Catheter-related atrial thrombus: tip of the iceberg?

Abstract

Although guidelines recommend catheters as a last resort for establishing a vascular access in patients undergoing dialysis, they continue to be used widely for this purpose. Catheter-related atrial thrombus (CRAT) is rarely reported in this group of patients, and it can lead to serious complications. The aim of this study was to determine the incidence of CRAT in patients undergoing hemodialysis with permanent-tunneled catheters. A total of 50 patients undergoing hemodialysis with permanent catheters were included in this study. The diagnosis of CRAT was based on transthoracic echocardiography findings. Thrombus was present in nine patients (18%) and related to the tip of the catheter in all cases. Except for one patient with two foci of thrombus, all patients had a single focus. There were no significant associations between the development of thrombus and the duration of catheter use or the location of the catheter. Furthermore, catheter-related atrial thrombus did not appear to have a significant effect on mortality. The asymptomatic character of CRAT can be responsible for the low reporting rates, and its exact role in increased mortality and morbidity related with catheter use remains unknown. While planning management strategies, information on different options for vascular access routes and possible catheter-related complications should be provided to all patients who will undergo dialysis, together with a discussion involving other replacement alternatives for end-stage renal disease.

• Chronic kidney disease
• echocardiography
• hemodialysis
• indwelling catheters
• thrombus

Introduction

While hemodialysis currently represents the most commonly utilized renal replacement therapy worldwide,1^,2 vascular access continues to be the Achilles’ heel of hemodialysis. The planning for the vascular access should be performed before hemodialysis is commenced as an integral component of the management of patients with chronic kidney disease. Among the three major vascular access options, i.e., native arteriovenous fistulas (AVF), arteriovenous grafts (AVG) and central venous catheters (CVC), AVF offers certain advantages over others such as the improved durability and decreased risk of infections, thrombosis and interventions.3^,4 Guidelines for hemodialysis patients recommend native AVF as the first-line vascular access option in this group of patients, with catheter use being recommended only as a last resort when other options fail or contraindicated.4–6 However, despite some variance between several countries in the reported use of CVC, its frequent use remains an important problem, particularly among patients newly started to hemodialysis.7^,8 On the other hand, use of catheters is associated with increased morbidity and mortality rates in hemodialysis patients.9–11

From a clinical viewpoint, major catheter-related issues are represented by catheter infections and catheter dysfunction. Furthermore, another less frequently reported problem – perhaps due to its asymptomatic course – is the right atrial thrombus formation. In hemodialysis patients with catheter-related atrial thrombus (CRAT) formation, several signs and symptoms such as high fever, dyspnea, chest pain, hemoptysis, palpitations and syncope may be seen in addition to serious outcomes such as death.12 In this study, our aim was to determine the incidence of right atrial thrombus formation using transthoracic echocardiography, in a group of patients undergoing hemodialysis with tunneled cuffed catheters in the center of Samsun.

Methods

A total of 50 patients from five different hemodialysis centers in Samsun city undergoing hemodialysis with permanent catheters between January 2012 and July 2012 were included. Informed consent was obtained from all patients. Demographic characteristics, comorbid conditions, interventions involving the vascular access route and use of antiaggregant or anticoagulant medications were recorded as well as the blood urea nitrogen, creatinine, albumin, hemoglobin, hematocrit, leukocyte, platelet and C-reactive protein results (CRP). Biochemical tests were performed in a modular device using standard colorimetric methods using the blood samples obtained from patients. For CRP determinations, a nephelometric method was used in a Date-Behring device.

For transthoracic echocardiographic examinations, a Vivid E9 device (GE Vingmed Ultrasound AS, Horten, Norway) was utilized. All echocardiographic assessments were made by the same experienced cardiologist. Standard echocardiographic assessments were performed in apical, parasternal and subcostal views in accordance with the relevant guidelines.13 The mobility of thrombus was described according to the echocardiographic criteria described in previously.14

Assessment of the dialysis catheter was performed using apical four-chamber and subcostal views. When a catheter-related thrombus was identified, its size, motion and echogenicity were assessed. In cases with suboptimal image quality of the dialysis catheter, a transesophageal echocardiography was done, with a multi-plane phased-array adult transesophageal probe connected to a Vivid i device (GE Vingmed Ultrasound AS). The midesophageal four-chamber and bicaval views were used to assess the dialysis catheter. Echocardiogram was performed once. This study protocol was approved by the Institutional Ethics Committee.

Statistical analyses

In order to detect significant differences in continuous variables in relation to certain categorical variables, Fisher’s exact test and Pearson Chi-Square tests were used. For between-group differences, t test was used. A one-way analysis of variance was performed, and the variables were expressed as “mean ± standard deviation”, while categorical variables were expressed as number and percentage, with the chi-square test being used for the assessment of their relationship. In order to detect a change in the frequency of the occurrence of thrombosis according to the number of catheterizations, a Z test was performed for comparison. A p level less than 0.05 was considered significant in all statistical assessments, which were performed using SPSS software, version 16 for Windows (SPSS Inc., Chicago, IL).

Results

The mean age of the study participants was 61.1 ± 13.1 years, with 29 (58%) female and 21 (42%) male patients. The duration of the history of chronic kidney disease was 59.10 ± 56.95 months, while the average duration of time since the first hemodialysis was 53.58 ± 52.60 months. Twenty-three patients (46%) had diabetes, while 30 (60%) had hypertension. A cardiovascular disease history was present in 28 patients. All patients were receiving erythropoietin, while 29 patients were on acetyl salicylic acid and three were on acetyl salicylic acid and warfarin because of cardiovascular disease or other problems. Classical heparin and low-molecular-weight heparin were being used by 38 and 12 of the subjects, respectively, during hemodialysis. Laboratory findings are listed in Table 1.

Table 1. Laboratory findings.

	Mean
BUN (mg/dL)	60.54 ± 34.37
Creatinine (mg/dL)	6.20 ± 2.45
Albumin (g/dL)	3.68 ± 0.45
WBC (×1000/µL)	6.838 ± 1.801
Hgb (g/dL)	10.99 ± 1.35
Hct (%)	33.13 ± 4.30
PLT (×1000/µL)	224.04 ± 67.35
CRP (mg/L)	26.97 ± 25.09

Note: BUN, blood urea nitrogen; WBC, white blood cell; Hgb, hemoglobin; Hct, hematocrit; PLT, platelet; CRP, C-reactive protein.

A total of 49 patients had at least one AVF (2.00 ± 1.29). In 14 patients, AVF was established prior to dialysis, while it was performed after the commencement of dialysis in other 35 patients. Of the catheters, 42 were placed in the right jugular vein (84%), 4 in the left jugular vein (8%), 3 in the right subclavian vein (6%) and one in the left subclavian vein (2%). The average duration of catheter use was 19.22 ± 17.63 months, with an average catheter insertion number of 1.14 ± 1.10 per patient.

Nine patients (18%) had CRAT (Table 2). All thrombotic foci were related with the tip of the catheter, one patient having two foci of thrombi, and the remaining having single focus. Furthermore, four of the thrombotic foci were mobile, while three were immobile and two were semi-mobile.

Table 2. The thrombus and patient characteristics in individuals with atrial thrombus formation.

	Gender	Age (years)	Duration of catheterization (months)	Number of thrombi	Size of the thrombi (mm)	Mobility
1	Female	67	4	1	20 × 15	Immobile
2	Female	33	20	1	14 × 7	Mobile
3	Female	38	12	1	12 × 2	Mobile
4	Female	62	6	1	9 × 10	Immobile
5	Female	83	24	1	6 × 3	Mobile
6	Female	64	75	1	18 × 14	Semi-mobile
7	Male	64	12	1	15 × 11	Semi-mobile
8	Female	53	60	1	21 × 13	Immobile
9	Female	67	6	2	20 × 8	Mobile
					11 × 4

The mean age in subjects with or without thrombus were 61.46 ± 12.5 and 59.89 ± 16.15 years, respectively, with no significant difference (p = 0.24). Female gender was prominent among patients with thrombus. Gender distribution was such as eight female (frequency among female subjects was 27.6%) and one male (the corresponding figure among male participants is 4.8%). There was no significant relationship between the frequency of thrombus formation and gender. The duration of catheterization in patients with or without thrombus was 24.66 ± 22.62 months and 18.02 ± 15.54 months, and there was no significant difference in duration of catheterization between the two groups (p = 0.84). Again, there was no significant association between the catheter location and thrombus formation (p > 0.05). Similarly, a history of catheter infection or the number of catheter placement was not associated with a significant difference in the frequency of thrombus formation (p values 0.57 and 0.34, respectively).

Of the 23 diabetic patients, 5 (21.7%) had thrombus, while 4 of the 27 non-diabetic individuals (14.8%) had thrombus, with no significant difference between the groups (p = 0.71). Thrombus formation was detected in 16.7% (5/30) and 20% (4/20) of hypertensive and non-hypertensive patients, respectively (p = 1.00). Furthermore, patients with or without thrombosis were not significantly different in terms of the duration of chronic kidney disease, total duration of dialysis and the number of AVF interventions. Presence of cardiac conditions (coronary artery disease or heart failure) did not significantly affect the incidence of thrombus formation (p = 0.34).

No significant differences with regard to hemoglobin, platelet, albumin, creatinine and CRP values between patients with or without thrombus were found. During the two-year of follow-up, death occurred in 19.5% (n = 8) of the patients without thrombus and 44.4% (n = 4) of the patients with thrombus (p = 0.2), without a statistical difference between the groups.

Discussion

The frequency of catheter use in hemodialysis patients has not been reduced despite tremendous efforts. Many different complications may develop during replacement of a CVC such as arterial puncture, pseudoaneurysm, AVF formation, hematoma, air embolism, pneumothorax and malposition.15 Furthermore, catheter infection and malfunction are commonly observed. On the other hand, right atrial thrombus is a less frequent complication but may lead to potentially serious consequences.16–18 As compared to AVF or AVG, use of catheters is associated with increased mortality in this group of patients.9–11 Other catheter-related complications include increased rates of infection or hospitalization, catheter dysfunction, central venous stenosis and occlusion.19

Chronic kidney disease is associated with an increased predisposition to thrombus formation, as evidenced by the increased frequency of deep venous thrombosis, pulmonary embolism, vascular access thrombosis or atherosclerosis-related thrombosis. Patients with chronic kidney disease have also been found to have increased tendency for thrombosis even before the development of end-stage renal disease. The tendency has been explained on the basis of several factors involving endothelium, blood flow and platelets. In addition, accumulation of toxic molecules due to uremia may have an impact on thrombotic and hemostatic processes.20 Presumed contributing factors in patients with catheters include mechanical trauma due to catheter, activation of the coagulation cascade following endothelial damage and blood flow changes in association with the localization (i.e. right atrium) of the tip of the catheter.21^,22 Despite limitations in the number of patients, studies have provided supportive evidence for an association between thrombus formation and thrombophilia.23^,24 Although most of the patients with CRAT are not routinely examined with regard to hypercoagulability factor, certain acquired or hereditary factors have been described in those who have been tested.12 Although routine screening for thrombophilia is not recommended in patients with catheter-related thrombus,25 it would be useful to study thrombotic potential of the blood in our study. The absence of any data regarding thrombotic potential of the blood was a weakness of this study.

The frequency of CRAT was found 18% (9/50) in our study. The data regarding the frequency of CRAT in hemodialysis patients is limited. In a retrospective study, Shah et al. found it to be 5.4%.26 Since CRAT may be asymptomatic, its frequency may be more common than diagnosed. Echocardiography was used to detect atrial thrombus in our study. Thrombi were visualized with transthoracic or transesophageal echocardiography in most of the published cases.12 Magnetic resonance imaging and computerized tomography of the heart were other methods used in the diagnosis of atrial thrombus.12 Echocardiography is the most frequently used imaging modality for assessment of intracardiac mass and it allows characterization of mass (location, attachment, shape, size and mobility). Echocardiography has many advantages over other imagine modalities. These include noninvasive, no radiation exposure, widespread availability and low cost. The main disadvantage of echo is its operator dependency.27^,28 Sheiban et al. reported that two-dimensional echocardiography has an 82.2% sensitivity and 95.3% specificity in detection of intracardiac masses.29

Our study shows more common atrial thrombus among female and diabetic patients compared to male and nondiabetic patients, but there were not any statistical significance probably due to limited number of the patients. Stavroulopoulos et al. also reported higher frequency of atrial thrombus in female patients. In their meta-analysis, 76% (54/71) of the case were female.12 It would be useful to conduct a new study over a larger number of patients. As expected, the duration of catheter was longer in patients having atrial thrombus compared to in patients without atrial thrombus, but this was also statistically not significant.

Our data did not show any significant relationship between the presence of atrial thrombus and mortality, although it was higher in patients with atrial thrombus. Since our study did not investigate the cause of death, the contribution of atrial thrombus to mortality is unclear.

Serious complications have been reported in patients with CRAT, and no standard management strategies have been defined for this group of patients. In the algorithm proposed by Stavroulopoulos et al. for patients with thrombus, removal of the catheter is recommended following administration of therapeutic anticoagulation that appropriate for the alternative vascular access to be used. Surgical intervention is advocated those with a contraindication for anticoagulation, a thrombus size greater than 6 cm, or when there is an indication for surgery due to cardiac abnormality or endocarditis. The target international normalized ratio (INR) is recommended between 2 and 3 for six months, while it is the best to continue anticoagulation as long as the catheter is in place for patients with thrombophilia.12

Studies examining the effect of several preventive strategies for catheter-related thrombus or infections such as the use of catheter lock solution or systemic anticoagulation have failed to demonstrate significant benefit for these approaches.30 A particular concern for the use of systemic anti-coagulants regards an increased rate of hemorrhagic events.31 Systemic anticoagulation in patients with chronic kidney disease is associated with possible risks such as wound bleeding or vascular calcification.32 The Kidney Disease Outcomes Quality Initiative guidelines point out to the failure of antiplatelet agents and anticoagulants in preventing catheter or vascular access thrombosis, with a recommendation against the use of antiplatelet agents due to increased risk of bleeding in patients with grafts. Furthermore, low-dose warfarin (1 mg/day) has been reported to be ineffective. There is need for further studies to define target INR.4 The Caring for Australians with Renal Impairment suggest the use of antiplatelet agents for one month in native AVF to reduce the incidence of primary failure, and a recommendation for fish-oil was made based on the results of a small pilot study for AVG, with no specific recommendations for catheters.33 It should be kept in mind that atrial thrombus is a venous thrombosis in which antiplatelet therapy is ineffective.

Until the maturation of the AVF, catheters are widely utilized as permanent vascular routes despite the initial plan to use them as a bridge. Increased rate of morbidity and mortality associated with the use of catheters have led to effort aiming at increasing the rate of patients with AVF be prepared before hemodialysis is commenced. However, this approach is largely underused in many countries. Higher rates of catheter use have been reported in the elderly or patients with comorbidities, and also physician or health-system related factors play a major role in the frequency of catheter use.9^,34 On the other hand, increased morbidity and mortality rates in patients undergoing dialysis with catheters are central to an ethic discussion. In all patients experiencing vascular route problems, the clinician should be asking himself or herself the following questions: “Does an alternative vascular route really not exist?” and “Can this patient also be suitable for alternative renal replacement therapies?” Initial use of peritoneal dialysis for the first few years of renal replacement therapy have been found to offer a survival advantage, which was explained by the use of catheters in patients undergoing hemodialysis. In a study by Perl et al., a higher rate of mortality was found among patients undergoing hemodialysis with catheter than in those undergoing peritoneal dialysis during a one-year follow-up, while no significant differences could be detected for patients with AVF or grafts, at five-years of follow up. Patients with catheter hemodialysis had a higher mortality as compared to those undergoing peritoneal dialysis, with lower rates of mortality in those who had AVF or grafts.35 A comprehensive and standard pre-dialysis training, thorough assessment of risks/benefits associated with specific renal replacement therapies, and provision of objective information on the effects of replacement therapies on the current clinical status of the individual in the context of a discussion involving the treating physician and the patient/family members are key to better outcomes in this group of patients.

Acknowledgments

We thank Soner Gumusova, Naci Ozveren and Ismet Uncu for providing clinical support.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.