Research ArticleCan Herbal Medicine Cause HematomaEnlargement of Hypertensive Intracerebral Hemorrhagewithin 24 hrs Time Window A Retrospective Study of256 Cases from a Single Center in China
1No 1 Neurology Department Guangdong Province Hospital of TCM The Second Teaching Hospital of Guangzhou University ofTraditional Chinese Medicine 111 Darsquode Road Yuexiu District Guangzhou Guangdong Province 510120 China2Neurology Department Qingyuan Traditional Chinese Medicine Hospital Qingyuan Guangdong Province 511500 China
Correspondence should be addressed to Jianwen Guo jianwen guomecom
Received 27 May 2014 Accepted 14 October 2014
Academic Editor Paul Posadzki
Copyright copy 2015 Yafa Xu et al This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
A retrospective review was performed of consecutive patients presenting with HICH within 24 hours of ictus presenting betweenMarch 2008 and March 2013 who were diagnosed as having HICH by CT scan Of the 256 patients who matched study inclusionstandard 43 patients hematoma was enlarged (168) The number of the patients who did not take PBC or RBC herbal medicinetook the PBC herbal medicine and took RBS herbal medicine was 19 (442) 2 (47) and 22 (512) in hematoma enlargementgroup and 78 (366) 26 (122) and 109 (512) in nonhematoma enlargement group individually There was no significantdifference between two groups (119875 = 0671) PBC and RBS herbal medicine did not increase the incidence of hematoma expansionof ICH within 24 hours after onset of symptom
1 Introduction
Hypertensive intracerebral hemorrhage (HICH) is the mostdevastating form of stroke Approximately 40 of patientswith intracerebral hemorrhage die within 30 days and themajority of survivors are left with severe disability [1 2]Hematoma growth occurs in up to two-third of ICH patientswithin 24 hours after the onset of symptoms [3] Furthermorehemorrhage expansion is an independent determinant ofdeath and disability [4 5] Several reasons may be relatedto the hematoma enlargement in the early stage of HICHincluding high blood pressure ldquospotrdquo sign of CT scan sexage time window and anticoagulation drugs [6] Herbalmedicine of promoting blood circulation (PBC) and remov-ing blood stasis (RBS) are widely used in Chinese hospitals totreat HICH however whether this herbalmedicine can causehematoma enlargement is undefined until now [7]
In order to evaluate the safety of PBC and RBS herbaldrugs we designed a retrospective study on the hematoma
enlargement in HICH patients of 256 cases treated withPBC and RBS herbal medicine within 24-hour time windowfrom the symptom onset in Guangdong Province Hospital ofTraditional Chinese Medicine
2 Material and Methods
21 Materials A retrospective review was performed of con-secutive patients presentingwith ICHwithin 24 hours of ictuspresenting between March 2008 and March 2013 who werediagnosed as having hypertensive intracerebral hemorrhagebyCT scanThe inclusion criteria also included the following(1) the patient had hypertensive history (2) patients gotfollow-up 24-hour unenhanced CT scan (3) the patientsadministrated the herbal medicine within 24 hours fromsymptom onset of HICH The exclusion criteria were (1) thetime window over 24 hrs from onset to the first CT scan (2)other reasons causing ICH such as cerebral tumor aneurysmarteriovenous malformation trauma anticoagulation drugs
Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2015 Article ID 868731 8 pageshttpdxdoiorg1011552015868731
2 Evidence-Based Complementary and Alternative Medicine
and hematological disorder (3) lack of second CT scan(4) lack of other important data of the study Finally twohundred and fifty-six cases were reviewed
22 Methods We searched the patients data from the elec-tronic medical record system platform developed by IBMinc The searching strategy was ldquodiagnosis=intracerebralhemorrhagerdquo OR ldquoThe International Statistical Classificationof Diseases and RelatedHealth Problems 10th Revision (ICD-10) [8]rdquo =I61 Intracerebral haemorrhage (Excl sequelae ofintracerebral haemorrhage) (I691) OR I610 Intracerebralhaemorrhage in hemisphere subcortical (Deep intracere-bral haemorrhage) OR I611 Intracerebral haemorrhage inhemisphere cortical (Cerebral lobe haemorrhage Superficialintracerebral haemorrhage) OR I612 (Intracerebral haem-orrhage in hemisphere unspecified) OR I613 (Intracerebralhaemorrhage in brain stem) OR I614 (Intracerebral haem-orrhage in cerebellum) OR I615 (Intracerebral haemorrhageintraventricular) OR I616 (Intracerebral haemorrhage mul-tiple localized) OR I618 (Other intracerebral haemor-rhage) OR I619 (Intracerebral haemorrhage unspecified)ldquoAdmission time=March 2008 toMarch 2013rdquo ldquoSEX=BOTHrdquoldquoAGE=ALLrdquo
The patientsrsquo raw data were recorded in the well-designedcase report forms (CRFs) by two researchers which con-tained human demographymedical history personal historyclinical feather CT scan laboratory examination and herbalmedicine treatment The hematoma volume was measuredby ABC2 Coniglobus formula [9 10] Hemorrhage growthwas operationally defined as an increase in the volume ofintracerebral hemorrhage of gt33 as measured by imageanalysis on the 24-hour CT compared with the baseline CTscan [11]
We defined the herbal medicine as PBC or RBS underthe criteria of Chinese Pharmacopoeia of 2010 version Thecombined herbal drugs such as relieving heat and calmingliver Yang decreasing wind and dispersing phlegm andloosing the bowels were also under the criteria of ChinesePharmacopoeia of 2010 version
Two neuroradiologists analysis on the CT scan data atthe work station independently We divided the patients intohematoma enlargement group and nonhematoma enlarge-ment group Thus all the data were analyzed in the statisticsoftware
23 Statistical Analysis Statistical Product and Service Solu-tions (SPSS Inc) 190 version was used in our study FirstlyUnivariate analysis was used 1205942 and nonpaired 119905-tests wereused to compare patients with and without hemorrhagegrowth as to the following variables age sex race currentsmoking prior stroke diabetes history of hypertensionblood pressure location of hemorrhage volume of ICH onbaseline CT time to first CT scan baseline platelet count andbaseline prothrombin and partial thromboplastin times TheWilcoxon rank sum test was used to compare the initial GCSscore in patients with and without hemorrhage growth TheWilcoxon rank sum test was also used to compare patientswith and without hemorrhage growth as to the change in
the GCS score hematoma enlargement from baseline to 24hours Logistic regression was used to investigate possiblemultiple risk factors and PBC herbal drugs or RBS herbaldrugs for growth in hemorrhage volume from baseline to 24hoursWe also analyzed the possible risk factors and PBC andRBS herbal drugs of 3-month outcome followup (mRS 0-1 asindependent outcome mRS 2ndash6 as dependent outcome) bylogistic regression All statistical tests were two-tailed and119875 le 005 was considered significant Data are presented asmean plusmn SD
3 Results
31 Patients Between March 2008 and March 2013 ICHwas diagnosed in 901 patients at our hospital Of these 901patients 31 were diagnosed as having bleeding infarction43 were diagnosed as having arteriovenous malformation(AVM) 19 were diagnosed as having intracerebral aneurysm9 were diagnosed as having cerebral tumor and 8 werediagnosed as having cerebral trauma So 791 who were causeby hypertension
Of the 791 ICH patients 357 who were admitted after 24hours of onset were excluded including 95 patients whoseduration was from 24 hrs to 2ws 96 patients from 2ws to6ms and 166 patients more than 6ms 70 failed to undergothe second CT because of surgery or death 108 receivedemergency surgery within 24 hours after first CT scan Thus256 patients all of whom underwent the first CT within 24hours of onset and the second CT within 24 hours after firstCT scan were reviewed in this retrospective study
We also reviewed the patients three months later afterentering hospital through telephone or outpatient depart-ment visitingThemodifiedRankin scale (mRS)was recordedin the followup (see Figure 1)
32 Hematoma Growth and the Age Of the 256 patients whomatched study inclusion standard 43 patients hematomawere enlarged (168) within 24 hrs from onset The meanage was 66 plusmn 2400 yrs in hematoma enlargement group and6500 plusmn 2200 yrs in nonhematoma group they included 173male patients and 83 female patients
33 PBC and RBS Herbal Medicine Use in Two Groups Thenumber of the patients who did not take the PBC and RBSherbal medicine was 19 (442) in hematoma enlargementgroup and 78 (366) in nonhematoma enlargement groupThenumber of the patients who took the PBC andRBS herbalmedicine was 24 (558) in hematoma enlargement groupand 135 (634) in nonhematoma enlargement group (119875 =0390) The number of the patients who took the PBC herbalmedicine was 2 (47) in hematoma enlargement group and26 (122) in nonhematoma enlargement groupThe numberof the patients who took the RBS herbal medicine were 22(512) in hematoma enlargement group and 109 (512) innonhematoma enlargement group There was no significantdifference between two groups (119875 = 0671) Thus PBC andRBS herbalmedicine could not cause hematoma enlargementof HICH within 24 hrs time window (Figure 2)
Evidence-Based Complementary and Alternative Medicine 3
N = 791
357 who were admitted after 24hoursof onset were excluded
901 cases from electronic medical record system were searched
Surgery within 24hrs (n = 108)
Figure 1 Patients recruited chart
19
78
2
26
22
109
Hem
atom
aen
larg
emen
tNon
hem
atom
aen
larg
emen
t
Not takenPBC
RBS
0 20 40 60 80 100
()
Figure 2 Comparison of PBC and RBS herbal medicine usebetween two groups
34 Univariate Analysis on the Hematoma Enlargement Wefound that patientsrsquo sex baseline GCS baseline NIHSSduration from onset to the first CT scan and aspartate
aminotransferase (AST) had significant difference betweentwo groups (119875 lt 005) (Table 1)
35 Multivariate Analysis on the Hematoma EnlargementPatientsrsquo sex baseline Glasgow coma scale baseline NIHSSduration from onset to the first CT scan aspartate amino-transferase (AST) and PBC and RBS herbal medicine usewere an independent variable in the multivariate logisticregression analysis and hematoma growth an outcome vari-able (dependent variable) (Table 2)
There were two independent factors that can causehematoma growthThe first one was patientrsquos sex (119875 = 0019)The second one was duration from onset to the first CT scan0-1 hr (119875 = 0046) 1-2 hrs (119875 = 0041) PBC herbal medicineuse (119875 = 0197) or RBS herbal medicine use (119875 = 0946) wasnot independent risk fact On the other hand the utilizationrate of PBC and RBS herbal medicine was higher in thenonhematoma growth group (634) than in the hematomagrowth group (558) The coefficient of regression 120573 of RBSherbal medicine use was minus1166 OR = 0312 The coefficientof regression 120573 of PBC herbal medicine use wasminus0026 OR =0975
4 Evidence-Based Complementary and Alternative Medicine
Table 1 The univariate analysis on the hematoma enlargement ()
Note lowast119875 lt 005 998771119905-test Mann-Whitney 119880 test econtinuous correction chi-square test Pearson chi-square test and Kruskal-Wallis test
Table 2 Multivariate regression analysis on the independent risk factors of hematoma enlargement in 256 patients
Independent variable Coefficient ofregression OR 95 CI
36 Comparison of Herbal Drugs Combined with PBS andRBC HICH patients were given herbal drugs formulaincluding several mixed herbal drugs besides PBS and RBSdrugs such as relieving heat and calming liver Yang decreas-ing wind and dispersing phlegm and loosing bowls Weanalyse the effect as in Table 3
The results showed that therewas no significant differencebetween two groups combined with the above three types ofherbal drugs (all 119875 gt 005)
37 Multivariate Analysis on the 3-Month Outcome Followup(mRS) Patientsrsquo sex baseline Glasgow coma scale baselineNIHSS duration from onset to the first CT scan aspartateaminotransferase (AST) PBC and RBS herbal medicine useand hematoma growth were an independent variable in themultivariate logistic regression analysis andmRS a dependentvariable We defined mRS 0-1 as independent outcome andmRS 2ndash6 as dependent outcome
The results showed that baseline NIHSS and hematomagrowthwere the independent risk factors of outcomeof three-month followup (see Table 4)
There were two independent factors that affect the 3-month outcome The first one was baseline NIHSS (119875 =0000) The second one was hematoma growth (119875 = 0003)PBC and RBS herbal medicine use was not independent riskfactor (119875 = 0651)
4 Discussion
The safety of the herbal medicine administration becamemore and more critical since aristolochic acids were reportedto cause renal injury in 1993 [12 13]
It is long history that PBC and RBS herbal medicine wereused inChina to treatHICHAmulticenter prospective clini-cal trial showed PBC andRBS herbalmedicine can reduce thedeath and also improve the neurological function [14] Meta-analysis showed that PBC and RBS herbal medicine seems
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Herbal drugs combined with PBS and RBC between two groups (119899 )
Combined herbal drugs
PBS and RBC used inhematoma enlargement
(119899 )(119899 = 24)
PBS and RBC used innonhematoma
enlargement (119899 )(119899 = 135)
Value 119875
Relieving heat and calmingliver Yang 21 (875) 116 (859) 0042 0837
effective to treat HICH [15] PBC and RBS were also adoptedby textbook and guideline in treating HICH [16]
However safety data about hematoma enlargement werealso reported Bin and Jian declared that danshen injec-tion and mailuoning injection (one of the PBC and RBSherbal medicine) could induce the uncontrolled bleeding[17] Leech prevents not only fibrinogen clotting but alsoother thrombin-catalyzed hemostatic reactions such as theactivation of clotting factors V VIII and XIII and thethrombin-induced platelet activation [18] Other researchersadvocated that PBC andRBCherbalmedicine should be usedwith few side effects in the clinical application because theyadded to some other stopping bleeding herbal medicine tomake the prescription balance [19] So it is necessary that weperform this study on the safety of treating HICH with PBCand RBS herbal medicine
In this study forty-three (168) of the 256 patientsdemonstrated enlargement of the hematoma after the first CTscanThe growth rate was near the rate 143 (60419) of Fujiiet alrsquos report [20] In this study 159 patients were admin-istrated PBC and RBS herbal medicine prescription within24-hour time window including 24 patients in hematomaenlargement group and 135 patients in no hematoma groupwhich were not significantly different (119875 gt 005)
Hematoma enlargement in HICH has significant associ-ations with the duration of time since onset of neurologicalsymptoms the shape and volume of the bleeding the initialsdeep comadegree the presence of liver dysfunction andmalepatients [20 21] In this study the univariate analysis showedthat duration baseline GCS andNIHSS the liver dysfunction(AST) and male patients were the risk factor of hematomaexpansion while the shape and size of the hematoma werenot significant because the sample was too small
There were only two risk factors that induced hematomagrowth according to the multivariate analysis male patientsand duration of onset since ICH symptoms Hematomaenlargement was the independent risk factor of outcomeof three-month followup the result was similar as SeijiKazuirsquos study [22] PBC and RBS herbal drug was not theindependent risk factor of hematoma growth of the outcomeof three-month followup
Someherbal drugs have strongPBCandRBS function forexample leech caused rebleeding [21] Some others have two-way adjustment pharmacological effect for example Radixnotoginseng can not only PBC but also stopping bleeding Inour opinion the prescription of Chinese medicine to learn isthrough reasonable compatibility other than a single drug toeliminate this rebleeding risk
PBC and RBS herbal medicine was administrated withinthe time window that was uncertain A majority (83) ofpatients with hematoma enlargement underwent the initialCT scan within 6 hours of onset Enlargement after 24hours of onset seems extremely rare [22] So some neu-rologists showed their opinion that PBC and RBS herbalmedicine should be used after 24 hrs of onset in order toprevent rebleeding risk [23] Others supported that PBC andRBS herbal medicine should be administrated as sooner aspossible [24] Guo and his colleaguesrsquo study did not showdeterioration of condition of the AICH patients who weretreated with herbal compound within 6 hrs time windowfrom onset [25]
PBC and RBS herbal medicine should be combined withother drugs correctly in the Traditional Chinese MedicineFormula in order to avoid the rebleeding risk as recordedin the Chinese Pharmacopoeia of 2010 version [26] In thisstudy the treatment of acute cerebral hemorrhage frequently
Evidence-Based Complementary and Alternative Medicine 7
used herbal medicine by turns as follows Leonurus japon-icus Houtt (148 cases) Rhizoma Polygoni Cuspidati (131cases) leech (131 cases) Radix Achyranthis Bidentatae (83cases) Ligusticum chuanxiong Hort (21 cases) Radix SalviaeMiltiorrhizae (18 cases) Radix et Rhizoma Rhei Palmati (6cases) Cortex moutan (15 cases) peach seed (13 cases) RadixCurcumae Wenyujin (12 cases) Radix notoginseng (6 cases)Carthamus tinctorius L (5 cases) Caulis Spatholobi (4 cases)and Rhizoma corydalis (2 cases) They were used in balancebetween two groups (119875 gt 005)
In this retrospective study 159 patients (24 in hematomagrowth group and 135 in no hematoma growth group) weregiven PBC and RBS herbal medicine prescription whichwas also combined with other herbal drugs (showed asTable 4) PBC and RBS drugs reasonable compatibility withother herbs perhaps reduced the risk of hematoma expansioncaused by single PBC and RBS herb This result undoubtedlyis instructive for further clinical application
This is the first retrospective study of the hematomagrowth on the early HICH treated with traditional Chinesemedicine since nowThough the results showed it seems safethe retrospective study has many limitations Firstly thereare too many herbals medication to control the quality ofthe clinical study Secondly a lot of patients were excludedbecause of important data absent for example their secondCT scan data Thirdly some scales including NIHSS andGCS had recall bias from raw medical records
In order to make up for these limitations we havedesigned a prospective 13 hospitals randomized placebocontrol clinical trial (clinicaltrialsgov NCT01918722) to con-firm if PBC and RBS herbal medicine induces the incidenceof hematoma enlargement of AICH patient within the 6 hrstime window from onset 62 cases have been recruited sinceFebruary 2014 and all 300 patients will be completed inDecember 2015
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgment
The authors thank Professor ZehuaiWen because he directedthe statistics of the data He is the director of Key Unit ofMethodology in Clinical Research of Guangdong ProvinceHospital of Traditional Chinese Medicine The authors alsothank China National Clinical Study Base Project of Tradi-tional Chinese Medicine sponsored by State Administrationof Traditional Chinese Medicine of the Peoplersquos Republic ofChina (Grant no JDZX2012074)
References
[1] A I Qureshi A D Mendelow and D F Hanley ldquoIntracerebralhaemorrhagerdquo The Lancet vol 373 no 9675 pp 1632ndash16442009
[2] C J van Asch M J Luitse G J Rinkel I van der Tweel AAlgra and C J Klijn ldquoIncidence case fatality and functional
outcome of intracerebral haemorrhage over time accordingto age sex and ethnic origin a systematic review and meta-analysisrdquoThe Lancet Neurology vol 9 no 2 pp 167ndash176 2010
[3] J K Lim H S Hwang B M Cho et al ldquoMultivariateanalysis of risk factors of hematoma expansion in spontaneousintracerebral hemorrhagerdquo Surgical Neurology vol 69 no 1 pp40ndash45 2008
[4] S M Davis J Broderick M Hennerici et al ldquoHematomagrowth is a determinant of mortality and poor outcome afterintracerebral hemorrhagerdquo Neurology vol 66 no 8 pp 1175ndash1181 2006
[5] G-Q Wang S-Q Li Y-H Huang et al ldquoCan minimally inva-sive puncture and drainage for hypertensive spontaneous BasalGanglia intracerebral hemorrhage improve patient outcomea prospective non-randomized comparative studyrdquo MilitaryMedical Research vol 1 article 10 2014
[6] J C Hemphill III D C Bonovich L Besmertis G T Manleyand S C Johnston ldquoThe ICH score a simple reliable gradingscale for intracerebral hemorrhagerdquo Stroke vol 32 no 4 pp891ndash896 2001
[7] G Jian-wen and L Ming-jie ldquoMeta-analysis of acute intrac-erebral hemorrhage treated with traditional Chinese medicineorand composition of promoting blood circulation and remov-ing blood stasisrdquo Journal of China-Japan Friendship Hospitalvol 15 no 5 pp 283ndash286 2001
[8] ICD-10 Version 2010 httpappswhointclassificationsicd10browse2010en
[9] R U Kothari T Brott J P Broderick et al ldquoThe ABCs ofmeasuring intracerebral hemorrhage volumesrdquo Stroke vol 27no 8 pp 1304ndash1305 1996
[10] J M Gebel C A Sila M A Sloan et al ldquoComparison of theABC2 estimation technique to computer-assisted volumetricanalysis of intraparenchymal and subdural hematomas compli-cating the GUSTO-1 trialrdquo Stroke vol 29 no 9 pp 1799ndash18011998
[11] T Brott J Broderick R Kothari et al ldquoEarly hemorrhagegrowth in patients with intracerebral hemorrhagerdquo Stroke vol28 no 1 pp 1ndash5 1997
[12] J-L Vanherweghem M Depierreux C Tielemans et alldquoRapidly progressive interstitial renal fibrosis in young womenassociation with slimming regimen including Chinese herbsrdquoThe Lancet vol 341 no 8842 pp 387ndash391 1993
[13] M Jadoul J F de Plaen J P Cosyns and C van Ypersele deStrihou ldquoAdverse effects from traditional Chinese medicinerdquoThe Lancet vol 341 no 8849 pp 892ndash893 1993
[14] P-X Huang Y Huang and M Lu ldquoTreatment of acuteintracerebral hemorrhage with a comprehensive protocol ofintegrated Chinese andWestern medicinerdquo Zhongguo Zhong XiYi Jie He Za Zhi vol 26 no 7 pp 590ndash593 2006
[15] J Guo and M Liu ldquoMeta-analysis of acute intracerebralhemorrhage treated with traditional Chinese medicine orandcomposition of promoting blood circulation and removingblood stasisrdquo Journal of China-Japan Friendship Hospital vol15 no 5 pp 283ndash286 2001
[16] W Mian-hua and W Xin-yue Traditional Chinese InternalMedicine China Press of Traditional Chinese Medicine 3rdedition 2000
[17] L Bin and L Jian ldquoClinical observation of early use promotingblood circulation and removing blood stasis herbal injectionto treat acute intracerebral hemorrhagerdquo Shandong Journal ofTraditional Chinese Medicine vol 19 no 8 pp 461ndash462 2000
8 Evidence-Based Complementary and Alternative Medicine
[18] F Markwardt ldquoThe development of hirudin as an antithrom-botic drugrdquo Thrombosis Research vol 74 no 1 pp 1ndash23 1994Review
[19] J W Guo Y F Cai and B X Du ldquoThinking and challengeinduced by the hypothesis of breaking stagnant and eliminatingblood stasis in Treating acute cerebral hemorrhage by rF VII ardquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 25 no 11 pp 1027ndash1029 2005 (Chinese)
[20] Y Fujii R Tanaka S Takeuchi T Koike T Minakawa and OSasaki ldquoHematoma enlargement in spontaneous intracerebralhemorrhagerdquo Journal of Neurosurgery vol 80 no 1 pp 51ndash571994
[21] L Liu J-A Duan Y Tang et al ldquoTaoren-Honghua herb pairand its main components promoting blood circulation throughinfluencing on hemorheology plasma coagulation and plateletaggregationrdquo Journal of Ethnopharmacology vol 139 no 2 pp381ndash387 2012
[22] S Kazui H Naritomi H Yamamoto T Sawada and TYamaguchi ldquoEnlargement of spontaneous intracerebral hem-orrhage incidence and time courserdquo Stroke vol 27 no 10 pp1783ndash1787 1996
[23] Y Wanzhng Z Zhilan Z Ming et al ldquoOnce again on bleedingafter cerebral hemorrhage and the time window for therapy ofldquopromoting blood circulation and removing blood stasisrdquordquo Chi-nese Journal of Integrative Medicine on Cardio-CerebrovascularDisease vol 11 pp 662ndash665 2004
[24] W Li ldquoDiscussion of early use promoting blood circulationand removing blood stasis herbal medicinerdquo Chinese Journal ofBasicMedicine in Traditional ChineseMedicine vol 5 pp 58ndash592003
[25] J-W Guo Y-C He and S-H Chen ldquoClinical study on thetherapeutic time window of acute intracerebral hemorrhagetreated with herbal composition of Zhongfengxingnao takenorallyrdquo Chinese Journal of Cerebrovascular Diseases vol 2 no6 pp 255ndash259 2005
[26] Chinese Pharmacopoeia Commission The Pharmacopoeia ofthe Peoplersquos Republic of China vol 1 Chemical Industry PressBeijing China 2010
2 Evidence-Based Complementary and Alternative Medicine
and hematological disorder (3) lack of second CT scan(4) lack of other important data of the study Finally twohundred and fifty-six cases were reviewed
22 Methods We searched the patients data from the elec-tronic medical record system platform developed by IBMinc The searching strategy was ldquodiagnosis=intracerebralhemorrhagerdquo OR ldquoThe International Statistical Classificationof Diseases and RelatedHealth Problems 10th Revision (ICD-10) [8]rdquo =I61 Intracerebral haemorrhage (Excl sequelae ofintracerebral haemorrhage) (I691) OR I610 Intracerebralhaemorrhage in hemisphere subcortical (Deep intracere-bral haemorrhage) OR I611 Intracerebral haemorrhage inhemisphere cortical (Cerebral lobe haemorrhage Superficialintracerebral haemorrhage) OR I612 (Intracerebral haem-orrhage in hemisphere unspecified) OR I613 (Intracerebralhaemorrhage in brain stem) OR I614 (Intracerebral haem-orrhage in cerebellum) OR I615 (Intracerebral haemorrhageintraventricular) OR I616 (Intracerebral haemorrhage mul-tiple localized) OR I618 (Other intracerebral haemor-rhage) OR I619 (Intracerebral haemorrhage unspecified)ldquoAdmission time=March 2008 toMarch 2013rdquo ldquoSEX=BOTHrdquoldquoAGE=ALLrdquo
The patientsrsquo raw data were recorded in the well-designedcase report forms (CRFs) by two researchers which con-tained human demographymedical history personal historyclinical feather CT scan laboratory examination and herbalmedicine treatment The hematoma volume was measuredby ABC2 Coniglobus formula [9 10] Hemorrhage growthwas operationally defined as an increase in the volume ofintracerebral hemorrhage of gt33 as measured by imageanalysis on the 24-hour CT compared with the baseline CTscan [11]
We defined the herbal medicine as PBC or RBS underthe criteria of Chinese Pharmacopoeia of 2010 version Thecombined herbal drugs such as relieving heat and calmingliver Yang decreasing wind and dispersing phlegm andloosing the bowels were also under the criteria of ChinesePharmacopoeia of 2010 version
Two neuroradiologists analysis on the CT scan data atthe work station independently We divided the patients intohematoma enlargement group and nonhematoma enlarge-ment group Thus all the data were analyzed in the statisticsoftware
23 Statistical Analysis Statistical Product and Service Solu-tions (SPSS Inc) 190 version was used in our study FirstlyUnivariate analysis was used 1205942 and nonpaired 119905-tests wereused to compare patients with and without hemorrhagegrowth as to the following variables age sex race currentsmoking prior stroke diabetes history of hypertensionblood pressure location of hemorrhage volume of ICH onbaseline CT time to first CT scan baseline platelet count andbaseline prothrombin and partial thromboplastin times TheWilcoxon rank sum test was used to compare the initial GCSscore in patients with and without hemorrhage growth TheWilcoxon rank sum test was also used to compare patientswith and without hemorrhage growth as to the change in
the GCS score hematoma enlargement from baseline to 24hours Logistic regression was used to investigate possiblemultiple risk factors and PBC herbal drugs or RBS herbaldrugs for growth in hemorrhage volume from baseline to 24hoursWe also analyzed the possible risk factors and PBC andRBS herbal drugs of 3-month outcome followup (mRS 0-1 asindependent outcome mRS 2ndash6 as dependent outcome) bylogistic regression All statistical tests were two-tailed and119875 le 005 was considered significant Data are presented asmean plusmn SD
3 Results
31 Patients Between March 2008 and March 2013 ICHwas diagnosed in 901 patients at our hospital Of these 901patients 31 were diagnosed as having bleeding infarction43 were diagnosed as having arteriovenous malformation(AVM) 19 were diagnosed as having intracerebral aneurysm9 were diagnosed as having cerebral tumor and 8 werediagnosed as having cerebral trauma So 791 who were causeby hypertension
Of the 791 ICH patients 357 who were admitted after 24hours of onset were excluded including 95 patients whoseduration was from 24 hrs to 2ws 96 patients from 2ws to6ms and 166 patients more than 6ms 70 failed to undergothe second CT because of surgery or death 108 receivedemergency surgery within 24 hours after first CT scan Thus256 patients all of whom underwent the first CT within 24hours of onset and the second CT within 24 hours after firstCT scan were reviewed in this retrospective study
We also reviewed the patients three months later afterentering hospital through telephone or outpatient depart-ment visitingThemodifiedRankin scale (mRS)was recordedin the followup (see Figure 1)
32 Hematoma Growth and the Age Of the 256 patients whomatched study inclusion standard 43 patients hematomawere enlarged (168) within 24 hrs from onset The meanage was 66 plusmn 2400 yrs in hematoma enlargement group and6500 plusmn 2200 yrs in nonhematoma group they included 173male patients and 83 female patients
33 PBC and RBS Herbal Medicine Use in Two Groups Thenumber of the patients who did not take the PBC and RBSherbal medicine was 19 (442) in hematoma enlargementgroup and 78 (366) in nonhematoma enlargement groupThenumber of the patients who took the PBC andRBS herbalmedicine was 24 (558) in hematoma enlargement groupand 135 (634) in nonhematoma enlargement group (119875 =0390) The number of the patients who took the PBC herbalmedicine was 2 (47) in hematoma enlargement group and26 (122) in nonhematoma enlargement groupThe numberof the patients who took the RBS herbal medicine were 22(512) in hematoma enlargement group and 109 (512) innonhematoma enlargement group There was no significantdifference between two groups (119875 = 0671) Thus PBC andRBS herbalmedicine could not cause hematoma enlargementof HICH within 24 hrs time window (Figure 2)
Evidence-Based Complementary and Alternative Medicine 3
N = 791
357 who were admitted after 24hoursof onset were excluded
901 cases from electronic medical record system were searched
Surgery within 24hrs (n = 108)
Figure 1 Patients recruited chart
19
78
2
26
22
109
Hem
atom
aen
larg
emen
tNon
hem
atom
aen
larg
emen
t
Not takenPBC
RBS
0 20 40 60 80 100
()
Figure 2 Comparison of PBC and RBS herbal medicine usebetween two groups
34 Univariate Analysis on the Hematoma Enlargement Wefound that patientsrsquo sex baseline GCS baseline NIHSSduration from onset to the first CT scan and aspartate
aminotransferase (AST) had significant difference betweentwo groups (119875 lt 005) (Table 1)
35 Multivariate Analysis on the Hematoma EnlargementPatientsrsquo sex baseline Glasgow coma scale baseline NIHSSduration from onset to the first CT scan aspartate amino-transferase (AST) and PBC and RBS herbal medicine usewere an independent variable in the multivariate logisticregression analysis and hematoma growth an outcome vari-able (dependent variable) (Table 2)
There were two independent factors that can causehematoma growthThe first one was patientrsquos sex (119875 = 0019)The second one was duration from onset to the first CT scan0-1 hr (119875 = 0046) 1-2 hrs (119875 = 0041) PBC herbal medicineuse (119875 = 0197) or RBS herbal medicine use (119875 = 0946) wasnot independent risk fact On the other hand the utilizationrate of PBC and RBS herbal medicine was higher in thenonhematoma growth group (634) than in the hematomagrowth group (558) The coefficient of regression 120573 of RBSherbal medicine use was minus1166 OR = 0312 The coefficientof regression 120573 of PBC herbal medicine use wasminus0026 OR =0975
4 Evidence-Based Complementary and Alternative Medicine
Table 1 The univariate analysis on the hematoma enlargement ()
Note lowast119875 lt 005 998771119905-test Mann-Whitney 119880 test econtinuous correction chi-square test Pearson chi-square test and Kruskal-Wallis test
Table 2 Multivariate regression analysis on the independent risk factors of hematoma enlargement in 256 patients
Independent variable Coefficient ofregression OR 95 CI
36 Comparison of Herbal Drugs Combined with PBS andRBC HICH patients were given herbal drugs formulaincluding several mixed herbal drugs besides PBS and RBSdrugs such as relieving heat and calming liver Yang decreas-ing wind and dispersing phlegm and loosing bowls Weanalyse the effect as in Table 3
The results showed that therewas no significant differencebetween two groups combined with the above three types ofherbal drugs (all 119875 gt 005)
37 Multivariate Analysis on the 3-Month Outcome Followup(mRS) Patientsrsquo sex baseline Glasgow coma scale baselineNIHSS duration from onset to the first CT scan aspartateaminotransferase (AST) PBC and RBS herbal medicine useand hematoma growth were an independent variable in themultivariate logistic regression analysis andmRS a dependentvariable We defined mRS 0-1 as independent outcome andmRS 2ndash6 as dependent outcome
The results showed that baseline NIHSS and hematomagrowthwere the independent risk factors of outcomeof three-month followup (see Table 4)
There were two independent factors that affect the 3-month outcome The first one was baseline NIHSS (119875 =0000) The second one was hematoma growth (119875 = 0003)PBC and RBS herbal medicine use was not independent riskfactor (119875 = 0651)
4 Discussion
The safety of the herbal medicine administration becamemore and more critical since aristolochic acids were reportedto cause renal injury in 1993 [12 13]
It is long history that PBC and RBS herbal medicine wereused inChina to treatHICHAmulticenter prospective clini-cal trial showed PBC andRBS herbalmedicine can reduce thedeath and also improve the neurological function [14] Meta-analysis showed that PBC and RBS herbal medicine seems
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Herbal drugs combined with PBS and RBC between two groups (119899 )
Combined herbal drugs
PBS and RBC used inhematoma enlargement
(119899 )(119899 = 24)
PBS and RBC used innonhematoma
enlargement (119899 )(119899 = 135)
Value 119875
Relieving heat and calmingliver Yang 21 (875) 116 (859) 0042 0837
effective to treat HICH [15] PBC and RBS were also adoptedby textbook and guideline in treating HICH [16]
However safety data about hematoma enlargement werealso reported Bin and Jian declared that danshen injec-tion and mailuoning injection (one of the PBC and RBSherbal medicine) could induce the uncontrolled bleeding[17] Leech prevents not only fibrinogen clotting but alsoother thrombin-catalyzed hemostatic reactions such as theactivation of clotting factors V VIII and XIII and thethrombin-induced platelet activation [18] Other researchersadvocated that PBC andRBCherbalmedicine should be usedwith few side effects in the clinical application because theyadded to some other stopping bleeding herbal medicine tomake the prescription balance [19] So it is necessary that weperform this study on the safety of treating HICH with PBCand RBS herbal medicine
In this study forty-three (168) of the 256 patientsdemonstrated enlargement of the hematoma after the first CTscanThe growth rate was near the rate 143 (60419) of Fujiiet alrsquos report [20] In this study 159 patients were admin-istrated PBC and RBS herbal medicine prescription within24-hour time window including 24 patients in hematomaenlargement group and 135 patients in no hematoma groupwhich were not significantly different (119875 gt 005)
Hematoma enlargement in HICH has significant associ-ations with the duration of time since onset of neurologicalsymptoms the shape and volume of the bleeding the initialsdeep comadegree the presence of liver dysfunction andmalepatients [20 21] In this study the univariate analysis showedthat duration baseline GCS andNIHSS the liver dysfunction(AST) and male patients were the risk factor of hematomaexpansion while the shape and size of the hematoma werenot significant because the sample was too small
There were only two risk factors that induced hematomagrowth according to the multivariate analysis male patientsand duration of onset since ICH symptoms Hematomaenlargement was the independent risk factor of outcomeof three-month followup the result was similar as SeijiKazuirsquos study [22] PBC and RBS herbal drug was not theindependent risk factor of hematoma growth of the outcomeof three-month followup
Someherbal drugs have strongPBCandRBS function forexample leech caused rebleeding [21] Some others have two-way adjustment pharmacological effect for example Radixnotoginseng can not only PBC but also stopping bleeding Inour opinion the prescription of Chinese medicine to learn isthrough reasonable compatibility other than a single drug toeliminate this rebleeding risk
PBC and RBS herbal medicine was administrated withinthe time window that was uncertain A majority (83) ofpatients with hematoma enlargement underwent the initialCT scan within 6 hours of onset Enlargement after 24hours of onset seems extremely rare [22] So some neu-rologists showed their opinion that PBC and RBS herbalmedicine should be used after 24 hrs of onset in order toprevent rebleeding risk [23] Others supported that PBC andRBS herbal medicine should be administrated as sooner aspossible [24] Guo and his colleaguesrsquo study did not showdeterioration of condition of the AICH patients who weretreated with herbal compound within 6 hrs time windowfrom onset [25]
PBC and RBS herbal medicine should be combined withother drugs correctly in the Traditional Chinese MedicineFormula in order to avoid the rebleeding risk as recordedin the Chinese Pharmacopoeia of 2010 version [26] In thisstudy the treatment of acute cerebral hemorrhage frequently
Evidence-Based Complementary and Alternative Medicine 7
used herbal medicine by turns as follows Leonurus japon-icus Houtt (148 cases) Rhizoma Polygoni Cuspidati (131cases) leech (131 cases) Radix Achyranthis Bidentatae (83cases) Ligusticum chuanxiong Hort (21 cases) Radix SalviaeMiltiorrhizae (18 cases) Radix et Rhizoma Rhei Palmati (6cases) Cortex moutan (15 cases) peach seed (13 cases) RadixCurcumae Wenyujin (12 cases) Radix notoginseng (6 cases)Carthamus tinctorius L (5 cases) Caulis Spatholobi (4 cases)and Rhizoma corydalis (2 cases) They were used in balancebetween two groups (119875 gt 005)
In this retrospective study 159 patients (24 in hematomagrowth group and 135 in no hematoma growth group) weregiven PBC and RBS herbal medicine prescription whichwas also combined with other herbal drugs (showed asTable 4) PBC and RBS drugs reasonable compatibility withother herbs perhaps reduced the risk of hematoma expansioncaused by single PBC and RBS herb This result undoubtedlyis instructive for further clinical application
This is the first retrospective study of the hematomagrowth on the early HICH treated with traditional Chinesemedicine since nowThough the results showed it seems safethe retrospective study has many limitations Firstly thereare too many herbals medication to control the quality ofthe clinical study Secondly a lot of patients were excludedbecause of important data absent for example their secondCT scan data Thirdly some scales including NIHSS andGCS had recall bias from raw medical records
In order to make up for these limitations we havedesigned a prospective 13 hospitals randomized placebocontrol clinical trial (clinicaltrialsgov NCT01918722) to con-firm if PBC and RBS herbal medicine induces the incidenceof hematoma enlargement of AICH patient within the 6 hrstime window from onset 62 cases have been recruited sinceFebruary 2014 and all 300 patients will be completed inDecember 2015
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgment
The authors thank Professor ZehuaiWen because he directedthe statistics of the data He is the director of Key Unit ofMethodology in Clinical Research of Guangdong ProvinceHospital of Traditional Chinese Medicine The authors alsothank China National Clinical Study Base Project of Tradi-tional Chinese Medicine sponsored by State Administrationof Traditional Chinese Medicine of the Peoplersquos Republic ofChina (Grant no JDZX2012074)
References
[1] A I Qureshi A D Mendelow and D F Hanley ldquoIntracerebralhaemorrhagerdquo The Lancet vol 373 no 9675 pp 1632ndash16442009
[2] C J van Asch M J Luitse G J Rinkel I van der Tweel AAlgra and C J Klijn ldquoIncidence case fatality and functional
outcome of intracerebral haemorrhage over time accordingto age sex and ethnic origin a systematic review and meta-analysisrdquoThe Lancet Neurology vol 9 no 2 pp 167ndash176 2010
[3] J K Lim H S Hwang B M Cho et al ldquoMultivariateanalysis of risk factors of hematoma expansion in spontaneousintracerebral hemorrhagerdquo Surgical Neurology vol 69 no 1 pp40ndash45 2008
[4] S M Davis J Broderick M Hennerici et al ldquoHematomagrowth is a determinant of mortality and poor outcome afterintracerebral hemorrhagerdquo Neurology vol 66 no 8 pp 1175ndash1181 2006
[5] G-Q Wang S-Q Li Y-H Huang et al ldquoCan minimally inva-sive puncture and drainage for hypertensive spontaneous BasalGanglia intracerebral hemorrhage improve patient outcomea prospective non-randomized comparative studyrdquo MilitaryMedical Research vol 1 article 10 2014
[6] J C Hemphill III D C Bonovich L Besmertis G T Manleyand S C Johnston ldquoThe ICH score a simple reliable gradingscale for intracerebral hemorrhagerdquo Stroke vol 32 no 4 pp891ndash896 2001
[7] G Jian-wen and L Ming-jie ldquoMeta-analysis of acute intrac-erebral hemorrhage treated with traditional Chinese medicineorand composition of promoting blood circulation and remov-ing blood stasisrdquo Journal of China-Japan Friendship Hospitalvol 15 no 5 pp 283ndash286 2001
[8] ICD-10 Version 2010 httpappswhointclassificationsicd10browse2010en
[9] R U Kothari T Brott J P Broderick et al ldquoThe ABCs ofmeasuring intracerebral hemorrhage volumesrdquo Stroke vol 27no 8 pp 1304ndash1305 1996
[10] J M Gebel C A Sila M A Sloan et al ldquoComparison of theABC2 estimation technique to computer-assisted volumetricanalysis of intraparenchymal and subdural hematomas compli-cating the GUSTO-1 trialrdquo Stroke vol 29 no 9 pp 1799ndash18011998
[11] T Brott J Broderick R Kothari et al ldquoEarly hemorrhagegrowth in patients with intracerebral hemorrhagerdquo Stroke vol28 no 1 pp 1ndash5 1997
[12] J-L Vanherweghem M Depierreux C Tielemans et alldquoRapidly progressive interstitial renal fibrosis in young womenassociation with slimming regimen including Chinese herbsrdquoThe Lancet vol 341 no 8842 pp 387ndash391 1993
[13] M Jadoul J F de Plaen J P Cosyns and C van Ypersele deStrihou ldquoAdverse effects from traditional Chinese medicinerdquoThe Lancet vol 341 no 8849 pp 892ndash893 1993
[14] P-X Huang Y Huang and M Lu ldquoTreatment of acuteintracerebral hemorrhage with a comprehensive protocol ofintegrated Chinese andWestern medicinerdquo Zhongguo Zhong XiYi Jie He Za Zhi vol 26 no 7 pp 590ndash593 2006
[15] J Guo and M Liu ldquoMeta-analysis of acute intracerebralhemorrhage treated with traditional Chinese medicine orandcomposition of promoting blood circulation and removingblood stasisrdquo Journal of China-Japan Friendship Hospital vol15 no 5 pp 283ndash286 2001
[16] W Mian-hua and W Xin-yue Traditional Chinese InternalMedicine China Press of Traditional Chinese Medicine 3rdedition 2000
[17] L Bin and L Jian ldquoClinical observation of early use promotingblood circulation and removing blood stasis herbal injectionto treat acute intracerebral hemorrhagerdquo Shandong Journal ofTraditional Chinese Medicine vol 19 no 8 pp 461ndash462 2000
8 Evidence-Based Complementary and Alternative Medicine
[18] F Markwardt ldquoThe development of hirudin as an antithrom-botic drugrdquo Thrombosis Research vol 74 no 1 pp 1ndash23 1994Review
[19] J W Guo Y F Cai and B X Du ldquoThinking and challengeinduced by the hypothesis of breaking stagnant and eliminatingblood stasis in Treating acute cerebral hemorrhage by rF VII ardquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 25 no 11 pp 1027ndash1029 2005 (Chinese)
[20] Y Fujii R Tanaka S Takeuchi T Koike T Minakawa and OSasaki ldquoHematoma enlargement in spontaneous intracerebralhemorrhagerdquo Journal of Neurosurgery vol 80 no 1 pp 51ndash571994
[21] L Liu J-A Duan Y Tang et al ldquoTaoren-Honghua herb pairand its main components promoting blood circulation throughinfluencing on hemorheology plasma coagulation and plateletaggregationrdquo Journal of Ethnopharmacology vol 139 no 2 pp381ndash387 2012
[22] S Kazui H Naritomi H Yamamoto T Sawada and TYamaguchi ldquoEnlargement of spontaneous intracerebral hem-orrhage incidence and time courserdquo Stroke vol 27 no 10 pp1783ndash1787 1996
[23] Y Wanzhng Z Zhilan Z Ming et al ldquoOnce again on bleedingafter cerebral hemorrhage and the time window for therapy ofldquopromoting blood circulation and removing blood stasisrdquordquo Chi-nese Journal of Integrative Medicine on Cardio-CerebrovascularDisease vol 11 pp 662ndash665 2004
[24] W Li ldquoDiscussion of early use promoting blood circulationand removing blood stasis herbal medicinerdquo Chinese Journal ofBasicMedicine in Traditional ChineseMedicine vol 5 pp 58ndash592003
[25] J-W Guo Y-C He and S-H Chen ldquoClinical study on thetherapeutic time window of acute intracerebral hemorrhagetreated with herbal composition of Zhongfengxingnao takenorallyrdquo Chinese Journal of Cerebrovascular Diseases vol 2 no6 pp 255ndash259 2005
[26] Chinese Pharmacopoeia Commission The Pharmacopoeia ofthe Peoplersquos Republic of China vol 1 Chemical Industry PressBeijing China 2010
901 cases from electronic medical record system were searched
Surgery within 24hrs (n = 108)
Figure 1 Patients recruited chart
19
78
2
26
22
109
Hem
atom
aen
larg
emen
tNon
hem
atom
aen
larg
emen
t
Not takenPBC
RBS
0 20 40 60 80 100
()
Figure 2 Comparison of PBC and RBS herbal medicine usebetween two groups
34 Univariate Analysis on the Hematoma Enlargement Wefound that patientsrsquo sex baseline GCS baseline NIHSSduration from onset to the first CT scan and aspartate
aminotransferase (AST) had significant difference betweentwo groups (119875 lt 005) (Table 1)
35 Multivariate Analysis on the Hematoma EnlargementPatientsrsquo sex baseline Glasgow coma scale baseline NIHSSduration from onset to the first CT scan aspartate amino-transferase (AST) and PBC and RBS herbal medicine usewere an independent variable in the multivariate logisticregression analysis and hematoma growth an outcome vari-able (dependent variable) (Table 2)
There were two independent factors that can causehematoma growthThe first one was patientrsquos sex (119875 = 0019)The second one was duration from onset to the first CT scan0-1 hr (119875 = 0046) 1-2 hrs (119875 = 0041) PBC herbal medicineuse (119875 = 0197) or RBS herbal medicine use (119875 = 0946) wasnot independent risk fact On the other hand the utilizationrate of PBC and RBS herbal medicine was higher in thenonhematoma growth group (634) than in the hematomagrowth group (558) The coefficient of regression 120573 of RBSherbal medicine use was minus1166 OR = 0312 The coefficientof regression 120573 of PBC herbal medicine use wasminus0026 OR =0975
4 Evidence-Based Complementary and Alternative Medicine
Table 1 The univariate analysis on the hematoma enlargement ()
Note lowast119875 lt 005 998771119905-test Mann-Whitney 119880 test econtinuous correction chi-square test Pearson chi-square test and Kruskal-Wallis test
Table 2 Multivariate regression analysis on the independent risk factors of hematoma enlargement in 256 patients
Independent variable Coefficient ofregression OR 95 CI
36 Comparison of Herbal Drugs Combined with PBS andRBC HICH patients were given herbal drugs formulaincluding several mixed herbal drugs besides PBS and RBSdrugs such as relieving heat and calming liver Yang decreas-ing wind and dispersing phlegm and loosing bowls Weanalyse the effect as in Table 3
The results showed that therewas no significant differencebetween two groups combined with the above three types ofherbal drugs (all 119875 gt 005)
37 Multivariate Analysis on the 3-Month Outcome Followup(mRS) Patientsrsquo sex baseline Glasgow coma scale baselineNIHSS duration from onset to the first CT scan aspartateaminotransferase (AST) PBC and RBS herbal medicine useand hematoma growth were an independent variable in themultivariate logistic regression analysis andmRS a dependentvariable We defined mRS 0-1 as independent outcome andmRS 2ndash6 as dependent outcome
The results showed that baseline NIHSS and hematomagrowthwere the independent risk factors of outcomeof three-month followup (see Table 4)
There were two independent factors that affect the 3-month outcome The first one was baseline NIHSS (119875 =0000) The second one was hematoma growth (119875 = 0003)PBC and RBS herbal medicine use was not independent riskfactor (119875 = 0651)
4 Discussion
The safety of the herbal medicine administration becamemore and more critical since aristolochic acids were reportedto cause renal injury in 1993 [12 13]
It is long history that PBC and RBS herbal medicine wereused inChina to treatHICHAmulticenter prospective clini-cal trial showed PBC andRBS herbalmedicine can reduce thedeath and also improve the neurological function [14] Meta-analysis showed that PBC and RBS herbal medicine seems
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Herbal drugs combined with PBS and RBC between two groups (119899 )
Combined herbal drugs
PBS and RBC used inhematoma enlargement
(119899 )(119899 = 24)
PBS and RBC used innonhematoma
enlargement (119899 )(119899 = 135)
Value 119875
Relieving heat and calmingliver Yang 21 (875) 116 (859) 0042 0837
effective to treat HICH [15] PBC and RBS were also adoptedby textbook and guideline in treating HICH [16]
However safety data about hematoma enlargement werealso reported Bin and Jian declared that danshen injec-tion and mailuoning injection (one of the PBC and RBSherbal medicine) could induce the uncontrolled bleeding[17] Leech prevents not only fibrinogen clotting but alsoother thrombin-catalyzed hemostatic reactions such as theactivation of clotting factors V VIII and XIII and thethrombin-induced platelet activation [18] Other researchersadvocated that PBC andRBCherbalmedicine should be usedwith few side effects in the clinical application because theyadded to some other stopping bleeding herbal medicine tomake the prescription balance [19] So it is necessary that weperform this study on the safety of treating HICH with PBCand RBS herbal medicine
In this study forty-three (168) of the 256 patientsdemonstrated enlargement of the hematoma after the first CTscanThe growth rate was near the rate 143 (60419) of Fujiiet alrsquos report [20] In this study 159 patients were admin-istrated PBC and RBS herbal medicine prescription within24-hour time window including 24 patients in hematomaenlargement group and 135 patients in no hematoma groupwhich were not significantly different (119875 gt 005)
Hematoma enlargement in HICH has significant associ-ations with the duration of time since onset of neurologicalsymptoms the shape and volume of the bleeding the initialsdeep comadegree the presence of liver dysfunction andmalepatients [20 21] In this study the univariate analysis showedthat duration baseline GCS andNIHSS the liver dysfunction(AST) and male patients were the risk factor of hematomaexpansion while the shape and size of the hematoma werenot significant because the sample was too small
There were only two risk factors that induced hematomagrowth according to the multivariate analysis male patientsand duration of onset since ICH symptoms Hematomaenlargement was the independent risk factor of outcomeof three-month followup the result was similar as SeijiKazuirsquos study [22] PBC and RBS herbal drug was not theindependent risk factor of hematoma growth of the outcomeof three-month followup
Someherbal drugs have strongPBCandRBS function forexample leech caused rebleeding [21] Some others have two-way adjustment pharmacological effect for example Radixnotoginseng can not only PBC but also stopping bleeding Inour opinion the prescription of Chinese medicine to learn isthrough reasonable compatibility other than a single drug toeliminate this rebleeding risk
PBC and RBS herbal medicine was administrated withinthe time window that was uncertain A majority (83) ofpatients with hematoma enlargement underwent the initialCT scan within 6 hours of onset Enlargement after 24hours of onset seems extremely rare [22] So some neu-rologists showed their opinion that PBC and RBS herbalmedicine should be used after 24 hrs of onset in order toprevent rebleeding risk [23] Others supported that PBC andRBS herbal medicine should be administrated as sooner aspossible [24] Guo and his colleaguesrsquo study did not showdeterioration of condition of the AICH patients who weretreated with herbal compound within 6 hrs time windowfrom onset [25]
PBC and RBS herbal medicine should be combined withother drugs correctly in the Traditional Chinese MedicineFormula in order to avoid the rebleeding risk as recordedin the Chinese Pharmacopoeia of 2010 version [26] In thisstudy the treatment of acute cerebral hemorrhage frequently
Evidence-Based Complementary and Alternative Medicine 7
used herbal medicine by turns as follows Leonurus japon-icus Houtt (148 cases) Rhizoma Polygoni Cuspidati (131cases) leech (131 cases) Radix Achyranthis Bidentatae (83cases) Ligusticum chuanxiong Hort (21 cases) Radix SalviaeMiltiorrhizae (18 cases) Radix et Rhizoma Rhei Palmati (6cases) Cortex moutan (15 cases) peach seed (13 cases) RadixCurcumae Wenyujin (12 cases) Radix notoginseng (6 cases)Carthamus tinctorius L (5 cases) Caulis Spatholobi (4 cases)and Rhizoma corydalis (2 cases) They were used in balancebetween two groups (119875 gt 005)
In this retrospective study 159 patients (24 in hematomagrowth group and 135 in no hematoma growth group) weregiven PBC and RBS herbal medicine prescription whichwas also combined with other herbal drugs (showed asTable 4) PBC and RBS drugs reasonable compatibility withother herbs perhaps reduced the risk of hematoma expansioncaused by single PBC and RBS herb This result undoubtedlyis instructive for further clinical application
This is the first retrospective study of the hematomagrowth on the early HICH treated with traditional Chinesemedicine since nowThough the results showed it seems safethe retrospective study has many limitations Firstly thereare too many herbals medication to control the quality ofthe clinical study Secondly a lot of patients were excludedbecause of important data absent for example their secondCT scan data Thirdly some scales including NIHSS andGCS had recall bias from raw medical records
In order to make up for these limitations we havedesigned a prospective 13 hospitals randomized placebocontrol clinical trial (clinicaltrialsgov NCT01918722) to con-firm if PBC and RBS herbal medicine induces the incidenceof hematoma enlargement of AICH patient within the 6 hrstime window from onset 62 cases have been recruited sinceFebruary 2014 and all 300 patients will be completed inDecember 2015
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgment
The authors thank Professor ZehuaiWen because he directedthe statistics of the data He is the director of Key Unit ofMethodology in Clinical Research of Guangdong ProvinceHospital of Traditional Chinese Medicine The authors alsothank China National Clinical Study Base Project of Tradi-tional Chinese Medicine sponsored by State Administrationof Traditional Chinese Medicine of the Peoplersquos Republic ofChina (Grant no JDZX2012074)
References
[1] A I Qureshi A D Mendelow and D F Hanley ldquoIntracerebralhaemorrhagerdquo The Lancet vol 373 no 9675 pp 1632ndash16442009
[2] C J van Asch M J Luitse G J Rinkel I van der Tweel AAlgra and C J Klijn ldquoIncidence case fatality and functional
outcome of intracerebral haemorrhage over time accordingto age sex and ethnic origin a systematic review and meta-analysisrdquoThe Lancet Neurology vol 9 no 2 pp 167ndash176 2010
[3] J K Lim H S Hwang B M Cho et al ldquoMultivariateanalysis of risk factors of hematoma expansion in spontaneousintracerebral hemorrhagerdquo Surgical Neurology vol 69 no 1 pp40ndash45 2008
[4] S M Davis J Broderick M Hennerici et al ldquoHematomagrowth is a determinant of mortality and poor outcome afterintracerebral hemorrhagerdquo Neurology vol 66 no 8 pp 1175ndash1181 2006
[5] G-Q Wang S-Q Li Y-H Huang et al ldquoCan minimally inva-sive puncture and drainage for hypertensive spontaneous BasalGanglia intracerebral hemorrhage improve patient outcomea prospective non-randomized comparative studyrdquo MilitaryMedical Research vol 1 article 10 2014
[6] J C Hemphill III D C Bonovich L Besmertis G T Manleyand S C Johnston ldquoThe ICH score a simple reliable gradingscale for intracerebral hemorrhagerdquo Stroke vol 32 no 4 pp891ndash896 2001
[7] G Jian-wen and L Ming-jie ldquoMeta-analysis of acute intrac-erebral hemorrhage treated with traditional Chinese medicineorand composition of promoting blood circulation and remov-ing blood stasisrdquo Journal of China-Japan Friendship Hospitalvol 15 no 5 pp 283ndash286 2001
[8] ICD-10 Version 2010 httpappswhointclassificationsicd10browse2010en
[9] R U Kothari T Brott J P Broderick et al ldquoThe ABCs ofmeasuring intracerebral hemorrhage volumesrdquo Stroke vol 27no 8 pp 1304ndash1305 1996
[10] J M Gebel C A Sila M A Sloan et al ldquoComparison of theABC2 estimation technique to computer-assisted volumetricanalysis of intraparenchymal and subdural hematomas compli-cating the GUSTO-1 trialrdquo Stroke vol 29 no 9 pp 1799ndash18011998
[11] T Brott J Broderick R Kothari et al ldquoEarly hemorrhagegrowth in patients with intracerebral hemorrhagerdquo Stroke vol28 no 1 pp 1ndash5 1997
[12] J-L Vanherweghem M Depierreux C Tielemans et alldquoRapidly progressive interstitial renal fibrosis in young womenassociation with slimming regimen including Chinese herbsrdquoThe Lancet vol 341 no 8842 pp 387ndash391 1993
[13] M Jadoul J F de Plaen J P Cosyns and C van Ypersele deStrihou ldquoAdverse effects from traditional Chinese medicinerdquoThe Lancet vol 341 no 8849 pp 892ndash893 1993
[14] P-X Huang Y Huang and M Lu ldquoTreatment of acuteintracerebral hemorrhage with a comprehensive protocol ofintegrated Chinese andWestern medicinerdquo Zhongguo Zhong XiYi Jie He Za Zhi vol 26 no 7 pp 590ndash593 2006
[15] J Guo and M Liu ldquoMeta-analysis of acute intracerebralhemorrhage treated with traditional Chinese medicine orandcomposition of promoting blood circulation and removingblood stasisrdquo Journal of China-Japan Friendship Hospital vol15 no 5 pp 283ndash286 2001
[16] W Mian-hua and W Xin-yue Traditional Chinese InternalMedicine China Press of Traditional Chinese Medicine 3rdedition 2000
[17] L Bin and L Jian ldquoClinical observation of early use promotingblood circulation and removing blood stasis herbal injectionto treat acute intracerebral hemorrhagerdquo Shandong Journal ofTraditional Chinese Medicine vol 19 no 8 pp 461ndash462 2000
8 Evidence-Based Complementary and Alternative Medicine
[18] F Markwardt ldquoThe development of hirudin as an antithrom-botic drugrdquo Thrombosis Research vol 74 no 1 pp 1ndash23 1994Review
[19] J W Guo Y F Cai and B X Du ldquoThinking and challengeinduced by the hypothesis of breaking stagnant and eliminatingblood stasis in Treating acute cerebral hemorrhage by rF VII ardquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 25 no 11 pp 1027ndash1029 2005 (Chinese)
[20] Y Fujii R Tanaka S Takeuchi T Koike T Minakawa and OSasaki ldquoHematoma enlargement in spontaneous intracerebralhemorrhagerdquo Journal of Neurosurgery vol 80 no 1 pp 51ndash571994
[21] L Liu J-A Duan Y Tang et al ldquoTaoren-Honghua herb pairand its main components promoting blood circulation throughinfluencing on hemorheology plasma coagulation and plateletaggregationrdquo Journal of Ethnopharmacology vol 139 no 2 pp381ndash387 2012
[22] S Kazui H Naritomi H Yamamoto T Sawada and TYamaguchi ldquoEnlargement of spontaneous intracerebral hem-orrhage incidence and time courserdquo Stroke vol 27 no 10 pp1783ndash1787 1996
[23] Y Wanzhng Z Zhilan Z Ming et al ldquoOnce again on bleedingafter cerebral hemorrhage and the time window for therapy ofldquopromoting blood circulation and removing blood stasisrdquordquo Chi-nese Journal of Integrative Medicine on Cardio-CerebrovascularDisease vol 11 pp 662ndash665 2004
[24] W Li ldquoDiscussion of early use promoting blood circulationand removing blood stasis herbal medicinerdquo Chinese Journal ofBasicMedicine in Traditional ChineseMedicine vol 5 pp 58ndash592003
[25] J-W Guo Y-C He and S-H Chen ldquoClinical study on thetherapeutic time window of acute intracerebral hemorrhagetreated with herbal composition of Zhongfengxingnao takenorallyrdquo Chinese Journal of Cerebrovascular Diseases vol 2 no6 pp 255ndash259 2005
[26] Chinese Pharmacopoeia Commission The Pharmacopoeia ofthe Peoplersquos Republic of China vol 1 Chemical Industry PressBeijing China 2010
Note lowast119875 lt 005 998771119905-test Mann-Whitney 119880 test econtinuous correction chi-square test Pearson chi-square test and Kruskal-Wallis test
Table 2 Multivariate regression analysis on the independent risk factors of hematoma enlargement in 256 patients
Independent variable Coefficient ofregression OR 95 CI
36 Comparison of Herbal Drugs Combined with PBS andRBC HICH patients were given herbal drugs formulaincluding several mixed herbal drugs besides PBS and RBSdrugs such as relieving heat and calming liver Yang decreas-ing wind and dispersing phlegm and loosing bowls Weanalyse the effect as in Table 3
The results showed that therewas no significant differencebetween two groups combined with the above three types ofherbal drugs (all 119875 gt 005)
37 Multivariate Analysis on the 3-Month Outcome Followup(mRS) Patientsrsquo sex baseline Glasgow coma scale baselineNIHSS duration from onset to the first CT scan aspartateaminotransferase (AST) PBC and RBS herbal medicine useand hematoma growth were an independent variable in themultivariate logistic regression analysis andmRS a dependentvariable We defined mRS 0-1 as independent outcome andmRS 2ndash6 as dependent outcome
The results showed that baseline NIHSS and hematomagrowthwere the independent risk factors of outcomeof three-month followup (see Table 4)
There were two independent factors that affect the 3-month outcome The first one was baseline NIHSS (119875 =0000) The second one was hematoma growth (119875 = 0003)PBC and RBS herbal medicine use was not independent riskfactor (119875 = 0651)
4 Discussion
The safety of the herbal medicine administration becamemore and more critical since aristolochic acids were reportedto cause renal injury in 1993 [12 13]
It is long history that PBC and RBS herbal medicine wereused inChina to treatHICHAmulticenter prospective clini-cal trial showed PBC andRBS herbalmedicine can reduce thedeath and also improve the neurological function [14] Meta-analysis showed that PBC and RBS herbal medicine seems
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Herbal drugs combined with PBS and RBC between two groups (119899 )
Combined herbal drugs
PBS and RBC used inhematoma enlargement
(119899 )(119899 = 24)
PBS and RBC used innonhematoma
enlargement (119899 )(119899 = 135)
Value 119875
Relieving heat and calmingliver Yang 21 (875) 116 (859) 0042 0837
effective to treat HICH [15] PBC and RBS were also adoptedby textbook and guideline in treating HICH [16]
However safety data about hematoma enlargement werealso reported Bin and Jian declared that danshen injec-tion and mailuoning injection (one of the PBC and RBSherbal medicine) could induce the uncontrolled bleeding[17] Leech prevents not only fibrinogen clotting but alsoother thrombin-catalyzed hemostatic reactions such as theactivation of clotting factors V VIII and XIII and thethrombin-induced platelet activation [18] Other researchersadvocated that PBC andRBCherbalmedicine should be usedwith few side effects in the clinical application because theyadded to some other stopping bleeding herbal medicine tomake the prescription balance [19] So it is necessary that weperform this study on the safety of treating HICH with PBCand RBS herbal medicine
In this study forty-three (168) of the 256 patientsdemonstrated enlargement of the hematoma after the first CTscanThe growth rate was near the rate 143 (60419) of Fujiiet alrsquos report [20] In this study 159 patients were admin-istrated PBC and RBS herbal medicine prescription within24-hour time window including 24 patients in hematomaenlargement group and 135 patients in no hematoma groupwhich were not significantly different (119875 gt 005)
Hematoma enlargement in HICH has significant associ-ations with the duration of time since onset of neurologicalsymptoms the shape and volume of the bleeding the initialsdeep comadegree the presence of liver dysfunction andmalepatients [20 21] In this study the univariate analysis showedthat duration baseline GCS andNIHSS the liver dysfunction(AST) and male patients were the risk factor of hematomaexpansion while the shape and size of the hematoma werenot significant because the sample was too small
There were only two risk factors that induced hematomagrowth according to the multivariate analysis male patientsand duration of onset since ICH symptoms Hematomaenlargement was the independent risk factor of outcomeof three-month followup the result was similar as SeijiKazuirsquos study [22] PBC and RBS herbal drug was not theindependent risk factor of hematoma growth of the outcomeof three-month followup
Someherbal drugs have strongPBCandRBS function forexample leech caused rebleeding [21] Some others have two-way adjustment pharmacological effect for example Radixnotoginseng can not only PBC but also stopping bleeding Inour opinion the prescription of Chinese medicine to learn isthrough reasonable compatibility other than a single drug toeliminate this rebleeding risk
PBC and RBS herbal medicine was administrated withinthe time window that was uncertain A majority (83) ofpatients with hematoma enlargement underwent the initialCT scan within 6 hours of onset Enlargement after 24hours of onset seems extremely rare [22] So some neu-rologists showed their opinion that PBC and RBS herbalmedicine should be used after 24 hrs of onset in order toprevent rebleeding risk [23] Others supported that PBC andRBS herbal medicine should be administrated as sooner aspossible [24] Guo and his colleaguesrsquo study did not showdeterioration of condition of the AICH patients who weretreated with herbal compound within 6 hrs time windowfrom onset [25]
PBC and RBS herbal medicine should be combined withother drugs correctly in the Traditional Chinese MedicineFormula in order to avoid the rebleeding risk as recordedin the Chinese Pharmacopoeia of 2010 version [26] In thisstudy the treatment of acute cerebral hemorrhage frequently
Evidence-Based Complementary and Alternative Medicine 7
used herbal medicine by turns as follows Leonurus japon-icus Houtt (148 cases) Rhizoma Polygoni Cuspidati (131cases) leech (131 cases) Radix Achyranthis Bidentatae (83cases) Ligusticum chuanxiong Hort (21 cases) Radix SalviaeMiltiorrhizae (18 cases) Radix et Rhizoma Rhei Palmati (6cases) Cortex moutan (15 cases) peach seed (13 cases) RadixCurcumae Wenyujin (12 cases) Radix notoginseng (6 cases)Carthamus tinctorius L (5 cases) Caulis Spatholobi (4 cases)and Rhizoma corydalis (2 cases) They were used in balancebetween two groups (119875 gt 005)
In this retrospective study 159 patients (24 in hematomagrowth group and 135 in no hematoma growth group) weregiven PBC and RBS herbal medicine prescription whichwas also combined with other herbal drugs (showed asTable 4) PBC and RBS drugs reasonable compatibility withother herbs perhaps reduced the risk of hematoma expansioncaused by single PBC and RBS herb This result undoubtedlyis instructive for further clinical application
This is the first retrospective study of the hematomagrowth on the early HICH treated with traditional Chinesemedicine since nowThough the results showed it seems safethe retrospective study has many limitations Firstly thereare too many herbals medication to control the quality ofthe clinical study Secondly a lot of patients were excludedbecause of important data absent for example their secondCT scan data Thirdly some scales including NIHSS andGCS had recall bias from raw medical records
In order to make up for these limitations we havedesigned a prospective 13 hospitals randomized placebocontrol clinical trial (clinicaltrialsgov NCT01918722) to con-firm if PBC and RBS herbal medicine induces the incidenceof hematoma enlargement of AICH patient within the 6 hrstime window from onset 62 cases have been recruited sinceFebruary 2014 and all 300 patients will be completed inDecember 2015
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgment
The authors thank Professor ZehuaiWen because he directedthe statistics of the data He is the director of Key Unit ofMethodology in Clinical Research of Guangdong ProvinceHospital of Traditional Chinese Medicine The authors alsothank China National Clinical Study Base Project of Tradi-tional Chinese Medicine sponsored by State Administrationof Traditional Chinese Medicine of the Peoplersquos Republic ofChina (Grant no JDZX2012074)
References
[1] A I Qureshi A D Mendelow and D F Hanley ldquoIntracerebralhaemorrhagerdquo The Lancet vol 373 no 9675 pp 1632ndash16442009
[2] C J van Asch M J Luitse G J Rinkel I van der Tweel AAlgra and C J Klijn ldquoIncidence case fatality and functional
outcome of intracerebral haemorrhage over time accordingto age sex and ethnic origin a systematic review and meta-analysisrdquoThe Lancet Neurology vol 9 no 2 pp 167ndash176 2010
[3] J K Lim H S Hwang B M Cho et al ldquoMultivariateanalysis of risk factors of hematoma expansion in spontaneousintracerebral hemorrhagerdquo Surgical Neurology vol 69 no 1 pp40ndash45 2008
[4] S M Davis J Broderick M Hennerici et al ldquoHematomagrowth is a determinant of mortality and poor outcome afterintracerebral hemorrhagerdquo Neurology vol 66 no 8 pp 1175ndash1181 2006
[5] G-Q Wang S-Q Li Y-H Huang et al ldquoCan minimally inva-sive puncture and drainage for hypertensive spontaneous BasalGanglia intracerebral hemorrhage improve patient outcomea prospective non-randomized comparative studyrdquo MilitaryMedical Research vol 1 article 10 2014
[6] J C Hemphill III D C Bonovich L Besmertis G T Manleyand S C Johnston ldquoThe ICH score a simple reliable gradingscale for intracerebral hemorrhagerdquo Stroke vol 32 no 4 pp891ndash896 2001
[7] G Jian-wen and L Ming-jie ldquoMeta-analysis of acute intrac-erebral hemorrhage treated with traditional Chinese medicineorand composition of promoting blood circulation and remov-ing blood stasisrdquo Journal of China-Japan Friendship Hospitalvol 15 no 5 pp 283ndash286 2001
[8] ICD-10 Version 2010 httpappswhointclassificationsicd10browse2010en
[9] R U Kothari T Brott J P Broderick et al ldquoThe ABCs ofmeasuring intracerebral hemorrhage volumesrdquo Stroke vol 27no 8 pp 1304ndash1305 1996
[10] J M Gebel C A Sila M A Sloan et al ldquoComparison of theABC2 estimation technique to computer-assisted volumetricanalysis of intraparenchymal and subdural hematomas compli-cating the GUSTO-1 trialrdquo Stroke vol 29 no 9 pp 1799ndash18011998
[11] T Brott J Broderick R Kothari et al ldquoEarly hemorrhagegrowth in patients with intracerebral hemorrhagerdquo Stroke vol28 no 1 pp 1ndash5 1997
[12] J-L Vanherweghem M Depierreux C Tielemans et alldquoRapidly progressive interstitial renal fibrosis in young womenassociation with slimming regimen including Chinese herbsrdquoThe Lancet vol 341 no 8842 pp 387ndash391 1993
[13] M Jadoul J F de Plaen J P Cosyns and C van Ypersele deStrihou ldquoAdverse effects from traditional Chinese medicinerdquoThe Lancet vol 341 no 8849 pp 892ndash893 1993
[14] P-X Huang Y Huang and M Lu ldquoTreatment of acuteintracerebral hemorrhage with a comprehensive protocol ofintegrated Chinese andWestern medicinerdquo Zhongguo Zhong XiYi Jie He Za Zhi vol 26 no 7 pp 590ndash593 2006
[15] J Guo and M Liu ldquoMeta-analysis of acute intracerebralhemorrhage treated with traditional Chinese medicine orandcomposition of promoting blood circulation and removingblood stasisrdquo Journal of China-Japan Friendship Hospital vol15 no 5 pp 283ndash286 2001
[16] W Mian-hua and W Xin-yue Traditional Chinese InternalMedicine China Press of Traditional Chinese Medicine 3rdedition 2000
[17] L Bin and L Jian ldquoClinical observation of early use promotingblood circulation and removing blood stasis herbal injectionto treat acute intracerebral hemorrhagerdquo Shandong Journal ofTraditional Chinese Medicine vol 19 no 8 pp 461ndash462 2000
8 Evidence-Based Complementary and Alternative Medicine
[18] F Markwardt ldquoThe development of hirudin as an antithrom-botic drugrdquo Thrombosis Research vol 74 no 1 pp 1ndash23 1994Review
[19] J W Guo Y F Cai and B X Du ldquoThinking and challengeinduced by the hypothesis of breaking stagnant and eliminatingblood stasis in Treating acute cerebral hemorrhage by rF VII ardquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 25 no 11 pp 1027ndash1029 2005 (Chinese)
[20] Y Fujii R Tanaka S Takeuchi T Koike T Minakawa and OSasaki ldquoHematoma enlargement in spontaneous intracerebralhemorrhagerdquo Journal of Neurosurgery vol 80 no 1 pp 51ndash571994
[21] L Liu J-A Duan Y Tang et al ldquoTaoren-Honghua herb pairand its main components promoting blood circulation throughinfluencing on hemorheology plasma coagulation and plateletaggregationrdquo Journal of Ethnopharmacology vol 139 no 2 pp381ndash387 2012
[22] S Kazui H Naritomi H Yamamoto T Sawada and TYamaguchi ldquoEnlargement of spontaneous intracerebral hem-orrhage incidence and time courserdquo Stroke vol 27 no 10 pp1783ndash1787 1996
[23] Y Wanzhng Z Zhilan Z Ming et al ldquoOnce again on bleedingafter cerebral hemorrhage and the time window for therapy ofldquopromoting blood circulation and removing blood stasisrdquordquo Chi-nese Journal of Integrative Medicine on Cardio-CerebrovascularDisease vol 11 pp 662ndash665 2004
[24] W Li ldquoDiscussion of early use promoting blood circulationand removing blood stasis herbal medicinerdquo Chinese Journal ofBasicMedicine in Traditional ChineseMedicine vol 5 pp 58ndash592003
[25] J-W Guo Y-C He and S-H Chen ldquoClinical study on thetherapeutic time window of acute intracerebral hemorrhagetreated with herbal composition of Zhongfengxingnao takenorallyrdquo Chinese Journal of Cerebrovascular Diseases vol 2 no6 pp 255ndash259 2005
[26] Chinese Pharmacopoeia Commission The Pharmacopoeia ofthe Peoplersquos Republic of China vol 1 Chemical Industry PressBeijing China 2010
Note lowast119875 lt 005 998771119905-test Mann-Whitney 119880 test econtinuous correction chi-square test Pearson chi-square test and Kruskal-Wallis test
Table 2 Multivariate regression analysis on the independent risk factors of hematoma enlargement in 256 patients
Independent variable Coefficient ofregression OR 95 CI
36 Comparison of Herbal Drugs Combined with PBS andRBC HICH patients were given herbal drugs formulaincluding several mixed herbal drugs besides PBS and RBSdrugs such as relieving heat and calming liver Yang decreas-ing wind and dispersing phlegm and loosing bowls Weanalyse the effect as in Table 3
The results showed that therewas no significant differencebetween two groups combined with the above three types ofherbal drugs (all 119875 gt 005)
37 Multivariate Analysis on the 3-Month Outcome Followup(mRS) Patientsrsquo sex baseline Glasgow coma scale baselineNIHSS duration from onset to the first CT scan aspartateaminotransferase (AST) PBC and RBS herbal medicine useand hematoma growth were an independent variable in themultivariate logistic regression analysis andmRS a dependentvariable We defined mRS 0-1 as independent outcome andmRS 2ndash6 as dependent outcome
The results showed that baseline NIHSS and hematomagrowthwere the independent risk factors of outcomeof three-month followup (see Table 4)
There were two independent factors that affect the 3-month outcome The first one was baseline NIHSS (119875 =0000) The second one was hematoma growth (119875 = 0003)PBC and RBS herbal medicine use was not independent riskfactor (119875 = 0651)
4 Discussion
The safety of the herbal medicine administration becamemore and more critical since aristolochic acids were reportedto cause renal injury in 1993 [12 13]
It is long history that PBC and RBS herbal medicine wereused inChina to treatHICHAmulticenter prospective clini-cal trial showed PBC andRBS herbalmedicine can reduce thedeath and also improve the neurological function [14] Meta-analysis showed that PBC and RBS herbal medicine seems
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Herbal drugs combined with PBS and RBC between two groups (119899 )
Combined herbal drugs
PBS and RBC used inhematoma enlargement
(119899 )(119899 = 24)
PBS and RBC used innonhematoma
enlargement (119899 )(119899 = 135)
Value 119875
Relieving heat and calmingliver Yang 21 (875) 116 (859) 0042 0837
effective to treat HICH [15] PBC and RBS were also adoptedby textbook and guideline in treating HICH [16]
However safety data about hematoma enlargement werealso reported Bin and Jian declared that danshen injec-tion and mailuoning injection (one of the PBC and RBSherbal medicine) could induce the uncontrolled bleeding[17] Leech prevents not only fibrinogen clotting but alsoother thrombin-catalyzed hemostatic reactions such as theactivation of clotting factors V VIII and XIII and thethrombin-induced platelet activation [18] Other researchersadvocated that PBC andRBCherbalmedicine should be usedwith few side effects in the clinical application because theyadded to some other stopping bleeding herbal medicine tomake the prescription balance [19] So it is necessary that weperform this study on the safety of treating HICH with PBCand RBS herbal medicine
In this study forty-three (168) of the 256 patientsdemonstrated enlargement of the hematoma after the first CTscanThe growth rate was near the rate 143 (60419) of Fujiiet alrsquos report [20] In this study 159 patients were admin-istrated PBC and RBS herbal medicine prescription within24-hour time window including 24 patients in hematomaenlargement group and 135 patients in no hematoma groupwhich were not significantly different (119875 gt 005)
Hematoma enlargement in HICH has significant associ-ations with the duration of time since onset of neurologicalsymptoms the shape and volume of the bleeding the initialsdeep comadegree the presence of liver dysfunction andmalepatients [20 21] In this study the univariate analysis showedthat duration baseline GCS andNIHSS the liver dysfunction(AST) and male patients were the risk factor of hematomaexpansion while the shape and size of the hematoma werenot significant because the sample was too small
There were only two risk factors that induced hematomagrowth according to the multivariate analysis male patientsand duration of onset since ICH symptoms Hematomaenlargement was the independent risk factor of outcomeof three-month followup the result was similar as SeijiKazuirsquos study [22] PBC and RBS herbal drug was not theindependent risk factor of hematoma growth of the outcomeof three-month followup
Someherbal drugs have strongPBCandRBS function forexample leech caused rebleeding [21] Some others have two-way adjustment pharmacological effect for example Radixnotoginseng can not only PBC but also stopping bleeding Inour opinion the prescription of Chinese medicine to learn isthrough reasonable compatibility other than a single drug toeliminate this rebleeding risk
PBC and RBS herbal medicine was administrated withinthe time window that was uncertain A majority (83) ofpatients with hematoma enlargement underwent the initialCT scan within 6 hours of onset Enlargement after 24hours of onset seems extremely rare [22] So some neu-rologists showed their opinion that PBC and RBS herbalmedicine should be used after 24 hrs of onset in order toprevent rebleeding risk [23] Others supported that PBC andRBS herbal medicine should be administrated as sooner aspossible [24] Guo and his colleaguesrsquo study did not showdeterioration of condition of the AICH patients who weretreated with herbal compound within 6 hrs time windowfrom onset [25]
PBC and RBS herbal medicine should be combined withother drugs correctly in the Traditional Chinese MedicineFormula in order to avoid the rebleeding risk as recordedin the Chinese Pharmacopoeia of 2010 version [26] In thisstudy the treatment of acute cerebral hemorrhage frequently
Evidence-Based Complementary and Alternative Medicine 7
used herbal medicine by turns as follows Leonurus japon-icus Houtt (148 cases) Rhizoma Polygoni Cuspidati (131cases) leech (131 cases) Radix Achyranthis Bidentatae (83cases) Ligusticum chuanxiong Hort (21 cases) Radix SalviaeMiltiorrhizae (18 cases) Radix et Rhizoma Rhei Palmati (6cases) Cortex moutan (15 cases) peach seed (13 cases) RadixCurcumae Wenyujin (12 cases) Radix notoginseng (6 cases)Carthamus tinctorius L (5 cases) Caulis Spatholobi (4 cases)and Rhizoma corydalis (2 cases) They were used in balancebetween two groups (119875 gt 005)
In this retrospective study 159 patients (24 in hematomagrowth group and 135 in no hematoma growth group) weregiven PBC and RBS herbal medicine prescription whichwas also combined with other herbal drugs (showed asTable 4) PBC and RBS drugs reasonable compatibility withother herbs perhaps reduced the risk of hematoma expansioncaused by single PBC and RBS herb This result undoubtedlyis instructive for further clinical application
This is the first retrospective study of the hematomagrowth on the early HICH treated with traditional Chinesemedicine since nowThough the results showed it seems safethe retrospective study has many limitations Firstly thereare too many herbals medication to control the quality ofthe clinical study Secondly a lot of patients were excludedbecause of important data absent for example their secondCT scan data Thirdly some scales including NIHSS andGCS had recall bias from raw medical records
In order to make up for these limitations we havedesigned a prospective 13 hospitals randomized placebocontrol clinical trial (clinicaltrialsgov NCT01918722) to con-firm if PBC and RBS herbal medicine induces the incidenceof hematoma enlargement of AICH patient within the 6 hrstime window from onset 62 cases have been recruited sinceFebruary 2014 and all 300 patients will be completed inDecember 2015
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgment
The authors thank Professor ZehuaiWen because he directedthe statistics of the data He is the director of Key Unit ofMethodology in Clinical Research of Guangdong ProvinceHospital of Traditional Chinese Medicine The authors alsothank China National Clinical Study Base Project of Tradi-tional Chinese Medicine sponsored by State Administrationof Traditional Chinese Medicine of the Peoplersquos Republic ofChina (Grant no JDZX2012074)
References
[1] A I Qureshi A D Mendelow and D F Hanley ldquoIntracerebralhaemorrhagerdquo The Lancet vol 373 no 9675 pp 1632ndash16442009
[2] C J van Asch M J Luitse G J Rinkel I van der Tweel AAlgra and C J Klijn ldquoIncidence case fatality and functional
outcome of intracerebral haemorrhage over time accordingto age sex and ethnic origin a systematic review and meta-analysisrdquoThe Lancet Neurology vol 9 no 2 pp 167ndash176 2010
[3] J K Lim H S Hwang B M Cho et al ldquoMultivariateanalysis of risk factors of hematoma expansion in spontaneousintracerebral hemorrhagerdquo Surgical Neurology vol 69 no 1 pp40ndash45 2008
[4] S M Davis J Broderick M Hennerici et al ldquoHematomagrowth is a determinant of mortality and poor outcome afterintracerebral hemorrhagerdquo Neurology vol 66 no 8 pp 1175ndash1181 2006
[5] G-Q Wang S-Q Li Y-H Huang et al ldquoCan minimally inva-sive puncture and drainage for hypertensive spontaneous BasalGanglia intracerebral hemorrhage improve patient outcomea prospective non-randomized comparative studyrdquo MilitaryMedical Research vol 1 article 10 2014
[6] J C Hemphill III D C Bonovich L Besmertis G T Manleyand S C Johnston ldquoThe ICH score a simple reliable gradingscale for intracerebral hemorrhagerdquo Stroke vol 32 no 4 pp891ndash896 2001
[7] G Jian-wen and L Ming-jie ldquoMeta-analysis of acute intrac-erebral hemorrhage treated with traditional Chinese medicineorand composition of promoting blood circulation and remov-ing blood stasisrdquo Journal of China-Japan Friendship Hospitalvol 15 no 5 pp 283ndash286 2001
[8] ICD-10 Version 2010 httpappswhointclassificationsicd10browse2010en
[9] R U Kothari T Brott J P Broderick et al ldquoThe ABCs ofmeasuring intracerebral hemorrhage volumesrdquo Stroke vol 27no 8 pp 1304ndash1305 1996
[10] J M Gebel C A Sila M A Sloan et al ldquoComparison of theABC2 estimation technique to computer-assisted volumetricanalysis of intraparenchymal and subdural hematomas compli-cating the GUSTO-1 trialrdquo Stroke vol 29 no 9 pp 1799ndash18011998
[11] T Brott J Broderick R Kothari et al ldquoEarly hemorrhagegrowth in patients with intracerebral hemorrhagerdquo Stroke vol28 no 1 pp 1ndash5 1997
[12] J-L Vanherweghem M Depierreux C Tielemans et alldquoRapidly progressive interstitial renal fibrosis in young womenassociation with slimming regimen including Chinese herbsrdquoThe Lancet vol 341 no 8842 pp 387ndash391 1993
[13] M Jadoul J F de Plaen J P Cosyns and C van Ypersele deStrihou ldquoAdverse effects from traditional Chinese medicinerdquoThe Lancet vol 341 no 8849 pp 892ndash893 1993
[14] P-X Huang Y Huang and M Lu ldquoTreatment of acuteintracerebral hemorrhage with a comprehensive protocol ofintegrated Chinese andWestern medicinerdquo Zhongguo Zhong XiYi Jie He Za Zhi vol 26 no 7 pp 590ndash593 2006
[15] J Guo and M Liu ldquoMeta-analysis of acute intracerebralhemorrhage treated with traditional Chinese medicine orandcomposition of promoting blood circulation and removingblood stasisrdquo Journal of China-Japan Friendship Hospital vol15 no 5 pp 283ndash286 2001
[16] W Mian-hua and W Xin-yue Traditional Chinese InternalMedicine China Press of Traditional Chinese Medicine 3rdedition 2000
[17] L Bin and L Jian ldquoClinical observation of early use promotingblood circulation and removing blood stasis herbal injectionto treat acute intracerebral hemorrhagerdquo Shandong Journal ofTraditional Chinese Medicine vol 19 no 8 pp 461ndash462 2000
8 Evidence-Based Complementary and Alternative Medicine
[18] F Markwardt ldquoThe development of hirudin as an antithrom-botic drugrdquo Thrombosis Research vol 74 no 1 pp 1ndash23 1994Review
[19] J W Guo Y F Cai and B X Du ldquoThinking and challengeinduced by the hypothesis of breaking stagnant and eliminatingblood stasis in Treating acute cerebral hemorrhage by rF VII ardquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 25 no 11 pp 1027ndash1029 2005 (Chinese)
[20] Y Fujii R Tanaka S Takeuchi T Koike T Minakawa and OSasaki ldquoHematoma enlargement in spontaneous intracerebralhemorrhagerdquo Journal of Neurosurgery vol 80 no 1 pp 51ndash571994
[21] L Liu J-A Duan Y Tang et al ldquoTaoren-Honghua herb pairand its main components promoting blood circulation throughinfluencing on hemorheology plasma coagulation and plateletaggregationrdquo Journal of Ethnopharmacology vol 139 no 2 pp381ndash387 2012
[22] S Kazui H Naritomi H Yamamoto T Sawada and TYamaguchi ldquoEnlargement of spontaneous intracerebral hem-orrhage incidence and time courserdquo Stroke vol 27 no 10 pp1783ndash1787 1996
[23] Y Wanzhng Z Zhilan Z Ming et al ldquoOnce again on bleedingafter cerebral hemorrhage and the time window for therapy ofldquopromoting blood circulation and removing blood stasisrdquordquo Chi-nese Journal of Integrative Medicine on Cardio-CerebrovascularDisease vol 11 pp 662ndash665 2004
[24] W Li ldquoDiscussion of early use promoting blood circulationand removing blood stasis herbal medicinerdquo Chinese Journal ofBasicMedicine in Traditional ChineseMedicine vol 5 pp 58ndash592003
[25] J-W Guo Y-C He and S-H Chen ldquoClinical study on thetherapeutic time window of acute intracerebral hemorrhagetreated with herbal composition of Zhongfengxingnao takenorallyrdquo Chinese Journal of Cerebrovascular Diseases vol 2 no6 pp 255ndash259 2005
[26] Chinese Pharmacopoeia Commission The Pharmacopoeia ofthe Peoplersquos Republic of China vol 1 Chemical Industry PressBeijing China 2010
effective to treat HICH [15] PBC and RBS were also adoptedby textbook and guideline in treating HICH [16]
However safety data about hematoma enlargement werealso reported Bin and Jian declared that danshen injec-tion and mailuoning injection (one of the PBC and RBSherbal medicine) could induce the uncontrolled bleeding[17] Leech prevents not only fibrinogen clotting but alsoother thrombin-catalyzed hemostatic reactions such as theactivation of clotting factors V VIII and XIII and thethrombin-induced platelet activation [18] Other researchersadvocated that PBC andRBCherbalmedicine should be usedwith few side effects in the clinical application because theyadded to some other stopping bleeding herbal medicine tomake the prescription balance [19] So it is necessary that weperform this study on the safety of treating HICH with PBCand RBS herbal medicine
In this study forty-three (168) of the 256 patientsdemonstrated enlargement of the hematoma after the first CTscanThe growth rate was near the rate 143 (60419) of Fujiiet alrsquos report [20] In this study 159 patients were admin-istrated PBC and RBS herbal medicine prescription within24-hour time window including 24 patients in hematomaenlargement group and 135 patients in no hematoma groupwhich were not significantly different (119875 gt 005)
Hematoma enlargement in HICH has significant associ-ations with the duration of time since onset of neurologicalsymptoms the shape and volume of the bleeding the initialsdeep comadegree the presence of liver dysfunction andmalepatients [20 21] In this study the univariate analysis showedthat duration baseline GCS andNIHSS the liver dysfunction(AST) and male patients were the risk factor of hematomaexpansion while the shape and size of the hematoma werenot significant because the sample was too small
There were only two risk factors that induced hematomagrowth according to the multivariate analysis male patientsand duration of onset since ICH symptoms Hematomaenlargement was the independent risk factor of outcomeof three-month followup the result was similar as SeijiKazuirsquos study [22] PBC and RBS herbal drug was not theindependent risk factor of hematoma growth of the outcomeof three-month followup
Someherbal drugs have strongPBCandRBS function forexample leech caused rebleeding [21] Some others have two-way adjustment pharmacological effect for example Radixnotoginseng can not only PBC but also stopping bleeding Inour opinion the prescription of Chinese medicine to learn isthrough reasonable compatibility other than a single drug toeliminate this rebleeding risk
PBC and RBS herbal medicine was administrated withinthe time window that was uncertain A majority (83) ofpatients with hematoma enlargement underwent the initialCT scan within 6 hours of onset Enlargement after 24hours of onset seems extremely rare [22] So some neu-rologists showed their opinion that PBC and RBS herbalmedicine should be used after 24 hrs of onset in order toprevent rebleeding risk [23] Others supported that PBC andRBS herbal medicine should be administrated as sooner aspossible [24] Guo and his colleaguesrsquo study did not showdeterioration of condition of the AICH patients who weretreated with herbal compound within 6 hrs time windowfrom onset [25]
PBC and RBS herbal medicine should be combined withother drugs correctly in the Traditional Chinese MedicineFormula in order to avoid the rebleeding risk as recordedin the Chinese Pharmacopoeia of 2010 version [26] In thisstudy the treatment of acute cerebral hemorrhage frequently
Evidence-Based Complementary and Alternative Medicine 7
used herbal medicine by turns as follows Leonurus japon-icus Houtt (148 cases) Rhizoma Polygoni Cuspidati (131cases) leech (131 cases) Radix Achyranthis Bidentatae (83cases) Ligusticum chuanxiong Hort (21 cases) Radix SalviaeMiltiorrhizae (18 cases) Radix et Rhizoma Rhei Palmati (6cases) Cortex moutan (15 cases) peach seed (13 cases) RadixCurcumae Wenyujin (12 cases) Radix notoginseng (6 cases)Carthamus tinctorius L (5 cases) Caulis Spatholobi (4 cases)and Rhizoma corydalis (2 cases) They were used in balancebetween two groups (119875 gt 005)
In this retrospective study 159 patients (24 in hematomagrowth group and 135 in no hematoma growth group) weregiven PBC and RBS herbal medicine prescription whichwas also combined with other herbal drugs (showed asTable 4) PBC and RBS drugs reasonable compatibility withother herbs perhaps reduced the risk of hematoma expansioncaused by single PBC and RBS herb This result undoubtedlyis instructive for further clinical application
This is the first retrospective study of the hematomagrowth on the early HICH treated with traditional Chinesemedicine since nowThough the results showed it seems safethe retrospective study has many limitations Firstly thereare too many herbals medication to control the quality ofthe clinical study Secondly a lot of patients were excludedbecause of important data absent for example their secondCT scan data Thirdly some scales including NIHSS andGCS had recall bias from raw medical records
In order to make up for these limitations we havedesigned a prospective 13 hospitals randomized placebocontrol clinical trial (clinicaltrialsgov NCT01918722) to con-firm if PBC and RBS herbal medicine induces the incidenceof hematoma enlargement of AICH patient within the 6 hrstime window from onset 62 cases have been recruited sinceFebruary 2014 and all 300 patients will be completed inDecember 2015
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgment
The authors thank Professor ZehuaiWen because he directedthe statistics of the data He is the director of Key Unit ofMethodology in Clinical Research of Guangdong ProvinceHospital of Traditional Chinese Medicine The authors alsothank China National Clinical Study Base Project of Tradi-tional Chinese Medicine sponsored by State Administrationof Traditional Chinese Medicine of the Peoplersquos Republic ofChina (Grant no JDZX2012074)
References
[1] A I Qureshi A D Mendelow and D F Hanley ldquoIntracerebralhaemorrhagerdquo The Lancet vol 373 no 9675 pp 1632ndash16442009
[2] C J van Asch M J Luitse G J Rinkel I van der Tweel AAlgra and C J Klijn ldquoIncidence case fatality and functional
outcome of intracerebral haemorrhage over time accordingto age sex and ethnic origin a systematic review and meta-analysisrdquoThe Lancet Neurology vol 9 no 2 pp 167ndash176 2010
[3] J K Lim H S Hwang B M Cho et al ldquoMultivariateanalysis of risk factors of hematoma expansion in spontaneousintracerebral hemorrhagerdquo Surgical Neurology vol 69 no 1 pp40ndash45 2008
[4] S M Davis J Broderick M Hennerici et al ldquoHematomagrowth is a determinant of mortality and poor outcome afterintracerebral hemorrhagerdquo Neurology vol 66 no 8 pp 1175ndash1181 2006
[5] G-Q Wang S-Q Li Y-H Huang et al ldquoCan minimally inva-sive puncture and drainage for hypertensive spontaneous BasalGanglia intracerebral hemorrhage improve patient outcomea prospective non-randomized comparative studyrdquo MilitaryMedical Research vol 1 article 10 2014
[6] J C Hemphill III D C Bonovich L Besmertis G T Manleyand S C Johnston ldquoThe ICH score a simple reliable gradingscale for intracerebral hemorrhagerdquo Stroke vol 32 no 4 pp891ndash896 2001
[7] G Jian-wen and L Ming-jie ldquoMeta-analysis of acute intrac-erebral hemorrhage treated with traditional Chinese medicineorand composition of promoting blood circulation and remov-ing blood stasisrdquo Journal of China-Japan Friendship Hospitalvol 15 no 5 pp 283ndash286 2001
[8] ICD-10 Version 2010 httpappswhointclassificationsicd10browse2010en
[9] R U Kothari T Brott J P Broderick et al ldquoThe ABCs ofmeasuring intracerebral hemorrhage volumesrdquo Stroke vol 27no 8 pp 1304ndash1305 1996
[10] J M Gebel C A Sila M A Sloan et al ldquoComparison of theABC2 estimation technique to computer-assisted volumetricanalysis of intraparenchymal and subdural hematomas compli-cating the GUSTO-1 trialrdquo Stroke vol 29 no 9 pp 1799ndash18011998
[11] T Brott J Broderick R Kothari et al ldquoEarly hemorrhagegrowth in patients with intracerebral hemorrhagerdquo Stroke vol28 no 1 pp 1ndash5 1997
[12] J-L Vanherweghem M Depierreux C Tielemans et alldquoRapidly progressive interstitial renal fibrosis in young womenassociation with slimming regimen including Chinese herbsrdquoThe Lancet vol 341 no 8842 pp 387ndash391 1993
[13] M Jadoul J F de Plaen J P Cosyns and C van Ypersele deStrihou ldquoAdverse effects from traditional Chinese medicinerdquoThe Lancet vol 341 no 8849 pp 892ndash893 1993
[14] P-X Huang Y Huang and M Lu ldquoTreatment of acuteintracerebral hemorrhage with a comprehensive protocol ofintegrated Chinese andWestern medicinerdquo Zhongguo Zhong XiYi Jie He Za Zhi vol 26 no 7 pp 590ndash593 2006
[15] J Guo and M Liu ldquoMeta-analysis of acute intracerebralhemorrhage treated with traditional Chinese medicine orandcomposition of promoting blood circulation and removingblood stasisrdquo Journal of China-Japan Friendship Hospital vol15 no 5 pp 283ndash286 2001
[16] W Mian-hua and W Xin-yue Traditional Chinese InternalMedicine China Press of Traditional Chinese Medicine 3rdedition 2000
[17] L Bin and L Jian ldquoClinical observation of early use promotingblood circulation and removing blood stasis herbal injectionto treat acute intracerebral hemorrhagerdquo Shandong Journal ofTraditional Chinese Medicine vol 19 no 8 pp 461ndash462 2000
8 Evidence-Based Complementary and Alternative Medicine
[18] F Markwardt ldquoThe development of hirudin as an antithrom-botic drugrdquo Thrombosis Research vol 74 no 1 pp 1ndash23 1994Review
[19] J W Guo Y F Cai and B X Du ldquoThinking and challengeinduced by the hypothesis of breaking stagnant and eliminatingblood stasis in Treating acute cerebral hemorrhage by rF VII ardquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 25 no 11 pp 1027ndash1029 2005 (Chinese)
[20] Y Fujii R Tanaka S Takeuchi T Koike T Minakawa and OSasaki ldquoHematoma enlargement in spontaneous intracerebralhemorrhagerdquo Journal of Neurosurgery vol 80 no 1 pp 51ndash571994
[21] L Liu J-A Duan Y Tang et al ldquoTaoren-Honghua herb pairand its main components promoting blood circulation throughinfluencing on hemorheology plasma coagulation and plateletaggregationrdquo Journal of Ethnopharmacology vol 139 no 2 pp381ndash387 2012
[22] S Kazui H Naritomi H Yamamoto T Sawada and TYamaguchi ldquoEnlargement of spontaneous intracerebral hem-orrhage incidence and time courserdquo Stroke vol 27 no 10 pp1783ndash1787 1996
[23] Y Wanzhng Z Zhilan Z Ming et al ldquoOnce again on bleedingafter cerebral hemorrhage and the time window for therapy ofldquopromoting blood circulation and removing blood stasisrdquordquo Chi-nese Journal of Integrative Medicine on Cardio-CerebrovascularDisease vol 11 pp 662ndash665 2004
[24] W Li ldquoDiscussion of early use promoting blood circulationand removing blood stasis herbal medicinerdquo Chinese Journal ofBasicMedicine in Traditional ChineseMedicine vol 5 pp 58ndash592003
[25] J-W Guo Y-C He and S-H Chen ldquoClinical study on thetherapeutic time window of acute intracerebral hemorrhagetreated with herbal composition of Zhongfengxingnao takenorallyrdquo Chinese Journal of Cerebrovascular Diseases vol 2 no6 pp 255ndash259 2005
[26] Chinese Pharmacopoeia Commission The Pharmacopoeia ofthe Peoplersquos Republic of China vol 1 Chemical Industry PressBeijing China 2010
Evidence-Based Complementary and Alternative Medicine 7
used herbal medicine by turns as follows Leonurus japon-icus Houtt (148 cases) Rhizoma Polygoni Cuspidati (131cases) leech (131 cases) Radix Achyranthis Bidentatae (83cases) Ligusticum chuanxiong Hort (21 cases) Radix SalviaeMiltiorrhizae (18 cases) Radix et Rhizoma Rhei Palmati (6cases) Cortex moutan (15 cases) peach seed (13 cases) RadixCurcumae Wenyujin (12 cases) Radix notoginseng (6 cases)Carthamus tinctorius L (5 cases) Caulis Spatholobi (4 cases)and Rhizoma corydalis (2 cases) They were used in balancebetween two groups (119875 gt 005)
In this retrospective study 159 patients (24 in hematomagrowth group and 135 in no hematoma growth group) weregiven PBC and RBS herbal medicine prescription whichwas also combined with other herbal drugs (showed asTable 4) PBC and RBS drugs reasonable compatibility withother herbs perhaps reduced the risk of hematoma expansioncaused by single PBC and RBS herb This result undoubtedlyis instructive for further clinical application
This is the first retrospective study of the hematomagrowth on the early HICH treated with traditional Chinesemedicine since nowThough the results showed it seems safethe retrospective study has many limitations Firstly thereare too many herbals medication to control the quality ofthe clinical study Secondly a lot of patients were excludedbecause of important data absent for example their secondCT scan data Thirdly some scales including NIHSS andGCS had recall bias from raw medical records
In order to make up for these limitations we havedesigned a prospective 13 hospitals randomized placebocontrol clinical trial (clinicaltrialsgov NCT01918722) to con-firm if PBC and RBS herbal medicine induces the incidenceof hematoma enlargement of AICH patient within the 6 hrstime window from onset 62 cases have been recruited sinceFebruary 2014 and all 300 patients will be completed inDecember 2015
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgment
The authors thank Professor ZehuaiWen because he directedthe statistics of the data He is the director of Key Unit ofMethodology in Clinical Research of Guangdong ProvinceHospital of Traditional Chinese Medicine The authors alsothank China National Clinical Study Base Project of Tradi-tional Chinese Medicine sponsored by State Administrationof Traditional Chinese Medicine of the Peoplersquos Republic ofChina (Grant no JDZX2012074)
References
[1] A I Qureshi A D Mendelow and D F Hanley ldquoIntracerebralhaemorrhagerdquo The Lancet vol 373 no 9675 pp 1632ndash16442009
[2] C J van Asch M J Luitse G J Rinkel I van der Tweel AAlgra and C J Klijn ldquoIncidence case fatality and functional
outcome of intracerebral haemorrhage over time accordingto age sex and ethnic origin a systematic review and meta-analysisrdquoThe Lancet Neurology vol 9 no 2 pp 167ndash176 2010
[3] J K Lim H S Hwang B M Cho et al ldquoMultivariateanalysis of risk factors of hematoma expansion in spontaneousintracerebral hemorrhagerdquo Surgical Neurology vol 69 no 1 pp40ndash45 2008
[4] S M Davis J Broderick M Hennerici et al ldquoHematomagrowth is a determinant of mortality and poor outcome afterintracerebral hemorrhagerdquo Neurology vol 66 no 8 pp 1175ndash1181 2006
[5] G-Q Wang S-Q Li Y-H Huang et al ldquoCan minimally inva-sive puncture and drainage for hypertensive spontaneous BasalGanglia intracerebral hemorrhage improve patient outcomea prospective non-randomized comparative studyrdquo MilitaryMedical Research vol 1 article 10 2014
[6] J C Hemphill III D C Bonovich L Besmertis G T Manleyand S C Johnston ldquoThe ICH score a simple reliable gradingscale for intracerebral hemorrhagerdquo Stroke vol 32 no 4 pp891ndash896 2001
[7] G Jian-wen and L Ming-jie ldquoMeta-analysis of acute intrac-erebral hemorrhage treated with traditional Chinese medicineorand composition of promoting blood circulation and remov-ing blood stasisrdquo Journal of China-Japan Friendship Hospitalvol 15 no 5 pp 283ndash286 2001
[8] ICD-10 Version 2010 httpappswhointclassificationsicd10browse2010en
[9] R U Kothari T Brott J P Broderick et al ldquoThe ABCs ofmeasuring intracerebral hemorrhage volumesrdquo Stroke vol 27no 8 pp 1304ndash1305 1996
[10] J M Gebel C A Sila M A Sloan et al ldquoComparison of theABC2 estimation technique to computer-assisted volumetricanalysis of intraparenchymal and subdural hematomas compli-cating the GUSTO-1 trialrdquo Stroke vol 29 no 9 pp 1799ndash18011998
[11] T Brott J Broderick R Kothari et al ldquoEarly hemorrhagegrowth in patients with intracerebral hemorrhagerdquo Stroke vol28 no 1 pp 1ndash5 1997
[12] J-L Vanherweghem M Depierreux C Tielemans et alldquoRapidly progressive interstitial renal fibrosis in young womenassociation with slimming regimen including Chinese herbsrdquoThe Lancet vol 341 no 8842 pp 387ndash391 1993
[13] M Jadoul J F de Plaen J P Cosyns and C van Ypersele deStrihou ldquoAdverse effects from traditional Chinese medicinerdquoThe Lancet vol 341 no 8849 pp 892ndash893 1993
[14] P-X Huang Y Huang and M Lu ldquoTreatment of acuteintracerebral hemorrhage with a comprehensive protocol ofintegrated Chinese andWestern medicinerdquo Zhongguo Zhong XiYi Jie He Za Zhi vol 26 no 7 pp 590ndash593 2006
[15] J Guo and M Liu ldquoMeta-analysis of acute intracerebralhemorrhage treated with traditional Chinese medicine orandcomposition of promoting blood circulation and removingblood stasisrdquo Journal of China-Japan Friendship Hospital vol15 no 5 pp 283ndash286 2001
[16] W Mian-hua and W Xin-yue Traditional Chinese InternalMedicine China Press of Traditional Chinese Medicine 3rdedition 2000
[17] L Bin and L Jian ldquoClinical observation of early use promotingblood circulation and removing blood stasis herbal injectionto treat acute intracerebral hemorrhagerdquo Shandong Journal ofTraditional Chinese Medicine vol 19 no 8 pp 461ndash462 2000
8 Evidence-Based Complementary and Alternative Medicine
[18] F Markwardt ldquoThe development of hirudin as an antithrom-botic drugrdquo Thrombosis Research vol 74 no 1 pp 1ndash23 1994Review
[19] J W Guo Y F Cai and B X Du ldquoThinking and challengeinduced by the hypothesis of breaking stagnant and eliminatingblood stasis in Treating acute cerebral hemorrhage by rF VII ardquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 25 no 11 pp 1027ndash1029 2005 (Chinese)
[20] Y Fujii R Tanaka S Takeuchi T Koike T Minakawa and OSasaki ldquoHematoma enlargement in spontaneous intracerebralhemorrhagerdquo Journal of Neurosurgery vol 80 no 1 pp 51ndash571994
[21] L Liu J-A Duan Y Tang et al ldquoTaoren-Honghua herb pairand its main components promoting blood circulation throughinfluencing on hemorheology plasma coagulation and plateletaggregationrdquo Journal of Ethnopharmacology vol 139 no 2 pp381ndash387 2012
[22] S Kazui H Naritomi H Yamamoto T Sawada and TYamaguchi ldquoEnlargement of spontaneous intracerebral hem-orrhage incidence and time courserdquo Stroke vol 27 no 10 pp1783ndash1787 1996
[23] Y Wanzhng Z Zhilan Z Ming et al ldquoOnce again on bleedingafter cerebral hemorrhage and the time window for therapy ofldquopromoting blood circulation and removing blood stasisrdquordquo Chi-nese Journal of Integrative Medicine on Cardio-CerebrovascularDisease vol 11 pp 662ndash665 2004
[24] W Li ldquoDiscussion of early use promoting blood circulationand removing blood stasis herbal medicinerdquo Chinese Journal ofBasicMedicine in Traditional ChineseMedicine vol 5 pp 58ndash592003
[25] J-W Guo Y-C He and S-H Chen ldquoClinical study on thetherapeutic time window of acute intracerebral hemorrhagetreated with herbal composition of Zhongfengxingnao takenorallyrdquo Chinese Journal of Cerebrovascular Diseases vol 2 no6 pp 255ndash259 2005
[26] Chinese Pharmacopoeia Commission The Pharmacopoeia ofthe Peoplersquos Republic of China vol 1 Chemical Industry PressBeijing China 2010
8 Evidence-Based Complementary and Alternative Medicine
[18] F Markwardt ldquoThe development of hirudin as an antithrom-botic drugrdquo Thrombosis Research vol 74 no 1 pp 1ndash23 1994Review
[19] J W Guo Y F Cai and B X Du ldquoThinking and challengeinduced by the hypothesis of breaking stagnant and eliminatingblood stasis in Treating acute cerebral hemorrhage by rF VII ardquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 25 no 11 pp 1027ndash1029 2005 (Chinese)
[20] Y Fujii R Tanaka S Takeuchi T Koike T Minakawa and OSasaki ldquoHematoma enlargement in spontaneous intracerebralhemorrhagerdquo Journal of Neurosurgery vol 80 no 1 pp 51ndash571994
[21] L Liu J-A Duan Y Tang et al ldquoTaoren-Honghua herb pairand its main components promoting blood circulation throughinfluencing on hemorheology plasma coagulation and plateletaggregationrdquo Journal of Ethnopharmacology vol 139 no 2 pp381ndash387 2012
[22] S Kazui H Naritomi H Yamamoto T Sawada and TYamaguchi ldquoEnlargement of spontaneous intracerebral hem-orrhage incidence and time courserdquo Stroke vol 27 no 10 pp1783ndash1787 1996
[23] Y Wanzhng Z Zhilan Z Ming et al ldquoOnce again on bleedingafter cerebral hemorrhage and the time window for therapy ofldquopromoting blood circulation and removing blood stasisrdquordquo Chi-nese Journal of Integrative Medicine on Cardio-CerebrovascularDisease vol 11 pp 662ndash665 2004
[24] W Li ldquoDiscussion of early use promoting blood circulationand removing blood stasis herbal medicinerdquo Chinese Journal ofBasicMedicine in Traditional ChineseMedicine vol 5 pp 58ndash592003
[25] J-W Guo Y-C He and S-H Chen ldquoClinical study on thetherapeutic time window of acute intracerebral hemorrhagetreated with herbal composition of Zhongfengxingnao takenorallyrdquo Chinese Journal of Cerebrovascular Diseases vol 2 no6 pp 255ndash259 2005
[26] Chinese Pharmacopoeia Commission The Pharmacopoeia ofthe Peoplersquos Republic of China vol 1 Chemical Industry PressBeijing China 2010
