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Scientific evidence for application of topical hemostats, tissue glues, and sealants in hepatobiliary surgery

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Page 1: Scientific evidence for application of topical hemostats, tissue glues, and sealants in hepatobiliary surgery

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COLLECTIVE REVIEWS

cientific Evidence for Applicationf Topical Hemostats, Tissue Glues,nd Sealants in Hepatobiliary Surgeryhomas W Kraus, MD, FACS, Arianeb Mehrabi, MD, Peter Schemmer, MD, Arash Kashfi, MD,

ascal Berberat, MD, Markus W Büchler, MD, FRCS

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orbidity after elective liver surgery has been markedlyeduced in hepatobiliary surgical centers, mainly because ofhe establishment of anatomically oriented resection tech-iques. Such techniques can reduce liver tissue necrosis,emorrhage, and bile leakage. Nevertheless, postoperativeleeding and bile leakage could not be completely pre-ented until now. Both factors are major determinants oforbidity after liver resection, encountered in 4% to 7% of

atients, and apparently very difficult to eradicate by con-entional surgical techniques for duct and vessel occlusionsutures, electrocoagulation, and clips).1 Despite taking allvailable intraoperative information into account, the indi-idual patient’s risk for rebleeding and particularly bileeakage from the hepatic resection surface during the post-perative course is hard to define at the time of operation.he adjunct application of an absorbable “dressing” to

over the raw resection surface and impose a watertightcclusive effect on vessels (blood, bile, lymphatic) and pa-enchymal microlesions, or to trigger clot formation, is anntriguing concept.

Driven by the goal to prevent complications, topicalgents are currently applied in many centers during liveresection or biliary reconstruction. A recent multicenternvestigation stated that topical agents were applied in0% of hospitals in Japan during liver surgery, withouttandardized indication. Most frequently used agentsere fibrin glues, oxidized cellulose, and collagen sheets.election of agents was neither dependent on center loador on resection technique.2 It can be assumed that theituation in Europe is comparable. Such widespread us-

resented at the 121st Congress of the German Society of Surgeons, Interna-ional Congress Center, Berlin, April 2004.

eceived June 29, 2004; Revised September 30, 2004; Accepted September0, 2004.rom the Department of General, Visceral, and Transplant Surgery, Univer-ity of Heidelberg, Heidelberg, Germany.orrespondence address: Thomas W Kraus, MD, FACS, Department ofeneral, Visceral, and Transplant Surgery, University of Heidelberg, INF

f10, 69120 Heidelberg, Germany.

4182005 by the American College of Surgeons

ublished by Elsevier Inc.

ge of topical hemostats, glues, and sealants in hepato-iliary surgery must be reviewed in sharp conflict with aeficit of scientific data to define indications and to doc-ment their clinical effectiveness.

ETHODSurrent indications for usage and choice of agents are het-

rogeneous, mostly based on the individual surgeon’s pref-rence. In addition, surgeons’ knowledge concerning phar-acodynamic characteristics and specific strengths of

roducts often appears to be rather poor. To evaluate theurrent status and evidence-based rationale for applicationf these agents in hepatobiliary surgery, a review of thevailable literature has been conducted.

All detected studies were differentiated according tocientific focus and quality. Study end points of topicalgent research in hepatobiliary surgery can focus eithern hemostatic or biliostatic effectiveness. Until now, theast majority of investigations have provided only dataoncerning hemostasis. Because of the potentially im-ense clinical impact of any proved effect of sealants on

iliostasis, these data were outlined in a separate section.A classification of study types should reflect the degree of

omparative, controlled analysis. We have separated basicxperimental research (designed to measure effects of com-onents on defined parameters: Type A study), purely de-criptive analysis of experimental or clinical experiencenoncomparative data:Type B study), and controlled, com-arative analyses of selected agents with respect to hemo-tatic, gluing, or sealant effectiveness (comparative data:ype C study).Type C studies were further divided into five

evels to reflect the progress of product development and,articularly, to outline if a direct comparison with alterna-ive agents was investigated.

ESULTStudies in hepatobiliary surgeryore than 2,300 publications are available in the various

ields of surgery regarding use of hemostats, glues, and seal-

ISSN 1072-7515/05/$30.00doi:10.1016/j.jamcollsurg.2004.09.047

Page 2: Scientific evidence for application of topical hemostats, tissue glues, and sealants in hepatobiliary surgery

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419Vol. 200, No. 3, March 2005 Kraus et al Hemostats, Glues, and Sealants in Liver Surgery

nts. A very limited number of studies that deliberatelyocused on applications in hepatobiliary and liver weredentified. No metaanalysis from the available randomizedeports was performed because the amount of existing dataas estimated as too little.Table 1 summarizes the scientificifferentiation of studies as described in detail in the follow-

ng text.

ype A studies—basic researchublished basic research models with a focus on hepaticpplication are scarce. Stenzl and colleagues3 cannulatedhe portal veins of excised rabbit livers 5 to 24 hours afterealing with fibrinogen/thrombin for volume load experi-ents. Up to 300 mmHg of portal pressure, no insuffi-

iency of the sealed surface was detected. These limitedxperiments stimulated clinical interest in the agents’ bilio-tatic potential. Bleeding from liver injuries in small animalodels could be effectively controlled with collagen fleece

pplication by triggering platelet aggregation.4,5

ype B studies—descriptive, noncomparative dataven sole descriptive, noncomparative data are very scarce

n liver surgery. The clinical significance of data remainsbscure in most studies of this type. A descriptive report onibrin glue application in liver surgery was given by Koeck-rling and associates;6 with the use of fibrin glue and otherechniques, center mortality after liver resection dropped

able 1. Overview of Type C Studies, which Reflect Levels oevel I Collagen

GelatinCellulose

vs not

evel II Collagen vs gelaevel III

Fibrinogen/thrombin combinationsvs notvs varivs � fvs � avs diff

Fibrinogen/thrombin � fleeceFibrinogen/thrombin/fluid matrix vs notSemisynthetic/synthetic sealants

evel IV CollagenGelatinCellulose

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evel VFibrinogen/thrombin combinations

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rom 11.5% (1960 to 1979) to 1.8% (1988 to 1992). It o

as advocated that fibrin glue is an effective aid for hemo-tasis and biliostasis, but with respect to the data presented,t remains unclear which contribution of topical agents hasdded to this achievement. Another report described these of fibrin glue in 98 patients with spleen and liverrauma. Here, fibrin glue successfully induced primary he-ostasis in 43 patients.7 Surgery in liver cirrhosis was ad-

ressed by Wakasugi and Shimada.8 Fibrin glue was appliedfter resection of hepatic cancer associated with cirrhosis insmall series of eight patients. Satisfactory hemostasis with-ut later abscess formation could be achieved in all cases.he use of fibrin glue, sprayed on the surface of living-

elated liver grafts before reperfusion, was described. Com-lete hemostasis could be achieved in this well-standardizedituation.9 Massive liver hemorrhage after liver rupturerom the HELLP (hemolysis, elevated liver enzymes, andow platelet count) syndrome could be successfully con-rolled after application of collagen fleeces coated with fi-rinogen; local packing was not sufficient.10 Clinical serieseporting technical sealing success rates up to 90% are alsovailable for needle tract occlusion after biopsy or interven-ional liver punctures.11

ype C studies—comparative dataype C studies deliver information on efficiency of seal-nts in direct comparison with no treatment control data

mparative Analysis of Topical Agents

vs cellulose

oncentrations of ingredientsXIIIninmodes of applications

n � thrombin combinationsn � thrombin � fleecen � thrombin � fluid matrixsealantsn � thrombin � fleecen � thrombin � fluid matrixsealantsn// vs Synthetic sealantsrix

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r in comparison with other topical agents. Of course,

Page 3: Scientific evidence for application of topical hemostats, tissue glues, and sealants in hepatobiliary surgery

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420 Kraus et al Hemostats, Glues, and Sealants in Liver Surgery J Am Coll Surg

fficiency of new sealants should be best evaluated inomparison with former therapeutic standards (“bestvailable agents”). Only this allows a valid estimation ofroduct progress and evolution. In order to differentiatehe scientific quality of studies with respect to the choicef control agents, different study levels were defined.

Level I and II studies. Level I and II studies investi-ate the efficiency of classical mechanical hemostatsompared with no treatment (Level I), and comparedith each other (Level II). These traditional agents haveo gluing or sealing capacity. No investigations are avail-ble in clinical hepatobiliary surgery, so data must bebtained from experimental analyses or clinical cardio-ascular trials. These data may be transferred with valid-ty in regard to liver surgery and conclusively affirm thatopical coagulation has improved. No superiority of anypecific material has so far been proved by direct com-arative analysis. Sealants with additional solid or solu-le matrix carriers are based on these results and aim tonhance their effects by adding gluing potential.

Level III studies. Level III studies investigate the ef-iciency of different families of hemostats with variablenherent degrees of sealing and gluing potential com-ared with untreated controls in experimental or clinicalettings. We have also integrated studies that analyze thempact of different concentrations of compositeibrinogen/thrombin, aprotinin, and factor XII into thisroup. Level III studies include investigation of differentenerations of topical agents; new generations do notecessarily imply improved efficiency.Obviously, a threshold degree or size of hepatic

rauma must exist to make any benefits of topical hemo-tats detectable. An impairment of systemic coagulationan shift this threshold. The application of fibrin seal-nts on a small liver surface trauma, such as the gallblad-er bed after cholecystectomy, had no effect on postop-rative peritoneal drainage volume in a randomizedomparison with no local treatment in 80 patients.12

iopsy channels are another form of minor, but well-tandardized liver trauma. An improved effectiveness ofibrin plugs after liver biopsies compared with untreatedontrols was shown in a porcine model with variousegrees of predefined anticoagulation.13 All other studiesere based on extended liver resections.The effect of a fibrin sealant for small vessel or bile

uct occlusion of hepatic surface planes has been dem-nstrated in a randomized prospective clinical study in

2 patients after variable forms of liver resection com- r

ared with untreated controls.14 Criteria for efficiencyncluded appearance of the liver margin at abdominallosure, volume, and bilirubin concentrations of drain-ge fluids. Average fluid drainage and bilirubin concen-ration during the first three postoperative days wereignificantly lower in patients treated with sealants. Noifference was found concerning hemoglobin concen-ration in drainage fluids. The appearance of the liverargin was judged dry in 97% of patients treated with

ealant, versus 81% of those without. Although a posi-ive hemostatic effect of sealant application was demon-trated, the incidence of subphrenic fluid collection wasot lower after fibrin glue application. Postoperativeorbidity was indifferent.14

One randomized multicenter trial investigated theemostatic efficiency of a fluid collagen matrix-basedealant compared with standard methods of surgical he-ostasis in a large panel of general, hepatic, cardiac, and

rthopaedic operations.15 Fifty-eight patients with vari-us forms of liver resection were included. Study endoints were the time required to achieve controlledleeding and percentage of complete hemostasis within0 minutes. “Superior hemostatic effectiveness” with theealant was realized in every specialty, including hepaticurgery; duration of bleeding was significantly shorter;nd no differences were detected between groups withegard to transfusion requirements. No data on morbid-ty and mortality were given.15

Level IV studies. Level IV studies compare the effi-iency of different families of hemostats with variablenherent degrees of sealing and gluing potential to anoptimized basic topical hemostasis,” using traditionalemostats, based on local tamponade and platelet stim-lation. This renders any comparative analysis of hemo-tatic efficiency more realistic because temporary appli-ation of low-cost cellulose, gelatin, or collagen can beeen as a basic technique to control bleeding in liverurgery. A well-conducted experimental study was pub-ished by Davidson and associates16 analyzing 34 pigsndergoing partial left hepatectomy by finger fracturender portal vascular inflow occlusion. Animals wereandomized to treatment of the resected surface withither fibrinogen/thrombin from pooled human plasma,xidized cellulose gauze, or they were left untreated. Me-ian blood loss from the resection margin was signifi-antly reduced with both types of fibrin glues comparedith controls. Time to hemostasis was also significantly

educed in both therapy groups. Differences between

Page 4: Scientific evidence for application of topical hemostats, tissue glues, and sealants in hepatobiliary surgery

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421Vol. 200, No. 3, March 2005 Kraus et al Hemostats, Glues, and Sealants in Liver Surgery

herapy groups were not significant. Animals were rein-estigated after 7 days. Intraabdominal fluid collections,dhesion formation, and histology of liver resection sur-ace were assessed; differences were insignificant. Onenimal treated with cellulose gauze presented with a sub-epatic bilioma. Standardization of the intervention andata sampling was outstanding compared with that inther studies. Data are given on the number of hepaticessels ligated, circumference of the resection margin,rea of the resection, wet weight of resected liver, andortal occlusion time. Adhesion formation was gradedy inspection. Because the sealant was prepared fromuman blood, reduced biocompatibility could have af-ected results.16

Chapman and coworkers17 have published a random-zed controlled clinical study (patients undergoing elec-ive hemihepatectomy or segmental resection, heteroge-eous indications, or liver trauma) comparing thefficiency of a composite of bovine microfibrillar colla-en and bovine thrombin mixed with autologous plasmauring operation to bleeding controls, managed with anbsorbable collagen sponge alone, and applied withanual pressure. Time to achieve controlled hemostasisas defined as the time that elapsed from the initial

pplication of either treatment or control interventionntil the bleeding from the exposed surface had slowedo a slight oozing and the time to complete hemostasisntil bleeding stopped entirely. Although all experimen-al group subjects achieved hemostasis within 10 min-tes, bleeding was controlled only in 70% of controlubjects within that time. Both median and total timeso complete hemostasis were statistically superior in thereatment group. It has to be stated that the type ofperation was rather heterogeneous, and it is not clearhether resection modes were homogeneously distrib-ted between groups. Three centers contributed 80% ofubjects. There were no differences regarding transfu-ion requirements.17

Another randomized trial compared the efficiency oflassical fibrinogen/thrombin glue with the applicationf collagen powder after various forms of elective liveresections in 62 patients.18 There were no significantifferences between the groups. Both methods showedimilar hemostatic effects. Primary hemostatic effi-iency, bile leakage, morbidity, and mortality were com-arable. A trend was noted that fibrin glue might reduce

iliary leakage. a

Level V studies. Level V studies compare modernatrix carrier-based and synthetic sealants with classical

omposite fibrin glues. Fluid fibrin glue products can beeen as the conventional gold standard, from their pastnd current frequency of application. Interestingly, onlyne rather preliminary clinical study of this importantype could be detected in the field of hepatobiliary sur-ery. In a randomized clinical investigation, Neuhausnd colleagues19 applied either conventional fibrinogen/hrombin glue or a solid matrix carrier (collagen fleecelus fibrinogen, aprotinin coating) on the hepatic rawurface of 60 patients undergoing various forms of elec-ive liver resections. Standardization of the patients wasood and the groups were comparable. Time to com-lete intraoperative hemostasis was identical in bothroups. On the other hand, there was a higher incidencef intraoperative rebleeding in the conventional fibrin-lue group (48% versus 9.6%), defined as an oozing ofhe liver surface. The clinical relevance of this temporaryntraoperative phenomenon was not demonstrated.

Experimental studies allow investigating adhesiveroperties of matrix carrier-based sealants. In vivo stan-ardized punch hole defects in the left lateral liver lobef rats were covered either with a fibrin glue–soakedeace of collagen, derived from pig skin by proteolyticreatment or covered by a collagen fleece alone.20 Fifteeninutes after insertion, the lobe was excised and me-

hanical pull-off experiments were performed with apecially designed apparatus. Fibrin-soaked collagenleeces demonstrated increased adhesive strength. Inter-stingly, distraction from liver parenchyma did not takelace at the parenchyma-fleece interface but amid theollagen sponge. Additionally, hemostatic potential wasnalyzed in anticoagulated rats, with or without porcineollagen for treatment of a standardized liver ruptureodel and after a partial left lateral lobe liver resection

40%). Animals treated with fibrin glue–soaked fleecesr fibrin glue alone were compared with animals withefect occlusion by catgut sutures. Fourteen-day survivalas significantly improved in fibrin glue and fibrin glue/

ollagen treated animals, compared with animals havingperation alone.20

Level VI studies. Level VI studies compare the effectsf various complex, active, and very heterogeneous phar-acodynamic approaches to hemostasis, sealing, and

luing, which also represent different generations of top-cal agents. Because former approaches primarily aimed

t hemostasis by induction of clot formation, mechani-
Page 5: Scientific evidence for application of topical hemostats, tissue glues, and sealants in hepatobiliary surgery

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422 Kraus et al Hemostats, Glues, and Sealants in Liver Surgery J Am Coll Surg

al sealing has come into major consideration. Untilow, there was no comparative clinical study in hepato-iliary surgery on this investigative level. Two compara-ive experimental studies have been conducted on theotential role of fibrin sealant dressings in experimental

iver injury in pigs, complicated by a dilutional and hy-othermic coagulopathy. Sealants were “home-esigned” and consisted of human fibrinogen, throm-in, and CaCl2, dried on a vicryl mesh packing.fficiency to induce hemostasis was compared with con-entional liver packing with gauze or an IgG-placebo-ressing. Blood loss in the fibrin sealant–dressing groupas significantly lower than in controls. One-hour sur-ival in the fibrin-dressing group was 83%, comparedith 0% in the other groups.21 In a subsequent study, theedian hepatic lobe was excised in pigs. Animals re-

eived a fibrin sealant foam (human fibrinogen andhrombin), IgG-placebo foam, or no treatment. Again,lood loss was significantly reduced in the treatmentroup. Thirty-minute survival was reported to be differ-nt but was not further specified.22

iliostatic efficiency of sealant applicationarious surgical sealants have been shown effective in aariety of settings, including air leaks after lung surgery;sophageal repairs; amnion membrane and dura materefects; and urinary, intestinal, and even pancreaticnastomoses. Given all the clinical data, which proclaimherapeutic sealing success on these operative fields, sur-ace sealing also appears to be a potentially interestingdjunct to biliary reconstruction and hepatic resection.nly a limited amount of work has been done so far in

valuating the potential of glues and sealants for treat-ent and prophylaxis of bile leakage in liver surgery.Couto and associates23 reported the principal applica-

ility of autologous fibrin sealants as an adjunct to su-ure closure of a choledochotomy subsequently placednder supraphysiologic pressures. Although no statisti-al tests were performed, a cessation of bile leaks aftersage of sealants was described. Another pure feasibilitytudy was undertaken by Kram and colleagues24 to testhether common bile duct anastomoses or defects coulde occluded with fibrin sealants. An experimental pri-ary end-to-end common bile duct anastomosis was

erformed in 10 dogs after sharp transection. Only twobsorbable sutures were used for each anastomosis, andhe anastomosis was covered with a self-made multicom-

onent fibrin glue. During glue application, the anasto- a

osis was temporarily stented internally. Examinationf specimens harvested 1 month after operation revealedomplete healing without significant inflammatory re-ponse. Only one dog presented with an anastomoticeak on cholangiography (time not identified). No con-rol group was investigated and information on the timeattern of postoperative reexamination was very sparse.he early bile duct leakage rate cannot be exactly defined

n this study.24

The feasibility and risk of laparoscopic choledochoje-unostomy in pigs by sole application of fibrin sealantas tested in another experimental investigation, com-aring results of open or laparoscopic choledochojeju-ostomy with sutured anastomosis. It is not clearhether circumferential application of the fibrin sealantas achieved, but the results showed a significant in-

rease in the bile leak rate in the fibrin sealant group.Theuthors concluded that the use of fibrin sealant de-reased operative time, with a reduced bile leakage rate.25

n a randomized controlled experimental study, a poly-thylene glycol/collagen biopolymer sealant was testedor its efficiency to seal a standardized one-sixth circum-erential anterior defect after incomplete end-to-endholedochocholedochostomy in pigs.26 Drains weresed to monitor leakage volume and bilirubin concen-ration. Cholangiography was performed on day 3 afterperation. The control group had a higher drainage out-ut rate over 4 postoperative days than the treatmentroup; 56% of controls and only 11% of treated animalsad a bile leak. The authors concluded that the sealantas effective in decreasing the incidence of bile leaks.26

Indirect data come from two clinical analyses, notrimarily designed to analyze biliostatic efficiency ofealants. To evaluate whether injection of isotonic so-ium chloride solution through the cystic duct is helpfulo detect intraoperative bile leakage and thereby preventostoperative leakage after liver resection (leakage test),03 patients were investigated in a randomized trial.27

o advantage could be found for the test. Postoperativeile leakage was observed in 6% in the test and 4% in theontrol group, defined as continuous drainage with ailirubin level of 86 �mol/L or more beyond 1 week.nterestingly, fibrinogen/thrombin glue had beenprayed over the transected surface in both groups. Onean conclude that fibrin sealing could not prevent bileeakage from the cut surface with certainty. On the otherand, the routine application of fibrin glue can be seen

s a methodologic pitfall of this study because minor,
Page 6: Scientific evidence for application of topical hemostats, tissue glues, and sealants in hepatobiliary surgery

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423Vol. 200, No. 3, March 2005 Kraus et al Hemostats, Glues, and Sealants in Liver Surgery

urgically noncorrectable bile duct lesions could haveeen sealed, preventing leakage rate differences betweenroups.27

In another large clinical investigation, the leakage test,n contrast, was found to be significantly correlated tohe incidence of postoperative bile leakage after liveresection. In this study, fibrin-glue application again waspplied in some (194 of 616) patients investigated; 7.8%f patients with glue and 4.7% without fibrin-glue ap-lication presented with bile leakage. The difference wastatistically insignificant. In accordance with the studyy Kohno and coworkers,18 application of fibrin glue hasdded no proved benefit with respect to biliostasis. Fi-ally, fibrin glue was sprayed for hemostatic and bilio-tatic prophylaxis on the cut surface of partial living-elated liver grafts. Although complete hemostasis in thisituation could be achieved, 3 of 70 livers showed someile leakage. We have to assume that even under optimalonditions, absolute biliostatic security could not bechieved after application of fluid fibrinogen/thrombinlue.9

ISCUSSIONemostatic efficiencyith regard to the vast literature on glues, sealants, and

opical hemostats in operative medicine, there is littleoubt that positive hemostatic effects can be achievedith a beneficial impact on blood loss. The often largeariation in efficiency detected when comparing studiesan be derived from the diversity of agents applied, theather heterogeneous compositions of classical fibrinlues tested, poor standardization of application tech-iques, and, especially, from differences in clinical set-ings. Most clinical data so far were derived from cardio-ascular surgery. The single trial that has provided theost significant data regarding hemostatic efficiencyas published by Rousou and associates.28 In this mul-

icenter randomized clinical trial, 333 patients undergo-ng emergency cardiac reoperation were randomized toreatment with classical fibrinogen/thrombin sealant orther conventional topical hemostatic agents (study typeII). Ninety-two percent of patients randomized to re-eive fibrin sealant had complete hemostasis at 5 min-tes, compared with only 12% treated with conven-ional topical hemostats. Data on transfusion were notvailable.28

In contrast to this well-defined, but rather extreme

urgical situation, a systematic metaanalysis of all ran- m

omized controlled trials was conducted to examine thefficiency of fibrin sealants in reducing perioperativelood loss and transfusions. Studies were recruited fromll fields of surgery. Only 12 trials have met the inclusionriteria (adult surgery, quantitative data on blood loss,nd transfusion). All studies were small, with fewer than0 participants in each arm. Sealant application resultedn a mean reduction of blood loss of 150 mL per patient,ith most of the benefit in the postoperative period.ibrin sealants were found to have reduced the rate oflood transfusion by about 0.6 units per patient. Thebserved variation was generally in terms of size, notirection of treatment. The authors pointed out thatven these results must be interpreted with caution, be-ause of the often poor quality of trials, in particular,ecause of a lack of blinding and the regular use of a veryubjective key measure, the decision to transfuse.29

The efficiency of sealants in promoting hemostasis isifficult to quantify in clinical practice for both practicalnd ethical reasons. The effect on total perioperativelood loss can only be indirectly inferred from drainutput and the number of units transfused. During op-rations, the speed of hemostasis was the investigativend-point parameter most often used. On the otherand, this parameter appears to be of minor impact onurgical decision making, because no correlation withlinical outcomes or treatment costs has ever beenhown. No proof is available demonstrating that the in-idence of postoperative rebleeding after liver resectionan be reduced by prophylactic surface sealing. The vol-me of blood loss during hepatic surgery is dependentn many factors, including systemic coagulation, under-ying disease that required operation, complexity andype of operation, surgeon’s expertise, central venousluid load, local hemodynamics (influenced by anesthe-ia), time to induce hemostasis after resection, and, fi-ally, the bias to prove effectiveness of agents under in-estigation. Although there was usually standardizationnd comparability of coagulation characteristics, stan-ardization of other factors was usually poor or evenndefined. No data on hepatic hemodynamics werevailable in previous investigations on the topic.

In this scenario, it is even more difficult to work outpecific differences between the topical agents currentlyvailable. From a marketing point of view, it is not sur-rising that most studies have only compared moderngents with no treatment controls or basic contact he-

ostats so far (cellulose, gelatin, or collagen). Direct
Page 7: Scientific evidence for application of topical hemostats, tissue glues, and sealants in hepatobiliary surgery

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omparison of modern topical agents has not been pub-ished in the field of hepatobiliary surgery. Even the rel-vance of additional mechanical dressings coated withibrin sealant as a dry layer to an absorbable matrix suchs collagen or synthetic polymers currently remains un-lear. There are no standardized assays yet on which toase the mechanical performance of these products.Ten-ile strength and wound strength have been measured inxperimental models for some products, but these fea-ures are irrelevant for many clinical indications.

iliostatic efficiency“watertight” sealing of small, undetected bile duct lesionsould be a great benefit in hepatobiliary surgery. The po-

ential of mechanical occlusion has been well demonstratedn various settings. Most experience has been gained ineurosurgery and pulmonary surgery. Nevertheless, it muste assumed that these results cannot be directly applied tohe biliary system. The variable type and aggressiveness ofifferent body fluids probably have to be taken into ac-ount. Leakage of bile and pancreatic juices should be farore difficult to control than leakage of pulmonary air or

f cerebral fluids. Additionally, in contrast to bleeding, bileeakage and its volume are far more difficult to define, toetect, and, particularly, to quantify. A number of criteriaave been used so far to establish bile leaks, such as rate ofutput volume, overall output volume, drain output bili-ubin concentration in comparison with serum bilirubinoncentration, and extravasation on cholangiography.easuring the degree of mechanical support (pressure pro-

iles, occlusive efficiency) offered by sealants could be anlternative scientific model. Mechanical support cannot beuantified with such techniques in human subjects for eth-cal reasons. Consequently, animal models are required forhis purpose. It remains to be shown that such experimentsave predictive value for the clinical situation in vivo, wheregents are biodegraded so bile leakage prevention from seal-ng can be altered or lost as time goes by. Looking at the veryimited number of available reports and studies, which fo-us on biliostasis from glues or sealants, we conclude thato evidence at all is currently available to support that aeduction of bile leakage can be achieved with the help ofhe agents investigated. Most importantly, no protocol haset demonstrated absolute protection from bile leakage af-er liver surgery.

To summarize, differences in outcomes after usage ofealants with respect to fluid leakage and prophylaxis of

ebleeding are the results of a complex interaction of t

ultiple factors. The prevailing shortage of scientificvidence, despite the enormous number of studies pub-ished, sheds light on the rather low quality of mosteports and studies that currently exist.

The specific potential of single groups of agents withegard to gluing, topical hemostasis, and sealing ofteniffers strongly. Although many surgeons (including au-hors in previous studies) incorrectly used the term tissuelue for very different forms of topical agents, it shoulde stressed that available substances, materials, androducts should strictly be seen in a differentiated way tooster optimal usage according to the specific inherenttrengths and potentials of these products. This shouldlso be reflected in all comparative future research.

Well designed, large, methodologically rigorous stud-es with clinical outcomes measures are needed to iden-ify advantages and shortcomings of topical formula-ions relative to each other and to competitive surgicalechniques, such as argon laser or mechanical woundupport, including surgical staplers. Suggestions on per-orming a randomized clinical trial in a multiinstitu-ional setting with definition of standardized study pa-ameters are outlined in the Appendix. Participatingurgeons cannot be blinded by the distinctive nature ofach material, allowing for bias of results. Conservativeethods should be used for evaluation of results. Each

ubject should contribute a single piece of data of therimary statistical analysis. This approach should be fa-ored as statistical methods that are based on commonrobability distributions, assuming independent obser-ations (no sample size inflation).

Standardization of baseline conditions is a prerequi-ite for detecting minor or marginal effects of adjunctiveeasures or processes. In this sense, future scientific

reatment protocols analyzing topical sealing agentsust first concentrate on an optimized standardization

f study conditions. This has only been realized in amall minority of investigations so far.

Hemostatic efficiency is hard to quantify.The often used0-minute primary efficiency end point is arbitrary. It isuestionable whether this end point has any clinical rele-ance or correlation. Authors have stated that it was selectedeliberately as a safety trigger to initiate alternative treat-ent if either study intervention failed to provide adequate

emostasis. Crossover pathways should be added to all fu-ure studies with this focus. It implies that hemostatic ef-ects should also be measured in patients, where conven-

ional techniques or other agents were found to be
Page 8: Scientific evidence for application of topical hemostats, tissue glues, and sealants in hepatobiliary surgery

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neffective after failure of the first line hemostatic agent.his has never been described so far.Modern research on surface sealants, hemostats, and

lues should have a strict comparative design. Only thenill this help surgeons identify the most effective topical

ool. Until now, most trials have been descriptive. If com-arative, most investigations have only compared topicalgents with untreated controls or solid collagen, cellulose,r gelatin matrices. Not surprisingly, many of these studiesere able to prove superiority of the agents tested over quite

raditional substances. Only very limited data can be de-ived from direct comparisons of modern multicomponentgents with strong sealant potential so far (level VI studies).t has to be stressed that no such data are yet available in theield of hepatobiliary surgery.

There is no real proof for biliostatic efficiency of top-cal sealing agents tested in the literature so far. Thisppears to be primarily a consequence of limited scien-ific interest in the topic. Detection of biliostatic effi-iency has only been a collateral investigative parametern the past. No clinical study has ever focused on thisotentially important clinical parameter. Experimentaltudies have investigated only leakage of bile duct recon-tructions in very preliminary settings. With the avail-bility of modern sealants, this research focus must beevitalized. We assume that this will be a primary targetf sealant research in the future.

Despite the current shortage of evidence about the effi-iency of sealant usage in hepatobiliary surgery, surgeonsill probably continue to use topical hemostats. Surgeonsill apply hemostats and sealants particularly when bleed-

ng cannot be controlled by conventional methods. In theseritical situations, action will be guided by the basic princi-le of trial and error. The presumably, often good experi-nces, derived from such potentially dangerous situationsy means of topical hemostats, appear to be the major stim-lus for use in extended indications (ie, for prophylacticurposes). So far, the extrapolation has not yet met withufficient scientific ground, so let us work on it.

ppendixuggested Study Features for General Assessmentnd Evaluation of Hemostats and Sealants withespect to Hemostasis and Biliostasis inepatobiliary Surgeryample size calculation

Considering sensitivity of sample size to success ratios

f agent application s

Most questions will need a multiinstitutional settingDefinition and documentation of patient characteristicsAge, gender, concomitant illnessesPreoperative septic symptomsRandomization of patients after eligibility screeningIntraoperative timing of randomization before

esectionExclusion criteriaPreexistent coagulation disordersAllergic reactions against thrombin, collagen, or hu-an fibrinogenLiver cirrhosis, previous liver surgeryEmergency surgery, major intraoperative bleeding

ncidentsBlinded usage of agentsNot feasible for most comparisons between agents

ecause of specification of applicationsStandardization of liver resectionClosed designs favoredElective surgery: anatomic resections suggested and

o atypical resectionsSurgical experience of the surgeonsExact definition of resection technique for the paren-

hymal phase:

Stapler, ultrasonic liver tissue dissector, etc

With or without use of argon-beamer

Count of surgical clips, stitch sutures, and vessel ligations

Mattress sutures performed before agent application(yes/no)

Description of additional surgical bleeding controlStandardization of hepatic inflow/outflow control

no Pringle maneuver is favored)Standardization of postoperative drainage protocol,

rainage time, and drain typesLiver resection surface parametersExact measurement of resection area and resection

olumeLiver parenchyma consistencyLiver histology (degree of fibrosis, fatty degeneration)

efore liver resectionHepatic and systemic hemodynamics before and after

esectionQuantification of liver perfusion (portal venous flow,

epatic artery flow, liver parenchymal microperfusion);ever realized so far and would be optimal for

tandardization
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426 Kraus et al Hemostats, Glues, and Sealants in Liver Surgery J Am Coll Surg

Quantification of systemic perfusion (including cen-ral venous pressure)

Mode and technique of agent applicationExact standardization of agent type, volume, size,

ompression times, etcExact definition of application mode, training of

urgeonsCharacterization of systemic coagulationExclusion of preexisting, preoperative coagulation

isordersPre- and postoperative coagulation testsChoice of comparator agentNo treatment control (only best surgical technique

vailable, electrocoagulation, argon-beamer, compres-ion, etc)

Conventional thrombocyte adhesion stimulationcollagen, oxygenated cellulose)

Modern generation sealants of choiceDefinition of study parameters “hemostatic”A) Primary efficiency variablesTime to hemostasis (intraoperative)Proportion of patients with hemostasis at 10/20 etcinutes after agent applicationLife table estimates for time to hemostasis, ie, fraction

f patients still bleeding at a given timeBlood loss until hemostasis (volume, hemoglobin, he-atocrit, etc)B) Secondary efficiency variablesBlood loss in the postoperative course after resectionTransfusion requirements, specification of transfu-

ion criteriaDrainage volume per day, hemoglobin concentration

n drain fluid per daySonography/CT scans for assessment of fluid

ollectionClinical followup (hematocrit, leukocyte count, etc)Mortality and morbidity

Surgical: wound infection, abscess, bilioma, biliary tractcomplications etc

Internal: pneumonia, pleural effusion, liver dysfunction,side effects of sealants

Center-specific analysisOptional, could show homogeneity of trendsDefinition of study parameters “biliostatic”A) Primary efficiency variablesOccurrence of biliary leakage after liver surface

ealing

Biliary leakage in postoperative course after resectionSonography and/or CT scan for assessment of fluid

ollectionsDrainage volume per day, bilirubin concentration in

rain fluid per dayB) Secondary efficiency variablesClinical followupMortality and morbidity (wound infection, abscess,

ilioma, biliary tract complications etc)

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