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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Even though numerous cases of massive thromboemboli have been reported in the literature, intracardiac thromboemboli (ICTs) incidentally found during orthotopic liver transplantation (OLT) have not been examined. In this study, we retrospectively examined the incidence, risk factors, and management of incidental ICTs during OLT. After institutional review board approval, adult patients who underwent OLT between January 2004 and December 2008 at our center were reviewed. ICTs were identified and confirmed by the examination of OLT datasheets, anesthesia records, and recorded transesophageal echocardiography (TEE) clips. The clinical presentation, management, and outcomes of the patients with ICTs were reviewed. Risk factors were analyzed by multivariate logistic regression. During the study period, 426 of the 936 adult OLT patients (45.5%) underwent intraoperative TEE monitoring. Incidental ICTs were identified in 8 of these 426 patients (1.9%). Two ICTs occurred before reperfusion, and 6 ICTs occurred after reperfusion. The treatment was at the discretion of the treating physicians; however, none of the patients received an anticoagulant or thrombolytics. Multivariate analysis identified 2 independent risk factors for intraoperative incidental ICTs: the presence of symptomatic or surgically treated portal hypertension (a history of gastrointestinal bleeding, a transjugular intrahepatic portosystemic shunt procedure, or portocaval shunt surgery) before OLT and intraoperative hemodialysis (odds ratios of 4.05 and 7.29, respectively; P < 0.05 for both). In conclusion, incidental ICTs during OLT occurred at a rate of 1.9% and were associated with several preoperative and intraoperative risk factors. The use of TEE allows early identification, which may be important. Our management for incidental ICTs is described; however, no conclusions can be made about the optimal therapy. Liver Transpl 16:1421–1427, 2010. © 2010 AASLD.

Thromboemboli occur only occasionally during orthotopic liver transplantation (OLT) yet pose a significant risk to these patients.1, 2 Most reported cases have a clinical presentation characterized by a sudden increase in the pulmonary artery (PA) pressure, severe hypotension, cardiovascular collapse, or cardiac arrest. The thromboemboli in these cases are usually described as large, massive, severe, or fatal; these terms refer to the clot size, the impact on hemodynamics, or the patient outcomes (the term massive is used throughout this report).3-14 The diagnosis of massive thromboemboli can be made on the basis of a typical clinical presentation with or without transesophageal echocardiography (TEE) evidence. Several strategies have been reported for the management of massive thromboemboli during OLT. Systemic heparin or thrombolytics (tissue plasminogen activator and urokinase) can be given after the identification of thromboemboli.6, 10 Surgical interventions such as thrombectomy, with or without cardiopulmonary bypass, have also been reported for the management of massive thromboemboli.6, 9-10, 13 Despite aggressive pharmaceutical or surgical interventions, the overall mortality rate for patients with thromboemboli during OLT remains high, and a majority of the patients die intraoperatively.

Intracardiac thromboemboli (ICTs) that are associated with transient mild hemodynamic changes have also been reported.15 The clinical importance of so-called incidental ICTs is not clear. However, some authors have suggested that an intracardiac clot can grow rapidly and be followed by the development of massive thromboemboli and hemodynamic collapse.6 Despite the potential risks, a systematic examination of incidental ICTs has not been reported, and the incidence of incidental ICTs is not known.

In this study, we attempted to (1) describe the clinical presentations of incidental ICTs during OLT, (2) investigate the incidence of such ICTs, (3) identify risk factors through a comparison of patients with ICTs and patients without ICTs via a multivariate logistic regression analysis, and (4) report our management of incidental ICTs during OLT and the outcomes of the patients.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

After institutional review board approval, medical records of patients who underwent OLT between January 2004 and December 2008 were retrospectively reviewed. Preoperative and intraoperative data were prospectively collected for the University of California Los Angeles transplantation database. Donor and postoperative data were collected retrospectively. Details of clinical events for those patients who developed ICTs were reviewed retrospectively.

Intraoperative anesthetic management followed the guidelines of the University of California Los Angeles liver transplant team. All adult patients were monitored with an intra-arterial catheter and a PA catheter for hemodynamics. Intraoperative TEE probe placement and monitoring were at the discretion of the anesthesiologists. Contraindications to TEE placement included active upper gastrointestinal bleeding, a recent history of esophageal variceal banding, difficulty with swallowing, and technical difficulties with TEE probe insertion. Pediatric patients (age <16 years old) were not monitored by intraoperative TEE and were excluded from the study.

Clinical coagulopathy was diagnosed by regular laboratory tests and surgical field assessment. Thromboelastography was not used during the study period. Coagulopathy was treated with blood components, which included fresh frozen plasma, platelets, and cryoprecipitate. An antifibrinolytic (tranexamic acid or ε-aminocaproic acid) was administered either as a bolus or as a continuous infusion at the discretion of the treating anesthesiologists. Neither aprotinin nor recombinant factor VIIa was used during the study period.

An ICT was identified by visualization of a thrombus or thrombi in the right atrium, right ventricle, or PA on TEE examination and was recorded on the prospective datasheet. The recorded ICT images were reviewed and confirmed by 2 anesthesiologists experienced in TEE. Hemodynamic changes or other associated findings such as an increase in PA pressure, systemic hypotension, or cardiac arrest were evaluated by a review of the anesthetic records. The management plan for each patient was made contemporaneously by transplant anesthesiologists, surgeons, and consultants, including cardiac surgeons, cardiologists, and cardiac anesthesiologists.

Data were expressed as means and standard deviations for continuous variables and as proportions for categorical variables. For risk factor analysis, baseline and intraoperative variables were compared between patients with ICTs and patients without ICTs with either the Student t test or chi-square test. The potentially significant variables (P < 0.2) were selected for multivariate analysis. The multivariate analysis was performed by stepwise forward and backward logistic regression. The results of the multivariate analysis were expressed as odds ratios, 95% confidence intervals, and P values. All analyses were performed with Statistical Package for the Social Sciences 16.0 (SPSS, Inc., Chicago, IL).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Incidence

Between January 2004 and December 2008, 936 adult patients underwent OLT at our medical center and were potential candidates for intraoperative TEE monitoring; 426 of these patients (45.5%) had intraoperative TEE monitoring (documented in the anesthesia record, OLT datasheet, or TEE recordings) and were included in the analysis. The mean age of the patients was 54.3 ± 10.6 years. The most common underlying liver disease was chronic hepatitis C or B. Intraoperative ICTs were identified in 10 patients. Two patients who were diagnosed with massive ICTs were excluded from the comparative analysis, and this left 8 patients with incidental ICTs for analysis. The calculated incidence of incidental ICTs was 1.9% (8/426). The majority of incidental ICTs (n = 6) occurred after reperfusion of the liver graft, and 2 occurred before reperfusion.

TEE Findings and Clinical Presentation

TEE images of ICTs are shown in Figs. 1 and 2 and in supporting video clips that are available online. Other clinical findings and characteristics are presented in Table 1. Under TEE examination, ICTs were found to be mostly located in the right atrium. Most of the incidental ICT patients had no hemodynamic findings. Two patients experienced a transient mild increase in the PA pressure and systemic hypotension. One patient had an increase in pulmonary pressure without systemic hypotension. One patient experienced intraoperative cardiac arrest and was successfully resuscitated. The cause of the cardiac arrest was suspected to be related to significantly elevated potassium concentrations (7.5 mmol/L in the anhepatic stage and 9.3 mmol/L immediately after reperfusion) and not to the ICT. The length of the time that the clot stayed in the right atrium varied. ICTs in 4 patients were no longer visible 30 minutes after their identification, and 3 other ICTs lasted more than 2 hours.

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Figure 1. TEE image (midesophageal, bicaval view) showing a thrombus (arrow) in the right atrium surrounding the PA catheter (case 8). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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thumbnail image

Figure 2. TEE image (midesophageal, 4-chamber view) showing a thrombus (arrow) in the right atrium (case 1). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Table 1. Clinical Presentation and Management of Patients With Incidental ICTs
 Case 1Case 2Case 3Case 4Case 5Case 6Case 7Case 8
SexFemaleFemaleFemaleMaleFemaleMaleMaleFemale
Age (years)6557615661485548
Model for End-Stage Liver Disease score3436282229262517
Reason for transplantationHepatitis CRetransplantHepatitis CHepatitis C and hepatocellular carcinomaCryptogenic cirrhosisPrimary sclerosing cholangitisAlcoholic cirrhosisHepatitis B
Venovenous bypassYesYesNoNoNoNoYesNo
Red blood cells (U)22266672081910
Fresh frozen plasma (U)36208691881412
AntifibrinolyticsYesYesYesNoYesNoNoYes
Time of ICT occurrenceBefore reperfusionAfter reperfusionAfter reperfusionAfter reperfusionAfter reperfusionBefore reperfusionAfter reperfusionAfter reperfusion
ICT duration under TEE examination>2 hours>2 hoursAbout 10 minutesUnknown30 minutes1 minute10 minutes>2 hours
Clinical presentationMild increase in PA pressure and systemic hypotensionPA pressure increase but no systemic hypotensionNo pulmonary hypertension or systemic hypotensionCardiac arrest due to hyperkalemia (not related to ICT)Brief increase in PA pressure and systemic hypotensionNo significant hemodynamic changeNo significant hemodynamic changeNo significant hemodynamic change
TreatmentDiscontinuation of tranexamic acidDiscontinuation of aminocaproic acidDiscontinuation of tranexamic acid and removal of PA catheterRemoval of PA catheterDiscontinuation of tranexamic acidNo special treatmentNo special treatmentDiscontinuation of aminocaproic acid
Survival>1 yearDeath 160 days after transplantation>2 years>1 year>1 year>1 year>1 year>1 year

Risk Analysis

The results of the comparison of patients with ICTs and patients without ICTs are shown in Table 2. Univariate analysis showed that patients with ICTs had a significantly higher frequency of symptomatic and/or surgically treated portal hypertension (gastrointestinal bleeding, a transjugular intrahepatic portosystemic shunt procedure, or portocaval shunt surgery before OLT). In addition, a significantly higher proportion of ICT patients had intraoperative dialysis. Notably, the baseline demographics, donor characteristics, use of antifibrinolytics, and use of venovenous bypass were not significantly different between the 2 groups. Multivariate logistic regression showed that symptomatic and/or surgically treated portal hypertension (odds ratio = 4.05, 95% confidence interval = 1.02-16.18, P = 0.048) and intraoperative hemodialysis (odds ratio = 7.29, 95% confidence interval = 1.71-31.04, P = 0.007) were significantly associated with an increased incidence of incidental ICTs during OLT. The area under the curve was 0.784.

Table 2. Univariate Analysis of Demographic and Intraoperative Variables for Patients With Incidental ICTs and Patients Without Incidental ICTs
 No ICT (n = 416)ICT (n = 8)P Value
Preoperative variables
 Age (years)54.3 ± 10.756.5 ± 5.90.557
 Sex (% male)60.762.50.918
 Model for End-Stage Liver Disease score28.9 ± 7.427.1 ± 6.10.506
 Weight (kg)78.6 ± 21.074.8 ± 16.80.606
 Acute hepatic failure (%)4.30.00.523
 Chronic hepatitis C (%)47.337.50.581
 Nonalcoholic steatohepatitis (%)4.612.50.297
 Cirrhosis due to alcohol (%)20.825.00.771
 Retransplantation (%)9.412.50.766
 Preoperative hemodialysis (%)27.312.50.352
 History of gastrointestinal bleeding, a transjugular intrahepatic portosystemic shunt procedure, or portocaval shunt surgery before OLT (%)36.675.00.026
 Ascites > 1 L (%)41.414.30.148
 Encephalopathy (%)36.237.50.941
 Preoperative ventilator requirement (%)17.512.50.711
Intraoperative variables   
 Baseline hematocrit (%)29.9 ± 5.729.6 ± 4.00.872
 Baseline platelets (×1,000/μL)74.5 ± 58.558.9 ± 28.30.449
 International normalized ratio1.7 ± 0.71.7 ± 0.40.946
 Fibrinogen (mg/dL)175.6 ± 87.8147.4 ± 38.30.366
 Creatinine (mg/mL)1.7 ± 1.61.0 ± 0.30.222
 Venovenous bypass (%)35.837.50.921
 Prereperfusion red blood cells (U)9.3 ± 7.810.3 ± 6.10.735
 Total red blood cells (U)16.3 ± 15.122.3 ± 19.50.271
 Prereperfusion fresh frozen plasma (U)11.5 ± 8.511.0 ± 7.30.866
 Total fresh frozen plasma (U)19.5 ± 15.523.1 ± 20.60.515
 Urine output (mL)558 ± 551804 ± 6940.281
 Lasix (%)32.550.00.297
 Any antifibrinolytic (%)37.362.50.145
 ε-Aminocaproic acid (%)21.125.00.790
 Tranexamic acid (%)18.037.50.157
 Intraoperative hemodialysis (%)5.625.00.022
 Surgery time (minutes)305 ± 99356 ± 860.305
Donor variables
 Age (years)40.6 ± 16.843.6 ± 14.20.641
 Cold ischemia time (minutes)406 ± 162479 ± 1380.209
 Warm ischemia time (minutes)39.6 ± 10.341.9 ± 7.30.529
 Highest sodium level (mmol/L)147 ± 9.5149 ± 6.10.637
 Hospital stay (days)4.6 ± 3.03.9 ± 2.20.521
 Intensive care unit stay (days)4.5 ± 2.93.9 ± 2.90.524
 Donation after cardiac death (%)6.114.30.376

Management and Outcomes

When ICTs were identified, surgeons were immediately notified. Antifibrinolytics, when they were in use (n = 5), were discontinued. The administration of clotting factors or platelets was discontinued or reduced. If the PA catheter was surrounded by thromboemboli, it was removed from the central venous system (n = 2). If ICTs were not associated with hemodynamic changes, they were simply monitored by continuous TEE. If ICTs were associated with an increase in PA pressure and systemic hypotension, supportive treatments were administered. No patients received systemic heparin or thrombolytics. Surgical interventions were not used. All patients (except for 1 patient who underwent repeat OLT) survived more than a year after the transplant surgery.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Since Kang et al.3 reported the first case in 1987, 105 cases involving ICTs, pulmonary embolisms, or both (including the cases of this study) have been documented in the literature.1, 15, 16 It is believed that intraoperative ICTs during OLT are greatly underdiagnosed and underreported.9 The need for TEE monitoring is an obstacle for the accurate diagnosis of intraoperative ICTs (particularly those without significant hemodynamic changes). In this study, using prospectively collected data, we demonstrated that the incidence of ICTs in patients who were monitored by TEE during OLT was 1.9%. This is consistent with previous estimated rates of 1.2% to 6.3%. However, several significant differences can be noted between our study and previous case reports. First, unlike previous case reports and case series, intraoperative TEE monitoring was used in all patients included in our analysis. Without TEE monitoring, many incidental ICTs would be missed, and the accuracy of the incidence cannot be guaranteed. Second, our patients had no or only transient mild increases in PA pressure and systemic hypotension. Transient hemodynamic changes are routinely seen during OLT and are not specific to ICTs. In contrast, most patients in previous reports had massive ICTs and presented with significant hemodynamic changes. It is still possible that our reported incidence remains underestimated because small thrombi may have passed without being identified if the TEE image was not monitored continuously.

The mechanism by which an intraoperative ICT develops in the setting of end-stage liver disease and severe coagulopathy is poorly understood. Nonetheless, many risk factors have been proposed. Several factors are related to the patient: sepsis, the migration of preexisting thrombi, intraoperative hypotension, and protein C and S deficiencies.4, 7, 9, 10, 12, 13, 17, 18 Others are inherent to the OLT procedure: excessive activation of the coagulation system, venous stasis during clamping of the portal vein and inferior vena cava, and release of activators from the liver graft.6, 7, 9 In addition, other conditions such as heparin-induced thrombocytopenia, factor V Leiden, and antithrombin deficiency can contribute to thrombosis and possibly ICTs during OLT. Finally, intraoperative management may play an important role: PA catheter placement; the administration of antifibrinolytics, anti–hepatitis B immunoglobulin, and blood products; and the intraoperative utilization of continuous venovenous filtration.2, 4, 7, 8, 10-14, 18-20 Risk factor analysis for ICTs during OLT has proved to be difficult because of the relatively low incidence. In this study, we showed that symptomatic and/or surgically treated portal hypertension and intraoperative hemodialysis were independent risk factors for the development of incidental ICTs during OLT. Patients who have variceal bleeding or require surgical intervention for the treatment of portal hypertension are prone to thrombosis. The dilated portal system, severe venous stasis, activation of the coagulation system, and occult bacterial infections are proposed mechanisms for thrombosis in these patients.21 In general, patients who have required intraoperative hemodialysis have experienced refractory metabolic acidosis or hyperkalemia or received massive blood transfusions in our practice. Planinsic et al.19 postulated that a clot could be formed in the continuous venovenous filtration system. However, it is also possible that activation of the coagulation system via contact with the dialysis system facilitates clot formation because a non–heparin-coated system was used for intraoperative dialysis at our center. Several factors that had been previously proposed failed to show a significant association in our analysis. Antifibrinolytics, including tranexamic acid and ε-aminocaproic acid, did not show any association with ICTs either alone or in combination. Venovenous bypass and blood product requirements did not show any protective or detrimental effects.

In this report, we have described our management after the identification of incidental ICTs during OLT. The core components of our management included communication with surgeons (who could assess the portal vein and the inferior vena cava and identify a potential source of thrombi), discontinuation of the clotting factors and antifibrinolytics, removal of the PA catheter, and hemodynamic support. No patients received systemic heparin or thrombolytics. Although the PA catheter was considered a source of clot formation by several investigators,4, 5, 10, 11 its removal may break the clot, cause a pulmonary embolism, and leave a patient without this important monitoring tool during a critical time. We considered removal of the catheter only when it was surrounded by clots and the patient was hemodynamically stable.

Two patients with massive ICTs who were excluded from the comparative analysis in this study should be mentioned as well. The clinical presentations were typical and were characterized by a sudden increase in PA pressure, severe systemic hypotension, and cardiac arrest. Despite immediate resuscitation, both patients died intraoperatively. Neither the systemic administration of heparin or tissue plasminogen activator nor invasive interventions such as thrombectomy were used after consultation with cardiologists and cardiac surgeons. Although the overall incidence of ICTs in our study was comparable to the rates in other reports, the incidence of massive ICTs (0.5%, 2/426) in our study was significantly lower in comparison with the rates in previous reports. When all 936 adult patients (with or without TEE monitoring) were included because TEE was not required for the diagnosis of massive ICTs, the incidence was even lower (0.2%, 2/936). It is not clear why the incidence of massive ICTs in our series is much lower than the rates previously reported. The relationship between an incidental ICT and a massive ICT is not known. Theoretically, a small ICT can develop into a massive clot, as suggested by others6; this did not seem to be the case in our series. Notably, a multivariate analysis including these 2 massive cases showed identical risk factors.

Several limitations are worth mentioning. The definitions of incidental and massive ICTs in this study are somewhat arbitrary. Nonetheless, the TEE findings and clinical presentations of these 2 types of ICTs appear different. The true incidence of ICTs in patients undergoing OLT remains elusive because we studied only patients who had intraoperative TEE monitoring at a single center. A potential selection bias and different patient populations in different centers may affect the incidence. Nevertheless, our report extends our current understanding and provides one of the most accurate ICT rates so far. The relatively low incidence of intraoperative ICTs during OLT made the analysis less reliable. A small change in the variables could produce a significant change in the results of the analysis. The risk factors identified in the study are not necessarily causal factors of ICTs. It is possible that the risk factors identified in our study are surrogate markers. Clinical practice, including intraoperative monitoring, blood product replacement, and management, varies greatly among transplant centers; therefore, caution should be exercised in the interpretation of our data.

In conclusion, incidental ICTs during OLT occurred at a rate of 1.9% and were associated with several preoperative and intraoperative risk factors. The use of TEE allows early identification, which may be important. Our management after the identification of incidental ICTs is described; however, no conclusions can be made about the optimal therapy.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
LT_22182_sm_suppmov1.mov7910KSupporting Movie 1
LT_22182_sm_suppmov2.mov8115KSupporting Movie 2
LT_22182_sm_suppmov3.mov14732KSupporting Movie 3
LT_22182_sm_suppmov4.mov7708KSupporting Movie 4
LT_22182_sm_suppmov5.mov19170KSupporting Movie 5
LT_22182_sm_suppmov6.mov15451KSupporting Movie 6
LT_22182_sm_suppmov7.mov5675KSupporting Movie 7
LT_22182_sm_suppmov8.mov7491KSupporting Movie 8

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