Y HOC VIET NAM THANG 9 - SO OAC BIET/2011
NGHIEN Cl)U TAG DUNG DIEU TRj CUA THUOC CHEN BETA GIAO CAM PROPRANOLOL 0 BENH NHAN
T R I / A N GTINH MACH THUTC QUAN DO XO GAN
TOM TAT
Muc tieu: Oanh gia tac dung dieu tri tru'dng tTnh mach thdc quan ciia propranolol.
Odi tu'dng nghien cuTu: 34 benh nhan nhap vien khoa Npi Tieu Hoa Benh vien Trung u'dng Hue t i i 10/2006 den 5/2007, dddc chan doan xd gan co bien chu'ng tru'dng tinh mach thUc quan.
PhUdng phap nghien cuTu: Cac benh nhan du'dc kham ghi nhan cac thong sd mach, huyet ap, tinh trang xuat huyet, do du'dng kinh tTnh mach ciia tren sieu am va danh gia mire do trUdng tTnh mach thdc quan tren npi soi, sau do dddc dieu tri vdi propranolol de dat muc tieu giam nhip tim > 25% so vdi nhip tim cd ban tru'dc dieu tri va giam huyet ap > 20mmHg cd ban tru'dc dieu trj. Tiep tuc dimg propranolol trong thdi gian mot thang, kiem tra lai cac thong sd tinh trang xuat huyet, du'dng kinh tTnh mach cCia va mu'c do tru'dng tTnh mach thi/c quan de danh gia mu'c dp dap uTng dieu trj.
Ket qua: Propranolol lam giam du'dng kinh tTnh mach ciia tren sieu am: Du'dng kinh tTnh mach CLia tru'dc dieu trj trung binh la:
15.74±2.19 mm, sau dieu trj trung binh la: 13.26
± 2.19 mm, sd thay doi la co y nghTa thdng ke, vdi p<0.05. Propranolol lam giam kfch thu'dc ciia tTnh mach tru'dng thdc quan qua no! soi: sau dieu tn vdi propranolol, co 07 benh nhan (20.6%) dat du'dc sd giam mire dp tru'dng tTnh mach thiTc quan, 26 benh nhan (76.5%) giu' nguyen mu'c do tru'dng tTnh mach thiic quan. Propranolol lam giam nguy cd xuat huyet do vd tTnh mach tru'dng thiTc quan: Tru'dc dieu trj cd 9 benh nhan (chiem ty le 26.5%) da hoac dang xuat huyet, sau dieu trj chi CO 4 benh nhan (11.8%) xuat huyet, sd khac biet cd y nghTa thdng ke, vdi p < 0.05. Ty le dap iing vdi propranolol la 82.3%, trong do dap
Triin Vict Dung, Pham N h u The irng tdt la 20.6%, dap irng vira la 61.8%. Ty le khong dap irng vdi dieu tri propranolol chi chiem ty le 17.7%.
Ket luan: Thong qua tac dung lam giam ap li/c tTnh mach ciia, propranolol lam giam dUdng ki'nh tTnh mach cira tren sieu am, giam kfch thu'dc ciia tTnh mach tru'dng thdc quan qua npi soi, va giam nguy cd xuat huyet do vd tTnh mach trUdng thi/c quan.
SUMMARY
A STUDY ON THE TREATMENT EFFECTS OF PROPRANOLOL I N ESOPHAGEAL VEIN
DISTENTED PATIENTS BECAUSE OF CIRRHOSIS
Objectives: To assess the treatment effects of Propranolol in esophageal varices due
»to cirrhosis.
Subjects: 34 patients were diagnosed with esophageal varices due to cirrhosis in Digestive Internal Department of Hue Central hospital from October, 2006 to May, 2007.
Methods: The patients were recorded the parameters of vessels, blood pressure, bleeding, arterial vein diameter by ultrasound and were assessed the levels of esophageal varices by endoscopy. Then they were treated with Propranolol to reduce heart rate > 25 percents and blood pressure > 20 mmHg compared to before treatment. They were used Propranolol during a month, then were tested all the parameters of bleeding, portal vein diameter and the levels of esophageal varices to assess the effects of treatment.
Results: Propranolol helps to reduce portal vein diameter by ultrasound: portal vein diameter before the average treatment Is 15.74 ± 2.19 mm, after the average treatment Is 13.26 ± 2.19
HOI NGHI KHOA HOC K? THUAT Md RONG LAN THOXII • BENH VI$N HCTU NGHI VIET NAM - CU BA D6NG_Hdl_
mm, the change was statistically significant, with p < 0.05. Propranolol helps to reduce the size of esophageal varices by endoscopy: 7 patients (20.6%) reduced the level of esophageal varices, 26 patients (76.5%) kept the level of esophageal varices. Propranolol also helps to reduce the risk of bleeding due to rupture of esophageal varices:
there were 9 patients (26.5%) bleeding before treatment, but after treatment, only 4 patients (11.8%) bleeding, the differences were stabstically significant, with p < 0.05. Response rate with Propranolol was 82.3%, in particular, good response rate was 20.6%, moderate response rate was 61.8%. No response rate was only 17.7%.
Conclusions: Through the effect to reduce the portal vein pressure. Propranolol reduces the portal vein diameter by ultrasound, the size of esophageal varices by endoscopy, and reduce the risk of bleeding due to mpture of esophageal varices.
I.
OAT VXN OEXa gan la mot benh canh dSc trung bdi hai hoi chimg la tang ap tinh mach cira vii suy chirc nang te bao gan, vdi rat nhieu bien chung nang trong dd xuat huyet do vd tTnh mach trudng thuc quan la hau qua true tiep cua tang ap tTnh mach cira \a la mot bien chimg rat nang. ty le tir \ ong cao.
Propranolol la mot thudc chen Beta giao cam khdng chon loc co chi dinh chinh trong tang huyet ap, mot sd rdi loan nhip tim \a benh dong mach vanh. Do co tiic dung giam luc h? thong tinh mach cua nen propranolol cdn dugc dimg de dieu tri giam ap tinh mach cira trong benh nhan xa gan. Tren the gidi da cd nhieu nghien ciru ve propranolol cho ket qua tot ve giam ty le xuat hu\et dot dau, giam ty le xuat huyet tai phat va giam ty le tir vong. Cimg vdi hai uu diem khac la re tien va san cd, phii hgp vdi dieu kien Viet Nam, propranolol nen dugc ap dung rong rai ban d
nhiing b(?nh nhim xa gan cd trudng tinh mach thuc quim.
Vi vay, chiing tdi ticn hanh nghien ciiru niiy nham muc tieu: Ddnh gid tdc dung dieu trj trudng tmh mgch thuc quan ciia propranolol.
II. o 6 l TUpNG VA PHUONG PHAP NGHIEN ClfU 2.1. Ddi tmrng nghien curu
Gom "(4 benh nhan nhap \ ien khoa Npi Tieu Iloii Ficnb vien Trung uang Hue hi
10/2006 den 5/2007. dugc chdn doan xa gan co bien chimg tnrimg tTnh mach thuc quan.
2.1.1. Tieu chudn chgn b^nh
Chiing ti)i chan doan xa gan dua vao 2 hoi chirng
2.1.1.1. Hgi chirng tdng dp luc tinh mgch cira
Lam sang: Cd trudng, lach Idn, tuan hoan bang be kieu cira chu. tTnh mach trudng thirc quan, tTnh mach trirdng da day do tang ap cira, trT.
Can lam sang: Sieu am bung: cau true gan tho dang hat, bd gan khong deu, goc gan til. Ducmg kinh TMC > 13mm, co the co dich tu do trong d bung, lach Idn. Ndi soi da day - thuc quim: cd trirdng tTnh mach thuc quan ciic mire do.
2.1.1.2. Hgi chirng suy te bdo gan
Lcim sang: Met mdi, chan an, co the co
\ang mk vimg da, giiln mach d gd ma, gian mach hinh sao d nguc, hdng ban d long ban ta)', chay mau chim rang, chay mau miii, xuat huyet dudi da. Can lam sang: Ty Prothrombin < 70%, Protid mau < 60g/L, Albumin < 30g/L.
2.1.2. Tieu chudn logi trir Xa gan kem ung thu gan.
Nhung benh nhan cd chdng chi dinh vdi propranolol.
Y HOC VIET NAM THANG 9 - SO DAC BIET/2011
Nhimg benh nhan khdng ddng y tham gia nghien cuu.
2.2. Phuang phap nghien curu
Toan bo 34 benh nhan dugc lira ebon se dugc kham ghi nhan cac thong s6 mach.
huyet ap, tinh trang xudt huyOt. do ducmg kinh tTnh mach cira tren sieu am vii danh gia muc do trudng tinh mach thuc quan tren noi soi, sau dd dugc dieu tri vdi propranolol trong thdi gian mot thang, ki^m tra lai cac thong sd ndi tren de danh gia muc do dap ung dieu tri.
Lieu khdi dau thucmg la propranolol 40 mg udng hang nga}- chia 2 lan sang \a chieu.
kiem tra mach \ a huyet ap cua benh nhan d^
dieu chinh lieu lugng thuoc sao cho dat dugc su giam nhip tim > 25% so vdi nhip tim ca ban trudc dieu tri va giam huyet ap >
2()miTil Ig CO ban trircVc dieu tri. [2,6].
Iheo d()i silt cac liic dung phu ciia propranolol trong qua trinh dieu tri, neu mach quii cham dudi 60 lim/phiit hoac huyet ap ha thap dudi lOOmmHg thi phai giam lieu, ngimg thucic khi xay ra tiic dung phu nghiem trong hoac khi benh nhiin tai phat xuat huyet.
Tieu chudn ddnh gid ddp ung dieu tri (1) tinh trang xuat huyet trong qua trinh dieu tri, (2) su thay doi ciia TMTTQ qua noi soi \a (3) su thay doi dudng kinh TMC tren sieu am [4,6,7,]
Bdng. Tom tat cac tieu chi danh gia dap img dieu tri vdi propranolol.
" " ^ ^ MuTc do
^ ^ | p u^ng Tieu chi ^""^-^
Tinh trang xuat huyet(1)
Noi soi (2)
Sieu am (3)
Dap uTng tdt (A) Khong xuat huyet
Giam dp nang ciia varices (vi du t i i dp 3 xudng dp 2) so vdi trUdc dieu tri
Giam du'dng kinh TMC > 3mm so vdi tru'dc dieu tri
Dap uTng vu'a (B)
Co the CO xuat huyet nhu'ng rniTc do nhe hdn tru'dc dieu tri
Op nang khong thay doi so vdl tru'dc dieu trj
Giam du'dng kinh TMC t i i l-3mm so vdi tru'dc dieu tri
Khdng dap u'ng (C)
Xuat huyet khong giam hoac tang them so vdi tru'dc dieu tri
Tang do nang ciia varices (vi du tir" do 2 len dp 3) so vdl tru'dc dieu tri
Oiidng kinh TMC khong giam hoac tang them so vdi tru'dc dieu tri
Nhdn xet: - Dap ung tdt: Cac benh nhan co dong thdi ca 3 tieu chi d cdt (A).
Khdng dap ung: Cac benh nhan co it nhat 1 trong 3 tieu chi d cdt (C).
Dap img vira: Cac benh nhan con lai.
2.3. Xirlyso lieu
Xir ly so lieu theo phuang phap thdng ke y hoc dua theo Excel 2003 va chuang trinh SPSS 13.0 (Statistical Package for Social Sciences).
III. KET QUA NGHIEN CCfU VA BAN LUAN 3.1. Phdn bd theo tuoi
Tudi trung binh: 48.4 ± 9.9. Tudi nho nhat: 25. Tudi Idn nhat: 66.
HQl NGHI KHOA HOC KY THUAT Md RONG LAN THIJ;XII • BENH VigN HPfU NGHj VigT NAM - CU BA D 6 N G H 6 |
Nhom tiKM CO tan siuit gap nhicu nhiit lii nhom tuoi 51 60, chiem ty le 38.2%, tdng cong cac nhdm tudi tien 30 chiem dai da so vcVi ty lc 94.1%. Dieu nay theo chiing tdi la hgp ly vi
\o- gan hi mt)t IxMih man tinh lii-n trii-n cham, lir khi niiic phai min nguyen nhan gay benh thi 10 - 20 nam sau mdi gii> xa gan.
4 0
1% l c •'<. .^O
o^
T,\ 4 0 41 5 0 5 1 N h o m tlidi
r,() > 6 0
Bieu dd 3.1. Phim bd theo nhdm tudi 3.2. Phdn bo theo gidi tinh
Nam gidi cd ty le mhc benh cao han nit gidi, ty le mdc benb nam/ nir: 2.7/1, Sir khac biet cd y nghTa thong ke \cVi p < 0.01.
2 6 . 5 % ^ ^ ^ ^ ^
73.5%
DNam
• NCr
Bleu do 3.2. Ty le phan bd theo gidi
Ket qua nay phii hgp vdi cac nghien ciru cua cac tac gia trong nircVc. Tuy nhien. theo cac tac gia nude ngoai thi ty le mac benh la ngang nhau giua nam \ a nfr. Cd sir khac biet nay, theo chimg tdi phai chang la do d Viet Nam, phiin Idn ngirdi nghien rugu la nam gidi. Trong nghien ciru ciia chiing tdi, tat ca ciic benh nhan xa gan do rircTU deu lii nam giai.
3.3. Mike dg trudng tinh mgi Bdng 3.1. Mire do trirdng tin
Mu'c dp tru'dng TMTQ 0 6 1
Do 2 06 3 Tong
:// thuc qudn tru&c dieu tri 1 mach thyc quan trudc dieu tri
n 0 22 12 34
TV le (O/o) 0 64.7 35.3 100
P
<0,05
Y HOC VIET NAM THANG 9 - SO OAC BIET/2011
Sd dl trong mau nghien ciru ciia chiing toi khong co benh nhan nao co TMTTQ do 1 la vi nhihig benh nhan nay khdng co chi dinh dihu tri du phong. Nhu'ng benh nhan nay nen dugc ndi soi theo doi moi 2 3 nam mot lan, trong trudng hgp benh gan ticn trien, hoac chi s6 Child Pugh tang thi noi soi moi nam mot lan [6,7].
Kht qua nghien ciru ciia chiing toi thi ty le TMTTQ dc) 2 cao ban TMTTQ do 3, dihu nay la do ddi vdi cac TMTTQ do 3, dac biet nhu kem theo cac dau hieu do thi phuang phap that tinh mach trucDng qua ndi soi thirdng dugc ua chuc)ng hem.
3.4. Gid tri trung binh cua tdn sd mgch trudc vd sau dieu trj Bdng 3.2. Gia tri trung binh ciia tan so mach trudc va sau dieu tri
Mach TrUdc dieu tri
Sau dieu tri
Trung binh (Ian/phut)
87.65 ± 4.89
65.38 ± 6.08 P < 0.01
Sir giam tan so mach dat muc tieu de ra la giam > 25% so vdi trudc dieu tri, sir khac biet CO y nghTa thdng ke vdi p <0.01.
Theo Hegab A.M va Lucketic V.A., tac dung ciia propranolol trong dieu tri hoi chimg tang ap cira dugc danh gia khi nhip tim giam tren 25% so vdi trudc dieu tri va HVPG < 12 mmHg. goi la khong dap img khi tan s6 mach giam < 10%, va HVPG > 12 mmHg [6].
3.5. Gid tri trung binh cua huyet dp trirdc vd sau dieu tri.
Bdng 3.3. Gia tri trung binh ciia huyet ap trudc va sau dieu tri
Huyet ap TrUdc dieu tri
Sau dieu tri
Trung binh 124.6 ± 8.6 102.7 ± 9.1
P
<0.01
Sir giam huyet ap dat muc tieu de ra la giam > 20mmHg so vdi trudc dieu tri. Propranolol lam giam huyet ap thdng qua cac ca che: giam nhip tim (nhip tim cham lai ca khi nghi lan khi gang sue), giam sue co bdp ca tim, dan den giam cung lugng tim, uc che than giai phong renin, phong be than kinh giao cam tir trung tam van mach tir nao di ra. Nhung tac dung nay lam huyet ap giam, ke ca ap luc tam thu that trai [8]. Huyet ap he thdng giam se dan tdi co mach tang phan xa, va do dd giam luu lugng mau trd ve TMC, giam ap luc he thong cira.
3.6. Gid tri trung binh dw&ng kinh tinh mgch cira tren sieu dm trw&c vd sau dieu tri Bdng 3.4. Gia tri trung binh cua ducmg kinh TMC trudc va sau dieu tri
Du'dng kinh TMC Tru'dc dieu tri
Sau dieu tri
Trung binh (mm) 15.74 ± 2.19 13.26 ± 2.39
P P < 0.05
Dudng kinh TMC trudc dieu tri trung binh la: 15.74 ±2.19 mm.
Dudng kinh TMC sau dieu tri trung binh la: 13.26 ± 2.39 mm, sir thay doi dudng kinh TMC sau mdt thang dieu tri la co y nghia thdng ke, vdi p < 0.05.
Theo Nguyen Phudc Bao Quan thi dudng kinh trung binh TMC d ngudi Viet Nam thudng < 12 mm [1]. Theo nghien cuu cua Bolondi L., va cdng sir tren 69 benh nhan xa gan thi ducmg kinh TMC binh thucmg < 13mm, trong TATMC ducmg kinh TMC > 13mm
Hpl NGHI KHOA HOC K? T H U A T M 6 R Q N G L A N T H L / X I I • B E N H V I E N H O U NGHI V I E T NAM - CU B A D 6 N G HC?I
(47.K"()), vii ket luan riing sir giiin lur dirimg kinh > 13mm ciia TMC la dau hieu ggi y TATMC |4|.
.?. 7. Ddp irng cua dudng kinh tinh mgch cua trudc vd sau dieu tri Bdng .^.5. Tha) do\ ciia duirng kinh TMC trudc vii sau dieu tri
MuTc do giam Giam >
Giam 1 Giam <
Tong
3 mm 3 mm 1 mm
n 8 23
3 34
Ty le (°/o) 23.5 67-7 _ .. A 8 _ .
100
Sau mot thiing dieu trj \(Vi propranolol, c() 8 henh nhiin dat dirge sir giam dirimg kinh TMC > 3 mm, chieMii ty le 23.5%, cd 23 hcnh nhan dat dirge sir giam dirimg kinh TMC 1 3 mm. chiem i\ le 67.7"o, chi co 8.8"o benh nhim dat ducrc sir giam dirimg kinh I MC < I mm.
3.8. Thay ddi cua tinh mgch trudng thuc qudn qua ngi soi trirdc vd sau dieu tri 3dng 3.6. rhay diii ciia '
Thay ddi Giam
Khong giam Tang len
I M T I Q qua noi n
soi IrircVc \ ii sau dieu tri 7
26 1
Tyrje^Co/oJ
20.6 76.5 2.9
P
<0,01
Sau mot thang dieu tri vdi propranolol, cd 07 benh nhan (20.6%) dat dugc su giam mire do trudng TMTQ (tir do 3 giam xudng do 2, tir do 2 giam xuong dp 1); cd 01 benh nhan (2.9%) tang muc do trucrng TMTQ (tir do 2 tang len do 3), 26 benh nhan (76.5%) cdn lai khdng thay doi.
Cac trucrng tmh mach la bien chimg true tiep cua TATMC. Dieu can luu y la, ciic trudng TMTQ khdng phai la hht biet. Chiing xuat hi?n va bien mat ciing \di sir thay doi the tich tuan hoan va nhirng thay ddi ap Krc
tmh mach cira [2,8].
Propranolol lam giam ap lire va liru lugng mau trong he thdng cira, vi \ay, lam thay doi dircmg kinh cung nhu sire cang tren thanh tinh mach trudng
3.9. Ket qud dieu tn
Sau mc)t thang dieu tri \di propranolol, chimg tiii diinh gia dap img dieu tri dua vao 3 tieu chi: (l)tinh trang xuat hu>et trong qua trinh dieu tri, (2)sir tha>' ddi ciia TMTTQ qua noi soi va (3) si,r tlia\ ddi ducmg kinh TMC tren sieu am, \ il thu dugc ket qua trong bang sau:
Bdng 3.7. Danh gia dap MuTc do dap u'ng Oap u'ng tot
Oap Ling viia Kh6ng dap iing
img dieu tri n 7 21
6
Ty le (O/o) 20.6 61.8 17.6
P
<0.01
Y HOC VIET NAM THANG 9 - SO DAC BIET/2011
Cd 6 benh nhan khdng dap img vdi dilu tri propranolol, chidm ty le 17.6%. Ty le dap img vdi propranolol la 82.35%, trong do dap irng t6t la 20.6%, dap u-ng \ua la 61.8%. Su khac biet co y nghTa thdng ke \ di p < 0.01.
Cac thudc chen beta giao cam khong chon loc (Non-selective beta blocker.s) lam giam ap lire he thdng tinh mach cira thong qua hai ca che:
(1): Tac dung chen p^-adreneric tren thanh cac ddng mach tang (dong mach than tang, cac dong mach mac treo) dSn tdi mk doi khang tac dung a-adreneric, gay co mach tang, do do lam giam luu lugng mau hoi luu
3.10. Cdc tdc dung phu cda propranolol Bdng 3.8. Cac tac dung phu cua propranolol
ve he thong TMC, va vi vay lam giam ap lire he thiing ttnh mach cira.
(2); Tiic dung chen [^-adreneric doi khang vdi tiic dung cua Catecholamine lam gicim nhip tim, giam sire co bop ca tim, giam cung lircrng tim va huyet ap he thong, gay co mach tang phan xa, do dd lam giam lun lugng mau hoi luu \e he thong TMC, vi viiy liim giam hem nua ap lire he thong tmh mach cira [3,6.7],
Cac tmh mach trircVng thuc quan va bien chimg xuiit huyet do vd TMTTQ deu la hau qua true tiep ciia tang ap cira. Thong qua ca che lam giam ap lire TMC, propranolol lam giam ty le xuat huyet
Tac dung phu
n Ty le %
Mach cham ( < 6 0 / m l n )
1 2.9
HA giam (<100mmHg)
1 2.9
Mach cham
& HA giam 4 11.8
Khac 1 2.9
To'ng 7 20.6
Trong qua trinh theo ddi dieu tri chung toi ghi nhan 7 benh nhan (20.6%) cd cac tac dung phu cua propranolol. Trong do mach cham <60/min ket hgp vdi huyet ap giam <
lOOmmHg chiem ty le cao nhdt (11.8%), mach cham dan thuan (2.9%), huyet ap giam dan thuan (2.9%), tac dung phu khac (met, mat ngu, chdng mat) gap d 1 benh nhan (2.9%). Cac benh nhan nay deu phai giam lieu propranolol, nhung khdng phai ngung dihu tri. Theo Hegab A.M. va Luketic V.A thi ty le cac benh nhan tang ap cira co cac tac dung phu khi dieu tri vdi propranolol la tir 3 27% [6].
IV. KET LUAN
Thdng qua tac dung lam giam ap lire tinh mach cira, propranolol lam giam ducmg kinh tinh mach cira tren sieu am, giam kich thudc ciia tmh mach trudng thuc quan qua npi soi, va giam nguy ca xuat huyet do vd tinh mach trudng thuc quan.
V KIEN NGHI
Nen chi dinh dieu tn propranolol cho cac benh nhan xa gan co tmh mach truchig thuc quan do 2 va do 3 (neu khong cd chong chi dinh) de du phong xuat huyet do vd tinh mach trucyng thuc quan.
HQI N G H ! K H O A HOC K? T H U A T Md RQNG L A N T H O X I I • B$NH VigN H O U NGHI V I E T NAM - CU B A D 6 N G H 6 |
TAI UEU THAM K H A O
1. Nfiiiyi-n IMimVc Bao Q i i i u i (2002), " X o gan;
I aiiL!, iip luc tinh mach cua" ,S'/<7/ dm hung tdiii^ipidt.lv. 71 - I 1 1; 211 216.
2. l)uon«» Hong Thiii, Danj; K i m O a n h , Nj;iiyon XTiii H i i n s , N m i v i n K h i u i h I'rach, Pham T h u Ho (2000), "Ngliicu ciiu hinh anh gian tTnh mach Ihtic quan o M.S iicnh nhim xo gan'' Thdng lin ) dirge .so dac hi^i chuyen dc tieu hod gan mat, tr. 55 58.
3. Hoang T r o n g T h a n g (2005), Vai tio cua thuoc chcn Beta trong dieu Iri du |ih6ng chay mau do gian tinh mach ih^rc quan" lap clii Y hoe tlurc hdnh .\('> dac hii't Hdi nghj lim mach mien trung mo rang Idn thir III, tr. 613 617.
4. Bolondi L., ct a l . (1982), "Ultrasonography in the diagnosis o f portal hypertention:
Diminished response o f portal vessels to respiration" Radiology. 142, pp. 827 - 832.
5. ( onn H . O . , Grace N.D., Bosch .J., et al.
(1991), "Propranolol in the prevention o f the llrsi hemorrhage from esophageal varices: A multiccntcr randomized clinical trial", llc/ialolagy. 13, pp. '^02 - 9 1 2 .
6. Hegab A . M . , L u k e t i c V . A . (2001),
"Bleeding esophageal varices: how to treat this dreaded complication of portal hypertention" Tostf^raduate medicine,
109(2), pp. 75 89.
7. .loshi N.G., Stanley A..J. (2005), "Update on the management o f variceal bleeding' Posli^raduate medicine, 132(1). pp. 174
188.
8. O r b a n - Schiopu A . M . , Popescu CR, (2003), "Long-term effects o f propranolol on portal pressure in cirrhosis patients" Rom J Gastoenterol, 12( I ) , pp. 25 30.
