MD1394Z - Method for endoscopic hemostasis of variceal hemorrhages in liver cirrhosis - Google Patents
Method for endoscopic hemostasis of variceal hemorrhages in liver cirrhosis Download PDFInfo
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- MD1394Z MD1394Z MDS20190069A MDS20190069A MD1394Z MD 1394 Z MD1394 Z MD 1394Z MD S20190069 A MDS20190069 A MD S20190069A MD S20190069 A MDS20190069 A MD S20190069A MD 1394 Z MD1394 Z MD 1394Z
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- variceal
- solution
- hemorrhages
- liver cirrhosis
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- 208000032843 Hemorrhage Diseases 0.000 title claims abstract description 17
- 230000023597 hemostasis Effects 0.000 title claims abstract description 13
- 208000019425 cirrhosis of liver Diseases 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims description 13
- 102000008946 Fibrinogen Human genes 0.000 claims abstract description 13
- 108010049003 Fibrinogen Proteins 0.000 claims abstract description 13
- 229940012952 fibrinogen Drugs 0.000 claims abstract description 13
- 108010039627 Aprotinin Proteins 0.000 claims abstract description 12
- 108090000190 Thrombin Proteins 0.000 claims abstract description 12
- 229960004405 aprotinin Drugs 0.000 claims abstract description 12
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 claims abstract description 12
- 229960004072 thrombin Drugs 0.000 claims abstract description 12
- 108010080379 Fibrin Tissue Adhesive Proteins 0.000 claims abstract description 9
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims abstract description 5
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 claims abstract description 5
- 229960004755 ceftriaxone Drugs 0.000 claims abstract description 5
- 229960004194 lidocaine Drugs 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 11
- 210000003462 vein Anatomy 0.000 claims description 3
- 206010046996 Varicose vein Diseases 0.000 abstract description 9
- 208000000624 Esophageal and Gastric Varices Diseases 0.000 abstract description 5
- 208000027185 varicose disease Diseases 0.000 abstract description 5
- 206010051012 Gastric varices Diseases 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 abstract 1
- 229910001628 calcium chloride Inorganic materials 0.000 abstract 1
- 239000001110 calcium chloride Substances 0.000 abstract 1
- 229960002713 calcium chloride Drugs 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 17
- 208000034158 bleeding Diseases 0.000 description 7
- 230000000740 bleeding effect Effects 0.000 description 7
- 108010073385 Fibrin Proteins 0.000 description 6
- 102000009123 Fibrin Human genes 0.000 description 6
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 6
- 229950003499 fibrin Drugs 0.000 description 6
- 244000005700 microbiome Species 0.000 description 5
- 230000005945 translocation Effects 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- 238000006116 polymerization reaction Methods 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 208000007232 portal hypertension Diseases 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 108010071289 Factor XIII Proteins 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- 108010051456 Plasminogen Proteins 0.000 description 2
- 102000013566 Plasminogen Human genes 0.000 description 2
- 206010056091 Varices oesophageal Diseases 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000024170 esophageal varices Diseases 0.000 description 2
- 201000010120 esophageal varix Diseases 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- 230000002008 hemorrhagic effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 206010005144 Bleeding varicose vein Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940105784 coagulation factor xiii Drugs 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940012444 factor xiii Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 201000001231 mediastinitis Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000007632 sclerotherapy Methods 0.000 description 1
- 229960000776 sodium tetradecyl sulfate Drugs 0.000 description 1
- UPUIQOIQVMNQAP-UHFFFAOYSA-M sodium;tetradecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCOS([O-])(=O)=O UPUIQOIQVMNQAP-UHFFFAOYSA-M 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Invenţia se referă la medicină, în special la hemostaza endoscopică a hemoragiilor din varice esofago-gastrice în caz de ciroză hepatică. The invention relates to medicine, in particular to endoscopic hemostasis of bleeding from esophageal-gastric varices in case of liver cirrhosis.
Este cunoscută metoda de hemostază endoscopică a hemoragiilor variceale cirogene cu utilizarea soluţiei alcoolice de tetradecil sulfat de sodiu, care provoaca sclerozarea vasului [1]. The method of endoscopic hemostasis of surgical variceal hemorrhages using an alcoholic solution of sodium tetradecyl sulfate, which causes vessel sclerosis, is known [1].
Dezavantajul metodei de sclerozare a varicelor consta în neeficacitatea utilizării ei în cazul varicelor de calibru mare, provocând dureri pronunţate după utilizare şi în unele cazuri necroze locale cu complicaţii severe şi anume perforaţii ale esofagului, mediastinite, iar la nivel sistemic poate duce la translocarea microorganismelor cu declanşarea stărilor septice. The disadvantage of the varicose vein sclerotherapy method is its ineffectiveness in the case of large varicose veins, causing severe pain after use and in some cases local necrosis with severe complications, namely perforations of the esophagus, mediastinitis, and at a systemic level it can lead to the translocation of microorganisms with the triggering of septic conditions.
Este cunoscută metoda de hemostază a hemoragiilor variceale, care constă în aplicarea ligaturilor elastice cu ajutorului unui dipozitiv de aplicare a ligaturilor elastice fixat pe endoscop [2]. The method of hemostasis of variceal hemorrhages is known, which consists of applying elastic ligatures with the help of an elastic ligature application device fixed to the endoscope [2].
Dezavantajele metodei menţionate constau în aceea că ligaturile elastice nu pot fi aplicate în cazul sângerărilor din varicele gastrice fundice, din cauza posibilităţilor reduse de manevrare ale aplicatorului endoscopului, iar în cazul varicelor de calibru mare (>1 cm) în timpul aplicării ligaturilor poate fi lezat peretele varicelui cu provocarea unei hemoragii abundente, iar la nivel sistemic poate duce la translocarea microorganismelor cu declansarea stărilor septice. The disadvantages of the mentioned method are that elastic ligatures cannot be applied in the case of bleeding from fundic gastric varices, due to the limited maneuverability of the endoscope applicator, and in the case of large-caliber varices (>1 cm) during the application of ligatures, the variceal wall may be damaged, causing profuse bleeding, and at the systemic level it may lead to the translocation of microorganisms, triggering septic conditions.
Este cunoscută metoda de utilizare a adezivului fibrinic pentru hemostaza endoscopică a hemoragiilor variceale în ciroza hepatică, care este compus din fibrinogen, factorul XIII de coagulare, fibronectină, plasminogen şi aprotinină, care se amestecă cu soluţie de trombină şi clorură de Ca+2 în următorul raport al componentelor la 1 ml: The method of using fibrin glue for endoscopic hemostasis of variceal hemorrhages in liver cirrhosis is known, which is composed of fibrinogen, coagulation factor XIII, fibronectin, plasminogen and aprotinin, which is mixed with thrombin and Ca+2 chloride solution in the following ratio of components per 1 ml:
fibrinogen (mg) 70...110 factorul XIII (IU) 10...50 fibronectină (mg) 2...9 plasminogen (mg) 20...120 aprotinină (KIU) 3000 trombină (IU) 500 clorură de Ca+2 (µmol) 40 [3].fibrinogen (mg) 70...110 factor XIII (IU) 10...50 fibronectin (mg) 2...9 plasminogen (mg) 20...120 aprotinin (KIU) 3000 thrombin (IU) 500 Ca+2 chloride (µmol) 40 [3].
Dezavantajul adezivului fibrinic cunoscut constă în aceea că polimerizarea lui are loc imediat după combinarea componentelor, ceea ce nu permite introducerea lui în lumenul varicelui sângerând prin cateterul de injectare al endoscopului lung de 150 cm, datorită polimerizării rapide a compusului cu obturarea lumenului cateterului, aderarea slabă la peretele vascular cu riscul expulzării spontane a cheagului fibrinic, iar la nivel sistemic poate duce la translocarea microorganismelor cu declansarea stărilor septice. The disadvantage of the known fibrin glue is that its polymerization occurs immediately after combining the components, which does not allow its introduction into the lumen of the bleeding variceal vein through the injection catheter of the 150 cm long endoscope, due to the rapid polymerization of the compound with the obstruction of the catheter lumen, poor adhesion to the vascular wall with the risk of spontaneous expulsion of the fibrin clot, and at the systemic level it can lead to the translocation of microorganisms with the onset of septic conditions.
Este cunoscută metoda de hemostază endoscopică a hemoragiilor variceale prin utilizarea adezivului fibrinic, care include soluţie de fibrinogen, care se amesteca cu soluţie de aprotinină, trombină şi clorură de Ca+2 în următorul raport al componentelor la 1 ml: The method of endoscopic hemostasis of variceal hemorrhages is known by using fibrin glue, which includes fibrinogen solution, which is mixed with aprotinin, thrombin and Ca+2 chloride solution in the following ratio of components per 1 ml:
fibrinogen (mg) 15...30 aprotinină (KIU) 250...1000 trombină (IU) 25...100 clorură de Ca+2(µmol) 15...30 adrenalină (mg) 0,1...0,3 [4].fibrinogen (mg) 15...30 aprotinin (KIU) 250...1000 thrombin (IU) 25...100 Ca+2 chloride (µmol) 15...30 adrenaline (mg) 0.1...0.3 [4].
Dezavantajele metodei constau în aceea că la injectarea componentelor adezivului în varicele sângerând cu formarea cheagului fibrinic poate surveni expulzarea spontană a cheagului din lumenul vasului din cauza presiunii venoase mari şi aderenţei reduse a cheagului de peretele vascular. The disadvantages of the method are that when injecting the adhesive components into bleeding varicose veins with the formation of a fibrin clot, spontaneous expulsion of the clot from the vessel lumen may occur due to high venous pressure and reduced adhesion of the clot to the vascular wall.
Problema invenţiei constă în elaborarea unei metode de hemostază endoscopică a hemoragiilor variceale în ciroza hepatică cu utilizarea adezivului fibrinic, care permite o hemostază eficientă cu evitarea expulzării spontane a cheagului fibrinic datorită unei aderări eficiente de peretele vascular cu evitarea recidivelor hemoragice şi totodată profilaxia complicaţiilor septice, care pot fi cauzate de translocarea microorganismelor. The problem of the invention consists in developing a method of endoscopic hemostasis of variceal hemorrhages in liver cirrhosis using fibrin glue, which allows for effective hemostasis while avoiding spontaneous expulsion of the fibrin clot due to effective adhesion to the vascular wall, avoiding hemorrhagic relapses and at the same time preventing septic complications, which can be caused by the translocation of microorganisms.
Esenţa invenţiei constă în aceea că endoscopic se injectează în lumenul varicelui o soluţie de ceftriaxon 0,5...1,0 g, dizolvat în 5,0...10,0 ml solutie de lidocaină de 2%, apoi se introduc concomitent componentele unui adeziv fibrinic şi anume, primul component include o soluţie de fibrinogen, iar al doilea component include un amestec de soluţii de aprotinină, trombină si clorură de Ca+2, în următorul raport al componentelor la 1 ml: The essence of the invention consists in endoscopically injecting into the lumen of the varicose vein a solution of ceftriaxone 0.5...1.0 g, dissolved in 5.0...10.0 ml of 2% lidocaine solution, then simultaneously introducing the components of a fibrin adhesive, namely, the first component includes a fibrinogen solution, and the second component includes a mixture of aprotinin, thrombin and Ca+2 chloride solutions, in the following ratio of components per 1 ml:
fibrinogen (mg) 15...30 aprotinină (KIU) 250...1000 trombină (IU) 25...100 clorură de Ca+2(µmol) 15...30.fibrinogen (mg) 15...30 aprotinin (KIU) 250...1000 thrombin (IU) 25...100 Ca+2 chloride (µmol) 15...30.
Rezultatul invenţiei constă în aceea că metoda revendicată permite o hemostază eficientă cu evitarea expulzării spontane a cheagului fibrinic, datorită unei aderări eficiente de peretele vascular cu evitarea recidivelor hemoragice şi totodată profilaxia complicaţiilor septice, care pot fi cauzate de translocarea microorganismelor. The result of the invention is that the claimed method allows for efficient hemostasis while avoiding spontaneous expulsion of the fibrin clot, due to efficient adhesion to the vascular wall, avoiding hemorrhagic relapses and at the same time preventing septic complications, which may be caused by the translocation of microorganisms.
Metoda se efectuează în modul urmator: pacientului diagnosticat cu hemoragie din varicele esofagiene în cazul hipertensiunii portale cauzate de ciroza hepatică i se efectuează lavajul gastric, apoi examenul endoscopic, apoi prin intermediul unui cateter introdus prin canalul de lucru al endoscopului se injectează în lumenul varicelui o soluţie de ceftriaxon 0,5...1,0 g, dizolvat în 5,0...10,0 ml solutie de lidocaină de 2%, apoi se introduc concomitent componentele unui adeziv fibrinic şi anume, primul component include o soluţie de fibrinogen, iar al doilea component include un amestec de soluţii de aprotinină, trombină si clorură de Ca+2, în următorul raport al componentelor la 1 ml: The method is performed as follows: the patient diagnosed with bleeding from esophageal varices in the case of portal hypertension caused by liver cirrhosis undergoes gastric lavage, then an endoscopic examination, then through a catheter inserted through the working channel of the endoscope, a solution of ceftriaxone 0.5...1.0 g, dissolved in 5.0...10.0 ml of 2% lidocaine solution, is injected into the lumen of the variceal vein, then the components of a fibrin adhesive are simultaneously introduced, namely, the first component includes a fibrinogen solution, and the second component includes a mixture of aprotinin, thrombin and Ca+2 chloride solutions, in the following ratio of components per 1 ml:
fibrinogen (mg) 15...30 aprotinină (KIU) 250...1000 trombină (IU) 25...100 clorură de Ca+2(µmol) 15...30.fibrinogen (mg) 15...30 aprotinin (KIU) 250...1000 thrombin (IU) 25...100 Ca+2 chloride (µmol) 15...30.
Soluţia de fibrinogen se aspiră într-o seringă, celelalte componente în combinaţie în altă seringă, care se injectează separat printr-un cateter trifurcat la capătul proximal. În interiorul cateterului ambele componente se combină, iniţiindu-se procesul de polimerizare cu formarea unui compus geliform, iar în interiorul varicelui are loc finisarea procesului de polimerizare cu formarea cheagului fibrinic stabil şi bine fixat de peretele vascular, care obturează lumenul vasului cu realizarea unei hemostaze eficiente şi o profilaxie a complicaţiilor septece. The fibrinogen solution is drawn into a syringe, the other components in combination into another syringe, which is injected separately through a trifurcated catheter at the proximal end. Inside the catheter, both components combine, initiating the polymerization process with the formation of a gel-like compound, and inside the varicose vein, the polymerization process is completed with the formation of a stable fibrin clot well fixed to the vascular wall, which occludes the lumen of the vessel with the achievement of effective hemostasis and prophylaxis of septic complications.
Metoda revendicată a fost utilizată la 236 pacienţi cu ciroză hepatică şi hipertensiune portală cu hemoragii variceale. The claimed method was used in 236 patients with liver cirrhosis and portal hypertension with variceal bleeding.
Exemplu Example
Pacienta C., 51 de ani, spitalizată în secţia chirurgie cu diagnosticul: Hemoragie profuză variceală. Şoc hemoragic gr.I. Ciroză hepatică HBV+D subcompensată, Child B (8). Hipertensiune portală gr. III. S-a efectuat fibroesofagogastroscopia, unde s-au stabilit varice esofagiene de gr. III în 1/3 inferioară al esofagului. Varicele peretelui anterio-medial cu o ruptură de 0,3 cm cu hemoragie în jet, Forrest Ia. S-a efectuat hemostaza endoscopică prin injectarea în lumenul varicelui de o soluţie de ceftriaxon 0,5 g dizolvată în 5,0 ml soluţie de lidocaină de 2%, apoi s-au introdus concomitent componentele adezivului fibrinic şi anume, primul component soluţia de fibrinogen, iar al doilea component amestecul de soluţie de aprotinină, trombină şi clorură de Ca+2. Patient C., 51 years old, hospitalized in the surgery department with the diagnosis: Profuse variceal hemorrhage. Hemorrhagic shock gr.I. Subcompensated HBV+D liver cirrhosis, Child B (8). Portal hypertension gr. III. Fibroesophagogastroscopy was performed, where esophageal varices of gr. III were established in the lower 1/3 of the esophagus. Varicose veins of the anteromedial wall with a 0.3 cm rupture with jet hemorrhage, Forrest Ia. Endoscopic hemostasis was performed by injecting into the lumen of the variceal a solution of ceftriaxone 0.5 g dissolved in 5.0 ml of 2% lidocaine solution, then the components of the fibrin glue were simultaneously introduced, namely, the first component the fibrinogen solution, and the second component the mixture of aprotinin, thrombin and Ca+2 chloride solution.
După injectare s-a obţinut formarea unui cheag fibrinic stabil şi bine fixat în lumenul variceal cu stoparea definitivă a hemoragiei. Varicele restante au fost de asemenea ocluzionate cu adeziv. After injection, a stable and well-fixed fibrin clot was formed in the varicose vein lumen, definitively stopping the bleeding. The remaining varicose veins were also occluded with adhesive.
Totodata, la pacientă nu s-au dezvoltat complicaţii septice. Externata peste 8 zile în stare satisfăcătoare. At the same time, the patient did not develop septic complications. She was discharged after 8 days in satisfactory condition.
1. Paquet K.J., Kuhn R. Prophylactic Endoscopic sclerotherapy in Patients with Liver Cirrhosis, Portal Hypertension and Esophageal Varices.- Hepato-Gastroenterology, 1997. no.44, p. 625-636 1. Paquet K.J., Kuhn R. Prophylactic Endoscopic sclerotherapy in Patients with Liver Cirrhosis, Portal Hypertension and Esophageal Varices.- Hepato-Gastroenterology, 1997. no.44, p. 625-636
2. Yoshida, H, Mamada, Y, Taniai, N, Yamamoto, K, Kawano, Y, Mizuguchi, Y, et al. A randomized trial control trial of bimonthly versus biweekly endoscopic variceal ligation of esophageal varices. Am. J. Gastroenterol., 2005, no.100, p. 2005-2009 2. Yoshida, H, Mamada, Y, Taniai, N, Yamamoto, K, Kawano, Y, Mizuguchi, Y, et al. A randomized control trial of bimonthly versus biweekly endoscopic variceal ligation of esophageal varices. I have. J. Gastroenterol., 2005, no.100, p. 2005-2009
3. AT 359652 1980.04.15 3. AT 359652 1980.04.15
4. MD 2328 F1 2003.12.31 4. MD 2328 F1 2003.12.31
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|---|---|---|---|
| FG9Y | Short term patent issued | ||
| KA4Y | Short-term patent lapsed due to non-payment of fees (with right of restoration) |