Surgery_Schwartz

Surgery_Schwartz. 24 hours after injury. Furthermore, TIC is a separate and distinct process from disseminated intravascular coagulopathy with its own specific components of hemostatic failure.As shown in Fig. 4-5, several non–mutually exclusive mechanisms have been proposed as the etiology of TIC,41 includ-ing activated protein C-mediated clotting factor deactivation,42 endothelial injury and “auto-heparinization” due to shedding of endothelial heparin sulfate and chondroitin sulfate into the circulation,43 platelet dysfunction,44 and hyperfibrinolysis.45 Hemorrhagic shock was previously thought to be an essential component of TIC, but isolated traumatic brain injury46 and pulmonary contusions47 have been shown to induce laboratory-defined TIC in the absence of shock, possibly due to a high pro-portion of endothelium in these organs. Traumatic brain injury may also induce TIC via a consumptive mechanism by the release of large amounts of tissue factor into the circulation.48 2Table 4-3Coagulation


Surgery_Schwartz

Surgery_Schwartz. of endothelium in these organs. Traumatic brain injury may also induce TIC via a consumptive mechanism by the release of large amounts of tissue factor into the circulation.48 2Table 4-3Coagulation factors synthesized by the liverVitamin K–dependent factors: II (prothrombin factor), VII, IX, XFibrinogenFactor VFactor VIIIFactors XI, XII, XIIIAntithrombin IIIPlasminogenProtein C and protein SBrunicardi_Ch04_p0103-p0130.indd 11129/01/19 11:05 AM 112BASIC CONSIDERATIONSPART IHowever, the relationship between laboratory-based coagula-tion abnormalities and true clinically evident coagulopathic bleeding is unclear. With the widespread application of damage control resuscitation, the frequency of clinical coagulopathy has decreased.Interestingly, the converse of hyperfibrinolysis, known as fibrinolytic shutdown, has also been associated with increased mortality after trauma.49 In a multicenter study of 2540 trauma patients, those with intermediate fibrinolytic activity (“physiologic,”


Surgery_Schwartz

Surgery_Schwartz. fibrinolytic shutdown, has also been associated with increased mortality after trauma.49 In a multicenter study of 2540 trauma patients, those with intermediate fibrinolytic activity (“physiologic,” 0.8% to 2.9% lysis) on admission had the lowest mortality (14%). Shutdown (<0.8% lysis) patients had increased mortality (22%), often due to late causes such as mul-tiple organ failure, while patients with hyperfibrinolysis (≥3% lysis) had the greatest mortality (34%) and most often died due to hemorrhage.50Acquired Coagulation InhibitorsAmong the most common acquired coagulation inhibitors is the antiphospholipid syndrome (APLS), which includes the lupus anticoagulant and anticardiolipin antibodies. These antibodies may be associated with either venous or arterial thrombosis, or both. In fact, patients presenting with recurrent thrombosis should be evaluated for APLS. Antiphospholipid antibodies are very common in patients with systemic lupus but may also be seen in association with


Surgery_Schwartz

Surgery_Schwartz. fact, patients presenting with recurrent thrombosis should be evaluated for APLS. Antiphospholipid antibodies are very common in patients with systemic lupus but may also be seen in association with rheumatoid arthritis and Sjögren’s syndrome. There are also individuals who will have no autoimmune disor-ders but develop transient antibodies in response to infections or those who develop drug-induced APLS. The hallmark of APLS is a prolonged aPTT in vitro but an increased risk of thrombosis in vivo.Anticoagulation and BleedingSpontaneous bleeding can be a complication of any antico-agulant therapy whether it is heparin, low molecular weight heparins, warfarin, factor Xa inhibitors, or new direct thrombin inhibitors. The risk of spontaneous bleeding related to heparin is reduced with a continuous infusion technique. Therapeutic anticoagulation is more reliably achieved with a low molecu-lar weight heparin. However, laboratory testing is more chal-lenging with these medications, as they


Surgery_Schwartz

Surgery_Schwartz. infusion technique. Therapeutic anticoagulation is more reliably achieved with a low molecu-lar weight heparin. However, laboratory testing is more chal-lenging with these medications, as they are not detected with conventional coagulation testing. However, their more reli-able therapeutic levels (compared to heparin) make them an attractive option for outpatient anticoagulation and more costeffective for the inpatient setting. If monitoring is required (e.g., in the presence of renal insufficiency or severe obesity), the drug effect should be determined with an assay for anti-Xa activity.Warfarin is used for long-term anticoagulation in various clinical conditions, including deep vein thrombosis, pulmonary embolism, valvular heart disease, atrial fibrillation, recurrent systemic emboli, recurrent myocardial infarction, prosthetic heart valves, and prosthetic implants. Due to the interaction of the P450 system, the anticoagulant effect of the warfarin is reduced (e.g., increased dose


Surgery_Schwartz

Surgery_Schwartz. recurrent myocardial infarction, prosthetic heart valves, and prosthetic implants. Due to the interaction of the P450 system, the anticoagulant effect of the warfarin is reduced (e.g., increased dose required) in patients receiving barbiturates as well as in patients with diets low in vitamin K. Increased warfarin requirements may also be needed in patients taking contraceptives or estrogen-containing compounds, corti-costeroids, and adrenocorticotropic hormone (ACTH). Medica-tions that can alter warfarin requirements are shown in Table 4-4.Although warfarin use is often associated with a signifi-cant increase in morbidity and mortality in acutely injured and emergency surgery patients, with rapid reversal, these com-plications can be reduced. There are several reversal options that include vitamin K administration, plasma, cryoprecipi-tate, recombinant factor VIIa, and factor concentrates. The 2012 CHEST guidelines for the Management of Anticoagulant Therapy Antithrombotic Therapy


Surgery_Schwartz

Surgery_Schwartz. vitamin K administration, plasma, cryoprecipi-tate, recombinant factor VIIa, and factor concentrates. The 2012 CHEST guidelines for the Management of Anticoagulant Therapy Antithrombotic Therapy and Prevention of Thrombo-sis recommends patients with major life-threatening bleeding TRAUMATICCLINICALCOAGULOPATHICBLEEDING?PlateletactivationEGLsheddingEndothelial activationAcidosisHypothermiaHemorrhageShock˜˜˜tPA &°PAI-1Hypo-perfusionClotting factorconsumptionPre-injuryanticoagulantmedicationIatrogenicresuscitationinjuryHemodilution˜Acidosis˜HypothermiaAuto-heparinization°Clotting factoractivityPlatelet dysfunctionHyperfibrinolysis˜Catecholamines˜APCFigure 4-5. Illustration of the pathophysiologic mechanism responsible for the acute coagulopathy of trauma. APC = activated protein C; EGL = endothelial glycocalyx; PAI-1 = plasminogen activator inhibitor 1; tPA = tissue plasminogen activator; TIC = trauma-induced coagulopathy. (Reproduced with permission from Chang R, Cardenas JC, Wade CE,


Surgery_Schwartz

Surgery_Schwartz. glycocalyx; PAI-1 = plasminogen activator inhibitor 1; tPA = tissue plasminogen activator; TIC = trauma-induced coagulopathy. (Reproduced with permission from Chang R, Cardenas JC, Wade CE, et al: Advances in the understanding of trauma-induced coagulopathy. Blood. 2016 Aug 25;128(8):1043-1049.)Table 4-4Medications that can alter warfarin dosing↓ warfarin effect↑ warfarin requirementsBarbiturates, oral contraceptives, estrogen-containing compounds, corticosteroids, adrenocorticotropic hormone↑ warfarin effect↓ warfarin requirementsPhenylbutazone, clofibrate, anabolic steroids, L-thyroxine, glucagons, amiodarone, quinidine, cephalosporinsBrunicardi_Ch04_p0103-p0130.indd 11229/01/19 11:05 AM 113HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4due to warfarin receive reversal with vitamin K and a rapid reversal agent such as plasma or prothrombin complex concen-trate (PCC).51 Vitamin K is given to sustain the effects of the plasma or PCC due to their short half-lives. In major


Surgery_Schwartz

Surgery_Schwartz. vitamin K and a rapid reversal agent such as plasma or prothrombin complex concen-trate (PCC).51 Vitamin K is given to sustain the effects of the plasma or PCC due to their short half-lives. In major bleeds, Vitamin K 10 mg given as a slow IV infusion is utilized for more rapid onset compared to the oral form. Studies have shown that PCC is superior to plasma for speed of reversal and has decreased risk of fluid overload, but it is equivalent in adverse and thromboembolic events and costlier.52,53 Prothrombin com-plex concentrate is available in two forms: three-factor PCC (factors II, IX, and X) and four-factor PCC (factors II, VII, IX, and X). Four-factor PCCs have been shown to have a more reli-able correction of INR compared to three-factor PCCs.54,55Direct oral anticoagulants (DOACs) include direct throm-bin inhibitors and factor Xa inhibitors and have no readily available method of detection of the degree of anticoagula-tion. More concerning is the difficulty in the reversal of


Surgery_Schwartz

Surgery_Schwartz. include direct throm-bin inhibitors and factor Xa inhibitors and have no readily available method of detection of the degree of anticoagula-tion. More concerning is the difficulty in the reversal of these new anticoagulants. Recently, idarucizumab, a humanized monoclonal antibody fragment that binds dabigatran, has been approved for use for reversal of the thrombin inhibitor, dabiga-tran, and dabigatran-related coagulopathy. Clinical studies have demonstrated normalization of laboratory tests.56,57Factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban currently lack a specific antidote. Two novel anti-dotes, andexanet alfa and ciraparantag (PER977), are currently undergoing clinical trials. Andexanet alfa is a recombinant human FXa variant,58,59 and ciraparantag is a cationic small molecule.60 These are both being evaluated for reversal of the factor Xa inhibitors. Until these agents are approved, attempts to reverse Factor Xa inhibitors should include four factor PCCs.61 In


Surgery_Schwartz

Surgery_Schwartz. molecule.60 These are both being evaluated for reversal of the factor Xa inhibitors. Until these agents are approved, attempts to reverse Factor Xa inhibitors should include four factor PCCs.61 In less urgent states, these drugs can be held for 36 to 48 hours prior to surgery without increased risk of bleeding in those with normal renal function. Alternatively, activated clotting time (stand alone or with rapid TEG) or ecarin clotting time can be obtained in those on dabigatran, and anti-factor Xa assays can be obtained in those taking rivaroxaban.Bleeding complications in patients on anticoagulants include hematuria, soft tissue bleeding, intracerebral bleeding, skin necrosis, and abdominal bleeding. Bleeding secondary to anticoagulation therapy is also a common cause of rectus sheath hematomas.Surgical intervention may prove necessary in patients receiving anticoagulation therapy. Increasing experience suggests that surgical treatment can be undertaken without full reversal of the


Surgery_Schwartz

Surgery_Schwartz. intervention may prove necessary in patients receiving anticoagulation therapy. Increasing experience suggests that surgical treatment can be undertaken without full reversal of the anticoagulant, depending on the procedure being performed.62 When the aPTT is less than 1.3 times control in a heparinized patient, or when the INR is less than 1.5 in a patient on warfarin, reversal of anticoagulation therapy may not be necessary. How-ever, meticulous surgical technique is mandatory, and the patient must be observed closely throughout the postoperative period.Certain surgical procedures should not be performed in concert with anticoagulation. In particular, cases where even minor bleeding can cause great morbidity, such as the central nervous system and the eye, surgery should be avoided. Emer-gency operations are occasionally necessary in patients who have been heparinized. The first step in these patients is to dis-continue heparin. For more rapid reversal, protamine sulfate is


Surgery_Schwartz

Surgery_Schwartz. Emer-gency operations are occasionally necessary in patients who have been heparinized. The first step in these patients is to dis-continue heparin. For more rapid reversal, protamine sulfate is effective. However, significant adverse reactions, especially in patients with severe fish allergies, may be encountered when administering protamine.63 Symptoms include hypotension, flushing, bradycardia, nausea, and vomiting. Prolongation of the aPTT after heparin neutralization with protamine may also be a result of the anticoagulant effect of protamine. In the elective surgical patient who is receiving warfarin-derivative therapy sufficient to effect anticoagulation, the drug can be discontinued several days before operation and the prothrombin concentration then checked.64 Rapid reversal of anticoagulation can be accom-plished with plasma or prothrombin complex concentrates in the emergent situation. An example of a warfarin reversal guideline using four-factor prothrombin complex


Surgery_Schwartz

Surgery_Schwartz. of anticoagulation can be accom-plished with plasma or prothrombin complex concentrates in the emergent situation. An example of a warfarin reversal guideline using four-factor prothrombin complex concentrate for patients with major or life-threatening bleeding or intracranial bleeding is shown in Fig. 4-6. Parenteral administration of vitamin K also is indicated in elective surgical treatment of patients with biliary obstruction or malabsorption who may be vitamin K deficient. However, if low levels of factors II, VII, IX, and X (vitamin K–dependent factors) exist as a result of hepatocellular dysfunc-tion, vitamin K administration is ineffective.The perioperative management of patients receiving long-term oral anticoagulation therapy is an increasingly common problem. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines from 2012 suggests periopera-tive “bridging” of anticoagulation.65 However, recent studies have found an increased risk of major


Surgery_Schwartz

Surgery_Schwartz. of Chest Physicians Evidence-Based Clinical Practice Guidelines from 2012 suggests periopera-tive “bridging” of anticoagulation.65 However, recent studies have found an increased risk of major bleeding without a change in thromboembolism rate when comparing bridging to no-bridg-ing for elective operations or procedures.66 Additional clinical trials are currently underway, but at the current time, physicians should carefully balance risks of bleeding vs. venous thromboembolism risks for individual patients when deciding on bridging of anticoagulation for procedures.67 For patients in whom the risk of venous thromboembolism out-weighs the risk of bleeding, a heparin infusion should be held for 4 to 6 hours before the procedure and restarted within 12 to 24 hours of the end of its completion. High-risk indications include mechanical heart valves, recent (within 30 days) myo-cardial infarction, stroke, or pulmonary embolism. Lower risk indications, such as thromboembolic events greater


Surgery_Schwartz

Surgery_Schwartz. High-risk indications include mechanical heart valves, recent (within 30 days) myo-cardial infarction, stroke, or pulmonary embolism. Lower risk indications, such as thromboembolic events greater than 30 days prior, hypercoagulable history, and atrial fibrillation, do not require such stringent restarting strategies.Cardiopulmonary Bypass. Under normal conditions, homeo-stasis of the coagulation system is maintained by complex inter-actions between the endothelium, platelets, and coagulation factors. In patients undergoing cardiopulmonary bypass (CPB), contact with circuit tubing and membranes results in abnormal platelet and clotting factor activation, as well as activation of inflammatory cascades, that ultimately results in excessive fibri-nolysis and a combination of both quantitative and qualitative platelet defects. Platelets undergo reversible alterations in mor-phology and their ability to aggregate, which causes sequestra-tion in the filter, partially degranulated platelets,


Surgery_Schwartz

Surgery_Schwartz. and qualitative platelet defects. Platelets undergo reversible alterations in mor-phology and their ability to aggregate, which causes sequestra-tion in the filter, partially degranulated platelets, and platelet fragments. This multifactorial coagulopathy is compounded by the effects of shear stress in the system, induced hypothermia, hemodilution, and anticoagulation.68While on pump, activated clotting time measurements are obtained along with blood gas measurements; however, con-ventional coagulation assays and platelet counts are not nor-mally performed until rewarming and after a standard dose of protamine has been given. TEG may give a better estimate of the extent of coagulopathy and may also be used to anticipate transfusion requirements if bleeding is present.68Empiric treatment with FFP and cryoprecipitate is often used for bleeding patients; however, there are no universally accepted transfusion thresholds. Platelet concentrates are given for bleeding patients in the


Surgery_Schwartz

Surgery_Schwartz. with FFP and cryoprecipitate is often used for bleeding patients; however, there are no universally accepted transfusion thresholds. Platelet concentrates are given for bleeding patients in the immediate postoperative period; however, studies have shown that indiscriminate plate-let therapy conferred no therapeutic advantage.69 It is in these 34Brunicardi_Ch04_p0103-p0130.indd 11329/01/19 11:05 AM 114BASIC CONSIDERATIONSPART Ipatients where rapid coagulation testing is required to assist with directed transfusion therapy.70 Many institutions now use antifibrinolytics, such as ε-aminocaproic acid and tranexamic acid, at the time of anesthesia induction after several studies have shown that such treatment reduced postoperative bleed-ing and reoperation. Aprotinin, a protease inhibitor that acts as an antifibrinolytic agent, has been shown to reduce transfusion requirements associated with cardiac surgery.71 Desmopressin acetate stimulates release of factor VIII from endothelial


Surgery_Schwartz

Surgery_Schwartz. that acts as an antifibrinolytic agent, has been shown to reduce transfusion requirements associated with cardiac surgery.71 Desmopressin acetate stimulates release of factor VIII from endothelial cells and may also be effective in reducing blood loss during cardiac surgery.Local Hemostasis. Significant surgical bleeding is usually caused by ineffective local hemostasis. The goal is therefore to prevent further blood loss from a disrupted vessel that has been incised or transected. Hemostasis may be accomplished by interrupting the flow of blood to the involved area or by direct closure of the blood vessel wall defect.Mechanical Procedures. The oldest mechanical method of bleeding cessation is application of direct digital pressure, either at the site of bleeding or proximally to permit more definitive action. An extremity tourniquet that occludes a major vessel proximal to the bleeding site or the Pringle maneuver for liver bleeding are good examples. Direct digital pressure is very


Surgery_Schwartz

Surgery_Schwartz. definitive action. An extremity tourniquet that occludes a major vessel proximal to the bleeding site or the Pringle maneuver for liver bleeding are good examples. Direct digital pressure is very effective and has the advantage of being less traumatic than hemostatic or even “atraumatic” clamps.When a small vessel is transected, a simple ligature is usu-ally sufficient. However, for larger pulsating arteries, a transfix-ion suture to prevent slipping is indicated. All sutures represent foreign material, and selection should be based on their intrinsic characteristics and the state of the wound. Direct pressure applied by “packing” a wound with gauze or laparotomy pads affords the best method of controlling diffuse bleeding from large areas, such as in the trauma situation. Packing bone wax on the raw surface to effect pressure can control bleeding from cut bone.Thermal Agents. Heat achieves hemostasis by denaturation of protein that results in coagulation of large areas of tissue.


Surgery_Schwartz

Surgery_Schwartz. wax on the raw surface to effect pressure can control bleeding from cut bone.Thermal Agents. Heat achieves hemostasis by denaturation of protein that results in coagulation of large areas of tissue. Elec-trocautery generates heat by induction from an alternating cur-rent source, which is then transmitted via conduction from the instrument directly to the tissue. The amplitude setting should be high enough to produce prompt coagulation, but not so high as to set up an arc between the tissue and the cautery tip. This avoids thermal injury outside of the operative field and also prevents exit of current through electrocardiographic leads, other moni-toring devices, or permanent pacemakers or defibrillators. A negative grounding plate should be placed beneath the patient to avoid severe skin burns, and caution should be used with certain Major bleeding/life-threatening bleeding orintracranial hemorrhage (lCH)Administer phytonadione 10 mg IV immediatelyCheck PT/INR, PTT, fibrinogen,


Surgery_Schwartz

Surgery_Schwartz. skin burns, and caution should be used with certain Major bleeding/life-threatening bleeding orintracranial hemorrhage (lCH)Administer phytonadione 10 mg IV immediatelyCheck PT/INR, PTT, fibrinogen, platelets, Hgb/HctEvaluate for relative contraindications to PCC4 (Kcentra®)• Thrombotic event in the past 3 months – myocardial infarction,stroke, pulmonary embolism, deep vein thrombosis• Very high risk of thrombosis, such as patients with clinical orlaboratory evidence of overt disseminated intravascularcoagulopathy, heparin-induced thrombocytopenia (HIT), high-riskthrombophilia, or antiphospholipid syndromeCheck PT/INR 1 hr, 6 hrs, and 24 hrs after completion of Kcentra®• If INR >1.5 at 1 hr, consider switching to FFP therapy• If INR >1.5 at 6 hrs, repeat phytonadione 10 mg IV over 30 min• If INR >1.5 at 24 hrs, repeat phytonadione 10 mg IV over 30 minINR 1.5–3.9Kcentra®25 units/kg(maximum 2500 units)INR 4–6Kcentra®35 units/kg(maximum 3500 units)INR >6Kcentra®50 units/kg(maximum 5000


Surgery_Schwartz

Surgery_Schwartz. If INR >1.5 at 24 hrs, repeat phytonadione 10 mg IV over 30 minINR 1.5–3.9Kcentra®25 units/kg(maximum 2500 units)INR 4–6Kcentra®35 units/kg(maximum 3500 units)INR >6Kcentra®50 units/kg(maximum 5000 units)Administer FFPYesNoContraindication toKcentra®Figure 4-6. Example of a warfarin reversal guideline using four-factor prothrombin complex concentrate for patients with major or life-threatening bleeding or intracranial bleeding.Brunicardi_Ch04_p0103-p0130.indd 11429/01/19 11:05 AM 115HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4anesthetic agents (diethyl ether, divinyl ether, ethyl chloride, ethylene, and cyclopropane) because of the hazard of explosion.A direct current also can result in hemostasis. Because the protein moieties and cellular elements of blood have a nega-tive surface charge, they are attracted to a positive pole where a thrombus is formed. Direct currents in the 20to 100-mA range have successfully controlled diffuse bleeding from raw surfaces, as has


Surgery_Schwartz

Surgery_Schwartz. surface charge, they are attracted to a positive pole where a thrombus is formed. Direct currents in the 20to 100-mA range have successfully controlled diffuse bleeding from raw surfaces, as has argon gas.Topical Hemostatic AgentsTopical hemostatic agents can play an important role in help-ing to facilitate surgical hemostasis. These agents are classified based on their mechanism of action, and many act at specific stages in the coagulation cascade and take advantage of natural physiologic responses to bleeding.72 The ideal topical hemo-static agent has significant hemostatic action, minimal tissue reactivity, nonantigenicity, in vivo biodegradability, ease of sterilization, low cost, and can be tailored to specific needs.73Achneck et al have published a comprehensive overview of absorbable, biologic, and synthetic agents.74 Absorbable agents include gelatin foams (Gelfoam), oxidized cellulose (Surgicel), and microfibrillar collagens (Avitene). Both gelatin foam and oxidized cellulose


Surgery_Schwartz

Surgery_Schwartz. biologic, and synthetic agents.74 Absorbable agents include gelatin foams (Gelfoam), oxidized cellulose (Surgicel), and microfibrillar collagens (Avitene). Both gelatin foam and oxidized cellulose provide a physical matrix for clotting initia-tion, while microfibrillar collagens facilitate platelet adherence and activation. Biologic agents include topical thrombin, fibrin sealants (FloSeal), and platelet sealants (Vitagel). Human or recombinant thrombin derivatives, which facilitate the forma-tion of fibrin clots and subsequent activation of several clotting factors, take advantage of natural physiologic processes, thereby avoiding foreign body or inflammatory reactions.73 Caution must be taken in judging vessel caliber in the wound because thrombin entry into larger caliber vessels can result in systemic exposure to thrombin with a risk of disseminated intravascular clotting or death. They are particularly effective in controlling capillary bed bleeding when pressure or ligation is


Surgery_Schwartz

Surgery_Schwartz. result in systemic exposure to thrombin with a risk of disseminated intravascular clotting or death. They are particularly effective in controlling capillary bed bleeding when pressure or ligation is insufficient; however, the bovine derivatives should be used with caution due to the potential immunologic response and worsened coagulopathy. Fibrin sealants are prepared from cryoprecipitate (homologous or synthetic) and have the advantage of not promoting inflam-mation or tissue necrosis.75 A recent study by Koea et al dem-onstrated in a prospective multicenter randomized trial that a fibrin sealant patch was safe and highly effective in controlling parenchymal bleeding following hepatectomy regardless of the type of resection.76 Platelet sealants are a mixture of collagen and thrombin combined with plasma-derived fibrinogen and platelets from the patient, which requires the additional need for centrifugation and processing.Topical agents are not a substitute for meticulous surgical


Surgery_Schwartz

Surgery_Schwartz. with plasma-derived fibrinogen and platelets from the patient, which requires the additional need for centrifugation and processing.Topical agents are not a substitute for meticulous surgical technique and only function as adjuncts to help facilitate surgi-cal hemostasis. The advantages and disadvantages of each agent must be considered, and use should be limited to the minimum amount necessary to minimize toxicity, adverse reactions, inter-ference with wound healing, and procedural costs.TRANSFUSIONBackgroundHuman blood replacement therapy was accepted in the late nine-teenth century. This was followed by the introduction of blood grouping by Landsteiner who identified the major A, B, and O groups in 1900, resulting in widespread use of blood products in World War I. Levine and Stetson in 1939 followed with the concept of Rh grouping. These and other breakthroughs in blood product preservation, storage, and infectious disease screening established the foundation from which the field


Surgery_Schwartz

Surgery_Schwartz. 1939 followed with the concept of Rh grouping. These and other breakthroughs in blood product preservation, storage, and infectious disease screening established the foundation from which the field of transfusion medicine has grown. Whole blood was considered the standard in transfusion until the late 1970s when component therapy began to take prominence. This change in practice was driven in part by blood bank economics, increasing the availability of specific blood products for patients with isolated deficien-cies (anemia, thrombocytopenia, clotting factor deficiencies), especially those associated with chemotherapy.77 However, this change occurred for all patients simultaneously without studies to identify the clinical ramifications in different patient popu-lations requiring blood product therapy. Interestingly, whole blood transfusion (the ultimate balanced transfusion product) is making a resurgence in both military and civilian practice for resuscitation of acute


Surgery_Schwartz

Surgery_Schwartz. blood product therapy. Interestingly, whole blood transfusion (the ultimate balanced transfusion product) is making a resurgence in both military and civilian practice for resuscitation of acute hemorrhage.Replacement TherapyTyping and Crossmatching. Serologic compatibility for A, B, O, and Rh groups is established routinely. Crossmatching between the donors’ red blood cells and the recipients’ sera (the major crossmatch) is performed. Rh-negative recipients should be transfused only with Rh-negative red blood cells. However, this group represents only 15% of the population. Therefore, the administration of Rh-positive red blood cells is acceptable if Rh-negative red blood cells blood is not available. However, Rh-positive red blood cells should not be transfused to Rhnegative females who are of childbearing age.In emergency situations, universal donor type O-negative red blood cells and type AB plasma may be transfused to all recip-ients. Platelets do not require crossmatching. Due


Surgery_Schwartz

Surgery_Schwartz. are of childbearing age.In emergency situations, universal donor type O-negative red blood cells and type AB plasma may be transfused to all recip-ients. Platelets do not require crossmatching. Due to a shortage of type AB plasma, low anti-B titer type A plasma has become widely adopted for emergency (uncrossmatched) transfusion.78 In the United States, 85% of individuals are type A or type O, mak-ing type A plasma compatible with the vast majority of poten-tial recipients. Uncrossmatched plasma is routinely transfused as part of platelet transfusions, with major transfusion reactions reported rarely,79 and type AB plasma currently carries a higher risk of TRALI compared to other plasma types.80 Many cen-ters have transitioned to low titer type A plasma for emergency transfusions, with no increase in adverse events.81 O negative and type-specific red blood cells are equally safe for emergency transfusion. In patients known to have clinically significant cold agglutinins, blood should


Surgery_Schwartz

Surgery_Schwartz. increase in adverse events.81 O negative and type-specific red blood cells are equally safe for emergency transfusion. In patients known to have clinically significant cold agglutinins, blood should be administered through a blood warmer. If these antibodies are present in high titer, hypother-mia is contraindicated.In patients who have been multiply transfused and who have developed alloantibodies or who have autoimmune hemo-lytic anemia with pan-red blood cell antibodies, typing and crossmatching is often difficult, and sufficient time should be allotted preoperatively to accumulate blood that might be required during the operation. Crossmatching should always be performed before the administration of dextran because it inter-feres with the typing procedure.81aBanked Whole Blood. Interest in whole blood as an ideal therapy for acute traumatic hemorrhagic shock has increased in the last several years with multiple reports of successful use in military and civilian trauma patients.


Surgery_Schwartz

Surgery_Schwartz. in whole blood as an ideal therapy for acute traumatic hemorrhagic shock has increased in the last several years with multiple reports of successful use in military and civilian trauma patients. However, there is still limited access in most civilian centers.Red Blood Cells and Frozen Red Blood Cells. Red blood cells are the traditional product of choice for most clinical Brunicardi_Ch04_p0103-p0130.indd 11529/01/19 11:05 AM 116BASIC CONSIDERATIONSPART Isituations requiring resuscitation, although deficits in oxygen delivery are rarely related to inadequate red cells. Concentrated suspensions of red blood cells can be prepared by removing most of the supernatant plasma after centrifugation. The prepa-ration reduces but does not eliminate reactions caused by plasma components. With sequential changes in storage solutions, the shelf life of red blood cells is now 42 days. However, recent evidence has demonstrated that the age of red cells may play a significant role in the


Surgery_Schwartz

Surgery_Schwartz. With sequential changes in storage solutions, the shelf life of red blood cells is now 42 days. However, recent evidence has demonstrated that the age of red cells may play a significant role in the inflammatory response and incidence of multiple organ failure.82 The changes in the red blood cells that occur during storage include reduction of intracellular ADP and 2,3-diphosphoglycerate (2,3-DPG), which alters the oxygen dissociation curve of hemoglobin, resulting in a decrease in oxy-gen transport. Stored RBCs progressively become acidotic with elevated levels of lactate, potassium, and ammonia. Addition-ally, the in vitro hemostatic potential of plasma83 and platelet84 products also decrease with storage.The morphologic and biochemical changes that occur over time in red cells may contribute to worsened outcomes. This limits the ability to bank large amounts of blood, particu-larly rarer blood types, for use in times of high demand and blood supply shortage, such as on the


Surgery_Schwartz

Surgery_Schwartz. may contribute to worsened outcomes. This limits the ability to bank large amounts of blood, particu-larly rarer blood types, for use in times of high demand and blood supply shortage, such as on the battlefield and after mass casualty events. Storage solutions, however, do not fully sup-press the metabolic and physical changes associated with aging RBCs. Newer evidence suggests that cryopreservation of red blood cells may provide a safe alternative means of storage. Cryopreservation uses the beneficial effects of ultra-low tem-peratures to suppress molecular motion and arrest metabolic and biochemical reactions. Frozen (cryopreserved) red blood cells have a shelf life of ten years at -80°C with improved cel-lular viability and maintenance of ATP and 2,3 DPG concen-trations.85 A trial of stable trauma patients randomized to old (>14 storage days) red blood cells, young (≤14 storage days) red blood cells, and cryopreserved red blood cells found that cryopreserved red blood cells were


Surgery_Schwartz

Surgery_Schwartz. stable trauma patients randomized to old (>14 storage days) red blood cells, young (≤14 storage days) red blood cells, and cryopreserved red blood cells found that cryopreserved red blood cells were as safe and effective as stan-dard red blood cells.85 Cryopreserved red blood cells required a thawing and preparation period of about 90 minutes, limiting immediate availability for emergency use. A recent study sug-gests that the post-thaw characteristics of cryopreserved units may not, however, be comparable to fresh red cells.86 Additional research needs to be done to optimize the process, but frozen cells likely represent a viable option for storage in the future.Leukocyte-Reduced and Leukocyte-Reduced/Washed Red Blood Cells. These products are prepared by filtration that removes about 99.9% of the white blood cells and most of the platelets (leukocyte-reduced red blood cells) and, if necessary, by additional saline washing (leukocyte-reduced/washed red blood cells). Leukocyte


Surgery_Schwartz

Surgery_Schwartz. 99.9% of the white blood cells and most of the platelets (leukocyte-reduced red blood cells) and, if necessary, by additional saline washing (leukocyte-reduced/washed red blood cells). Leukocyte reduction prevents almost all febrile, nonhemolytic transfusion reactions (fever and/or rigors), allo-immunization to HLA class I antigens, and platelet transfu-sion refractoriness and cytomegalovirus transmission. In most Western nations, it is the standard red blood cell transfusion product. Supporters of universal leukocyte reduction argue that allogenic transfusion of white cells predisposes to postoperative bacterial infection and multiorgan failure. Reviews of random-ized trials and meta-analyses have not provided convincing evi-dence either way,87,88 although a large Canadian retrospective study suggests a decrease in mortality and infections.89Platelet Concentrates. The indications for platelet transfu-sion include thrombocytopenia caused by massive blood loss and replacement with


Surgery_Schwartz

Surgery_Schwartz. study suggests a decrease in mortality and infections.89Platelet Concentrates. The indications for platelet transfu-sion include thrombocytopenia caused by massive blood loss and replacement with platelet-poor products, thrombocytopenia caused by inadequate production, and qualitative platelet dis-orders. Platelets are stored at room temperature under constant agitation to prevent clumping and have a shelf life of 5 days from time of donation due to risk of bacterial overgrowth. One unit of platelet concentrate has a volume of approximately 50 mL. Platelet preparations are capable of transmitting infec-tious diseases and can account for allergic reactions similar to those caused by red blood cell transfusion. A therapeutic level of platelets is in the range of 50,000 to 100,000/μL, but is very dependent on the clinical situation. Recent evidence suggests that earlier use of platelets may improve outcomes in bleeding patients.90In rare cases, in patients who become alloimmunized


Surgery_Schwartz

Surgery_Schwartz. but is very dependent on the clinical situation. Recent evidence suggests that earlier use of platelets may improve outcomes in bleeding patients.90In rare cases, in patients who become alloimmunized through previous transfusion or patients who are refractory from sensitization through prior pregnancies, HLA-matched platelets can be used.Plasma. Plasma is the usual source of the vitamin K–dependent factors, the only source of factor V, and carries similar infectious risks as other component therapies. Several plasma products are available. Fresh frozen plasma (FFP) is frozen within hours of donation and can be stored for up to two years at -18°C, but requires 20 to 30 minutes to thaw prior to use, limiting immedi-ate availability. Thawed FFP can be relabeled as thawed plasma, which is immediately transfusable and can be stored for up to 5 days at 2° to 4°C. Liquid plasma is never frozen and can be stored for up to 26 days at 2° to 4°C. In vitro studies demonstrate that liquid plasma


Surgery_Schwartz

Surgery_Schwartz. transfusable and can be stored for up to 5 days at 2° to 4°C. Liquid plasma is never frozen and can be stored for up to 26 days at 2° to 4°C. In vitro studies demonstrate that liquid plasma has a better hemostatic profile than thawed plasma.91 Freeze-dried (lyophilized) plasma (FDP) has been recently “rediscovered” as an ideal resuscitation product for patients in remote and austere environments. FDP is distributed as a powder that is shelf-stable for up to 2 years at room tem-perature and relatively stable at temperature extremes.92 It was used extensively as a primary resuscitation fluid during World War II, but production was stopped due to risk of disease trans-mission. FDP is currently manufactured by updated processes in France, Germany, and South Africa. Several noncomparative studies in the literature have documented its ease of use, rapid reconstitution within minutes, clinical efficacy similar to other plasma products, and lack of apparent adverse events.93,94 The Israeli


Surgery_Schwartz

Surgery_Schwartz. in the literature have documented its ease of use, rapid reconstitution within minutes, clinical efficacy similar to other plasma products, and lack of apparent adverse events.93,94 The Israeli Defense Force has reported successful use of FDP at the point of injury,95 just as it was used in World War II. Beside limited use by U.S. Special Forces under the U.S. Federal Drug Administration’s (FDA) Investigational New Drug (IND) pro-gram, no FDP product is currently approved for general use in the United States. These products have the advantage of being pathogen reduced, have expanded storage capabilities, and can be quickly reconstituted.96Tranexamic Acid. Tranexamic acid (TXA; trade name: Cyk-lokapron) is an antifibrinolytic that inhibits both plasminogen activation and plasmin activity, thus preventing clot breakdown rather than promoting new clot formation. It occupies the lysine-binding sites on plasminogen, thus preventing its binding to lysine residues on fibrin. This reduces


Surgery_Schwartz

Surgery_Schwartz. thus preventing clot breakdown rather than promoting new clot formation. It occupies the lysine-binding sites on plasminogen, thus preventing its binding to lysine residues on fibrin. This reduces plasminogen activation to plasmin. Similarly, blockade of lysine-binding sites on circu-lating plasmin prevents binding to fibrin and thus prevents clot breakdown. TXA is 10 times more potent in vitro than aminoca-proic acid. At therapeutically relevant concentrations, TXA does not affect platelet count or aggregation or coagulation param-eters. It is excreted largely unchanged in urine and has a half-life of about 2 hours in circulation. It has been used to decrease bleeding and the need for blood transfusions in coronary artery Brunicardi_Ch04_p0103-p0130.indd 11629/01/19 11:05 AM 117HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4bypass grafting (CABG), orthotopic liver transplantation, hip and knee arthroplasty, and other surgical settings. TXA has been used to treat injured


Surgery_Schwartz

Surgery_Schwartz. SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4bypass grafting (CABG), orthotopic liver transplantation, hip and knee arthroplasty, and other surgical settings. TXA has been used to treat injured patients in both civilian and military settings.97,98 A recent practice guideline by the Eastern Associa-tion for the Surgery of Trauma (EAST) conditionally recom-mended the use of tranexamic acid as a hemostatic adjunct in severely injured patients when used early after injury.99 There is some controversy if its use should be empiric in patients with hemorrhage or based on documented hyperfibrinolysis. Results of prehospital studies with TXA are not yet available, but there are five ongoing trials. The true risk of venous thrombotic events is also not well established. Therefore, tranexamic acid should not be used with active intravascular clotting and should not be given with activated prothrombin complex concentrate or factor IX complex concentrates.Indications for Replacement of Blood and


Surgery_Schwartz

Surgery_Schwartz. not be used with active intravascular clotting and should not be given with activated prothrombin complex concentrate or factor IX complex concentrates.Indications for Replacement of Blood and Its ElementsImprovement in Oxygen-Carrying Capacity. Oxygencarrying capacity is primarily a function of the red blood cells. Thus, transfusion of red blood cells should augment oxygen-carrying capacity. Additionally, hemoglobin is fundamental to arterial oxygen content and thus oxygen delivery. Despite this obvious association, there is little evidence that actually sup-ports the premise that transfusion of red blood cells equates with enhanced cellular delivery and utilization. The reasons for this apparent discrepancy are related to changes that occur with stor-age of blood. The decrease in 2,3-DPG and P50 impair oxygen offloading, and deformation of the red cells impairs microcir-culatory perfusion.100Treatment of Anemia: Transfusion Triggers. The concept of transfusion triggers refers


Surgery_Schwartz

Surgery_Schwartz. 2,3-DPG and P50 impair oxygen offloading, and deformation of the red cells impairs microcir-culatory perfusion.100Treatment of Anemia: Transfusion Triggers. The concept of transfusion triggers refers primarily to the nonactively bleed-ing ICU patient. A 1988 National Institutes of Health Consensus Report challenged the dictum that a hemoglobin value of less than 10 g/dL or a hematocrit level less than 30% indicates a need for preoperative red blood cell transfusion. This was veri-fied in a prospective randomized controlled trial in critically ill patients that compared a restrictive transfusion threshold to a more liberal strategy and demonstrated that maintaining hemo-globin levels between 7 and 9 g/dL had no adverse effect on mortality. In fact, patients with APACHE II scores of ≤20 or patients age <55 years actually had a lower mortality.101One unresolved issue related to transfusion triggers is the safety of maintaining a hemoglobin of 7 g/dL in a patient with ischemic heart


Surgery_Schwartz

Surgery_Schwartz. or patients age <55 years actually had a lower mortality.101One unresolved issue related to transfusion triggers is the safety of maintaining a hemoglobin of 7 g/dL in a patient with ischemic heart disease. Data on this subject are mixed, and many studies have significant design flaws, including their ret-rospective nature. However, the majority of the published data favors a restrictive transfusion trigger for patients with non–ST-elevation acute coronary syndrome, with many reporting worse outcomes in those patients receiving transfusions.102,103 Recent guidelines from the American Association of Blood Banks (AABB) recommend a minimum threshold of 7 g/dL for hemodynamically stable patients and 8 g/dL for patients under-going cardiac surgery, orthopedic surgery, and those with pre-existing cardiovascular disease.104 However, both the SCCM/EAST and AABB guidelines recommend taking into account patient-specific characteristics and the overall clinical context when considering RBC


Surgery_Schwartz

Surgery_Schwartz. cardiovascular disease.104 However, both the SCCM/EAST and AABB guidelines recommend taking into account patient-specific characteristics and the overall clinical context when considering RBC transfusions in non-acutely hemorrhag-ing patients. Patients with symptomatic anemia should be trans-fused one RBC unit at a time, and isolated asymptomatic anemia in and of itself is rarely an indication for RBC transfusion.Volume ReplacementThe most common indication for blood transfusion in surgical patients is the replenishment of the blood volume; however, the quantification of actual intravascular volume deficit is often difficult to accurately and quickly determine. Measure-ments of hemoglobin or hematocrit levels are frequently used to assess blood loss, but can be occasionally misleading in the face of acute loss.105 Both the amount and the rate of bleeding are factors in the development of signs and symptoms of blood loss.Loss of blood in the operating room can be roughly evalu-ated by


Surgery_Schwartz

Surgery_Schwartz. the face of acute loss.105 Both the amount and the rate of bleeding are factors in the development of signs and symptoms of blood loss.Loss of blood in the operating room can be roughly evalu-ated by estimating the amount of blood in the wound and on the drapes, weighing the sponges, and quantifying blood suctioned from the operative field. Significant blood loss will require a balanced resuscitation including red blood cells, FFP, and plate-lets (detailed later in this chapter) (Table 4-5).New Concepts in ResuscitationTraditional resuscitation algorithms were sequentially based on crystalloid followed by red blood cells and then plasma and platelet transfusions, and they have been in widespread use since the 1970s. No quality clinical data supported this concept. Recently the damage control resuscitation (DCR)105a strategy, with simultaneous measures to acquire mechanical hemorrhage control, has become the standard for treatment of substantial traumatic hemorrhage. DCR emphasizes


Surgery_Schwartz

Surgery_Schwartz. resuscitation (DCR)105a strategy, with simultaneous measures to acquire mechanical hemorrhage control, has become the standard for treatment of substantial traumatic hemorrhage. DCR emphasizes rapid maneuvers that promote hemostasis (balanced resuscitation with early delivery of plasma and platelets) while limiting iatrogenic insults that exacerbate bleeding (i.e., minimization of crystalloid and artifi-cial colloid, permissive hypotension), combined with multiple adjuncts for hemorrhage control.Rationale. In urban civilian trauma systems, nearly half of all deaths happen before a patient reaches the hospital.106 Patients who survive to an emergency center have a high incidence of truncal hemorrhage, and deaths in this group of patients may be potentially preventable. Truncal hemorrhage patients in shock often present with the early coagulopathy of trauma in the emer-gency department and are at significant risk of dying.107-109Many of these patients have suffered substantial bleeding,


Surgery_Schwartz

Surgery_Schwartz. in shock often present with the early coagulopathy of trauma in the emer-gency department and are at significant risk of dying.107-109Many of these patients have suffered substantial bleeding, generally defined as requiring the administration of ≥3 units of red blood cells within any hour of admission, and may have received a massive transfusion (MT), traditionally defined as ≥10 units of red blood cells in 24 hours.110 The traditional defi-nition is admittedly arbitrary and fails to identify many patients who truly receive large volume transfusions in a short period of time, further promoting survival bas. Newer definitions evaluating massive transfusion do so by taking into account both volume transfused as well as the rate at which transfu-sions are given. The critical administration threshold (CAT) has been prospectively validated and shown to be a superior predictor of mortality when compared to the conventional defi-nition of MT.110 By this measure, CAT-positive status is


Surgery_Schwartz

Surgery_Schwartz. threshold (CAT) has been prospectively validated and shown to be a superior predictor of mortality when compared to the conventional defi-nition of MT.110 By this measure, CAT-positive status is defined by transfusion of 3 units of red blood cells within a 60-minute period, and this is additive for each additional time this measure is reached. CAT-positive status is associated with a two-fold increase in risk of mortality. CAT is more sensitive than tra-ditional definitions of bleeding and allows for both earlier and more accurate identification of injured patients at greatest risk of death.Although 25% of all severely injured trauma admissions receive a unit of blood early after admission, only a small Brunicardi_Ch04_p0103-p0130.indd 11729/01/19 11:05 AM 118BASIC CONSIDERATIONSPART ITable 4-5Replacement of clotting factorsFACTORNORMAL LEVELLIFE SPAN IN VIVO (HALF-LIFE)FATE DURING COAGULATIONLEVEL REQUIRED FOR SAFE HEMOSTASISIDEAL AGENT ACD BANK BLOOD (4°C [39.2°F])IDEAL AGENT


Surgery_Schwartz

Surgery_Schwartz. 4-5Replacement of clotting factorsFACTORNORMAL LEVELLIFE SPAN IN VIVO (HALF-LIFE)FATE DURING COAGULATIONLEVEL REQUIRED FOR SAFE HEMOSTASISIDEAL AGENT ACD BANK BLOOD (4°C [39.2°F])IDEAL AGENT FOR REPLACING DEFICITI (fibrinogen)200–400 mg/100 mL72 hConsumed60–100 mg/100 mLVery stableBank blood; concentrated fibrinogenII (prothrombin)20 mg/100 mL (100% of normal level)72 hConsumed15%–20%StableBank blood; concentrated preparationV (proaccelerin, accelerator globulin, labile factor)100% of normal level36 hConsumed5%–20%Labile (40% of normal level at 1 wk)Fresh frozen plasma; blood under 7 dVII (proconvertin, serum prothrombin conversion accelerator, stable factor)100% of normal level5 hSurvives5%–30%StableBank blood; concentrated preparationVIII (antihemophilic factor, antihemophilic globulin)100% of normal level (50%–150% of normal level)6–12 hConsumed30%Labile (20%–40% of normal level at 1 wk)Fresh frozen plasma; concentrated antihemophilic factor; cryoprecipitateIX (Christmas factor,


Surgery_Schwartz

Surgery_Schwartz. of normal level (50%–150% of normal level)6–12 hConsumed30%Labile (20%–40% of normal level at 1 wk)Fresh frozen plasma; concentrated antihemophilic factor; cryoprecipitateIX (Christmas factor, plasma thromboplastin component)100% of normal level24 hSurvives20%–30%StableFresh-frozen plasma; bank blood; concentrated preparationX (Stuart-Prower factor)100% of normal level40 hSurvives15%–20%StableBank blood; concentrated preparationXI (plasma thromboplastin antecedent)100% of normal levelProbably 40–80 hSurvives10%Probably stableBank bloodXII (Hageman factor)100% of normal levelUnknownSurvivesDeficit produces no bleeding tendencyStableReplacement not requiredXIII (fibrinase, fibrin-stabilizing factor)100% of normal level4–7 dSurvivesProbably <1%StableBank bloodPlatelets150,000–400,000/μL8–11 dConsumed60,000–100,000/μLVery labile (40% of normal level at 20 h; 0 at 48 h)Fresh blood or plasma; fresh platelet concentrate (not frozen plasma)ACD = acid-citrate-dextrose.Reproduced with


Surgery_Schwartz

Surgery_Schwartz. dConsumed60,000–100,000/μLVery labile (40% of normal level at 20 h; 0 at 48 h)Fresh blood or plasma; fresh platelet concentrate (not frozen plasma)ACD = acid-citrate-dextrose.Reproduced with permission from Kinney JM, Egdahl RH, Zuidema GD: Manual of Preoperative and Postoperative Care, 2nd ed. Philadelphia, PA: WB Saunders/Elsevier; 1971.Brunicardi_Ch04_p0103-p0130.indd 11829/01/19 11:05 AM 119HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4percentage of patients receive a massive transfusion. In the military setting, the percentage of massive transfusion patients almost doubles.111Damage Control Resuscitation. Prior to DCR, resuscitation guidelines advocated volume replacement with crystalloid, fol-lowed by packed red blood cell and only later plasma or platelets.112 This conventional massive transfusion practice was based on a several small uncontrolled retrospective studies that used blood products containing increased amounts of plasma, which are no longer


Surgery_Schwartz

Surgery_Schwartz. This conventional massive transfusion practice was based on a several small uncontrolled retrospective studies that used blood products containing increased amounts of plasma, which are no longer available.113 Because of the known early coagulopathy of trauma, the current approach to managing the exsanguinating patient involves early implementation of DCR. Although most of the attention to hemorrhagic shock resuscitation has centered on higher ratios of plasma and platelets, DCR is actually composed of four basic components: permissive hypotension, minimizing crystalloid-based resusci-tation, the immediate release and administration of predefined balanced blood products (red blood cells, plasma, and platelets) in ratios similar to those of whole blood, and the use of hemo-static adjuncts.The shift to DCR began in earnest in 2007 when a retro-spective study of 246 military casualties reported that patients with high plasma:RBC ratio (median 1:1.4) had substantially reduced mortality


Surgery_Schwartz

Surgery_Schwartz. shift to DCR began in earnest in 2007 when a retro-spective study of 246 military casualties reported that patients with high plasma:RBC ratio (median 1:1.4) had substantially reduced mortality (19% vs. 65%) compared to patients with low plasma:RBC ratio (median 1:8).114 Subsequent observational studies among civilian and military trauma patients corrobo-rated these findings.115-118 In particular, the prospective, obser-vational, multicenter, major trauma transfusion (PROMMTT) study119 found that hemorrhagic death occurred rapidly (median of 2 to 3 hours after hospital arrival) and that plasma:RBC and platelet:RBC ratios significantly varied during massive trans-fusion. Increased plasma:RBC (adjusted hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.16-0.58) and increased platelet:RBC (adjusted HR 0.55, 95% CI 0.31-0.98) were associated with reduced 6-hour mortality, when risk of hemor-rhagic death was highest. After 6 hours, however, increasing plasma:RBC and platelet:RBC were


Surgery_Schwartz

Surgery_Schwartz. (adjusted HR 0.55, 95% CI 0.31-0.98) were associated with reduced 6-hour mortality, when risk of hemor-rhagic death was highest. After 6 hours, however, increasing plasma:RBC and platelet:RBC were no longer associated with reduced mortality due to increasing competing risk for non-hemorrhagic death (e.g., traumatic brain injury). The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial120 randomized 680 bleeding trauma patients across 12 highest-level trauma centers to resuscitation with 1:1:1 vs. 1:1:2 plasma to platelets to RBCs. Although there was no significant difference in mortality at 24 hours (13% vs. 17%) or 30 days (22% vs. 26%), the 1:1:1 group had significantly decreased mortality due to hemorrhage at 24 hours (9% vs. 15%) and more patients achieving hemostasis (86% vs. 78%). Despite fears that resuscitation with increased plasma volumes would lead to more inflammatory complications, there were no between-group differences in 23 prespecified secondary


Surgery_Schwartz

Surgery_Schwartz. (86% vs. 78%). Despite fears that resuscitation with increased plasma volumes would lead to more inflammatory complications, there were no between-group differences in 23 prespecified secondary outcomes, including acute respiratory distress syndrome, sepsis, multiple organ failure, and venous thromboembolism. A recent system-atic review/meta-analysis and practice management guideline from EAST reported reduced mortality (31% vs. 38%) in 5292 patients receiving high (≥1:1) versus low (<1:2) plasma to RBC, and reduced mortality (28% vs. 43%) in 1607 patients receiving high versus low platelet to RBC.99 The authors therefore recom-mend high and balanced ratio (≥1:1) of plasma and platelet to RBC for resuscitation of severely injured trauma patients.The mechanism for these benefits are unclear. While cor-rection of hypovolemia as well as augmention of the patient’s hemostatic potential with clotting factors and platelets are impor-tant, other plasma proteins likely play key roles as well.


Surgery_Schwartz

Surgery_Schwartz. While cor-rection of hypovolemia as well as augmention of the patient’s hemostatic potential with clotting factors and platelets are impor-tant, other plasma proteins likely play key roles as well. Recently, plasma resuscitation has been shown to reverse endothelial injury in animal models of hemorrhagic shock, particularly by repair of the endothelial glycocalyx layer (EGL).121,122 The EGL is the primary determinant of vascular permeability.123 Hemorrhage results in shedding of EGL components and vascular perme-ability. Crystalloid and artificial colloid-based resuscitation increases the hydrostatic pressure without repairing the EGL, which likely contributes to the myriad of edema-related com-plications seen in the pre-DCR era. Plasma, on the other hand, repairs the EGL, limiting extravascular leakage and edema. However, the exact protein moieties that mediate these benefits have yet to be identified and remain an area of investigation. Nevertheless, several studies have reported


Surgery_Schwartz

Surgery_Schwartz. leakage and edema. However, the exact protein moieties that mediate these benefits have yet to be identified and remain an area of investigation. Nevertheless, several studies have reported decreased inflam-matory and edema-related complications with increased plasma and decreased crystalloid utilization. In trauma patients, there are strong correlations between increasing circulating levels of glycocalyx components such as syndecan-1 and trauma severity, coagulopathy, and mortality,124-126 although it remains unclear if these relationships are causative or merely associative. Finally, the use of DCR principles to guide transfusion of substantial nontraumatic hemorrhage is intuitive, although there is little evidence in the literature to support this practice.It is essential that the trauma center has an established mechanism to deliver these products quickly and in the correct amounts to these critically injured patients.99 An example of an adult massive transfusion clinical


Surgery_Schwartz

Surgery_Schwartz. the trauma center has an established mechanism to deliver these products quickly and in the correct amounts to these critically injured patients.99 An example of an adult massive transfusion clinical guideline specifying the early use of component therapy is shown in Table 4-6. Specific rec-ommendations for the administration of component ther-apy during a massive transfusion are shown in Table 4-7.Because only a small percentage of trauma patients require a massive transfusion and because blood products in general are in short supply, there is a need for early prediction models.127 A comparison of results from existing models in both civilian and military studies is shown in Table 4-8.128-132 While compel-ling, many of these models require laboratory data, complicated injury severity scores, or calculated values that are not readily available or feasible to obtain in the urgent setting of bleeding. The Assessment of Blood Consumption (ABC) score is a sim-plified score to predict


Surgery_Schwartz

Surgery_Schwartz. scores, or calculated values that are not readily available or feasible to obtain in the urgent setting of bleeding. The Assessment of Blood Consumption (ABC) score is a sim-plified score to predict massive transfusion after trauma using immediately available data (heart rate, blood pressure, FAST exam, mechanism of injury).132 The ABC score has been vali-dated across multiple trauma centers; however, it may be limited in some centers by the variable use of and operator-dependent FAST examination. In using the ABC score as it was intended, less than 5% of patients who will require massive transfusion will be missed; and 85% of all major trauma patients will be correctly identified.Prehospital TransfusionIn bleeding patients, earlier initiation of appropriate therapy improves outcomes. For example, decreased overall blood product use and increased 30-day survival was observed after moving four units of universal donor, ready-to-transfuse plasma from the blood bank to the emergency


Surgery_Schwartz

Surgery_Schwartz. For example, decreased overall blood product use and increased 30-day survival was observed after moving four units of universal donor, ready-to-transfuse plasma from the blood bank to the emergency department and using the plasma as a primary resuscitation fluid.133 A prehospital retrospective study that analyzed 1677 severely injured trauma patients who were transported by helicopter found that in-flight plasma transfusion was associated with less deranged physiol-ogy on admission and reduced early mortality in the most criti-cally ill patients.134 Prehospital RBC transfusion has also been 56Brunicardi_Ch04_p0103-p0130.indd 11929/01/19 11:05 AM 120BASIC CONSIDERATIONSPART ITable 4-6Adult transfusion clinical practice guidelineA. Initial Transfusion of Red Blood Cells (RBCs):1. Notify blood bank immediately of urgent need for RBCs.O negative uncrossmatched (available immediately).As soon as possible, switch to O negative for females and O positive for males.Type-specific


Surgery_Schwartz

Surgery_Schwartz. blood bank immediately of urgent need for RBCs.O negative uncrossmatched (available immediately).As soon as possible, switch to O negative for females and O positive for males.Type-specific uncrossmatched (available in approximately 5–10 min).Completely crossmatched (available in approximately 40 min).2. A blood sample must be sent to blood bank for a type and cross.3. The Emergency Release of Blood form must be completed. If the blood type is not known and blood is needed immediately, O-negative RBCs should be issued.4. RBCs will be transfused in the standard fashion. All patients must be identified (name and number) prior to transfusion.5. Patients who are unstable or receive 1–2 RBCs and do not rapidly respond should be considered candidates for the massive transfusion (MT) guideline.B. Adult Massive Transfusion Guideline:1. The Massive Transfusion Guideline (MTG) should be initiated as soon as it is anticipated that a patient will require massive transfusion. The blood bank should


Surgery_Schwartz

Surgery_Schwartz. Massive Transfusion Guideline:1. The Massive Transfusion Guideline (MTG) should be initiated as soon as it is anticipated that a patient will require massive transfusion. The blood bank should strive to deliver plasma, platelets, and RBCs in a 1:1:1 ratio. To be effective and minimize further dilutional coagulopathy, the 1:1:1 ratio must be initiated early, ideally with the first 2 units of transfused RBCs. Crystalloid infusion should be minimized.2. Once the MTG is activated, the blood bank will have 6 RBCs, 6 FFP, and a 6-pack of platelets packed in a cooler available for rapid transport. If 6 units of thawed FFP are not immediately available, the blood bank will issue units that are ready and notify appropriate personnel when the remainder is thawed. Every attempt should be made to obtain a 1:1:1 ratio of plasma:platelets:RBCs.3. Once initiated, the MT will continue until stopped by the attending physician. MT should be terminated once the patient is no longer actively


Surgery_Schwartz

Surgery_Schwartz. made to obtain a 1:1:1 ratio of plasma:platelets:RBCs.3. Once initiated, the MT will continue until stopped by the attending physician. MT should be terminated once the patient is no longer actively bleeding.4. No blood components will be issued without a pickup slip with the recipient’s medical record number and name.5. Basic laboratory tests should be drawn immediately on ED arrival and optimally performed on point-of-care devices, facilitating timely delivery of relevant information to the attending clinicians. These tests should be repeated as clinically indicated (e.g., after each cooler of products has been transfused). Suggested laboratory values are:• CBC• INR, fibrinogen• pH and/or base deficit• TEG, where availableCBC = complete blood count; ED = emergency department; FFP = fresh frozen plasma; INR = international normalized ratio; TEG = thromboelastography.Table 4-7Component therapy administration during massive transfusionFresh frozen plasma (FFP)As soon as the need for


Surgery_Schwartz

Surgery_Schwartz. frozen plasma; INR = international normalized ratio; TEG = thromboelastography.Table 4-7Component therapy administration during massive transfusionFresh frozen plasma (FFP)As soon as the need for massive transfusion is recognized.For every 6 red blood cells (RBCs), give 6 FFP (1:1 ratio).PlateletsFor every 6 RBCs and plasma, give one 6-pack of platelets. 6 random-donor platelet packs = 1 apheresis platelet unit.Platelets are in every cooler.Keep platelet counts >100,000.CryoprecipitateAfter first 6 RBCs, check fibrinogen level. If ≤200 mg/dL, give 20 units cryoprecipitate (2 g fibrinogen). Repeat as needed, depending on fibrinogen level, and request appropriate amount of cryoprecipitate.Table 4-8Comparison of massive transfusion prediction studiesAUTHORVARIABLESROC AUC VALUEMcLaughlin et al128SBP, HR, pH, Hct0.839Yücel et al129SBP, HR, BD, Hgb, male, + FAST, long bone/pelvic fracture0.892Moore et al130SBP, pH, ISS >250.804Schreiber et al131Hgb ≤11, INR >1.5, penetrating


Surgery_Schwartz

Surgery_Schwartz. et al128SBP, HR, pH, Hct0.839Yücel et al129SBP, HR, BD, Hgb, male, + FAST, long bone/pelvic fracture0.892Moore et al130SBP, pH, ISS >250.804Schreiber et al131Hgb ≤11, INR >1.5, penetrating injury0.80Cotton et al132HR, SBP, FAST, penetrating injury0.83–0.90AUC = area under the curve; BD = base deficit; FAST = focused assessment with sonography for trauma; Hct = hematocrit; Hgb = hemoglobin; HR = heart rate; INR = international normalized ratio; ISS = injury severity score; ROC = receiver operating characteristic; SBP = systolic blood pressure.Brunicardi_Ch04_p0103-p0130.indd 12029/01/19 11:05 AM 121HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4Nonhemolytic Reactions. Febrile, nonhemolytic reactions are defined as an increase in temperature (>1°C) associated with a transfusion and are fairly common (approximately 1% of all transfusions). Preformed cytokines in donated blood and recipi-ent antibodies reacting with donated antibodies are postulated eti-ologies. The incidence


Surgery_Schwartz

Surgery_Schwartz. and are fairly common (approximately 1% of all transfusions). Preformed cytokines in donated blood and recipi-ent antibodies reacting with donated antibodies are postulated eti-ologies. The incidence of febrile reactions can be greatly reduced by the use of leukocyte-reduced blood products. Pretreatment with acetaminophen reduces the severity of the reaction.Bacterial contamination of infused blood is rare. Gram-negative organisms, which are capable of growth at 4°C, are the most common cause. Most cases, however, are associated with the administration of platelets that are stored at 20°C or, even more commonly, with apheresis platelets stored at room tem-perature. Cases from FFP thawed in contaminated water baths have also been reported.150 Bacterial contamination can result in sepsis and death in up 25% of patients.151 Clinical manifesta-tions includes systemic signs such as fever and chills, tachycar-dia and hypotension, and gastrointestinal symptoms (abdominal cramps, vomiting,


Surgery_Schwartz

Surgery_Schwartz. and death in up 25% of patients.151 Clinical manifesta-tions includes systemic signs such as fever and chills, tachycar-dia and hypotension, and gastrointestinal symptoms (abdominal cramps, vomiting, and diarrhea). If the diagnosis is suspected, the transfusion should be discontinued and the blood cultured. Emergency treatment includes oxygen, adrenergic blocking agents, and antibiotics.Allergic Reactions. Allergic reactions are relatively frequent, occurring in about 1% of all transfusions. Reactions are usually mild and consist of rash, urticaria, and flushing. In rare instances, anaphylactic shock develops. Allergic reactions are caused by the transfusion of antibodies from hypersensitive donors or the trans-fusion of antigens to which the recipient is hypersensitive. Allergic reactions can occur after the administration of any blood product but are commonly associated with FFP and platelets. Treatment and prophylaxis consist of the administration of antihistamines. In more serious


Surgery_Schwartz

Surgery_Schwartz. can occur after the administration of any blood product but are commonly associated with FFP and platelets. Treatment and prophylaxis consist of the administration of antihistamines. In more serious cases, epinephrine or steroids may be indicated.Respiratory Complications. Respiratory compromise may be associated with transfusion-associated circulatory overload (TACO), which is an avoidable complication. It can occur with rapid infusion of blood, plasma expanders, and crystalloids, par-ticularly in older patients with underlying heart disease. Central venous pressure monitoring should be considered whenever large amounts of fluid are administered. Overload is manifested by a rise in venous pressure, dyspnea, and cough. Rales can gen-erally be heard at the lung bases. Treatment consists of diuresis, slowing the rate of blood administration, and minimizing fluids while blood products are being transfused.The syndrome of TRALI is defined as noncardiogenic pulmonary edema related to


Surgery_Schwartz

Surgery_Schwartz. of diuresis, slowing the rate of blood administration, and minimizing fluids while blood products are being transfused.The syndrome of TRALI is defined as noncardiogenic pulmonary edema related to transfusion.152 It can occur with the administration of any plasma-containing blood product. Symptoms are similar to circulatory overload with dyspnea and associated hypoxemia. However, TRALI is characterized as noncardiogenic and is often accompanied by fever, rigors, and bilateral pulmonary infiltrates on chest X-ray. It most com-monly occurs within 1 to 2 hours after the onset of transfusion but virtually always before 6 hours. Toy et al reported a decrease in the incidence of TRALI with the reduction transfusion of plasma from female donors, due to a combination of reduced transfusion of strong cognate HLA class II antibodies and HNA antibodies in patients with risk factors for acute lung injury.153 TRALI now occurs less than 1 in 10,000 units transfused and is usually self-limited with


Surgery_Schwartz

Surgery_Schwartz. cognate HLA class II antibodies and HNA antibodies in patients with risk factors for acute lung injury.153 TRALI now occurs less than 1 in 10,000 units transfused and is usually self-limited with supportive therapy. Treatment of TRALI entails discontinuation of any transfusion, notification of the transfusion service, and pulmonary support, which may vary from supplemental oxygen to mechanical ventilation.associated with similar findings.135 In the military setting, imple-mentation of prehospital transfusion protocols in conjunction with other measures, including more rapid transport times, was also associated with reduced mortality.136Whole Blood ResuscitationMilitary experience with whole blood for the resuscitation of traumatic hemorrhage is extensive, going back to the American Civil War. In the modern era, more than 10,000 whole blood units were transfused during Operations Enduring Freedom and Iraqi Freedom. One key advantage of whole blood ver-sus component therapy is that


Surgery_Schwartz

Surgery_Schwartz. War. In the modern era, more than 10,000 whole blood units were transfused during Operations Enduring Freedom and Iraqi Freedom. One key advantage of whole blood ver-sus component therapy is that platelets are often unavailable in the remote and austere settings. Two retrospective studies of military casualties treated at a combat support hospital and forward surgical teams found that whole blood was associated with improved survival compared to component (plasma and RBC) therapy.137,138 Whole blood has higher hematocrit, clotting factor activity, and platelet count compared to 1:1:1 component therapy due to relatively less diluent volume in whole blood. During the Vietnam War, low anti-A and anti-B titer whole blood was transfused universally with a low incidence of hemo-lytic reactions (1 per 9600 units).139 An in vitro study found that the hemostatic potential of whole blood was preserved for up to 14 days with cold storage.140 Pilot trials have reported success-ful use of


Surgery_Schwartz

Surgery_Schwartz. (1 per 9600 units).139 An in vitro study found that the hemostatic potential of whole blood was preserved for up to 14 days with cold storage.140 Pilot trials have reported success-ful use of crossmatched modified whole blood (leukoreduced and platelet-poor)141 and uncrossmatched low-titer whole blood (leukoreduced, containing platelets)142 in the initial resuscita-tion of civilian trauma patients. In the future, whole blood may return as the therapy of choice for the initial resuscitation of substantial hemorrhage.143Fibrinogen ReplacementFibrinogen is the first coagulation factor to fall to critically low levels during major hemorrhage, and low systemic concentra-tions of fibrinogen are associated with increased severity of injury and coagulopathy and are independently predictive of mortality.144,145 Additionally, fibrinogen levels drop in the pre-hospital phase of injury, suggesting early administration by fibrinogen concentrate (not FDA-approved) or cryoprecipitate is needed.146


Surgery_Schwartz

Surgery_Schwartz. Additionally, fibrinogen levels drop in the pre-hospital phase of injury, suggesting early administration by fibrinogen concentrate (not FDA-approved) or cryoprecipitate is needed.146 Fibrinogen concentrate is stored as a lyophilized powder at room temperature and can be reconstituted quickly allowing for rapid administration without delays for thawing or crossmatching.147 In contrast to plasma, viral inactivation steps are routinely included in the manufacturing process for fibrino-gen concentrate, thus minimizing the risk of viral transmission. A pilot trial of massively transfused trauma patients randomized to a massive transfusion protocol or a massive transfusion pro-tocol with early cryoprecipitate found that early cryoprecipitate delivery was feasible and that these patients had higher fibrino-gen levels at all time points during resuscitation, although there was no mortality difference.148 A randomized control trial in Austria of prehospital fibrinogen concentrate versus


Surgery_Schwartz

Surgery_Schwartz. higher fibrino-gen levels at all time points during resuscitation, although there was no mortality difference.148 A randomized control trial in Austria of prehospital fibrinogen concentrate versus placebo has been completed with publication of results pending.149Complications of Transfusion (Table 4-9)Transfusion-related complications are primarily related to blood-induced proinflammatory responses. Transfusion-related149a events are estimated to occur in approximately 10% of all trans-fusions, but less than 0.5% are serious in nature. Transfusionrelated deaths, although exceedingly rare, do occur and are related primarily to transfusion-related acute lung injury (TRALI), ABO hemolytic transfusion reactions, and bacterial contamination of platelets.Brunicardi_Ch04_p0103-p0130.indd 12129/01/19 11:05 AM 122BASIC CONSIDERATIONSPART IHemolytic Reactions. Hemolytic reactions can be classified as either acute or delayed. Acute hemolytic reactions occur with the administration of


Surgery_Schwartz

Surgery_Schwartz. 12129/01/19 11:05 AM 122BASIC CONSIDERATIONSPART IHemolytic Reactions. Hemolytic reactions can be classified as either acute or delayed. Acute hemolytic reactions occur with the administration of ABO-incompatible blood and can be fatal in up to 6% of cases. Contributing factors include errors in the laboratory of a technical or clerical nature or the administra-tion of the wrong blood type. Immediate hemolytic reactions are characterized by intravascular destruction of red blood cells and consequent hemoglobinemia and hemoglobinuria. DIC can be initiated by antibody-antigen complexes activating factor XII and complement, leading to activation of the coagulation cas-cade. Finally, acute renal insufficiency results from the toxicity associated with free hemoglobin in the plasma, resulting in tubu-lar necrosis and precipitation of hemoglobin within the tubules.Delayed hemolytic transfusion reactions occur 2 to 10 days after transfusion and are characterized by extravascular


Surgery_Schwartz

Surgery_Schwartz. resulting in tubu-lar necrosis and precipitation of hemoglobin within the tubules.Delayed hemolytic transfusion reactions occur 2 to 10 days after transfusion and are characterized by extravascular hemolysis, mild anemia, and indirect (unconjugated) hyperbili-rubinemia. They occur when an individual has a low antibody titer at the time of transfusion, but the titer increases after trans-fusion as a result of an anamnestic response. Reactions to non-ABO antigens involve immunoglobulin G-mediated clearance by the reticuloendothelial system.If the patient is awake, the most common symptoms of acute transfusion reactions are pain at the site of transfusion, facial flushing, and back and chest pain. Associated symptoms include fever, respiratory distress, hypotension, and tachycardia. In anesthetized patients, diffuse bleeding and hypotension are the hallmarks. A high index of suspicion is needed to make the diag-nosis. The laboratory criteria for a transfusion reaction are


Surgery_Schwartz

Surgery_Schwartz. In anesthetized patients, diffuse bleeding and hypotension are the hallmarks. A high index of suspicion is needed to make the diag-nosis. The laboratory criteria for a transfusion reaction are hemo-globinuria and serologic criteria that show incompatibility of the donor and recipient blood. A positive Coombs’ test indicates Table 4-9Transfusion-related complicationsABBREVIATIONCOMPLICATIONSIGNS AND SYMPTOMSFREQUENCYMECHANISMPREVENTIONNHTRFebrile, nonhemolytic transfusion reactionFever0.5%–1.5% of transfusionsPreformed cytokinesHost Ab to donor lymphocytesUse leukocyte-reduced bloodStore platelets <5 d Bacterial contaminationHigh fever, chillsHemodynamic changesDICEmesis, diarrheaHemoglobinuria<0.01% of blood<0.05% of plateletsInfusion of contaminated blood Allergic reactionsRash, hivesItching0.1%–0.3% of unitsSoluble transfusion constituentsProvide antihistamine prophylaxisTACOTransfusion-associated circulatory overloadPulmonary edema1:200–1:10,00 of transfused patientsLarge volume


Surgery_Schwartz

Surgery_Schwartz. of unitsSoluble transfusion constituentsProvide antihistamine prophylaxisTACOTransfusion-associated circulatory overloadPulmonary edema1:200–1:10,00 of transfused patientsLarge volume of blood transfused into an older patient with CHFIncrease transfusion timeAdminister diureticsMinimize associated fluidsTRALITransfusion-related acute lung injuryAcute (<6 h) hypoxemiaBilateral infiltrates ± Tachycardia, hypotension Anti-HLA or anti-HNA Ab in transfused blood attacks circulatory and pulmonary leukocytesLimit female donors Hemolytic reaction, acuteFeverHypotensionDICHemoglobinuriaHemoglobinemiaRenal insufficiency1:33,000–1:1,500,000 unitsTransfusion of ABO-incompatible bloodPreformed IgM Ab to ABO AgTransfuse appropriately matched blood Hemolytic reaction, delayed (2–10 d)AnemiaIndirect hyperbilirubinemiaDecreased haptoglobin levelPositive result on direct Coombs’ test IgG mediatedIdentify patient’s Ag to prevent recurrenceAb = antibody; Ag = antigen; CHF = congestive heart failure; DIC


Surgery_Schwartz

Surgery_Schwartz. haptoglobin levelPositive result on direct Coombs’ test IgG mediatedIdentify patient’s Ag to prevent recurrenceAb = antibody; Ag = antigen; CHF = congestive heart failure; DIC = disseminated intravascular coagulation; HLA = human leukocyte antigen; HNA = anti-human neutrophil antigen; IgG = immunoglobulin G; IgM = immunoglobulin M.Brunicardi_Ch04_p0103-p0130.indd 12229/01/19 11:05 AM 123HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4transfused cells coated with patient antibody and is diagnostic. Delayed hemolytic transfusions may also be manifested by fever and recurrent anemia. Jaundice and decreased haptoglobin usu-ally occur, and low-grade hemoglobinemia and hemoglobinuria may be seen. The Coombs’ test is usually positive, and the blood bank must identify the antigen to prevent subsequent reactions.If an immediate hemolytic transfusion reaction is sus-pected, the transfusion should be stopped immediately, and a sample of the recipient’s blood drawn and sent along with


Surgery_Schwartz

Surgery_Schwartz. subsequent reactions.If an immediate hemolytic transfusion reaction is sus-pected, the transfusion should be stopped immediately, and a sample of the recipient’s blood drawn and sent along with the suspected unit to the blood bank for comparison with the pretransfusion samples. Urine output should be monitored and adequate hydration maintained to prevent precipitation of hemo-globin within the tubules. Delayed hemolytic transfusion reac-tions do not usually require specific intervention.Transmission of Disease. Malaria, Chagas’ disease, brucel-losis, and, very rarely, syphilis are among the diseases that have been transmitted by transfusion. Malaria can be transmitted by all blood components. The species most commonly implicated is Plasmodium malariae. The incubation period ranges from 8 to 100 days; the initial manifestations are shaking chills and spiking fever. Cytomegalovirus (CMV) infection resembling infectious mononucleosis also has occurred.Transmission of hepatitis C and


Surgery_Schwartz

Surgery_Schwartz. 8 to 100 days; the initial manifestations are shaking chills and spiking fever. Cytomegalovirus (CMV) infection resembling infectious mononucleosis also has occurred.Transmission of hepatitis C and HIV-1 has been dra-matically minimized by the introduction of better antibody and nucleic acid screening for these pathogens. The residual risk among allogeneic donations is now estimated to be less than 1 per 1,000,000 donations. The residual risk of hepatitis B is approximately 1 per 300,000 donations.154 Hepatitis A is very rarely transmitted because there is no asymptomatic carrier state. Improved donor selection and testing are responsible for the decreased rates of transmission. Recent concerns about the rare transmission of these and other pathogens, such as West Nile virus, are being addressed by current trials of “pathogen inactivation systems” that reduce infectious levels of all viruses and bacteria known to be transmittable by transfusion. Prion dis-orders (e.g.,


Surgery_Schwartz

Surgery_Schwartz. are being addressed by current trials of “pathogen inactivation systems” that reduce infectious levels of all viruses and bacteria known to be transmittable by transfusion. Prion dis-orders (e.g., Creutzfeldt-Jakob disease) also are transmissible by transfusion, but there is currently no information on inactivation of prions in blood products for transfusion.Recently, there is heightened concern of transmission of Zika virus by blood product transfusion. Studies in endemic areas have shown rates of Zika infection detected in donor blood as high as 2.8%.155 Although no such cases have been reported in the United States, transmission of Zika virus via platelet products have been reported in Brazil.156 Zika virus may result in serious birth defects including microcephaly when infection occurs in pregnant women. Because the majority of cases in adults produce nonspecific or no symptoms, Zika screening cannot be accomplished by questionnaires.157 The Centers for Disease Control and


Surgery_Schwartz

Surgery_Schwartz. occurs in pregnant women. Because the majority of cases in adults produce nonspecific or no symptoms, Zika screening cannot be accomplished by questionnaires.157 The Centers for Disease Control and Prevention has issued guidelines for screen-ing of Zika virus in donated blood. Although no tests have been FDA-approved, laboratory testing is currently being performed under the FDA’s IND program.TESTS OF HEMOSTASIS AND BLOOD COAGULATIONThe initial approach to assessing hemostatic function is a careful review of the patient’s clinical history (including previous abnor-mal bleeding or bruising), drug use, and basic laboratory testing.Conventional Coagulation Tests. Common screening labo-ratory testing includes platelet count, PT or INR, and aPTT. Platelet dysfunction can occur at either extreme of platelet count. The normal platelet count ranges from 150,000 to 400,000/μL. Whereas a platelet count greater than 1,000,000/μL may be associated with bleeding or thrombotic complications,


Surgery_Schwartz

Surgery_Schwartz. extreme of platelet count. The normal platelet count ranges from 150,000 to 400,000/μL. Whereas a platelet count greater than 1,000,000/μL may be associated with bleeding or thrombotic complications, increased bleeding complications may be observed with major surgical procedures when the platelets are below 50,000/μL and with minor surgical procedures when counts are below 30,000/μL, and spontaneous hemorrhage can occur when the counts fall below 20,000/μL. Despite a lack of evidence supporting their use, platelet transfusions are still recommended in ophthalmo-logic and neurosurgical procedures when the platelet count is less than 100,000/μL.The PT and aPTT are variations of plasma recalcifica-tion times initiated by the addition of a thromboplastic agent. The PT reagent contains thromboplastin and calcium that, when added to plasma, leads to the formation of a fibrin clot. The PT test measures the function of factors I, II, V, VII, and X. Factor VII is part of the extrinsic pathway,


Surgery_Schwartz

Surgery_Schwartz. and calcium that, when added to plasma, leads to the formation of a fibrin clot. The PT test measures the function of factors I, II, V, VII, and X. Factor VII is part of the extrinsic pathway, and the remaining factors are part of the common pathway. Factor VII has the shortest half-life of the coagulation factors, and its synthesis is vitamin K dependent. The PT test is best suited to detect abnor-mal coagulation caused by vitamin K deficiencies and warfarin therapy.Due to variations in thromboplastin activity, it can be dif-ficult to accurately assess the degree of anticoagulation on the basis of PT alone. To account for these variations, the INR is now the method of choice for reporting PT values. The Interna-tional Sensitivity Index (ISI) is unique to each batch of thrombo-plastin and is furnished by the manufacturer to the hematology laboratory. Human brain thromboplastin has an ISI of 1, and the optimal reagent has an ISI between 1.3 and 1.5.The INR is a calculated number


Surgery_Schwartz

Surgery_Schwartz. and is furnished by the manufacturer to the hematology laboratory. Human brain thromboplastin has an ISI of 1, and the optimal reagent has an ISI between 1.3 and 1.5.The INR is a calculated number derived from the follow-ing equation:INR = (measured PT/normal PT)ISIThe aPTT reagent contains a phospholipid substitute, acti-vator, and calcium, which in the presence of plasma leads to fibrin clot formation. The aPTT measures function of factors I, II, and V of the common pathway and factors VIII, IX, X, and XII of the intrinsic pathway. Heparin therapy is often monitored by following aPTT values with a therapeutic target range of 1.5 to 2.5 times the control value (approximately 50 to 80 seconds). Low molecular weight heparins are selective Xa inhibitors that may mildly elevate the aPTT, but therapeutic monitoring is not routinely recommended.Additional medications may significantly impair hemo-static function, such as antiplatelet agents (clopidogrel and GP IIb/IIIa inhibitors),


Surgery_Schwartz

Surgery_Schwartz. but therapeutic monitoring is not routinely recommended.Additional medications may significantly impair hemo-static function, such as antiplatelet agents (clopidogrel and GP IIb/IIIa inhibitors), anticoagulant agents (hirudin, chondroitin sul-fate, dermatan sulfate), and thrombolytic agents (streptokinase, tPA). If abnormalities in any of the coagulation studies cannot be explained by known medications, congenital abnormalities of coagulation or comorbid disease should be considered.Unfortunately, while conventional coagulation tests (PT, aPTT) capture the classic intrinsic and extrinsic coagulation cas-cade, they do not reflect the complexity of in vivo coagulation.158 Although they are useful to follow warfarin and heparin thera-pies, they poorly reflect the status of actively bleeding patients. This is not surprising given that these tests use only plasma and not whole blood to provide their assessment of the patient’s clot-ting status. To better assess the complex and rapidly


Surgery_Schwartz

Surgery_Schwartz. patients. This is not surprising given that these tests use only plasma and not whole blood to provide their assessment of the patient’s clot-ting status. To better assess the complex and rapidly changing hemostatic function of an actively bleeding patient, many cen-ters have moved to whole blood viscoelastic testing.Brunicardi_Ch04_p0103-p0130.indd 12329/01/19 11:05 AM 124BASIC CONSIDERATIONSPART IViscoelastic Assays. Viscoelastic assays, such as TEG or rotational thromboelastometry (ROTEM), monitor hemostasis as a dynamic process rather than revealing information from isolated conventional coagulation screens.159 Both tests measure the viscoelastic properties of blood as clotting is induced under a low-shear environment. The patterns of change in shear elas-ticity enable determination of the kinetics of clot formation and growth as well as the strength and stability of the formed clot. The strength and stability provide information about the ability of the clot to perform the


Surgery_Schwartz

Surgery_Schwartz. of the kinetics of clot formation and growth as well as the strength and stability of the formed clot. The strength and stability provide information about the ability of the clot to perform the work of hemostasis, while the kinet-ics determines the adequacy of quantitative factors available for clot formation.Continuous improvements in this technique have made this test a valuable tool for medical personnel interested in coagulation. A sample of celite-activated whole blood is placed into a prewarmed cuvette, and the clotting process is activated with reagents, such as kaolin for standard TEG, and kaolin plus tissue factor for rapid TEG. Both TEG and ROTEM employ a vertical pin which is lowered into the activated blood sample. In TEG, the cuvette oscillates in an arc around the stationary pin. As the blood clots, fibrin strands and platelet aggregates form between the pin and inner walls of the cuvette. The resulting torque on the pin is measured and converted to an electrical


Surgery_Schwartz

Surgery_Schwartz. pin. As the blood clots, fibrin strands and platelet aggregates form between the pin and inner walls of the cuvette. The resulting torque on the pin is measured and converted to an electrical signal. In ROTEM, the cuvette is stationary while the pin oscil-lates within the sample. The extent to which the pin can oscillate is reduced as the blood clots, and this is measured by the angle of deflection of a beam of light directed at the pin.160 In TEGs, the strength of a clot is graphically represented over time as a characteristic cigar-shaped figure (Fig. 4-7).Several parameters are generated from the TEG tracing. The r-value (reaction time) represents the time between the start of the assay and initial clot formation. This reflects clotting fac-tor activity and initial fibrin formation and is increased with fac-tor deficiency or severe hemodilution. The k-time (clot kinetics) is the time needed to reach specified clot strength and repre-sents the interactions of clotting factors and


Surgery_Schwartz

Surgery_Schwartz. is increased with fac-tor deficiency or severe hemodilution. The k-time (clot kinetics) is the time needed to reach specified clot strength and repre-sents the interactions of clotting factors and platelets. As such, the k-time is prolonged with hypofibrinogenemia and signifi-cant factor deficiency. Prolonged r-value and k-time are com-monly addressed with plasma transfusions. The alpha or angle (∝) is the slope of the tracing and reflects clot acceleration. The angle reflects the interactions of clotting factors and platelets. The slope is decreased with hypofibrinogenemia and platelet dysfunction. Decreased angles are treated with cryoprecipitate transfusion or fibrinogen administration. The maximal ampli-tude (mA) is the greatest height of the tracing and represents clot strength. Its height is reduced with dysfunction or deficiencies in platelets or fibrinogen. Decreased mA is addressed with platelet transfusion and, in cases where the angle is also decreased, with cryoprecipitate


Surgery_Schwartz

Surgery_Schwartz. is reduced with dysfunction or deficiencies in platelets or fibrinogen. Decreased mA is addressed with platelet transfusion and, in cases where the angle is also decreased, with cryoprecipitate (or fibrinogen) as well. The G-value is a para-metric measure derived from the mA value and reflects overall clot strength or firmness. An increased G-value is associated with hypercoagulability, whereas a decrease is seen with hypo-coagulable states. Finally, the LY30 is the amount of lysis occur-ring in the clot, and the value is the percentage of amplitude reduction at 30 minutes after mA is achieved. The LY30 rep-resents clot stability and when increased fibrinolysis is present.TEG and ROTEM are the only tests measuring all dynamic steps of clot formation until eventual clot lysis or retraction. TEG has also been shown to identify on admission those patients likely to develop thromboembolic complications after injury and postoperatively.161Recent trauma data have shown TEG to be useful in


Surgery_Schwartz

Surgery_Schwartz. TEG has also been shown to identify on admission those patients likely to develop thromboembolic complications after injury and postoperatively.161Recent trauma data have shown TEG to be useful in pre-dicting early transfusion of red blood cells, plasma, platelets, and cryoprecipitate.162 TEG can also predict the need for life-saving interventions shortly after arrival, 24-hour and 30-day mortality, and can be used to guide administration of TXA to injured patients with hyperfibrinolysis.163,164 Lastly, some cen-ters have demonstrated that the graphic display options allow for more rapid return of results and may be less expensive than standard coagulation panels. Given the strong association of viscoelastic tests with clinical outcomes, some centers now use TEG rather than conventional coagulation tests to evaluate injured patients in the emergency department.165EVALUATION OF EXCESSIVE INTRAOPERATIVE OR POSTOPERATIVE BLEEDINGExcessive bleeding during or after a surgical procedure may


Surgery_Schwartz

Surgery_Schwartz. tests to evaluate injured patients in the emergency department.165EVALUATION OF EXCESSIVE INTRAOPERATIVE OR POSTOPERATIVE BLEEDINGExcessive bleeding during or after a surgical procedure may be the result of ineffective hemostasis, blood transfusion, unde-tected hemostatic defect, consumptive coagulopathy, and/or fibrinolysis. Excessive bleeding from the operative field unas-sociated with bleeding from other sites usually suggests inad-equate mechanical hemostasis.Massive blood transfusion is a well-known cause of throm-bocytopenia. Bleeding following massive transfusion can occur because of hypothermia, dilutional coagulopathy, platelet dys-function, fibrinolysis, or hypofibrinogenemia. Another cause of hemostatic failure related to the administration of blood is a hemolytic transfusion reaction. The first sign of a transfusion reaction may be diffuse bleeding. The pathogenesis of this bleed-ing is thought to be related to the release of ADP from hemolyzed red blood cells, resulting