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Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey
Address correspondence and reprint requests to Douglas Jackson, MD, JD, Department of Anesthesiology, UMDNJ, MSB E-538b, 185 South Orange Avenue, Newark, NJ 07101. Address e-mail to jacksod1{at}umdnj.edu.
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Abstract |
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-aminocaproic acid and clotting factors. Shortly after hepatic artery clamping the patient developed a massive intracardiac/intravascular thrombosis that resulted in cardiac arrest. After diagnosis by transesophageal echocardiography, the patient was treated with recombinant tissue plasminogen activator through a central venous catheter advanced into the right atrium. After treatment with recombinant tissue plasminogen activator, the patient’s hemodynamic status improved, permitting the liver transplant to be completed. The patient was ultimately discharged to home. We report the successful intraoperative resuscitation of a patient with acute intracardiac/intravascular thrombosis during an orthotopic liver transplantation using thrombolytic therapy. |
Introduction |
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-aminocaproic acid (EACA), aprotinin, and/or clotting factors were used (1–3). We present a case in which a patient received EACA and clotting factors and soon thereafter developed a massive IC/PE that resulted in cardiac arrest. After diagnosis by transesophageal echocardiography (TEE) the patient was successfully treated with recombinant tissue plasminogen activator (rTPA). |
Case Report |
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General anesthesia was induced and maintained with midazolam, fentanyl, cisatracurium, and isoflurane. A radial arterial catheter and a central venous catheter were placed. Vital signs after induction were unremarkable: mean arterial blood pressure (MAP) was 130/70 mm Hg and heart rate (HR) was 80 bpm. By protocol, 30 min after induction, an initial dose of 5 g of EACA was administered over 30 min with an infusion maintained at 1 g/h. Ten units of cryoprecipitate was administered during the second hour and 10 units of platelets were administered during the third hour of the procedure to help prevent diffuse oozing during liver dissection.
Shortly after clamping of the hepatic artery, the patient’s MAP suddenly decreased from 130/80 mm Hg to 60/40 mm Hg and her HR increased from 90 bpm to 140 bpm. End-tidal CO2 (ETco2) decreased from 31 torr to 10 torr. Despite the rapid infusion of 500 mL of lactated Ringer’s solution and approximately 10 bolus doses of phenylephrine (80 µg/mL per bolus, 800 µg total dose), her vital signs remained unchanged. Ventricular fibrillation developed that was resistant to precordial electrical defibrillation (250 joules, biphasic x 3). The surgeons obtained access to the heart through the diaphragm. The heart was dilated and not beating. Direct cardiac compressions were started and bilateral chest tubes were inserted to eliminate the possibility of a tension pneumothorax. After administration of amiodarone 150 mg bolus and a subsequent electrical defibrillation, sinus rhythm at 110 bpm was finally restored approximately 12 min after the initial arrest. Her MAP remained at 75 mm Hg, with central venous pressure (CVP) at 35 mm Hg and ETco2 of 8 torr. An infusion of epinephrine (4 µg/min) and norepinephrine (4 µg/min) was started. Initial arterial blood gas sample showed pH: 7.12; Pco2: 37 mm Hg; Po2: 97 mm Hg; HCO3: 12 mEq/L; BE: –15.9. A TEE probe was placed and revealed the presence of a massive thrombus within the right atrium, coronary sinus (Fig. 1a), right ventricle (RV), superior vena cava, and inferior vena cava and the proximal pulmonary artery (PA) (Fig. 2a). The TEE examination also revealed a dilated and hypokinetic RV. The left ventricle was hypokinetic but was noted to be underfilled. The EACA infusion was stopped.
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An invasive radiologist was consulted who recommended treatment with rTPA. A cardiothoracic surgeon was consulted who opined that given the frequent mortality of operative removal, embolectomy should only be performed if treatment with rTPA was unsuccessful. Approximately 45 min after the initial arrest, rTPA 50 mg in 50 mL normal saline was given over 5 min via the central venous catheter, which was first advanced into the RV under TEE guidance. No changes in clot size or contractility were noted on TEE but ETco2 improved to12 torr and CVP decreased to 28 mm Hg within 5 min of the end of the administration of the rTPA. To direct hemodynamic management, a PA catheter (PAC) was placed with TEE guidance. Initial readings were: HR 115 bpm, PA pressure (PAP), 30/12 mm Hg; mean PAP 18 mm Hg, CVP 28 mm Hg; cardiac index (CI) 1.6 L/min/m2; Svo2 40%. Milrinone (0.5 µg·kg-1·min–1) and vasopressin (5 U/h) infusions were started. Over the next 30 min her HR remained at 115 bpm, ETco2 was 14–16 torr, and MAP was maintained at 110/60 mm Hg. CI increased to 2 L/min/m2 and PAP increased to 40/18 mm Hg and mean PAP to 25 mm Hg.
A second dose of rTPA 50 mg was given 30 min after the first dose. No sudden hemodynamic response was noted to this second dose of rTPA. Over the next several hours, although the inotropic infusions were left unchanged, ETco2 increased to 22–26 torr, the CVP declined to 10–12 mm Hg and the CI increased to over 2.5 L/min/m2. These hemodynamic changes were accompanied by improved RV function and improved left ventricular filling, as noted on TEE. Arterial blood gas values improved as follows: pH: 7.26; Pco2: 37 mm Hg; Po2: 433 mm Hg; HCO3: 16.5 mEq/L; base excess: –9.6.
The surgeons proceeded to successfully complete the OLT, although the total time in the operating room was 21 h. Case management included phenylephrine boluses 80 µg/mL and 100-µg boluses of epinephrine to support MAP around the time of liver reperfusion. There was substantial difficulty in controlling surgical bleeding during the case. Six hours after the second dose of rTPA, during the neohepatic stage, the prothrombin time was 54.1 s, partial thromboplastin time was >100 s, and the international normalized ratio was 11.51. Blood product requirements after rTPA was administered were: 10 U of cryoprecipitate, 20 U of platelets, 17 U of fresh-frozen plasma, and 26 U of packed red blood cells. Fluid totaled 9 L of crystalloids. Urine output was maintained at 25–35 mL/h. There was no change to the appearance of the clot by TEE at the conclusion of the case.
The patient was stable with adequate oxygenation on surgical intensive care arrival. On postoperative day 3, a repeat TEE (Fig. 1b and 2b) revealed no signs of thrombosis in the cardiac chambers. The patient’s subsequent surgical intensive care unit course was prolonged as a result of the development of acute renal failure requiring dialysis and respiratory failure requiring prolonged ventilatory support. After a total hospital course of 8 wk, the patient, who was neurologically intact, was discharged to home.
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Discussion |
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Fibrinolysis has been recognized to occur during OLT and to be the source of substantial bleeding (6). Increased levels of TPA during OLT have been implicated as the cause of increased fibrin degradation with resultant bleeding. Because significant morbidity is associated with intraoperative blood loss during OLT, practitioners have sought to limit bleeding by the prophylactic administration of antifibrinolytic drugs (7–9).
Three drugs, EACA, aprotinin, and tranexamic acid (TA), have been widely used in an effort to control blood loss (4). EACA acts by attaching to lysine-binding sites on plasminogen and inhibiting binding of plasmin to fibrinogen, thereby preventing fibrinolysis of newly formed clots (7). TA works through a similar mechanism (8). Aprotinin, a serine protease inhibitor, is thought to have several modes of action. It directly inhibits plasmin by forming aprotinin-enzyme complexes. It also inhibits many other proteases involved in the coagulation and inflammation cascades and may also enhance platelet function (9).
Although widely used, the evidence for the efficacy of these drugs is not uniformly compelling. EACA has been used since the 1980s, but there are few randomized prospective studies to support its use. In the most recent prospective study, EACA was no better than placebo for reducing bleeding (10). Its use is still common at many centers because of its low cost and long history of use (4). TA and aprotinin have been more widely studied and have generally been shown to be effective in reducing blood and blood product requirements (5). A recent randomized study comparing TA and aprotinin demonstrated that both were equally effective for reducing blood requirements (9).
Despite widespread use and efficacy, there have been numerous case reports of thromboembolic phenomena associated with some of these drugs. A recent review (4) summarized 30 reported cases of intraoperative thrombosis. Mortality exceeds 50%. Eighty percent (24/30) of the patients had received fibrinolytics. Eleven patients had received aprotinin, 10 had received EACA, and 3 had received aprotinin and EACA, although no patient had received TA. The relationship between the antifibrinolytic drugs and thrombosis remains anecdotal and the case reports also confirm that thrombosis can occur in the absence of antifibrinolytic drugs. There are many other factors that may be responsible for thrombosis in the heterogeneous population of patients who present for OLT. Many other possible causes of IC/PE have been suggested, including migration of preexisting thrombi, disseminated intravascular coagulation, sepsis, hepatitis B immunoglobulin, transfusion of platelets, clotting factors and blood, protein C or S deficiency and hepatorenal syndrome (5). Because IC/PE is rare and has not been definitively related to antifibrinolytics in a carefully controlled study, firm recommendations concerning their continued use cannot be made (4,5). Practitioners must, however, be mindful of the possible association and be prepared to manage this complication should it occur.
It should also be noted that in the case we are reporting, the patient also received cryoprecipitate and platelets while the EACA was infusing as per our standard protocol. It is possible that the administration of these drugs, particularly in the setting of normal fibrinogen, may be a predisposing factor to thrombus formation. We no longer routinely administer these blood products to all transplant patients.
The intraoperative development of a massive IC/PE is typically a catastrophic event. The diagnosis is suggested by systemic hypotension, a decrease in the ETco2, and hypoxemia. The electrocardiogram may show signs of RV strain (11). If PAC measurements are available, the triad of increased CVP, increased PAP (with normal PA occlusion pressure), and decreased cardiac output will be seen (12). In the presence of massive RV failure, as with our patient, PA pressures may be deceptively low because the forward flow through the PA is diminished; the CVP, however, will still be increased. As RV function, and thus PA flow is restored, the PA pressures would be expected to increase, as was seen in our patient.
There is not widespread consensus that PACs should be routinely used in all OLTs (13). Many patients have normal cardiac function that has been worked-up before surgery and many practitioners are comfortable managing these patients without a PAC. However, in patients with known cardiac dysfunction, particularly pulmonary hypertension, there have been reports of adverse outcome (14). Although there are no studies that demonstrate improved outcome with the use of PACs, PAC placement may be justified in patients with known cardiac diseases or in patients who develop hemodynamic derangements that are not easily diagnosed or managed. Although we do not routinely place a PAC, we do routinely place an introducer sheath, which minimizes the difficulty of floating a PAC under urgent conditions. Even though there is some risk of dislodging thrombus during passage of a PAC, we felt that the benefits of the PAC to guide management of this patient in cardiogenic shock justified its use and outweighed the potential risks. In a less severely compromised patient the risks of placing the PAC might have been judged unacceptable. Once the PAC was placed, it was extremely useful to guide the patient’s response to therapy. The changes in CI and PAP provided evidence that the therapeutic interventions were effective and that the patient was being appropriately managed.
The definitive intraoperative diagnosis of IC/PE can be made with TEE. In addition to potentially permitting direct visualization of the thrombus, TEE can detect the development of RV dysfunction. TEE signs of RV dysfunction include RV dilation, tricuspid regurgitation, and leftward shift of the interatrial and interventricular septa (15). In our case, the TEE was placed before the PAC and the diagnosis was easily made. The clot was visualized and there were obvious signs of RV dysfunction. We concur with authors who suggest that TEE is extremely valuable for the diagnosis and management of IC/PE (12). TEE is even less commonly used intraoperatively than a PAC. One survey indicated that only 11.3% of centers use it routinely for OLT (13). Although there are no prospective studies to support the notion that outcomes are improved, reports have documented its safety and utility in this patient population (17). Definitive recommendations for routine use cannot be made based on the present literature. As with the PAC, the patient’s preoperative status and/or intraoperative events must be evaluated to determine whether or not to place this useful monitoring modality. It should be noted that in urgent situations, a TEE (if readily available), is typically easier and faster to place than a PAC.
Once diagnosed, there is no consensus for treatment of intraoperative IC/PE. In the medical setting, there is substantial evidence that thombolytic therapy, despite the increased risk of major hemorrhage, reduces mortality in patients with shock resulting from massive pulmonary embolism (15,16). For example, Chartier et al. (18) demonstrated a superior survival rate from thrombolytic therapy, with rTPA showing improved survival (77% survival) over embolectomy (53% survival), invasive radiological embolectomy (50% survival), or heparin (38% survival). Evidence suggests that thrombolytic therapy should also be used in submassive thrombosis if RV dysfunction is demonstrated by TEE (15,19).
Drugs available for thrombolytic therapy include streptokinase and rTPA (alteplase). Although no drug has been shown to be superior, rTPA is most typically used (16). rTPA acts by binding to fibrin within a clot and converting plasminogen into plasmin, which is responsible for the enzymatic degradation of fibrin clots. The free circulating half-life of rTPA is approximately 5 minutes; however the fibrinolytic action of r-TPA will continue for up to 1 hour at the site of fibrin-bound plasminogen (20). The recommended dosing is 100 mg as a peripheral IV infusion over 2 hours, although considerable variation in the dosing is reported by investigators (16). Catheter-directed thrombolysis has been advocated as a technique that would reduce hemorrhagic complications, accelerate clot lysis, and restore pulmonary circulation more rapidly. However, there is no clear-cut evidence that local catheter delivery of thrombolytics is superior (21), nor is there a universally accepted dosing regimen for catheter delivery (22).
The most common complication of rTPA treatment is adverse bleeding. Monitoring of fibrinogen levels has been proposed as a means of reducing the incidence of adverse bleeding associated with continuous infusions of rTPA. A fibrinogen concentration <100 mg/dL has been suggested as an unsafe level (although it has not been rigorously tested) that should be corrected by decreasing the rTPA infusion rate (20). Cryoprecipitate can also be administered if adverse bleeding is problematic.
The evidence for choice of therapy for intraoperative occurrences of massive IC/PE during OLT is more anecdotal. Case reports have suggested various techniques. There have been reports of patients who have been successfully treated with heparin and inotropic support (12,23). When more aggressive therapy is needed, surgical embolectomy is generally the chosen intervention over thrombolytic therapy (3,12,23) because of the perceived risk of bleeding from thrombolytic therapy (18). Thrombolytic therapy, however, has the advantages of simplicity, rapid initiation, and the ability to dissolve clot that forms in disparate anatomic locations. There are two previous reports of thrombolytic therapy during OLT, but neither was successful. One of the patients reported by O’Connor et al. (24) received urokinase but required veno-venous bypass for successful completion of the OLT and never regained consciousness. The one patient reported by Gologorsky et al. (12) who received rTPA died intraoperatively.
We chose to use rTPA in the present circumstances because of surgical reluctance to proceed to embolectomy. Although there cannot be certainty that the rTPA was responsible for the patient’s survival, the dramatic improvement in the patient’s hemodynamics in the hours after rTPA treatment is highly suggestive. We cannot, of course, exclude that the patient might have improved with inotropic support alone.
The decision to proceed with the OLT immediately after rTPA use was made because the patient’s hemodynamic status improved to the point where she could be supported through the case. The visible bleeding on the surgical field was acceptable and the case was concluded successfully, although with considerable blood product usage. Consideration was given to aborting the procedure, so that the patient’s hemodynamic, ventilatory, and coagulation status could be addressed more completely before OLT. It was felt, however, that the patient’s acute RV failure might have further damaged her failing liver and as a result it was not certain that she could be supported without proceeding to OLT immediately.
We believe this is the first reported case of successful use of rTPA intraoperatively during OLT. In the face of a massive IC/PE, thrombolytic therapy may be a therapeutic option that can prevent what might otherwise be a catastrophic outcome.
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Footnotes |
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This article has been cited by other articles:
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  M. Carron and C. Ori Thrombolysis for massive pulmonary tumour embolism in a patient with cavoatrial renal carcinoma Br. J. Anaesth., August 1, 2008; 101(2): 285 - 286. [Full Text] [PDF]
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 R. M. Planinsic, I. A. Hilmi, and T. Sakai Prevention of Intracardiac/Pulmonary Thrombosis During Liver Transplantation Anesth. Analg., November 1, 2006; 103(5): 1329 - 1329. [Full Text] [PDF]
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