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When It Rains It Pours

Feller, Erika D.

doi: 10.1097/MAT.0000000000001056
Invited Commentary
Free

From the Adult Heart Failure & Cardiothoracic Transplant Program, University of Maryland Medical Center, Baltimore, Maryland.

Twitter: @Twitter

Submitted for consideration July 2019; accepted for publication in revised form July 2019.

Disclosure: The author has no conflicts of interest to report.

Correspondence: Erika D. Feller, MD, Medical Director, Advanced Heart Failure, Cardiac Transplant & VAD, 29 S. Greene Street, Suite 430, Baltimore, Maryland 21201. Email: efeller@som.umaryland.edu.

Current centrifugal left ventricular assist devices (LVADs) have improved survival and quality of life compared to earlier generations of LVADs. Although the external and internal LVAD components have significantly improved in efficiency, efficacy, and portability over time, the adverse side effects contributing to morbidity and mortality remain. These negative clinical outcomes include infection, bleeding, neurological events, and pump dysfunction or pump failure. Many of these adverse events may not happen in isolation but are interrelated.

There has been an increase, over the past several decades, in the number of people diagnosed with heart failure. Thus, there has been an increase in patients implanted with LVADs. LVAD-related infections are an important problem that significantly affect morbidity and mortality. LVAD-related infections are common, especially drive-line exit site infections. The treatment is often difficult and lengthy and may require multiple courses of antibiotics, debridements, packing, and re-tunneling the drive line. The definitive treatment is LVAD explant, which many times is not feasible and must rely either on recovery of left ventricular function or organ donor availability.

One prospective study showed a 22% overall infection rate of LVADs and a 1-year mortality between 5-6 times greater with infections2. LVAD infections are also associated with increased risk of pump thrombosis, bleeding complications, increased hospital length of stay, need for LVAD exchange, and failure achieve bridge to transplant. Bloodstream infections in patients with LVAD are not well studied but likely confer higher risk.

As more patients live with LVADs for longer times, it is important to realize the sequelae of LVAD-related infection and to adopt aggressive preventive, early detection, and treatment strategies to improve the course of patients living with LVAD.

Bloodstream infections in patients with LVAD are not well studied but likely confer higher risk.

In this issue of the ASAIO Journal, Cho et al.1 present a case crossover-study assessing the risk of intracranial hemorrhage with active infection and coagulopathy in LVAD patients. Their hypothesis is that active infection and high international normalized ratio (INR) at the time of hemorrhage affect the acute risk of intracranial hemorrhage. They seek to shed light on the relationship between infection and intracranial hemorrhage. In addition, the authors seek to differentiate three types of intracranial hemorrhage: intracerebral hemorrhage, (ICH) subdural hematoma (SDH), and subarachnoid hematoma (SAH). Previously, few risk factors, apart from chronic warfarin therapy and antiplatelet therapy, were implicated in the higher rate of hemorrhagic cerebral vascular accidents. A recent prospective review confirmed a high prevalence of intracranial hemorrhage in LVAD patients, suggesting that additional LVAD-specific risk factors play a role in the pathophysiology of intracranial hemorrhage2.

Their findings suggest that both active infection and higher INR were associated with an increased risk of acute hemorrhagic stroke. There have been few studies that have shown that bloodstream infection is related to intracranial hemorrhage.3 In other reviews, blood stream infections were associated with increased risk of neurological events and predisposed to hemorrhagic stroke in patients with centrifugal flow LVAD4,5,6. Cho et al speculate that other risk factors may be playing a role and may include acquired von Willebrand disease, cerebrovascular hemodynamic change, autoregulatory dysfunction, and breakdown of the blood-brain barrier1.

What remains to be elucidated is the mechanism(s), or pathway(s) by which an infection leads to increased rate in intracranial bleeding. In previous studies, primarily from the infectious disease and hematology literature, systemic infection leads to an increase in inflammation whereby coagulation factors are affected. Bacterial endotoxin can activate platelets directly, in addition to many pro-inflammatory cytokines that are capable of further inducing platelet activation. Sepsis leads to unbalanced coagulation, ranging from mild alterations to severe disseminated intravascular coagulation7. Patients can present with thromboembolic disease or microvascular fibrin deposition causing multi-organ dysfunction. Patients can present with bleeding, thrombosis or both. Tumor necrosis factor and IL-6, pro-inflammatory cytokines, are abundant in sepsis and can initiate the coagulation pathway, amplifying thrombin generation. This pathway is counteracted by inhibitors: antithrombin, protein c and s and tissue factor pathway inhibitor. Paradoxically, INR levels can increase dramatically but platelets become more activated-thus hypercoagulable.

For LVAD recipients, this predicament can be a clinical and management conundrum and frequently leads to either bleeding, clotting or both. What has been reported in a recent study is individualized evaluation and treatment of an LVAD patient’s platelet reactivity8. This individualized approach to antithrombosis therapy led to a decrease in stroke in once center’s LVAD patients, below reported literature8. By using platelet function assays, a trend in platelet function can be monitored as baseline but also in disease states.

It is clear that more multi-disciplinary, randomized clinical studies are needed to elucidate the cause and effect of LVAD infection and hemorrhagic stroke. This study sought to further the understanding of the relationship of active infection and high INR affecting the acute risk of intracranial hemorrhage and the different types of intracranial hemorrhage; even further understanding is required to develop strategies to decrease the impact of LVAD infection and its sequelae.

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References

1. Cho SM, Lee T, Starling R. The Impact of Infection and Elevated INR in LVAD-Associated Intracranial Hemorrhage: A Case-Crossover Study. ASAIO J 2019.65: 545–550.
2. Gordon RJ, Weinberg AD, Pagani FD,F., et al. Prospective Multicenter Study of Ventricular Assist Device Infection Study Group: Prospective, multicenter study of ventricular assist device infections. CirculationInfections. Circulation 2013.127: 691–702.
3. Kilic A. The future of left ventricular assist devices. J Thorac Dis 2015.7: 2188–2193.
4. Aggarwal A, Gupta A, Kumar S. Are blood stream infections associated with an increased risk of hemorrhagic stroke in patients with a left ventricular assist device? ASAIO J 2012.58: 509–513.
5. Aldeiri M, Alvarez P, Cordero-Reyes AM. Pseudomonas aeruginosa bacteremia in patients supported with a left ventricular assist device is associated with an increased risk of hemorrhagic stroke. J Card Fail 1: S77–2013.
6. Trachtenberg BH, Aldeiri M, Cordero-Reyes AM. Persistent blood stream infections are associated with cerebrovascular accidents in patients with continuous flow LVADS. J Heart Lung Transplant 2014.1: S21–S22.
7. Saracco P, Vitale P, Scolfaro C. Coagulopathy in Sepsis: Significance and Implications for Treatment. Pediatric Reports 2011.3: e30.
8. Sorensen E, Dees L. Individualized Antithrombotic Therapy in Heartware HVAD Recipients. ASAIO J 2019.65:29–35.
Keywords:

left ventricular assist device; infection; coagulopathy; intracranial hemorrhage, platelet activation

Copyright © 2019 by the American Society for Artificial Internal Organs