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The Successful Use of Low-Dose Recombinant Tissue Plasminogen Activator for Treatment of Intracardiac/Pulmonary Thrombosis During Liver Transplantation

Boone, James D. MD; Sherwani, Saadia S. MD; Herborn, Joshua C. MD; Patel, Kinjal M. MD; De Wolf, Andre M. MD

doi: 10.1213/ANE.0b013e31820472d4
Cardiovascular Anesthesiology: Case Report
Chinese Language Editions

Intracardiac thrombosis and pulmonary embolism are uncommon complications during liver transplantation but carry a high mortality rate. We report the successful use of low-dose recombinant tissue plasminogen activator (0.5–4 mg) administration in 4 patients. Early diagnosis through transesophageal echocardiography and pulmonary artery catheterization may have contributed to the rapid thrombolysis.

Published ahead of print December 2, 2010 Supplemental Digital Content is available in the text.

From the Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

The authors declare no conflicts of interest.

Address correspondence and reprint requests to Andre M. De Wolf, MD, Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, 251 E. Huron St., F5-704, Chicago, IL 60611. Address e-mail to a-dewolf@northwestern.edu.

Accepted October 22, 2010

Published ahead of print December 2, 2010

Intraoperative intracardiac thrombosis (ICT) and pulmonary embolism (PE) are potentially devastating complications of liver transplantation (LTx). The estimated incidence of ICT/PE during LTx is low (1%–1.5%), but it has a very high mortality rate (>50%).1 3 Treatment options are limited, and there is only anecdotal information on the potential treatment with recombinant tissue plasminogen activator (rTPA).1,2 In the medical setting, acute pulmonary thromboembolism with hemodynamic decompensation may be treated by rTPA, with doses ranging from 40 to 100 mg over 2 hours.4,5 However, this treatment is associated with a risk of hemorrhage.5 In the setting of LTx, a safe yet effective dose of rTPA is unknown. We now report 4 cases of successful use of low-dose rTPA (0.5–4 mg) for treatment of intraoperative ICT/PE during LTx. Oral and written informed consent were obtained for all 4 patients.

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CASE DESCRIPTIONS

Patient 1

A 58-year-old woman with hepatitis C cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 40 presented for LTx. During the dissection and anhepatic stages, she maintained stable hemodynamics despite considerable surgical bleeding that required significant blood product transfusion including cryoprecipitate and platelets. After the hepatic artery anastomosis was finished, she developed sudden systemic hypotension and pulmonary hypertension requiring epinephrine infusion. A transesophageal echocardiography (TEE) probe was promptly placed and showed massive clots in the right atrium and in both right and left pulmonary arteries. Within a few minutes, 4 mg rTPA was administered through the central venous port of the pulmonary artery catheter. Resolution of the clots and normalization of the hemodynamics were noted immediately, and she was transferred to the intensive care unit in stable condition. The patient received a total of 69 U fresh frozen plasma (FFP) and 65 U packed red blood cells (PRBCs) for the entire case. The patient recovered well initially; however, she died 4 weeks later of multiorgan failure.

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Patient 2

A 59-year-old man with nonacute steatohepatic cirrhosis, hepatocellular carcinoma, and portal vein thrombosis presented for LTx (MELD score of 27). During the anhepatic stage, the patient developed sudden hypotension and bradycardia, which were treated with IV fluid administration and epinephrine. Despite aggressive resuscitation, the patient remained hypotensive with an increase in pulmonary artery pressures (PAPs) (38/13 to 54/20 mm Hg) and a decrease in pulse oximetry (SaO2) to 77%. During the resuscitation, a large, mobile right atrial thrombus and a smaller left atrial thrombus were noted on TEE. Heparin (5000 U) was administered IV. Because there was no hemodynamic improvement within 3 minutes, two 1-mg doses of rTPA were given through the central venous port of the pulmonary artery catheter. Two minutes after rTPA administration, the intracardiac thrombus disappeared on TEE, and 5 minutes later, SaO2 returned to 100%. Epinephrine infusion was weaned down from 10 μg/min to 4 μg/min. Hemodynamics were stable for the remainder of the case. The patient received a total of 12 U FFP and 10 U PRBCs for the entire case. The patient was transferred to the intensive care unit with stable hemodynamics, tracheally extubated on postoperative day (POD) 1, and discharged from the intensive care unit on POD 2.

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Patient 3

A 55-year-old man with hepatitis C and alcoholic cirrhosis presented for LTx with a MELD score of 33. The dissection stage was notable for significant surgical bleeding, and 17 U PRBCs, 17 U FFP, and 1 U pooled platelets were transfused. The anhepatic stage was prolonged because of portal vein thrombosis. Reperfusion of the liver was uneventful. After anastomosis of the hepatic artery, the patient became increasingly hemodynamically unstable despite multiple boluses of phenylephrine, norepinephrine, and epinephrine. An increase in the central venous pressure (from 12 to 24 mm Hg) and PAP (from 25/10 to 47/31 mm Hg) was noted. The liver became markedly enlarged and congested. A TEE probe was promptly placed, demonstrating clot in the right atrium. Heparin (5000 U) was given IV without immediate improvement, and subsequently 0.5 mg rTPA was given through the central venous port of the pulmonary artery catheter. Within minutes, the hemodynamics improved, the liver congestion resolved, and the clot was no longer visible on TEE. The LTx was completed uneventfully. A total of 47 U PRBCs, 45 U FFP, 3 U cryoprecipitate, and 8 U pooled platelets were transfused. However, only 17 U PRBCs, 10 U FFP, 4 U platelets, and 2 U cryoprecipitate were transfused after rTPA administration. The patient gradually recovered and was tracheally extubated 8 days after LTx with good liver function.

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Patient 4

A 58-year-old woman who received an LTx in 1997 for hepatitis C virus cirrhosis presented for retransplantation because of recurrent hepatitis C (MELD score of 34). The surgical plan also included kidney transplantation. A TEE probe was placed to provide additional monitoring. Despite massive blood product transfusion during the first 2 stages of the operation (66 U PRBCs, 55 U FFP, and 3 U pooled platelets), the patient remained hemodynamically stable. However, soon after liver reperfusion, the patient developed systemic hypotension unresponsive to norepinephrine and vasopressin boluses and an acute increase in central venous pressure and PAP (39/28 mm Hg). TEE showed a large thrombus extending from the right atrium to the right ventricle (Fig. 1), and rTPA was ordered. Meanwhile, persistent hypotension required chest compressions and epinephrine boluses. When rTPA became available (within 3 minutes), 2 mg rTPA was administered through the central venous port. Within 5 minutes, hemodynamics recovered and the thrombus was clearly smaller on TEE (Fig. 2). After 90 minutes, the thrombus resolved completely. The remainder of the procedure was uneventful. Total transfusion requirements were 88 U PRBCs, 82 U FFP, 7 U pooled platelets, and 2 U cryoprecipitate. The patient was tracheally extubated on POD 3 with adequate liver and kidney function.

Figure 1

Figure 1

Figure 2

Figure 2

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DISCUSSION

The best treatment of ICT/PE during LTx is not known.1 3 In a systematic review of ICT/PE during LTx, Warnaar et al.2 found that thrombolysis or thrombectomy (with or without cardiopulmonary bypass) was used in 19 of 74 (26%) reported cases of ICT/PE, but these aggressive interventions did not result in a better outcome. Thrombolysis was used in 6 of these patients, and some of these cases have been presented as individual case reports; 4 patients received rTPA, 1 received urokinase, and the thrombolytic therapy in the final patient could not be further specified (Personal communication, N. Warnaar, MD. Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands).2 One patient received the frequently recommended dose of rTPA (100 mg) with success,6 but another patient who received 110 mg rTPA experienced massive hemorrhage and died intraoperatively.1 A third patient received urokinase (4400 IU/kg followed by 4400 IU/kg/h), but never regained consciousness, presumably because of multiple cerebral infarctions.7 Thrombolytic therapy is controversial during any kind of surgery because of the potential for massive bleeding, and it seems likely that the concern for exsanguination has made it an unattractive choice in patients undergoing LTx. However, when ICT/PE occurs during LTx, frequently clots are found in several different intravascular/intracardiac locations. This makes thrombolysis a more logical approach than the alternative therapy, thrombectomy.

In this report, we present 4 cases of ICT/PE that were treated with low-dose rTPA. These 4 cases were observed in a 4.5-year period, during which 566 LTxs were performed, an incidence of ICT/PE of 0.71%. In all 4 cases, rapid diagnosis of ICT/PE was made by the severe hypotension associated with large increases in PAPs and by direct visualization of intracardiac clot by TEE. Immediately after diagnosis, rTPA (doses of 0.5–4 mg) was given through the central venous port of the pulmonary artery catheter. Resolution of the ICT/PE, documented by shrinking or disappearance of clot on TEE and improvement in hemodynamics, were seen within minutes of rTPA administration (except in patient 4 for whom complete resolution took 90 minutes). The LTx was completed successfully in each patient, but it is possible that patient 1 who died 4 weeks after LTx experienced multiorgan failure that could have been the result of ICT/PE. Although transfusion requirements were large in patients 1 and 4, none of the patients exsanguinated. Although it is possible that the thrombi could have resolved without the rTPA, the clinical course in each case strongly suggests that the rTPA had a critical role.

There are no previous reports on the use of low-dose rTPA in the setting of LTx. This dose was chosen out of concern for the potential for massive hemorrhage associated with larger doses. Because our pharmacy stocks rTPA in 2-mg vials for declotting central venous catheters, we were able to rapidly acquire this dose of rTPA in each case. It is possible that the early treatment (aided by prompt diagnosis with PAP monitoring and TEE use) allowed a small dose of rTPA to be effective. In addition, the concentration of plasminogen activator inhibitor may be low in patients undergoing LTx.8,9 Also, inactivation of rTPA may be delayed in the presence of liver dysfunction,8,10 thus amplifying the effectiveness of such a small dose of rTPA. The use of low-dose rTPA may result in fewer bleeding complications as compared with the recommended dose of rTPA (100 mg), making use of low-dose rTPA a viable option in the treatment of ICT/PE during LTx. Furthermore, other than the inherent hemorrhagic risk, there seems to be a low risk of adverse reactions to this medication at this dose. No allergic-type reactions were observed in trials in patients treated with rTPA.11

In conclusion, routine monitoring with a pulmonary artery catheter and TEE in patients undergoing LTx may aid in the early diagnosis of ICT/PE. This may allow low-dose rTPA (0.5–4 mg) to be used as a safe and effective therapy.

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DISCLOSURES

Name: James D. Boone, MD.

Attestation: Contributed to manuscript preparation.

Name: Saadia S. Sherwani, MD.

Attestation: Contributed to manuscript preparation.

Name: Joshua C. Herborn, MD.

Attestation: Contributed to manuscript preparation.

Name: Kinjal M. Patel, MD.

Attestation: Contributed to manuscript preparation.

Name: Andre M. De Wolf, MD.

Attestation: Contributed to manuscript preparation.

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