infection rates remain unacceptably high and as revealed in our study, continue to be a serious contributor to mortality in these patients. In fact, BSI was associated with the highest mortality risk in our study, along with age, DT designation, pump thrombosis, and cerebrovascular accident.
The impact of BSI on transplantation has been evaluated before. Some investigators suggested that infections delay time-to-transplantation,20,32 whereas others have shown no difference. In our study, when analyzed as a time-varying parameter among patients who received heart transplant, BSIs expedited time-to-transplantation. To our knowledge, this is the first study to capture this finding, which, nonetheless, is anticipated as BTT LVAD recipients with LVAD-related BSIs may be upgraded to United Network for Organ Sharing priority 1A.35 Nonetheless, BTT patients with BSI had significantly worse outcomes, lost the “BTT advantage” over DT patients, and experienced higher waitlist mortality (Figure 2). Regarding the risk of infection relapse post-transplant, numerous studies have suggested that transplantation is safe with low risk for infection relapse as long as extradevice sources have been controlled.6,9,22,36,37 It is unknown whether the often feared vasoplegia at time of transplant in LVAD patients is further exacerbated by having history of BSI, with or without SIRS. The potential physiologic insult of vasodilatory cytokine release with a BSI could increase the risk of poor post-transplant outcomes in LVAD patients, beyond that of specific infection relapse, and merits future study.
Our study has several limitations. First, the retrospective nature and long review period present inherent limitations to the analysis and generalizability of our results. We studied a relatively heterogeneous group of patients, including those from earlier years. This might have resulted in missing data, such as superficial DLIs managed in the outpatient setting. Nonetheless, we feel that patient heterogeneity and shifts in practice and LVAD management, especially with respect to LVAD-associated infections and BSIs over time, are likely similar for other large LVAD programs with evolving LVAD candidacy thresholds and unstandardized approaches to managing such device complications. To account for these limitations within this single-center study, we focused on objective clinical outcomes, such as all-cause mortality and transplantation, and performed multivariate analyses with adjustments for time-varying parameters.
In summary, CF-LVAD patients frequently suffer from BSIs which lead to prolonged hospitalization and increased mortality, even in the BTT population who experience an upgrade in listing status from this complication event. Because of LVAD physiology and altered hemodynamic profiles, these patients do not reliably present with classic signs and symptoms of endovascular infection. The SIRS, when present in association with BSI, indicates greater illness severity and carries elevated mortality risk. Deep DLI is the strongest risk factor for BSI and should stimulate future studies for best practice management. The BSI should be regarded as a serious event, similar to that of pump thrombosis and stroke, with the intention to be managed aggressively. More research is needed for better detection and treatment algorithms of this complication.
The authors thank Parag Mahale, MBBS, MPH, PhD, for his assistance with the statistical analysis.
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