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Open AcceResearch articleIn-hospital cerebrovascular complications following orthotopic liver transplantation: A retrospective studyLi Ling1, Xiaoshun He2, Jinsheng Zeng*1 and Zhijian Liang1,3

Address: 1Department of Neurology and Stroke Centre, First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou, 510080, PR China, 2Department of Organ Transplantation, First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou, 510080, PR China and 3Department of Neurology and Stroke Centre, First Affiliated Hospital, Guangxi Medical University, No. 23, Shuangyong Road, Nanning, 530021, PR China

Email: Li Ling - linglirabbit@163.com; Xiaoshun He - gdtrc@163.com; Jinsheng Zeng* - zengjs@pub.guangzhou.gd.cn; Zhijian Liang - lzj2004152000@yahoo.com.cn

* Corresponding author

AbstractBackground: Cerebrovascular complications are severe events following orthotopic livertransplantation (OLT). This study aimed to observe the clinical and neuroimaging features andpossible risk factors of in-hospital cerebrovascular complications in the patients who underwentOLT.

Patients and methods: We retrospectively reviewed 337 consecutive patients who underwent358 OLTs. Cerebrovascular complications were determined by clinical and neuroimagingmanifestations, and the possible risk factors were analyzed in the patients with intracranialhemorrhage.

Results: Ten of 337 (3.0%) patients developed in-hospital cerebrovascular complications (8 casesexperienced intracranial hemorrhage and 2 cases had cerebral infarction), and 6 of them died. Theclinical presentations were similar to common stroke, but with rapid deterioration at early stage.The hematomas on brain CT scan were massive, irregular, multifocal and diffuse, and most of themwere located at brain lobes and might enlarge or rebleed. Infarcts presented lacunar and multifocallesions in basal gangliar but with possible hemorrhagic transformation. The patients withintracranial hemorrhage had older age and a more frequency of systemic infection than non-intracranial hemorrhage patients. (P = 0.011 and 0.029, respectively).

Conclusion: Posttransplant cerebrovascular complications have severe impact on outcome of thepatients who received OLT. Older age and systemic infection may be the possible risk factors ofin-hospital intracranial hemorrhage following OLT.

BackgroundWith the rapid development of transplant technique andimmunosuppressive therapy, orthotopic liver transplanta-tion (OLT) has been carried out all over the world andaccepted as one of the most effective treatments for the

patients with end-stage liver diseases. However, postoper-ative complications are still the most important causesresulting in death of patients undergoing OLT. The inci-dences of posttransplant cerebrovascular complications orintracranial hemorrhage were 2.2%–3.9% in United

Published: 22 December 2008

BMC Neurology 2008, 8:52 doi:10.1186/1471-2377-8-52

Received: 26 July 2008Accepted: 22 December 2008

This article is available from: http://www.biomedcentral.com/1471-2377/8/52

© 2008 Ling et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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States [1-3], 3.3% in United Kingdom[4], 3.7% inChile[5], 6% in Spain[6], 6.5% in Hong Kong[7] clini-cally, and 32.7% in post-mortem patients after OLT inUnited States[8]. But cerebrovascular complications fol-lowing OLT in patients of mainland China have not beenreported. In the present study, we reported the incidence,mortality and clinical and neuroimaging features, thenanalyzed the possible risk factors of in-hospital cerebrov-ascular complications in patients following OLT at acenter in southern China.

MethodsPatientsWe retrospectively reviewed 337 consecutive patients whounderwent 358 OLTs in which 19 patients had a secondtransplant, and one had a third transplant, at an organtransplant center in southern China from Janurary1st,1996 to June 30th, 2005. The mean age was 47 ± 11.5years (3 months to 75 years), and 288 of 337 patientswere males. The primary liver diseases before OLT arelisted in Table 1.

ManagementAll patients underwent OLT using Piggyback techniqueand were managed in an intensive care unit before beingtransferred to a general ward following surgery. FK506,cyclosporine A or corticosteroids were used as immuno-suppressives and their serum level was measured dailypostoperativly. Blood tests such as blood platelet counts,prothrombin time (PT), activated partial prothrombintime (APPT), the function of the liver and kidney andother necessary tests were measured routinely. Brain com-puted tomography (CT) or magnetic resonance imaging(MRI) was performed in patients when neurologicalsymptoms occurred after OLT.

We focused on the clinical and neuroimaging features ofthe patients with in-hospital cerebrovascular complica-

tions following OLT, and analyzed the possible risk fac-tors in the patients with intracranial hemorrhage.

The research protocol was approved by the local ethicalcommittee for clinical research and all procedures involv-ing the participant were conducted according to institu-tional guidelines in compliance with the regulations. Bothoral and written informed consents were obtained fromthe patients or their families.

Statistical analysisAll statistical calculations were performed on microcom-puter using SPSS13.0 (SPSS Inc). Continuous variableswere compared using two tails student's t-test, and cate-gorical variables analyzed by a chisquare analysis orFisher's exact test. A p value less than 0.05 was consideredsignificantly.

ResultsIn all 10 patients (6 males, 4 females) aged 56 ± 8.4 years(40 to 67 years) developed in-hospital cerebrovascularcomplications following OLT, resulting in an incidence of3.0% in 337 patients. The mean in-hospital time were 39± 21.7 days (8 to 70 days). All patients with cerebrovascu-lar complications had brain CT scan. Among them, eightpatients (8/337, 2.4%) experienced intracranial hemor-rhage, including 5 with lobe hematomas, 2 with subduralhematomas, and 1 with lobe and subarachnoid hemor-rhage, and 7 of 8 intracranial hemorrhages occurredwithin posttransplant 1 month. The clinical presenta-tions, such as unconsciousness, headache, aphasia, hemi-paresis, seizures, were similar to common hemorrhagicstroke, but with rapid deterioration at early stage. Five of8 patients with intracranial hemorrhage deteriorated clin-ically and then died within two weeks after onset, includ-ing two patients with enlargement of hematoma andintraventricular mass, and a marked midline shift onrepeated CT. Two of 337 (0.6%) patients had lacunar cer-

Table 1: The primary liver diseases before orthotopic liver transplantation

The primary liver diseases Cases (%)

Primary hepatic carcinoma 198 (58.75%)Cirrhosis 94 (27.89%)Hepatitis B 21 (8.01%)Secondary hepatic carcinoma 6 (1.78%)Polycystic liver disease 4 (1.19%)Giant hemangioma of the liver 3 (0.89%)Primary sclerosing cholangitis 3 (0.89%)Drug-induced hepatitis 2 (0.59%)Congenital biliary atresia 2 (0.59%)Hepatitis C 1 (0. 30%)Congenital hepatic fibrosis 1 (0. 30%)Budd-Chiari syndrome 1 (0. 30%)Acute fatty liver and liver function failure of pregnancy 1 (0. 30%)Total 337 (100%)

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ebral infarctions on the 6th and the 58th postoperativeday respectively. One patient's lesions located in basalganglia and cerebellum, the other patient with generalizedseizures at the oneset had a lacunar infarction at left basalganglia. Although the seizure stopped soon after antiepi-leptic therapy, the aptient became apathia and reactive-less, then persistent coma. Neurological examinationshowed bilateral unclear papilla opticas with left papillaoptica retinal vein bleeding and stiff neck. It's a pity thatthe repeat CT scan was not done due to the severe condi-tions. The patient died of multiple organ failure on the11th days after OLT. All clinical and laboratory data, aswell as brain CT findings of patients with cerebrovascularcomplications following OLT are shown in an AdditionalTable (see additional file 1).

Among the 8 patients with intracranial hemorrhage, twoof them received decompressive craniectomy and evacua-tion of intracranial hematoma, but both died of brain her-niation soon after the surgery. Other 6 patients receivedmedical treatement, and 3 of them survived. One of 2patients with cerebral infarction died. Altogether, six of 10patients with in-hospital cerebrovascular complicationsdied following OLT.

To analyze the possible risk factors and outcome of intrac-ranial hemorrhage following OLT, we compared the clin-ical and laboratory data between the patients with andwithout intracranial hemorrhage (Table 2). In our series,the patients with intracranial hemorrhage had older ageand a more frequency of systemic infection than non-intracranial hemorrhage patients (56.3 ± 8.7 vs 46.7 ±11.7 years old,p = 0.011; 7/8 vs152/329, p = 0.029, respec-

tively). The patients over 55 years were prone to haveintracranial hemorrhage than those less than 55 years (5/75 vs 3/262, p = 0.015). Additionly, seven of 8 patientswith systemic bacterial or fungal infection experiencedintracranial hemorrhage, which had a more frequencythan those without infection (7/155 vs 1/182, p = 0.026).The patients over 55 years with systemic infection hadmore frequency of intracranial hemorrhage than thoseless than 55 years and without systemic infection (5/37 vs1/52,p = 0.043). Seven of 8 patients with intracranialhemorrhage had infection, including 4 patients experi-enced bacterial pneumonia, one had an aspergillus pneu-monia, an aspergillus combinded Candida tropicalispneumonia and a bacterial pneumonia combinded uri-nary tract infection respectively. The patients with intrac-ranial hemorrhage had a higher mortality rate than thosewithout intracranial hemorrhage (5/8 vs 74/329, p =0.019).

DiscussionIncidence and mortality rateIn the past 20 years, more and more patients with variousend-stage diseases have benefited from organ transplanta-tion. But cerebrovascular events, especially intracranialhemorrhage, have been concerned as severe neurologicalcomplications after transplantation. The reported clinicalincidences of cerebrovascular complications were 1.7%–6.5% [1-7], and the mortality rate of cerebrovascular com-plications or intracranial hemorrhage were 57%–100%following OLT[1,3,7]. Moreover, the incidence was 32.7%in autopsy cases of patients who underwent OLT[8]. Cer-ebrovascular complications are also common in othertransplantation patients. It has been reported that the

Table 2: Comparison of clincal features between the patients with and without intracranial hemorrhage after orthotopic liver transplantation

Features intracranial hemorrhage(n = 8)

non-intracranial hemorrhage(n = 329)

age (years) 56.3 ± 8.7 (40–67) 46.7 ± 11.7 (0.3–75)*>55 years 5 (62.5%) 70 (21.3%)≤55 years 3 (37.5%) 259 (78.7%)

operative time (h) 6.3 ± 0.5 (5.5–10.0) 7.2 ± 1.9 (4–15)previous abdominal surgery 4 (50%) 113 (34.3%)retranplatation 0 (0) 20 (6.1%)introperative blood loss volume (ml) 4312.5 ± 4566.5 (1500–15000) 3900.0 ± 4389.7 (100–38000)thrombocytopenia 1 (12.5%) 66 (20.1%)PT(s) 16.3 ± 5.2 (9.8–22.6) 18.8 ± 6.4 (9.7–46.3)APTT(s) 35.7 ± 11.4 (26.1–58.6) 39.2 ± 13.6 (22.9–180)preoperative hypertension 0 (0) 5 (1.5%)introperative hypotension 5 (62.5%) 110 (33.4%)postoperative hypertension 2 (25%) 23 (7.0%)bacterial or fungal infections 7 (87.5%) 148 (45.0%)*sepsis 1 (12.5%) 29 (8.8%)bleeding at extracerebral sites 1 (12.5%) 31 (9.4%)death 5 (62.5%) 74 (22.5%)*

*: vs intracranial hemorrhage, p < 0.05. PT: prothrombin time; APTT: activated partial prothrombin time.

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incidence of ischemic and hemorrhagic strokes was 6.8%after kidney transplantation[9], 2.9% after bone marrowtransplantation[10], 0.9% after reduced-intensity stemcell transplantation[11] and 2% in pediatric patients aftercardiac transplantation[12]. Our study showed that theincidence of cerebrovascular complications in patients ofsouthern China who underwent OLT was 3.0%, and 6 of10 died, which was similar to the previous internationalreports [1-7]. These data indicate cerebrovascular events,especially intracranial hemorrhage, are severe posttrans-plant complications which deserve more attention for theneurologists, neuro-intensivists and surgeons for organtransplantion, and more endeavours should be done pro-spectively to identify or aviod such complications in clin-ical practice.

Clinical and neuroimaging featuresIn our study, the intracranial hemorrhage patients pre-sented with unconsciousness, headache, aphasia, hemi-paresis, seizures, which was consistent with the findingsof previous report[2]. These presentations were similar tocommon stroke, but with more urgent onset, progressingclinical course and rapid deterioration at early stage. Inour experience, sudden conscious disturbance (or loss ofconsciousness) after OLT was strongly associated withintracranial hemorrhage. In the present of coagulopathy,metabolic disturbance or multiple organ failure in earlypostoperative time, liver transplantation recipients wereprone to developed massive intracranial hematomas.Moreover, these hematomas were not prone to ceasespontaneously and might enlarge gradually or rebleed,even with a tendency to form cerebral herniation, whichresults in the death. It is important to examine the con-sciousness and pupils in patients after OLT. Brain CT scanshoud be performed promptly to identify whether intrac-ranial hemorrhage occurs once the patient has suddenconscious disturbance or loss of consciousness followingOLT. Additionally, liver transplantation recipients mayoccurr ischemic infarction due to the haemodynamicchange and coagulopathy, and then develop hemorrhagicinfarction, then deteriorated rapidly.

Possible risk factorsMost liver transplantation recipients are in the end-stageof liver diseases, preoperative liver dysfunction even liverfailure results in thrombocytopenia and absence of coag-ulation factors. Moreover, liver function may not return tonormal level in the postoperative early stage. All thesecould result in coagulopathy, which can trigger intracra-nial hemorrhage after OLT[2]. But in our series, no signif-icant differences were found in the incidence ofthrombocytopenia, PT, or APPT between the patients withand without intracranial hemorrhage, which suggests thatthe causes of intracranial hemorrhage after OLT are multi-ple and complex, except for coagulopathy, there may be

other factors responsible for this complication. In ourstudy, we found that intracranial hemorrhage patientswere older than non-intracranial hemorrhage patients,moreover, the patients over 55 years had a more frequencyof intracranial hemorrhage than those less than 55 yearsold. Additionly, the patients with systemic infection had amore frequency of intracranial hemorrhage than thosewithout infection. The results indicate that older age andsystemic infection might be important risk factors ofintracranial hemorrhage following OLT. Cox and col-leagues[13] reported that an 11-year-old boy who hadcystic fibrosis died of an intraventricular and intracerebralhemorrhage caused by an aspergillus brain abscess on the48th day after OLT. Wijdicks and colleagues[2] reportedthat in the group of 8 patients with intracranial hemor-rhage after OLT, one had a Candida-associated mycoticaneurysm demonstrated by autopsy and another had dis-seminated aspergillosis. Generally, it is presumed thatunder the condition of systemic infection related toimmunosuppresion following OLT, aspergillus, toxo-plasma and any virulent bacterial organism may lead toinflammation of the arterial wall and formation of ananeurysm[2,14-16]. In our series, seven of the 8 patientswith intracranial hemorrhage had systemic bacterial orfungal infection, and all that them had pneumonia,including 4 with bacterial pneumonia, one with aspergil-lus pneumonia, one with aspergillus combinded Candidatropicalis pneumonia and one with bacterial pneumoniacombinded urinary tract infection respectively. But it wasvery pitiful that no evidence to support bacterial or fungalinfection is the direct cause of intracranial hemorrhagedue to no vascular image or post-mortem exams in thepresent study. A published study showed that patientswith introperative hypotension were prone to develop cer-ebral infarction after OLT[7]. In the present study, onepatient over 60 years old with cerebral infarction indeedhad introperative hypotension, indicating introperativehypotension may be a potential risk factor of cerebral inf-arction after OLT.

ConclusionAlthough posttransplant cerebrovascular complicationsare not common, they have severe impact on outcome ofthe patients who received OLT. Age and systemic infectionmay be the possible risk factors of in-hospital intracranialhemorrhage following OLT. More effctive measuresshould be taken to prevent posttransplant infection, suchas improvement of patient's systemic condition, bacterio-logic surveillance and infection control measures. It isurgent to early diagnosis and take more prompt systemicantibiotic/antifungal therapy once infection occurs, espe-cially in old patients. Further prospective study is neces-sary to explore the risk factors and optimize the preventiveand therapeutic regimen of intracranial hemorrhage fol-lowing OLT.

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Competing interestsThe authors declare that they have no competing interests.

Authors' contributionsLL collected the data and wrote the primary manuscript.HX participated in the study. ZJ designed the study, inter-preted the results and critically revised the manuscript. LZassisted with the statistical analysis. All authors read andapproved the final manuscript.

Additional material

AcknowledgementsThis study was supported by the grants from the Teaching and Research Award Program for Outstanding Young Teachers in Higher Education Insti-tutions of the Ministry of Education, China (2002), the China Medical Board of New York Inc. (CMB 00-730, No.06837), the Fund for Priority Subjects in Clinical Medicine, Chinese Ministry of Health (2004), the Key and Scien-tific Project of the Natural Science Foundation of Guangdong Province, China (Nos. 2003B30303, and 2003D30301).

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Additional file 1All clinical and laboratory data, as well as brain CT findings of patients with cerebrovascular complications following orthotopic liver transplantation are shown this additional table.Click here for file[http://www.biomedcentral.com/content/supplementary/1471-2377-8-52-S1.doc]

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