560 burns 37 (2011) 559–565 3.7. Systemic therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 3.8. Blood conserving protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 4.1. Study limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5641. Introduction Boolean search terms, from the establishment of the database until Jan 2010. Searches were conducted withoutOver the past 30 years, techniques of early excision and grafting language restriction. The bibliographies of all retrievedalong with enhancement of critical care have signiﬁcantly articles were then manually searched for relevant missedimproved survival following severe burn. Despite these advance- articles. The search terms were: ‘‘‘‘haemostasis’’[All Fields]ments, large volume blood loss associated with surgical OR ‘‘hemostasis’’[MeSH Terms] OR ‘‘hemostasis’’[All Fields])intervention continues to be a challenging aspect of burn surgery. AND (‘‘burns’’[MeSH Terms] OR ‘‘burns’’[All Fields] OR Traditionally, blood was transfused when the hemoglobin ‘‘burn’’[All Fields]) AND (‘‘surgery’’[Subheading] OR ‘‘surger-levels fell bellow 10 mg/dl. This originated from the fear of the y’’[All Fields] OR ‘‘surgical procedures, operative’’[MeSHdeleterious effects of anemia on oxygen consumption, cardiac Terms] OR (‘‘surgical’’[All Fields] AND ‘‘procedures’’[Allfunction and tissue perfusion [1,2]. However, such liberal use Fields] AND ‘‘operative’’[All Fields]) OR ‘‘operative surgicalof blood has come under question. procedures’’[All Fields] OR ‘‘surgery’’[All Fields] OR ‘‘general Multiple studies questioned the harmful effects of blood surgery’’[MeSH Terms] OR (‘‘general’’[All Fields] AND ‘‘sur-component transfusion. Blood component transfusions can be gery’’[All Fields]) OR ‘‘general surgery’’[All Fields]) ANDassociated with transfusion related acute lung injury, infec- (‘‘hemorrhage’’[MeSH Terms] OR ‘‘hemorrhage’’[All Fields]tion, immunomodulation, age of the transfused component, OR (‘‘blood’’[All Fields] AND ‘‘loss’’[All Fields]) OR ‘‘bloodmulti organ dysfunction, acute respiratory syndrome and loss’’[All Fields]’’.increase in mortality [3–7]. Due to the risks associated withblood component transfusion, restrictive transfusion prac- 2.2. Inclusion criteriatices are recommended for both adult and pediatric patients[7–10]. Furthermore, this has been extrapolated and demon- All articles reporting efﬁcacy and/or outcome with the use ofstrated in the burn patient [4,5,11]. hemostatic techniques and/or agents in humans during burn Unfortunately, the surgical treatment of burn patients is surgery were included. Individual case reports were excluded.associated with substantial blood loss [12–16]. Multiple hemo- The techniques were used for the management of excisedstatic techniques have been proposed for this problem. To wounds and/or donor sites in adults and children. A ﬂowchartaddress this issue, a review of the hemostatic techniques was of the search results is provided in Fig. 1. The two reviewersundertaken and we present here the ﬁndings for assessment. independently applied the inclusion criteria and any differ- ences were resolved through discussion.2. Methods 2.3. Data extraction and synthesis2.1. Literature search strategies Data was extracted by the researchers, to determine interven- tion, management of burn and/or management of donor site,A systematic search was conducted of Ovid MEDLINE, number of patients, age (pediatric or adult), and result ofEMBASE, Cochrane Library, CINAHL, and PubMed using intervention.[()TD$FIG] Fig. 1 – Flowchart of search results.
burns 37 (2011) 559–565 561 Table 1 – Included studies. Study ref. Type of study Site Intervention N Type of Range of (patients) patients % TBSA  Comparative Burn Tourniquet versus No Tourniquet 10 All 3–31  Descriptive Burn Tourniquet + Topical Epinephrine 52a NS <12  Descriptive Burn Tourniquet + Thrombin 17 All 0.5–15  Comparative Burn Epinephrine Tumescence or Tourniquet versus 44 Adult >5% Historical Controls  Descriptive Burn/donor Epinephrine/Bupivicaine Tumescence 29 Pediatric 1–12  Descriptive Burn Epinephrine Tumescence 10 Adult 5–50%  Comparative Burn/donor Epinephrine Tumescence + Thrombin 20 Adult 14–52% versus 0.45% NS + Thrombin  Comparative Burn/donor Topical/Tumescence Epinephrine + Thrombin 42 Pediatric 11–66% versus 0.45% NS + Thrombin  Comparative Donor Epinephrine/Lidocaine Tumescence + Topical 56 All 10–51% Epinephrine versus 0.45% NS Tumescence + Topical Epinephrine  Descriptive Burn Thrombin 72 All 1–4%  Comparative Donor Topical Epinephrine versus Thrombin 32 All NS  Comparative Donor Topical Phenylephrine versus Thrombin 24 NS NS  Comparative Donor Thrombin versus Bovine collagen sheet 20 NS NS  Comparative Donor Thrombin Ointment versus Thrombin Solution 11 All NS  Comparative Donor Thrombin versus Fibrin Sealant 46 Adult NS  Comparative Donor Fibrin Sealant versus No Fibrin Sealant 61 All 2–8%b  Comparative Donor Fibrin Sealant versus No Fibrin Sealant 47 All <15%  Comparative Donor Thrombin + Fibrin versus Thrombin + Placebo 10 NS NS  Comparative Burn Electrocautery knife with air spray versus No air spray 6 NS 10–30%  Comparative Systemic Terlipressin versus Placebo 51 All 10–20%  Descriptive Systemic rFVIIa 4 All 50–72%  Comparative Systemic rFVIIa versus No rFVIIa 18 Adult 12–60%  Descriptive Blood Conserving Protocol 23 Pediatric 1–55%  Comparative Blood Conserving Protocol 2461 NS 1–>40%  Comparative Blood Conserving Protocol 35 Adult 1–36%  Comparative Blood Conserving Protocol 392 Pediatric 10–>50%  Comparative Blood Conserving Protocol 30 Adult 8–46% NS: not stated. a Upper extremities. b Donor percent total body area.3. Results However, as part of their intraoperative protocol the wounds in both groups were sprayed with thrombin solution and3.1. Description of included studies wrapped with epinephrine soaked gauze. Three other studies described the use and beneﬁt ofA total of 27 studies were included (see Table 1.) From the tourniquets in the treatment of burns [18–20]. Smootincluded studies 8 are descriptive and 19 are comparative described the use of intermittent release and rapid reinﬂationhemostatic interventions. Speciﬁcally, 5 studies compared the of the tourniquet to allow for assessment of tissue viabilityimplementation of blood conserving protocols at single . This method was used in combination with epinephrineinstitutions. Most studies discussed the use of subcutaneous soaks and compression wraps. Similarly, Sawada andand topical agents to assist in hemostasis. However, 3 studies Yotsuyanagi described the use of a tourniquet and sprayingdiscussed the use of systemic pharmacoactive agents to assist the wound with thrombin prior to, and after, removal of thewith hemostasis. tourniquet along with pressure bandages . Djurickovic et al. described the use of a tourniquet during tangential3.2. Tourniquets excision of the extremity . After completion of the excision the tourniquet was deﬂated to evaluate areas ofO’Mara et al. directly studied the value of tourniquet inadequate excision and then reinﬂated. After reinﬂation,application without exsanguination of the limb prior to areas of major bleeding where coagulated and meshedtourniquet inﬂation to improve visualization of viable tissue autograft was then placed along with cotton gauze dressingduring excision . In this study they found that blood loss and elastic bandages. Furthermore, four out of the ﬁve studiesper area excised was less with tourniquet control that describe blood conserving protocols include tourniquets(0.10 Æ 0.29 cc/cm2) versus no tourniquet (0.32 Æ 0.56 cc/cm2) as part of the hemostatic protocol [21–24]. It was felt by these(P = 0.04). Additionally they demonstrated similar graft take authors that the use of tourniquet is an important adjunct tobetween the two groups (98.2% versus 96.8%) (P > 0.1). limit bleeding.
562 burns 37 (2011) 559–5653.3. Epinephrine tumescence Four studies compared the hemostatic efﬁcacy of thrombin (bThrombin) versus other products [33–36]. Brezel et al.Three articles described the technique of epinephrine subcu- compared the visual amount of blood loss form donor sitestaneous inﬁltration as a hemostatic agent [20,25,26]. Djur- on 32 patients that were treated with thrombin (100 U/ml) orickovic et al. described the use of 1:1,000,000 epinephrine epinephrine solution (1:200,000) . They demonstrated asolution inﬁltrated to the burn in 23 patients . They superior hemostatic effect from the epinephrine treated donorestimated a 3.42 Æ 0.39% blood volume loss per 1% body site. Caucci et al. compared the hemostatic effect ofsurface area excised. Fujita et al. preoperatively marked the phenylephrine (1:20,000) versus thrombin (100 U/ml) on theburn wound of 10 consecutive patients with a 5 Â 5 cm square donor sites of 24 patients . They demonstrated a superiorgrid using crystal violet . This grid was used a guide to hemostatic effect with phenylephrine compared to thrombininject 20 ml of a dilute epinephrine solution (1 mg/l) per when comparing blood absorbed in a paper ﬁlter disk coveringsquare. They felt that this provided an aide and safeguard to the donor site after treatment with the agents (P < 0.005).the amount of epinephrine used with the tumescent tech- Prasad et al. compared thrombin versus a bovine collagennique. Beausang et al. reported on 29 pediatric patients in dressing on the donor sites of 21 patients . Although, theywhich the donor sites and burn wounds were inﬁltrated with a did not describe the concentration of the thrombin spray, they1:500,000 epinephrine with bupivicane . Bupivicane (0.25% did demonstrated superior hemostatic control with the sprayplain) was added to the solution at a 3 mg per kg body weight thrombin. Mean blood loss with thrombin (5.25 Æ 8.68 ml)concentration. They reported no adverse effects and a versus collagen (8.24 Æ 13.54 ml) (P = 0.057). Sawada et al.decrease of postoperative pain with this technique. compared the use of thrombin ointment versus thrombin Three articles compared the use of epinephrine tumes- solution on the donor sites of 11 patients . They created thecence to determine effect on hemostasis [27–29]. Barret et al. ointment by mixing 10,000 units of powdered thrombin withcompared the use of topical and subcutaneous epinephrine on 10 g of petroleum jelly based gentamicin ointment. Again, thisa cohort of 42 pediatric patients . Half of these patients study did not describe the concentration of the thrombinreceived topical epinephrine (1:10,000 sprayed and 1:200,000 solution. However, the mean bleeding time with the thrombincompresses) to the excised wound and donor sites and ointment (11.5 s) was less than that of the thrombin solutionsubcutaneous infusion (1:300,000) to scalp donor sites only. (25.5 s, P < 0.01).The other half of patients followed the same protocol using One study described the efﬁcacy of the recombinant0.45% normal saline solution. Additionally, both groups human Thrombin (rThrombin) as a hemostatic agent in burnreceived topical thrombin (1000 units/ml) to the excised surgery. Greenhalgh et al. conducted a single-arm, open labelwounds and donor sites. They found no difference in the study of rThrombin (1000 U/ml) on the burn wounds of 72amount of bleeding per square centimeter excised patients after excision . Hemostasis at 20 min was(0.48 Æ 0.12 ml/cm2 versus 0.51 Æ 0.15 ml/cm2, P = 0.681) be- achieved in 91.5% of the patients. Further application oftween the two groups. Robertson et al. compared the results of rThrombin ensued hemostasis in all but 4 patients. Also, they20 patients (26 operations) using epinephrine (1 mg/ml) demonstrated a low rate of anti-rThrombin antibody forma-tumescence at the excision and donor sites to 10 patients tion (1.6%) without associated human thrombin neutraliza-(11 operations) . Also, topical thrombin spray was utilized tion, a concern that originated from the use of bThrombin [39–in both groups. They demonstrated almost a 70% reduction in 42]. Furthermore, one out of the four studies that describe ablood loss per unit area excised in the tumescent group blood conserving protocol utilize thrombin in their protocol(0.37 Æ 0.2 ml/cm2 versus 1.15 Æ 0.28 ml/cm2, P 0.0001). .Gacto et al. performed a prospective, randomized, controlled,blinded trial of 56 patients . Both groups received 3.5. Fibrin sealantsubcutaneous inﬁltration at donor sites with either epineph-rine (1:500,000) solution with added lidocaine (5%, w/v) or with Fibrin sealants are human derived factors that are designed to0.45% normal saline. They concluded that the inﬁltration of reproduce the ﬁnal steps of the physiologic coagulationthis solution decreased intraoperative bleeding and decreased cascade of a stable ﬁbrin clot [43,44]. Besides hemostaticpostoperative pain. Furthermore, four out of the ﬁve studies properties ﬁbrin sealant have adhesive properties that can bethat describe blood conserving protocols utilize epinephrine utilized during skin grafts and ﬂap procedures . Drake andtumescence as part of the protocol [22–24,30]. Wong compared the hemostatic effect of a patient derived ﬁbrin sealant against thrombin (100 U/ml) on the donor sites of3.4. Thrombin 46 patients . They determined the time to hemostasis to be less with the ﬁbrin sealant (31 s) versus thrombin (58 s,Topical thrombin as a hemostatic agent is commonly used on a P = 0.0012). Achauer et al. conducted a study on 10 patientsvariety of surgeries . Thrombin is a clotting factor that with half of the donor site sprayed with thrombin and plasmaconverts ﬁbrinogen into ﬁbrin that is the foundation of a blood placebo while the other half was sprayed with thrombin andclot. Typically the thrombin is applied directly to the wound via ﬁbrin glue . They found no difference in blood loss betweena spray system or in combination with an absorbable gelatin or the two areas. Both Greenhalgh et al. and Nervi et al. comparedcollagen sponge. Historically, thrombin (bThrombin) has been the effects of hemostasis of ﬁbrin sealant versus no ﬁbrinderived from bovine plasma via different puriﬁcation processes. sealant on donor wounds [48,49]. Greenhalgh et al. felt thatCurrently, human plasma (hThrombin) derived and human bleeding at the donor sites were well controlled with the ﬁbrinrecombinant thrombin (rThrombin) products are available . sealant as demonstrated by surgeon estimates . However,
burns 37 (2011) 559–565 563the treatment failed to demonstrate beneﬁt on semi quantita- pediatric patients . The protocol consisted of debridementtive measurements. On the contrary, Nervi et al. demonstrated of full thickness burns with electrocautery and partiala reduction in the mean time to hemostasis of approximately thickness burns with dermabrasion. All donor sites were200 s with the use of ﬁbrin sealants (ﬁbrin 193 Æ 131 s, control subcutaneously injected with a solution of epinephrine and392 Æ 153 s, P < 0.001) . The use of ﬁbrin sealants is not saline. No more than 10 mg/kg of epinephrine was adminis-described in the four studies that describe a blood conserving tered subcutaneously at one time. However, staggered injec-protocol. tions were utilized that often resulted in total dose of epinephrine being greater than 10 mg/kg. Additionally, all3.6. Electrocautery debrided or harvested surgical sites were treated with epinephrine solution soaked pads. Following this protocolMost of the studies describe the use of electrocautery as an they report an average blood loss per percent TBSA treated toadjunct to achieve hemostasis. However, Mitsukawa et al. be 17 ml.describes a novel use for an electrocautery attachment to Cartotto et al. compared the results of a comprehensiveassist with hemostasis during large burn area excisions . intraoperative blood conservation strategy and its effects onThey attached a smoke aspiration tip to the electrocautery. blood loss and wound outcome to a historical cohort . TheInstead of utilizing the aspiration tip to aspirate they used it as blood conservation technique was as follows: Donor sitesa conduit to expel air. This stream of air cleared blood and ﬂuid were inﬁltrated subcutaneously with a 1:500,000 adrenalinefrom the tip allowing for improved visualization and electro- solution. After the grafts were harvested the sites werecautery function. Compared to regular electrocautery this new dressed with epinephrine (1:33,333) soaked pads. Burndevice reduced the duration of surgery by 10% and the amount wounds on limbs where tangentially excised under tourni-of blood loss by 14% for a 30% TBSA burn. quet control. After completion of excision, the wounds were dressed with epinephrine (1:33,333) soaked pads and a ﬁrm3.7. Systemic therapies circumferential wrapping was performed for full 10 min prior to deﬂating the tourniquet. After deﬂation of theThree studies discuss the use of systemic therapies to assist tourniquet major bleeding was cauterized and the extremitywith hemostasis in burn surgery [51–53]. Terlipressin is an rewrapped with epinephrine soaked pads for another 5 min.analogue of vasopressin used as a vasoactive drug in the When the tourniquet could not be utilized the woundmanagement of hypotension. It has been found to be effective received subcutaneous inﬁltration with epinephrine solu-when norepinephrine does not help. Mzezewa et al. describes tion (1:500,000) prior to excision. After the excision wasthe results of a randomized trial comparing the use of completed the wound was dressed with epinephrineterlipressin or placebo on 51 patients undergoing early (1:33,333) soaked pads. Final hemostasis was achieved usingexcision and grafting of burns between 10 and 20% TBSA serial application of the epinephrine pads and electrocau-. Use of other hemostatic adjuncts where not described. In tery. Utilizing this blood conserving protocol, the estimatedthis study the medication was given intravenously at a dose of blood loss was reduced from 211 Æ 166 ml per %TBSA excised20 m/kg body weight and repeated every 4 h for 24 h. Following and grafted in the historical group to 123 Æ 106 ml in thethis protocol, terlipressin reduced blood loss on average 21% protocol driven group (P = 0.02). Furthermore, the intra-compared to placebo. operative transfusion requirement was reduced from Johansson et al. described a technique of utilizing recom- 3.3 Æ 3.1 units per case, in the historical group, to 0.1 Æ 0.3binant factor VIIa (rFVIIa) at a dose of 100 mg/kg on 4 patients units per case in the protocol driven group (P < 0.001). Alsoundergoing major wound excision that developed periopera- they reported no compromise on wound outcome and grafttive uncontrollable bleeding . They report hemostasis take with the new protocol.within 15 min of administering the drug and no adverse Sheridan and Szyfelbein compared blood use between twoeffects with the treatment. In a subsequent study, Johansson matched groups of 392 pediatric patients who where managedet al. conducted a single centre, randomized, double blind, during the calendar years of 1982–1985 and 1992–1995 (bloodplacebo controlled trial on 18 consecutive patients . The conserving protocol) . Three groups were analyzed:patients were randomized to receive either placebo or 40 mg/kg children with 10–24%, 25–49% and 50–100% TBSA. Thedose of rFVIIa at the time of skin incision and a second dose of techniques for intraoperative blood conservation included:placebo or rFVIIa (40 mg/kg) 90 min later. They demonstrated a clear preparation of excision plan, performing all extremitydecease in the total number of units of blood components excisions under tourniquet, and wrapping the extremity in atransfused per patient compared to placebo (0.9 versus 2.2, hemostatic dressing prior to tourniquet deﬂation, conductingP = 0.0013). Furthermore, they demonstrated a decrease in all fascial excision under electrocautery, performing allfresh frozen plasma units and platelet units transfused tangential excisions as early as possible, executing all torsoutilizing this protocol. tangential excision after subcutaneous epinephrine injection, and maintaining patient euthermic. They demonstrated a3.8. Blood conserving protocols reduction in the use of PRBC’s in the 10–24% TBSA from 1.9 Æ 0.2 units per child to 0.2 Æ 0.1 units per child (P < 0.001),Five studies directly address the implementation of multiple in the 25–49% TBSA from 6.9 Æ 1.1 to 2.5 Æ 0.6 units per childhemostatic techniques as a blood conserving protocol to (P < 0.001), and in the 50–100% TBSA 49.5 Æ 10.3 to 10 Æ 1.7decrease requirements for blood component transfusion units per child (P < 0.001) with the implementation of the[21,23,24,54]. Losee et al. described a protocol followed on 23 blood conserving protocol.
564 burns 37 (2011) 559–565 Gomez et al. performed a retrospective review of the variability on the surgical techniques in the use andrequirement of blood products in 30 randomly selected adult concentration of tumescence, thrombin, ﬁbrin, epinephrinepatients with more than 10% TBSA burns, who had an and systemic hemostatic agents. Unfortunately, a clearoperation . The patients were stratiﬁed into 2 groups. conclusion as to the best hemostatic agent cannot be made.Group 1 consisted of 15 patients that received treatment with However, as demonstrated by the studies comparing bloodimplementation of a blood conserving protocol. Group 2 conserving protocols that the best option is not a single agentconsisted of 15 patients receiving the traditional surgical but a fusion of techniques. These studies demonstrate thattechnique. The traditional surgical technique involved use of diligent implementation of blood conserving protocols canepinephrine-thrombin (1 ml of 1:1000 epinephrine, 10,000 U of decrease blood component requirements in burn surgery.thrombin in 1 l saline) soaked gauze compresses for 10 min,and electrocautery on the remaining bleeding points untilhemostasis was achieved. The blood conserving protocol Conﬂict of interestinvolved the use of tourniquets for extremity harvesting andexcisions, subcutaneous inﬁltration of epinephrine The author(s) declare that there are no conﬂicts of interest in(1:1,000,000) solution of donor and burn sites, use of epineph- the writing of this manuscript.rine (1:1000) soaked wraps, and the use of electrocautery forremaining bleeding areas. They demonstrated a decrease in referencesthe total blood volume transfused 6293 Æ 5141 to3147 Æ 4585 ml (P = 0.031) utilizing the blood conservingprotocol. Furthermore, they demonstrated a decrease in themean blood units transfused intraoperatively per patient from  Spence RK, Cernaianu AC, Carson J, DelRossi AJ. Transfusion in surgery. Curr Probl Surg 1993;30:1112–80.8.9 Æ 8 to 4.7 Æ 7.8 units (P = 0.026). This trend was also noted  Harvey JS, Watkins G, Sherman R. Emergent burn care.with other blood component transfusions. Southern Med J 1984;77:204–14. O’Mara et al. performed an analysis of 3 year periods before  Rutan RL, Bjarnason DL, Desai MH, Herndon DN. Incidenceand after initiation of a blood conserving protocol . In the of HIV seroconversion in paediatric burn patients. Burnsearly period after excision and harvesting, the sites where 1992;18:216–9.covered with epinephrine and/or thrombin soaked gauze.  Graves T, Ciofﬁ W, Mason A, McManus W, Pruit B. Relationship of transfusion and infection in a burnPressure was applied to all sites for a minimum of 10–15 min. population. J Trauma 1989;29:948–52.Electrocautery was used to coagulate further hemorrhage and  Palmieri TL, Caruso DM, Foster KN, et al. Effect of bloodpressure reapplied as needed. In the later period, extremities transfusion on outcome after major burn injury: awere excised under tourniquet control. The thorax was multicenter study. Crit Care Med 2006;34:1602–7.excised to fascia for burns greater than 10% contiguous  Morris JJ, Wilcox T, Reed G, et al. Safety of the blood supply.surface area otherwise tangential excision was utilized. After Surrogate testing and transmission of hepatitis C in patientsexcision and harvesting, a permeable synthetic ﬁlm sprayed after massive transfusion. Ann Surg 1994;219:517–25.  Marik P, Corwin H. Efﬁcacy of red blood cell transfusion inwith thrombin solution was placed over all areas of the wound the critically ill: a systematic review of the literature. 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