Patient Blood Management: Autologous Blood Procurement, Recombinant Factor VIIa Therapy, and Blood Utilization LAWRENCE T. GOODNOUGH • TERRI G. MONK
Key Points •The two primary reasons for employing autologous transfusion are avoidance of complications associated with allogeneic transfusion and conservation of blood resources. •The three types of autologous blood transfusion are preoperative autologous donation (PAD), acute normovolemic hemodilution (ANH), and intraoperative and postoperative blood recovery (salvage). •PAD became accepted as a standard practice in certain elective surgical settings such as total joint replacement surgery, so that by 1992 more than 6% of the blood transfused in the United States was autologous. Subsequently, substantial improvements in blood safety were accompanied by a decline in PAD as well as an interest in ANH as an alternative, lower-cost strategy. The criteria for autologous donors are different from those for allogeneic donors. Transfusion service policies, implemented under the auspices of hospital transfusion committees, differ regarding
collection and use of autologous blood with positive viral markers. It is common practice to exclude autologous blood reactive for hepatitis B surface antigen and hepatitis C and human immunodeficiency viruses because of patients’ safety concerns related to wrong blood unit transfused to wrong patient (mistransfusion). Contraindications to autologous blood donation include evidence of infection and risk of bacteremia, scheduled surgery for correction of aortic stenosis, and unstable angina. •The costs associated with PAD are higher than those associated with the collection of allogeneic blood. •ANH is the removal of whole blood from a patient while restoring the circulating blood volume with an acellular fluid shortly before an anticipated significant surgical blood loss. The chief benefit of ANH is the reduction of red blood cell losses when whole blood is shed perioperatively at the lower hematocrit levels associated with ANH. •The term intraoperative blood collection or recovery describes the technique of collecting and reinfusing blood lost by a patient during surgery. The oxygen transport properties of recovered red blood cells are equivalent to those of stored allogeneic red blood cells. The survival of recovered blood cells appears to be at least comparable to that of transfused allogeneic red blood cells. •Postoperative blood collection denotes the recovery of blood from surgical drains followed by reinfusion, with or without processing. Postoperative autologous blood salvage and reinfusion are practiced widely but not uniformly. •Recombinant factor VIIa (rfVIIa) has been approved for treatment of bleeding in patients with hemophilia and inhibitors to factors VIII or IX. Pharmacologic doses of rfVIIa enhance the thrombin generation on activated platelets and therefore may also be of benefit in providing hemostasis in other situations such as those characterized by consumptive coagulopathies or platelet conditions with impaired thrombin generation. •Level I evidence and guidelines support restrictive transfusion practices. However, no one hemoglobin level should be used as a transfusion trigger, and transfusion decisions should be made for individual patients (see also Chapter 61). •Bloodless medicine and surgery use a multidisciplinary team approach that incorporates anemia management, controlled hemostasis, autologous blood procurement, and pharmacologic alternatives to blood transfusion.
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Blood management has been defined as “the appropriate
use of blood and blood components, with a goal of minimizing their use.”1 This goal has been motivated historically by (1) known blood risks, (2) unknown blood risks, (3) preservation of the national blood inventory, and (4) constraints from escalating costs. Known risks of blood include transmissible infectious disease, transfusion reactions, and potential effects of immunomodulation (e.g., postoperative infection or tumor progression). Unknown risks include emerging pathogens transmissible by blood (e.g., new variant Creutzfeldt-Jakob disease and West Nile virus).2,3 Several studies have linked allogeneic blood transfusions with unfavorable outcomes, including increased risk of mortality and various morbidities.4 Blood management has been 1 of the 10 key advances in transfusion medicine since the 1960s.5 Patient blood management encompasses an evidence-based medical and surgical approach that is multidisciplinary (transfusion medicine specialists, surgeons, anesthesiologists, and critical care specialists) and multiprofessional (physicians, nurses, pump technologists, and pharmacists).6 Preventive strategies are emphasized: to identify, evaluate, and manage anemia7-9 (e.g., pharmacologic therapy10 and reduced iatrogenic blood losses from diagnostic testing)11; to optimize hemostasis (e.g., pharmacologic therapy12 and point-ofcare testing13); and to establish decision thresholds (e.g., guidelines) for the appropriate administration of blood therapy.14,15 In the United States, The Joint Commission developed patient blood management performance measures and submitted these to the National Quality Forum for endorsement. The National Quality Forum did not endorse these submitted performance measures because of a lack of data on the outcomes proposed; as a result, these measures currently do not carry consequences if not met. Because these performance measures were process based rather than outcomes based, data on proposed outcomes are difficult to retrieve. The Joint Commission has placed these performance measures in their Topic Library, where they are to be used as additional patient safety activities and/or quality improvement projects by provider institutions as accreditation goals.15 The principles of these performance indicators are summarized in Box 63-1.
AUTOLOGOUS BLOOD PROCUREMENT The three types of autologous blood transfusion are preoperative autologous donation (PAD), acute normovolemic hemodilution (ANH), and intraoperative and postoperative blood recovery (blood salvage). The advantages, disadvantages, applications, and complications vary with the techniques used. The two primary reasons for employing autologous transfusion are avoidance of complications associated with allogeneic transfusion and conservation of the national blood inventory. Patients with rare blood phenotypes or alloantibodies can also benefit from autologous transfusion because compatible allogeneic blood may not always be available.16 Potential complications of
Principles A.Formulate a plan of proactive management for avoiding and controlling blood loss tailored to the clinical management of individual patients, including anticipated procedures. B.Employ a multidisciplinary treatment approach to blood management using a combination of interventions (e.g., pharmacologic, therapy, point-of-care testing). C.Promptly investigate and treat anemia. D.Exercising clinical judgment, be prepared to modify routine practices (e.g., transfusion triggers) when appropriate. E.Restrict blood drawing for unnecessary laboratory tests. F.Decrease or avoid the perioperative use of anticoagulants and antiplatelet agents.
RBC, Red blood cell; TJC, The Joint Commission.
allogeneic transfusion that can be eliminated or minimized when autologous blood is administered include acute and delayed hemolytic reactions, alloimmunization, allergic and febrile reactions, and transfusion-transmitted infectious diseases. Intraoperative blood recovery may be the only option for providing a sufficient volume of compatible blood when severe, rapid blood loss occurs. ANH provides the only practical source of fresh whole blood. The role of autologous blood procurement in surgery is evolving, based on improved blood safety, increased blood costs, and emerging pharmacologic alternatives to blood transfusion.17-19 PAD became accepted as a standard practice in certain elective surgical settings such as total joint replacement surgery; by 1992 more than 6% of the blood transfused in the United States was autologous.20 Subsequently, substantial improvements in blood safety were accompanied by a decline in PAD, as well as an interest in ANH as an alternative strategy.21 Nevertheless, public perception of blood safety and the reluctance to accept allogeneic blood transfusion in the elective transfusion setting,22 along with possible future blood inventory shortages and the potential for new, emerging blood pathogens, continue to give autologous blood procurement strategies an important role in the surgical arena.
PREOPERATIVE BLOOD DONATION Patient Selection The criteria for autologous donors are not as stringent as are those for allogeneic donors. The AABB (formerly,
Chapter 63: Patient Blood Management
the American Association of Blood Banks) standards for blood banks and transfusion services require that the donor patient’s hemoglobin be no less than 11 g/dL or the hematocrit be no less than 33% before each donation.23 No age or weight limits exist, and patients may donate 10.5 mL/kg, in addition to testing samples. Donations may be scheduled more than once a week, but the last donation should occur no less than 72 hours before surgery, to allow time for restoration of intravascular volume and for transport and testing of the donated blood. Transfusion service policies, implemented under the auspices of hospital transfusion committees, differ regarding collection and use of autologous blood with positive viral markers. Some hospitals exclude use of autologous blood reactive for hepatitis B surface antigen, hepatitis C virus, or human immunodeficiency virus (HIV) because of concerns for patients’ safety related to a wrong blood unit transfused to the wrong patient (mistransfusion). Other hospitals accept and transfuse autologous blood with any positive viral markers because denying patients infected with HIV the opportunity to receive their own blood may have implications related to the Americans with Disabilities Act.24 Candidates for preoperative blood collection are patients scheduled for elective surgical procedures in which blood transfusion is likely. The most common surgical procedures for which autologous blood is predonated are total joint replacements.25 For procedures that are unlikely to require transfusion (i.e., a maximal surgical blood ordering schedule [MSBOS] suggests that crossmatched blood should not be ordered),26 the use of preoperative blood collection is not recommended. Autologous blood should not be collected for procedures that seldom (<10% of cases) require transfusion, such as cholecystectomy, herniorrhaphy, vaginal hysterectomy, and uncomplicated obstetric delivery.27 In special circumstances, preoperative autologous blood collection can be performed for patients who would not ordinarily be considered for autologous donation. Availability of medical support is important in assessing a patient’s suitability. With appropriate volume modification, parental cooperation, and attention to preparation and reassurance, pediatric patients can participate in preoperative blood collection programs.28 Patients with significant cardiac disease are considered poor risks for autologous blood donation. Despite reports of safety in small numbers of such patients who underwent autologous blood donation,29 the risks associated with autologous blood donation30 in these patients are greater than current estimated risks of allogeneic transfusion.2,3 Box 63-2 summarizes the medical contraindications to a patient’s participation in an autologous blood donation program.31 The collection of autologous blood from women during routine pregnancy is unwarranted,32 because blood is so seldom needed. PAD can be considered for women with alloantibodies to multiple or high-incidence antigens or with placenta previa or other conditions placing them at high risk for antepartum or intrapartum hemorrhage.27 AABB standards no longer permit allogeneic transfusion of unused autologous units (“crossover”) because autologous donors are not, in the strictest sense, volunteer donors.23
BOX 63-2 Contraindications to Participation in Autologous Blood Donation Programs 1.Evidence of infection and risk of bacteremia 2.Scheduled surgery to correct aortic stenosis 3.Unstable angina 4.Active seizure disorder 5.Myocardial infarction or cerebrovascular accident within 6 months of donation 6.Significant cardiac or pulmonary disease in patients who have not yet been cleared for surgery by their treating physician 7.High-grade left main coronary artery disease 8.Cyanotic heart disease 9.Uncontrolled hypertension
Attempts to stratify patients into groups at high and low risk for needing transfusion based on the baseline level of hemoglobin and on the type of procedure show some promise. In a Canadian study using a point score system, 80% of patients undergoing orthopedic procedures were identified to be at low risk (<10%) for transfusion, and therefore autologous blood procurement for these patients would not be recommended.33 However, one problem with algorithms that consider the estimated blood loss and preoperative hematocrit is that blood losses are difficult to measure34 or predict because specific surgical procedures performed even by the same surgeon can be accompanied by a wide range of blood loss. Although autologous blood donation programs are popular with patients, the costs associated with autologous blood collection are higher than are those associated with allogeneic blood. The reduced risk of allogeneic blood transfusions has made PAD poorly cost effective.35,36
The Role of Aggressive Phlebotomy and the Use of Erythropoiesis-Stimulating Agents The efficacy of PAD depends on the degree to which the patient’s compensatory erythropoiesis increases the production of red blood cells (RBCs).37 The endogenous erythropoietin response and compensatory erythropoiesis are suboptimal under “standard” conditions of 1 unit of blood donated weekly.38 As shown in Table 63-1, weekly PAD is accompanied by an expansion in RBC volume of 11% (with no oral iron supplementation) to 19% (with oral iron supplementation), which is not sufficient to prevent increasing anemia in patients undergoing PAD. If the erythropoietic response to autologous blood phlebotomy does not maintain the patient’s hematocrit level during the donation interval, the donation of autologous blood actually may be harmful by causing perioperative anemia and an increased likelihood of any blood transfusion.37,38 A mathematic model has been published to demonstrate the relationships among anticipated surgical blood losses, the desired hematocrit, and the need for autologous blood donation.39 In contrast to autologous blood donation under “standard” conditions, studies of “aggressive” autologous blood phlebotomy (twice weekly for 3 weeks, beginning 25 to 35 days before surgery) have demonstrated that endogenous erythropoietin levels do increase,
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TABLE 63-1 ENDOGENOUS ERYTHROPOIETIN-MEDIATED ERYTHROPOIESIS IN AUTOLOGOUS BLOOD DONORS* RBC (mL ) Standard phlebotomy
220 331 315 397
11 17 16 19
None PO PO, IV None
Goodnough et al, 198940 Messmer et al, 198647 Messmer et al, 198647 Messmer et al, 198647 Brecher and Rosenfeld, 199448 Brecher and Rosenfeld, 199448 Brecher and Rosenfeld, 199448 Weiskopf, 199551 and Petry et al, 199452 Monk et al, 199953
22 45 41 30
590 621 603 540
From Goodnough LT, Skikne B, Brugnara C: Erythropoietin, iron, and erythropoiesis, Blood 96:823-833, 2000. IV, Intravenous; PO, oral; RBC, red blood cell. *Data are expressed as means.
TABLE 63-2 ADVANTAGES AND DISADVANTAGES OF AUTOLOGOUS BLOOD DONATION Advantages
Prevents transfusiontransmitted disease Prevents red cell alloimmunization Supplements the blood supply Provides compatible blood for patients Prevents some adverse transfusion reactions
Does not affect risk of bacterial contamination Does not affect risk of ABO incompatibility error Is more costly than allogeneic blood Results in wastage of blood not transfused with alloantibodies Has an increased incidence of adverse reactions to autologous donation Subjects patient to perioperative anemia and increased likelihood of transfusion
Provides reassurance to patients concerned about blood risks
along with enhanced erythropoiesis representing RBC volume expansion of 19% to 26% (see Table 63-1). The use of erythropoiesis-stimulating agents to stimulate erythropoiesis further (≤50% RBC volume expansion)40-42 during autologous donation has been approved in the European Union, Canada, and Japan, but not in the United States.43 Perisurgical erythropoietin therapy is also approved in the United States and Canada for anemic (hematocrit < 39%) patients who are scheduled for noncardiac, nonvascular surgical procedures.
Transfusion Trigger Advantages and disadvantages of autologous blood transfusion are summarized in Table 63-2. Disagreement exists about the proper hemoglobin and hematocrit levels (“transfusion trigger”) at which autologous blood should be given (see Chapter 61).44 In general, autologous and allogeneic blood transfusion triggers should be similar because the risks from administrative errors associated with both autologous and allogeneic blood are higher
than are risks related to the transfusion of allogeneic blood.45
ACUTE NORMOVOLEMIC HEMODILUTION ANH is the removal of whole blood from a patient while restoring the circulating blood volume with an acellular fluid shortly before an anticipated significant surgical blood loss. To minimize the manual labor associated with hemodilution, the blood should be collected in standard blood bags containing anticoagulant on a tilt-rocker with automatic cutoff through volume sensors. The blood is then stored at room temperature and reinfused during surgery after major blood loss has ceased, or sooner if indicated. Simultaneous infusions of crystalloid (3 mL crystalloid for each 1 mL of blood withdrawn) and colloid (dextrans, starches, gelatin, albumin [1 mL for each 1 mL of blood withdrawn]) have been recommended.46 Blood units are reinfused in the reverse order of collection because the first unit collected and therefore the last to be infused will have the highest hematocrit and concentration of coagulation factors and platelets.
Reduction of Red Blood Cell Losses The chief benefit of ANH is the reduction of RBC losses when whole blood is shed perioperatively at lower hematocrit levels associated with ANH.47 Mathematic modeling suggests that severe ANH to preoperative hematocrit levels of less than 20%, accompanied by substantial blood losses, would be required before the RBC volume “saved” by ANH would become clinically important.48 A clinical analysis of patients who had undergone “minimal” ANH (representing ≤15% of patients’ blood volume) estimated that only 100 mL of RBCs (the equivalent of 0.5 unit of blood)49 was “saved” under these conditions.50 With moderate hemodilution (target hematocrit levels of 28%), the “savings” become more substantial. The removal of 3 blood units in a patient who subsequently underwent a blood loss of 2600 mL resulted in surgical RBC losses
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factors is minimal. The hemostatic value of blood collected by ANH is questionable for orthopedic or urologic surgery because plasma and platelets are rarely indicated in this setting. Its value in protecting plasma and platelets from the acquired coagulopathy of extracorporeal circulation in cardiac surgery (known as “blood pooling”) is better established.52
RBC Volume Lost (mL)
1000 800 No. 3
600 No. 2
Blood lost (mL) Figure 63-1. The relationship between whole blood volume (mL) lost (abscissa) and red blood cell (RBC) volume lost (ordinate) in a 100-kg patient undergoing hemodilution: RBC volume lost with 2800 mL whole blood lost intraoperatively after hemodilution of 1500 mL whole blood (solid blue line); RBC volume lost with 2800 mL whole blood lost during hemodilution at each of three 500 mL volumes (solid orange line); cumulative RBC volume lost intraoperatively, derived for 2800 mL whole blood lost if hemodilution had not been performed (blue dashed line). A net of 215 mL reduction in RBC volume lost with hemodilution is illustrated by the divergence of the two curves. (From Goodnough LT, Grishaber JE, Monk TG, et al: Acute normovolemic hemodilution in patients undergoing radical suprapubic prostatectomy: a case study analysis, Anesth Analg 78:932-937, 1994, with permission.)
“saved” by hemodilution of 215 mL, or the equivalent of 1 unit of allogeneic blood (Fig. 63-1).50 This RBC volume approaches the RBC volume expansion generated by autologous blood predonation under standard phlebotomy conditions. The benefit of ANH has been determined in a mathe matic model46. An adult with an estimated 5-L blood volume and an initial hematocrit of 40%, with surgical blood losses of up to 3000 mL, would have a hematocrit level that would remain 25% postoperatively without an autologous blood intervention. This level is generally considered safe for patients without known risk factors. In this model, the performance of ANH with initial hematocrit levels of 40% to 45% would allow up to 2500 to 3500 mL of surgical blood loss, yet the nadir level of hematocrit could be maintained at 28%.
Improved Oxygenation Withdrawal of whole blood and replacement with crystalloid or colloid solution decrease arterial oxygen content, but compensatory hemodynamic mechanisms and the existence of surplus oxygen delivery capacity make ANH safe. A sudden decrease in RBC concentration reduces blood viscosity, thereby decreasing peripheral resistance and increasing cardiac output. If cardiac output can effectively compensate, oxygen delivery to the tissues at a hematocrit of 25% to 30% is as good as, but no better than, oxygen delivery at a hematocrit of 30% to 35%.51
Preservation of Hemostasis Because blood collected by ANH is stored at room temperature and is usually returned to the patient within 8 hours of collection, deterioration of platelets or coagulation
Prospective randomized studies in patients undergoing radical prostatectomy,53 knee replacement,54 and hip replacement55 suggested that ANH can be considered equivalent to PAD as a method of autologous blood procurement. Selected clinical trials of ANH are summarized in Table 63-3.56-72 Commentaries on the relative merits of ANH have been published.73-75 When ANH and reinfusion are accomplished in the operating room by on-site personnel, the procurement and administration costs are minimized. Blood obtained during ANH does not require the commitment of the patient’s time, transportation, costs, and loss of work time that can be associated with PAD. The wastage of PAD units (approximately 50% of units collected)27 also is eliminated with ANH. Additionally, autologous blood units procured by ANH require no inventory or testing costs. Because the blood never leaves the patient’s room, ANH minimizes the possibility of an administrative or clerical error that could lead to an ABO-incompatible blood transfusion and death, as well as bacterial contamination associated with prolonged storage at 4° C. An ANH program has some important practical considerations. Decisions about ANH should be based on the surgical procedure and on the patient’s preoperative blood volume and hematocrit, target hemodilution hematocrit, and other physiologic variables. The institution’s policy and procedures and the mechanisms for educating staff should be established and periodically reviewed. The patient’s circulating volume and perfusion status should be carefully monitored during the procedure. Blood must be collected in an aseptic manner, ordinarily into standard blood collection bags with citrate anticoagulant. Units must be properly labeled and stored. The label must contain, at a minimum, the patient’s full name, medical record number, date and time of collection, and the statement “For Autologous Use Only.” Room temperature storage should not exceed 8 hours. If more time elapses between collection and transfusion, the blood should be stored in a monitored refrigerator. Suggested criteria for patient selection are listed in Box 63-3.
Cost-Effective Analysis of Acute Normovolemic Hemodilution Versus Preoperative Autologous Donation Most clinical trials compared ANH to PAD as the “standard of care.” Medicolegal concerns may also prevent the inclusion of a treatment arm consisting of only allogeneic blood transfusion because blood safety acts in several states mandate that physicians offer autologous blood options before elective surgical procedures.18 These studies found ANH to be similar to PAD in eliminating
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TABLE 63-3 SELECTED CLINICAL TRIALS OF ACUTE NORMOVOLEMIC HEMODILUTION
Estimated Blood Loss (mL)
Postoperative Hematocrit (%)
Allogeneic RBC-Containing Units or Liters ( ) Transfused
Type of Surgery
Semkiw et al, 198956 Eng et al, 199057 Roberts et al, 199158 Martin et al, 199259 Ward et al, 199360 Umlas et al, 199461 De Haan et al, 199562 Matot et al, 200263 Jarnagin et al, 200864 Fischer et al, 201065
Modified from Brecher ME, Rosenfeld M: Mathematical and computer modeling of acute normovolemic hemodilution, Transfusion 34:176-179, 1994. ANH, Acute normovolemic hemodilution; NR, not reported; NS, not significant; RBC, red blood cell.
BOX 63-3 Criteria for Selection of Patients for Acute Normovolemic Hemodilution 1.Likelihood of transfusion exceeding 10% (i.e., blood requested for crossmatch according to a maximum surgical blood order schedule) 2.Preoperative hemoglobin level of at least 12 g/dL 3.Absence of clinically significant coronary, pulmonary, renal, or liver disease 4.Absence of severe hypertension 5.Absence of infection and risk of bacteremia
the need for allogeneic blood transfusions during elective surgery.76 Other outcomes including anesthesia and surgery times, intraoperative hemodynamic values, and length of hospital stays were also equivalent in PAD and ANH. Even though only a few studies included economic evaluations comparing the cost of autologous blood techniques, all these studies demonstrated that ANH is much less costly than PAD.76 Therefore, ANH can be considered a cost-minimizing technique for autologous blood procurement for elective surgery.
INTRAOPERATIVE CELL SALVAGE The term intraoperative blood collection or recovery or cell salvage describes the technique of collecting and reinfusing blood lost by a patient during surgery. The oxygen transport properties of recovered RBCs are equivalent to those of stored allogeneic RBCs. The survival of recovered RBCs appears to be at least comparable to that of transfused allogeneic
RBCs.77 Intraoperative collection is contraindicated when certain procoagulant materials (e.g., topical collagen) are applied to the surgical field because systemic activation of coagulation may result. Microaggregate filters (40 μm) are most often used because recovered blood may contain tissue debris, small blood clots, or bone fragments. Cell washing devices can provide the equivalent of 12 units/hour of banked blood to a massively bleeding patient.77 Data on adverse events of reinfusion of recovered blood have been published.78 Air embolus is a potentially serious problem. Three fatalities from air embolus were reported over a 5-year interval to the New York State Department of Public Health, for an overall fatality risk of 1 in 30,000.35 Hemolysis of recovered blood can occur during suctioning from the surface instead of from deep pools of shed blood. For this reason, manufacturers’ guidelines recommend a maximum vacuum setting of no more than 150 mm Hg; one study found that vacuum settings as high as 300 mm Hg could be used, when necessary, without causing excessive hemolysis.79 Patients exhibit a level of plasma free hemoglobin that is usually higher than after allogeneic transfusion. The clinical importance of free hemoglobin in the concentrations usually seen has not been established, although excessive free hemoglobin may indicate inadequate washing. Positive bacterial cultures from recovered blood are sometimes observed; however, clinical infection is rare.80 Most programs use machines that collect shed blood, wash it, and concentrate the RBCs. This process typically results in 225-mL units of saline-suspended RBCs with a hematocrit of 50% to 60%.
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Clinical Studies As with PAD and ANH, collection and recovery of intraoperative autologous blood should undergo scrutiny with regard to both safety and efficacy.81 A controlled study in cardiothoracic surgery demonstrated a lack of efficacy when transfusion requirements and clinical outcomes were followed.80 A second study found that only a minority of patients undergoing major orthopedic and cardiac surgery achieved cost equivalence with intraoperative blood recovery using semiautomated instruments compared with banked blood.82 Although the collection of a minimum of one blood unit equivalent is possible for less expensive (with unwashed blood) methods, at least two blood unit equivalents must be recovered using a cell recovery instrument (with washed blood) to achieve cost effectiveness.83 The value of intraoperative blood collection is apparent for vascular surgical procedures with large blood losses, such as aortic aneurysm repair and liver transplantation.84 However, a prospective, randomized trial of intraoperative recovery and reinfusion in patients undergoing aortic aneurysm repair showed no benefit in a reduction of allogeneic blood exposure.83 The value of this technology may be in cost savings and blood inventory considerations in patients with substantial blood losses.85 Collection devices that neither concentrate nor wash shed blood before reinfusion increase the risk of adverse effects. Shed blood has undergone varying degrees of coagulation or fibrinolysis and hemolysis, and infusion of large volumes of washed or unwashed blood has been described in association with disseminated intravascular coagulation (DIC).84 In general, blood collected at low flow rates or during slow bleeding from patients who are not systemically anticoagulated will have undergone coagulation and fibrinolysis and will not contribute to hemostasis on reinfusion. The high suction pressure and surface skimming during aspiration and the turbulence or mechanical compression that occurs in roller pumps and plastic tubing make some degree of hemolysis inevitable. High concentrations of free hemoglobin may be nephrotoxic to patients with impaired renal function. Many programs limit the quantity of recovered blood that may be reinfused without processing. To minimize hemolysis, the vacuum level should ordinarily not exceed 150 mm Hg, although higher levels of suction may occasionally be needed during periods of rapid bleeding. An alternative approach is to collect blood in a canister system designed for direct reinfusion and then to concentrate and wash the recovered RBCs in a blood bank cell washer. Intraoperatively collected and recovered blood must be handled in the transfusion service laboratory similarly to any other autologous unit. The unit should be reinfused through a filter. Some practical considerations for cell recovery programs are listed in Box 63-4. If collected under aseptic conditions with a saline-wash device and if properly labeled, blood may be stored at room temperature for up to 4 hours or at 1° C to 6° C for up to 24 hours, provided storage at 1° C to 6° C is begun within 4 hours of ending the collection.23 The allowable interval of room temperature storage is
BOX 63-4 Practical Considerations for Intraoperative Cell Recovery, Storage, and Reinfusion 1.If not transfused immediately, units collected from a sterile operating field and processed with a device for intraoperative blood collection that washes with 0.9% saline, USP, shall be stored under one of the following conditions before initiation of transfusion: a.At room temperature for up to 4 hours after terminating collection b.At 1° C to 6° C for up to 24 hours, provided storage at 1° C to 6° C is begun within 4 hours of ending the collection 2.Transfusion of blood collected intraoperatively by other means shall begin within 6 hours of initiating the collection. 3.Each unit collected intraoperatively shall be labeled with the patient’s first name, last name, and hospital identification number; the date and time of initiation of collection and of expiration; and the statement “For Autologous Use Only.” 4.If stored in the blood bank, the unit shall be handled like any other autologous unit. 5.The transfusion of shed blood collected under postoperative or posttraumatic conditions shall begin within 6 hours of initiating the collection.
shorter for recovered blood (4 hours) than for ANH blood (8 hours). Storage times are the same for recovered blood whether unwashed or washed.
POSTOPERATIVE CELL SALVAGE Postoperative blood collection denotes the recovery of blood from surgical drains followed by reinfusion, with or without processing.62 In some programs, postoperative shed blood is collected into sterile canisters and reinfused, without processing, through a microaggregate filter. Recovered blood is dilute, is partially hemolyzed and defibrinated, and may contain high concentrations of cytokines. For these reasons, most programs set an upper limit on the volume (e.g., 1400 mL) of unprocessed blood that can be reinfused. If transfusion of blood has not begun within 6 hours of initiating the collection, the blood must be discarded.
Clinical Studies The evolution of cardiac surgery has been accompanied by broad experience in postoperative conservation of blood. Postoperative autologous blood transfusion is practiced widely but not uniformly. Prospective and controlled trials have disagreed over the efficacy of postoperative blood recovery in cardiac surgical patients; at least three such studies demonstrated lack of efficacy,58,60 whereas at least two studies showed benefit.57 The disparity of results in these studies may be explained, in part, by differences in transfusion practices. Modification of physicians’ transfusion practices may have been an uncredited intervention in these blood conservation studies. In the postoperative orthopedic surgical setting, several reports have similarly described the successful recovery and reinfusion of washed56 and unwashed59 wound drainage blood from patients undergoing arthroplasty. The volume of reinfused drainage blood
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has been reported to be as great as 3000 mL and averages more than 1100 mL in patients undergoing cementless knee replacement.59 Because the RBC content of the fluid collected is low (hematocrit levels of 20%) the volume of RBCs reinfused is often small.61 A prospective, randomized study of postoperative salvage and reinfusion in patients undergoing total knee or hip replacement found no differences in perioperative hemoglobin levels or allogeneic blood transfusions between patients who had joint drainage devices and those who did not.86 The safety of reinfused unwashed orthopedic wound drainage has been controversial. Theoretic concerns have been expressed regarding infusion of potentially harmful materials in recovered blood, including free hemoglobin, RBC stroma, marrow fat, toxic irritants, tissue or methacrylate debris, fibrin degradation products, activated coagulation factors, and complement. Although two small studies reported complications,87,88 several larger studies reported no serious adverse effects when the drainage was passed through a standard 40-μm blood filter.56,59,89 The potential for decreasing exposure to allogeneic blood among orthopedic patients undergoing postoperative blood collection, whether the blood is washed or unwashed, is greatest for cementless bilateral total knee replacement, revision hip or knee replacement, and long-segment spinal fusion. As in the case of intraoperative recovery, blood loss must be sufficient to warrant the additional cost of processing technology.90 One study demonstrated comparable costs between postoperative cell salvage and allogeneic transfusion for patients undergoing total knee arthroplasty, but the investigators found that cell salvage represented a significant savings in patients undergoing total hip arthroplasty.91 As in the selection of patients who can benefit from PAD and ANH, the prospective identification of patients who can benefit from intraoperative and postoperative autologous blood recovery is possible if patients’ preoperative hemoglobin level, anticipated surgical blood loss, and perioperative “transfusion trigger” are taken into account.
RECOMBINANT FACTOR VIIa Recombinant factor VIIa (rfVIIa) has been approved for treatment of bleeding in patients with hemophilia who have inhibitors, patients with congenital factor VII deficiency, and patients with inherited qualitative platelet defects. Pharmacologic doses of rfVIIa enhance the thrombin generation on platelets and therefore may also likely be of benefit in providing hemostasis in clinical settings characterized by profuse bleeding and impaired thrombin generation,92 such as in patients with thrombocytopenia and in those with functional platelet defects.93,94 Additionally, it has been used successfully in a variety of less well-characterized surgical bleeding situations in patients with dilutional or consumptive coagulopathies and in patients with impaired liver function.95-97 Policies for the approval of rfVIIa therapy in nonapproved settings should therefore undergo
periodic review and revision as relevant new information and data are generated.98 Because of the trends in rfVIIa usage in nonapproved settings, significant concerns about the safety, efficacy, and costs of rfVIIa have arisen. Additionally, dosing of rfVIIa for these potentially broad clinical applications is not standardized.
COMPLEX SURGERY AND TRAUMA RESULTING IN PROFUSE BLEEDING A hemostatic effect has been demonstrated after the administration of rfVIIa in a limited number of patients after trauma and bleeding (see also Chapters 61 and 62).95,96 Seven trauma patients treated with rfVIIa after failure of conventional measures to achieve hemostasis reported cessation of diffuse bleeding and correction of abnormal coagulation assays; three of the seven patients died of reasons other than bleeding or thromboembolism.96 Anecdotal case reports have been published that describe the successful use of rfVIIa in patients with substantial perisurgical bleeding. The experience of rfVIIa use in trauma with excessive bleeding, as well as in profuse postoperative bleeding, based largely on case reports, has indicated a hemostatic effect of rfVIIa given in doses ranging from 20 to 120 μg/kg. The issue of preemptive, preoperative rfVIIa (40 to 90 μg/kg) was studied in nine patients with coagulopathy and urgent neurosurgical intervention.99 Post-rfVIIa coagulation parameters normalized as early as 20 minutes after infusion, with no noted procedural or operative complications. No associated thromboembolic complications were observed. Subsequently, a prospective, randomized study of rfVIIa (20 or 40 μg/kg) versus placebo perioperatively in 36 patients undergoing radical retropubic prostatectomy found that the cohorts receiving rfVIIa had substantially less median operative blood loss compared with placebo (1235 mL, 1089 mL, and 2688 mL, respectively).100 This study was not powered to demonstrate reductions in blood transfusions. In single-center series, 51 patients undergoing rfVIIa therapy for intractable blood loss after cardiac surgery were compared with 51 matched controls.101 The investigators found that bleeding 1 hour after therapy was reduced in the treated cohort, compared with the control cohort. No differences in serious adverse events were noted. A subsequent review from the same institution of 114 cardiac surgical patients who received rfVIIa compared with 541 concurrent patients who did not receive rfVIIa concluded that rfVIIa is not associated with increased risk of adverse events, and early treatment may be associated with better outcomes.102 A second series of rfVIIa in 53 patients during cardiac surgery found a significant decrease in doses of all blood products.103 However, a third series of 24 patients treated with rfVIIa for refractory bleeding after cardiac surgery, compared with 24 matched controls, found no differences in RBC or plasma units transfused over a 24-hour period.104 A pilot study of 20 patients undergoing complex noncoronary cardiac surgery who were randomized to receive either placebo or rfVIIa (90 μg/kg) prophylactically after completion of cardiopulmonary bypass and
Chapter 63: Patient Blood Management
reversal of heparin found a significantly reduced need for allogeneic transfusion in the cohort who received rfVIIa.105 However, a pediatric study of 76 pediatric patients undergoing surgery for congenital heart disease found no benefit of rfVIIa (40 μg/kg) prophylaxis as determined by chest closure time after cardiopulmonary bypass106 (see also Chapter 94). Two randomized placebo-controlled trials of rfVIIa as adjunctive therapy for control of bleeding in trauma patients were published.107 In an analysis of 143 patients with blunt trauma, the percentage of patients alive at 48 hours after receiving more than 20 units of RBCs was reduced from 33% to 14% (P = .03). For 143 patients with penetrating trauma, the reduction from 19% to 7% was not significant (P = .08). No differences in serious adverse events between the rfVIIa-treated and placebo cohorts were observed (see also Chapters 62 and 81).
DOSE A retrospective review of 40 patients with coagulopathic bleeding in a variety of medical and surgical settings from 13 hospitals in an Internet-based database (excluding history of coagulopathy and trauma patients) who received rfVIIa (15 to 180 μg/kg, with 38 patients receiving fewer than 5 doses) found that 32 patients (80%) achieved complete (n = 18) or partial (n = 14) cessation of bleeding.108 Responses occurred in all dose ranges, without any evidence of a dose-response effect; the percentages of complete, partial, or absent responses were not different at doses of less than 70 μg/kg, 70 to 90 μg/kg, or more than 90 μg/kg. Significantly fewer blood products were administered after rfVIIa therapy. Twenty-three (58%) patients died, thus reflecting the unstable clinical status of the patients at the decision point for considering rfVIIa therapy. On the basis of this study, one recommended dosage strategy is for a 4.8-mg vial administered to an adult patient weighing 50 to 100 kg, which represents a 100 to 50 μg/kg dose.98
PATIENTS RECEIVING ORAL ANTICOAGULANT THERAPY One report described the use of rfVIIa in seven adult patients with a prolonged international normalized ratio (INR); three of these patients required surgery. The doses administered ranged from 20 to 90 μg/kg, and all patients were reported to have a positive outcome.109 These observations indicate that rfVIIa may be used to reverse the effect of warfarin (Coumadin) or other vitamin K–antagonist therapy when the administration of vitamin K alone has been found to be insufficient. Two published reports of a total of 15 patients treated with rfVIIa for reversal of excessive anticoagulation with warfarin supported a dosage of 20 μg/kg, or 1.2 mg for an adult patient.110,111 A review of 12 patients with acute warfarin-associated intracranial hemorrhage over this same time period at one institution (all these patients received rfVIIa [30 to 135 μg/kg] as well as vitamin K [10 mg/day for 3 days] and fresh frozen plasma [1307 ± 652 mL] for treatment) found that treatment was associated with rapid correction of the INR, and single doses appeared safe in this high-risk
population.112 However, more recent guidelines from several medical societies have discouraged the off-label use of rfVIIa in this setting12 (see also Chapter 62).
PATIENTS WITH IMPAIRED LIVER FUNCTION A multicenter trial studied 71 patients with advanced liver disease who were undergoing laparoscopic liver biopsy.115 The patients were randomized to receive 1 of 4 doses of rfVIIa (5, 20, 80, or 120 μg/kg); 48 (74%) of 65 patients achieved hemostasis within 10 minutes. One thrombotic event and a single case of DIC were reported, and they were not believed to be related to rfVIIa therapy. Despite these complications, the authors concluded that laparoscopic liver biopsy can be performed safely and reliably by using rfVIIa in patients in whom the standard procedure may be contraindicated because of coagulopathy. The safety and efficacy of rfVIIa in patients with cirrhosis and upper gastrointestinal hemorrhage were studied in a randomized study of 245 patients with a composite primary end point including failure to control bleeding within 24 hours after first dose, failure to prevent rebleeding within 24 hours to 5 days, or death within 5 days.116 No significant differences were found between the placebo compared with the rfVIIa (8 doses at 100 mg/kg over 30 hours) cohorts: failures on composite end point were 16% and 14%, respectively (P = .72). Similarly, a randomized controlled study of patients with cirrhosis who underwent partial hepatectomy found no benefit to rfVIIa compared with placebo when the volume of blood products administered, or the percentage of patients transfused, was analyzed.115 Finally, no value for periadjuvant rfVIIa was found in patients undergoing liver transplantation, when compared with placebo114 (see also Chapter 62).
PATIENTS WITH NORMAL HEPATIC FUNCTION A prospective, randomized, double-blind multicenter study evaluated the efficacy of two different doses of rfVIIa compared with placebo on RBC transfusions for adult patients without cirrhosis who were undergoing partial hepatectomy.117 Mean RBC volume transfused was 1024, 1354, and 1036 mL for placebo, 20 μg/kg rfVIIa, and 80 μg/kg rfVIIa, respectively (P > .05). Similarly, no differences were noted in the percentage of patients transfused and in intraoperative blood losses. Serious adverse event rates were not different.
PATIENTS WITH HEMORRHAGIC STROKE A prospective, randomized, double-blind placebo- controlled trial of three doses of rfVIIa compared with placebo was reported in patients presenting with acute (<4 hours) hemorrhagic stroke.118 At 24 hours after treatment, the percentage of patients showing expansion was 28%, 16%, 14%, and 11% for the placebo, 40 μg/kg, 80 μg/kg, and 160 μg/kg, respectively (P < .05 treatment cohorts versus placebo). The percentage
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of patients who died was 29%, 18%, 18%, and 19%, respectively (P < .05, treatment cohorts versus placebo). Impairment scored at 90 days was also improved in the treatment cohorts compared with placebo. However, a follow-up, clinical trial (placebo, 40 μg/kg, and 80 μg/ kg) failed to show a mortality benefit for rfVIIa compared with placebo.119
SAFETY Of the more than 170,000 standard doses of rfVIIa given after its approval (almost all to patients with hemophilia and inhibitors), only rare (<1 in 11,300) thrombotic events have been reported.92 Thrombotic complications have also been reported with rfVIIa therapy in patients without inhibitors to factor VIII or IX. An acute cerebrovascular accident and death occurred in a clinical trial of rfVIIa (90 μg/kg) before and after minor surgery or dental procedures in patients with factor XII deficiency.120 The last of 10 patients enrolled in an open-label, doseescalation trial to prevent rebleeding after subarachnoid hemorrhage developed middle cerebral artery thrombosis after receiving rfVIIa.121 In a high-risk trauma population, 3 of 40 (7.5%) patients who were deemed at high risk for thrombosis developed thrombotic complications after receiving rfVIIa.122 Although significant adverse events and thrombotic events were distributed evenly among treatment and placebo cohorts in several large randomized clinical trials of patients undergoing radical prostatectomy,100 trauma,109 upper gastrointestinal bleeding,114 or partial hepatectomy,120 an uneven distribution of thromboembolic events was found in the clinical trial of patients with hemorrhagic stroke.120 Total events in this last trial were 2 (2%), 7 (6%), 4 (5%), and 10 (10%) for the placebo, 40, 80, and 160 μg/kg cohorts, respectively. Most of these events were arterial, including thrombotic stroke and myocardial infarction. Whether these serious adverse events can be attributed to rfVIIa or to a population at risk for these events will need to be determined in a follow-up clinical trial. A summary of thromboembolic events reported to the U.S. Food and Drug Administration (FDA) from March 1999 to December 2004 indicated a total of 151 events in settings with unlabeled indications for rfVIIa.123 These events included deep vein thrombosis (42), cerebrovascular accident (39), acute myocardial infarction (34), pulmonary thromboembolus (32), arterial thrombosis (26), and clotted devices (10). Thirty-eight percent of cases had concomitant use of other hemostatic agents. In 36 (72%) of 50 reported deaths, rfVIIa was listed as the probable cause. The authors concluded that randomized clinical trials are necessary to demonstrate the safety and efficacy of rfVIIa in nonapproved settings. A subsequent report analyzed safety data from 13 clinical trials in patients treated with rfVIIa for cirrhosis, trauma, or reversal of anticoagulant therapy.124 The authors reported thrombotic adverse events in 5.3% of patients who received placebo, compared with 6.0% in patients who received rfVIIa (P = .57). In cardiac surgical patients, cohort-matched studies100,101 and a systematic review found no differences in serious adverse events in patients treated with rfVIIa125
(see also Chapter 62). We reported a patient who had fatal thrombosis after administration of activated prothrombin complex concentrate (PCC) and who had also received two doses of rfVIIa more than 6 hours earlier, while supported by extracorporeal membrane oxygenation.126 Because of this experience, we recommend that patients should not receive combination therapy with both activated PCC and rfVIIa. In summary, the safety profile of rfVIIa in controlled trials in patients with spontaneous intracerebral hemorrhage suggests that an increased risk of thrombotic arterial events may be underreported by treating physicians.127 Thromboembolic events associated with rfVIIa were reported to the FDA in approximately 2% of treated patients in clinical trials, but sufficient data were not available to identify the incidence in patients who received rfVIIa for warfarin reversal.123 A careful case review of 285 trauma patients revealed that 27 (9.4%) had thromboembolic complications after administration of rfVIIa, including 3 patients who were treated for warfarin reversal.128 Levi and colleagues analyzed 35 randomized trials with 4468 subjects and found that 11.1% had thromboembolic events. Rates of venous thromboembolic events were similar for subjects who received rfVIIa compared with placebo (5.3% and 5.7%, respectively); arterial events, however, were significantly higher (5.5% versus 3.2%, P < .003) in subjects receiving rfVIIa compared with placebo, particularly for older patients (>75 years of age) and/or higher doses.129 Dose, timing, and safety of rfVIIa have yet to be defined in this diverse patient population, and formal prospective trials are needed. Consensus-based recommendations on the use of rfVIIa in nonapproved settings have been developed.130 The decisions on when and where to use rfVIIa for patients with uncontrolled bleeding must be made by individual physicians, assisted by their hospital pharmacotherapeutic or transfusion committees.98,131
BLOOD UTILIZATION Of the estimated 39 million discharges in the United States in 2004, 5.8% (2.3 million) were associated with blood transfusion.132 Blood transfusion occurred in more than 10% of all hospital stays that included a procedure and was the most frequently performed procedure in 2009. The rate of blood transfusion more than doubled from 1997 to 2009.133 Increased provider awareness of the costs associated with blood transfusion134 and recognition of the potential negative outcomes have stimulated multidisciplinary, multiprofessional, and institutionbased approaches to patient blood management (see also Chapter 61). Guidelines for blood transfusion attest to the inadequacy of discrete hemoglobin levels as “triggers” for transfusion, and in addition to recommending transfusion of one blood unit each treatment event, they also acknowledge the necessity of considering other more physiologic criteria.14 It is generally agreed that transfusion is not of benefit when hemoglobin levels are greater than 10 g/dL and is beneficial when hemoglobin levels are lower than 6 g/dL.15,135 The variability in transfusion
Chapter 63: Patient Blood Management
outcomes in patients undergoing cardiothoracic surgery continues to persist even after adjusting for patient- and institution-related factors.136,137 Moreover, prospective randomized trials in patients undergoing cardiac138 and noncardiac139,140 surgery demonstrated that such patients can tolerate perioperative anemia without transfusion to hemoglobin levels between 7 and 8 g/dL, and these patients have equivalent clinical outcomes comparable to transfusions to hemoglobin levels greater than 10 g/dL. The FOCUS trial found that older (mean > 80 years of age) high-risk (factors for coronary artery disease) patients who underwent hip fracture surgery tolerated a hemoglobin trigger as low as 8 g/dL (or higher if symptomatic).140 A Cochrane meta-analysis of prospective randomized trials comparing “high” and “low” hemoglobin thresholds in more than 3700 patients found that (1) “low” hemoglobin thresholds were well tolerated, (2) RBC transfusions were reduced (≈37%) significantly in patients randomized to the “low” hemoglobin cohorts, (3) infections were reduced by 34% in patients in the “low” hemoglobin cohorts, and (4) a hemoglobin of 7 g/dL was sufficient for most patients.141 More recently, a randomized controlled trial of 2016 older patients with history or risk factors of cardiovascular disease who underwent hip surgery demonstrated that mortality rates, inability to walk independently, and in-hospital morbidity rates were similar in patients transfused according to liberal criteria and in patients transfused according to restrictive guidelines despite significantly fewer transfusions in the restrictive group.140 On the basis of this study, the AABB guidelines recommend the use of a restrictive transfusion approach (hemoglobin 7 to 8 g/dL) in stable patients who do not have cardiovascular risk factors.142 Data from the most recent National Blood Collection and Utilization Survey show a progressive annual decrease in the number of patients and the percentage of hospitals who have canceled elective surgical procedures because of blood inventory constraint.143 Current initiatives in research for blood transfusions are reflected in the growing literature on adverse effects of blood storage and their possible implications for oxygen delivery by blood transfusion.144
INDICATIONS FOR PLASMA TRANSFUSION In an evidence-based review, the Transfusion Practices Committee of the AABB recommended plasma therapy for only a few clinical indications, based on the available evidence in the literature (which was assessed to be of “weak quality”145): trauma patients with substantial hemorrhage, patients undergoing complex cardiovascular surgery, and patients with intracranial hemorrhage requiring emergency reversal of warfarin-associated coagulopathy146 (see also Chapter 62). Patients with mild prolongations of the INR (< 1.7) are not at risk of bleeding and do not need plasma therapy for minor procedures.147 Therefore, for most clinical settings, ample evidence indicates that plasma transfusions are inappropriate. However, logistic or technical barriers that prevent effective and timely plasma therapy (possibly resulting in plasma therapies that are “too little, too late”) have probably contributed to the paucity of evidence demonstrating any benefit for plasma therapy.12
Lack of enthusiasm and logistic or technical barriers in this and other settings have led to approaches for plasma therapy that are perhaps too little, too late. First, transfusion services must identify the patient’s blood group type before issuing blood type–compatible plasma; for patients unknown to the institution and/or without a historic blood type in the patient record within the past year, considerable time (up to 60 minutes) can elapse from presentation until a blood type can be ordered, drawn, and determined by the transfusion service. Second, because plasma is stored frozen at −18° C, further time (30 to 45 minutes) may be required to thaw and issue plasma. Third, the volume for each plasma unit infused (≈200 to 250 mL) represents a challenge regarding volume overload, which occurs commonly in an older population who may have preexisting comorbidities such as atrial fibrillation or other cardiovascular disease. The dosing of plasma needed to correct the coagulopathy has often been underestimated and therefore may be subtherapeutic in some clinical practices; plasma therapy of 15 to 30 mL/kg is necessary to restore hemostatic clotting factor levels to 30% to 50% of normal in acute reversal of warfarin toxicity.12 In the coagulopathy of liver disease, plasma therapy may not represent appropriate management.148 In liver disease, the extent of coagulopathy as measured by the prothrombin time or INR is not predictive of bleeding complications.149-151 Thrombin-generation assays,152,153 which measure platelet procoagulant activity, have found that patients with cirrhosis have primary hemostasis through cell-mediated pathways that are not measured by traditional laboratory assays such as prothrombin time and partial thromboplastin time. Increasing evidence indicates that these patients can undergo major hemostatic challenges such as liver biopsies and surgical procedures without plasma therapy and without bleeding complications.154 Moreover, normalization of laboratory tests in this setting is rarely achieved by plasma therapy.155 The most clinically relevant bleeding problems are a consequence of local vascular abnormalities and increased venous pressures.151,156 Thus, a more conservative plasma therapy approach would be to avoid volume and fluid overload that paradoxically favors hemorrhage, such as portal hypertension and endothelial damage.157 Alternative therapies to plasma infusion have been proposed to improve hemostasis in patients with liver disease, including the infusion of low-volume PCCs or antifibrinolytic agents, which lack the side effects of volume overload.148 One of the largest prospective studies of plasma transfusions and their effect on INR and bleeding included both medical and surgical patients with pretransfusion INR of between 1.1 and 1.85.158 The authors reported that less than 1% of patients had normalization of their INR and only 15% had at least 50% correction. The median dose of plasma was 2 units (only 5 to 7 mL/ kg), and no correlation was found between plasma dose and change in INR. This study had many of the limitations common to other reports154 in this clinical arena: lack of control groups, only modest prolongation in coagulation tests, poorly defined clinical end points (e.g., change in hemoglobin or need for transfusion), and/or an inadequate dose of plasma therapy. Point-of-care testing, coupled with algorithms for targeted plasma therapy
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TABLE 63-4 CURRENTLY APPROVED PROTHROMBIN COMPLEX CONCENTRATE PRODUCTS Factor Levels (International Units/mL)* Product (Manufacturer) I. Available in the USA: A. Four factor KCentra (CSL Behring) B. PCCs, three factor (II, IX, X) 1. Profilnine SD (Grifols)‡ 2. Bebulin VH (Baxter, Deerfield, Ill.)‡ II. Available outside the USA: A. PCCs, four factor (II, VII, IX, X) 1. Beriplex (CSL Behring, King of Prussia, Pa.)§ 2. Octaplex (Octapharma, Lachen, Switzerland)‖ 3. Cofact (Sanquin, Amsterdam)¶ 4. Prothromplex T (Baxter)# 5. Proplex T (Baxter)** B. PCCs, three factor (II,IX,X) 1. Prothromplex HT (Baxter)†† 2. Prothrombinex VF†† (CSL Bioplasma, Broadmeadows, Australia) III. Activated PCC FEIBA (Baxter)‡‡
14-35 30 20
7-20 25 20
25 30 20
14-35 30 20
32 ± 8
38 ± 5
35 ± 2.5
28 ± 5
Modified from Goodnough LT, Shander AS: How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage, Blood 117:6091-6099, 2011. PCC, Prothrombin complex concentrate. *The values given for factor contents are the number of units (International Units/mL) present per 100 factor IX units in each vial. ‡Product insert specifies: “Indicated for replacement of factor IX in patient with hemophilia B. Not indicated for treatment of factor VII deficiency.” §United Kingdon and European Union. ‖United Kingdom, Canada, and European Union. ¶European Union. #Austria. **Japan. ††Australia. ‡‡Factor VIII inhibitor bypass activity calculated for 25 U/mL vial. NB product insert specifies FEIBA is contraindicated for treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to factors VIII or IX.
in settings such as cardiothoracic surgery, liver transplantation, and trauma surgery, shows promise in improving blood utilization and patient outcomes159 (see also Chapter 61). The paucity of evidence for benefit of plasma transfusion therapy is accompanied by growing evidence that risks of plasma have been underrecognized. In a prospective study, 6% of transfused patients developed transfusion-associated excessive cardiac volume,160 a percentage that is much higher than previously reported rates in retrospective studies.161,162 Transfusion-related acute lung injury is a significant cause of morbidity and mortality from blood transfusions.163 The incidence of this complication has declined with use of plasma from male donors or from female donors who have no history of pregnancy.164
PROTHROMBIN COMPLEX CONCENTRATES PCCs are either activated (i.e., to allow for bypassing inhibitors to factor VIII or factor IX in the treatment of patients with hemophilia A or B) or nonactivated. The nonactivated PCC products currently available worldwide are listed in Table 63-4,12 and they are further categorized based on the presence (four factor) or absence (three factor) of sufficient levels of factor VII.165 PCCs
that contain all four (including factor VII) of the vitamin K–dependent clotting factors are approved in the European Union,166 as well as in various other countries such as Canada and Australia, and are now approved in the United States for emergency reversal of warfarin coagulopathy in patients with major bleeding167,168 and also for perioperative management of patients receiving warfarin therapy.169 Three-factor PCCs are approved in the United States only for the replacement of factor IX. Use of these three-factor PCCs for reversal of warfarin is controversial; although these agents can be demonstrated to normalize INR,170 one report showed a suboptimal effect in correcting INR because of minimal increments in levels of factor VII.165 A review of the role of PCCs and other options for reversing warfarin-associated coagulopathy has been published.12 Guidelines for acute reversal of warfarin coagulopathy have been published by several medical societies (Table 63-5).171-177 One review of emergency reversal of anticoagulation therapy in neurosurgical patients recommended the concomitant administration of a threefactor concentrate (4000 International Units) and rfVIIa (1.0 mg) for patients treated at one trauma center in the United States.178 Another review of PCCs for reversal of warfarin concluded that “PCC should be compared directly in randomized controlled trials [with] other
Chapter 63: Patient Blood Management TABLE 63-5 P UBLISHED GUIDELINES FOR REVERSAL OF WARFARIN ANTICOAGULATION IN PATIENTS WITH INTRACEREBRAL HEMORRHAGE Society (Year)
Australian (2004) EU Stroke (2006) ACCP (2012) AHA (2010) French (2010) British Standards (2011)
IV (5-10 mg) IV (5-10 mg) IV (5-10 mg) IV (NS) Oral or IV (10 mg) IV (5 mg)
Yes (NS) Yes (10-40) No (NS) Yes (10-15) Yes (NS)‡ No
ACCP, American College of Chest Physicians; AHA, American Heart Association; EU, European Union; IV, intravenous; NS, not specified; PCC, prothrombin complex concentrate; rfVIIa, recombinant human activated factor VII. *If a three-factor PCC is administered, fresh frozen plasma is also recommended as a source of factor VII. †Use of PCCs or rfVIIa may vary depending on availability. ‡Use of plasma only when PCCs not available.
treatment strategies including fresh frozen plasma and rfVIIa, evaluating effect on patient outcomes.”179 Normalization of the INR is just a surrogate end point.180 The role of PCC therapy relative to plasma therapy is in evolution, in part related to the following: the variability in PCC contents and clotting factor levels165,181; their regulatory approval status in different countries; their uncertain availability among hospital formularies, particularly in community hospitals; and their potential risks of thrombogenicity. Product information for activated PCCs such as FEIBA VH Immuno and Autoplex-T (Baxter, Deerfield, Ill.) states, under warnings, that these agents “must be used only for patients with circulating inhibitors to one or more coagulation factors and should not be used for the treatment of bleeding episodes resulting from coagulation factor deficiencies.”182,183 Additionally, the presence of DIC is a stated contraindication to PCC use in the package inserts. The safety of PCCs in the setting of emergency reversal of warfarin anticoagulation remains a subject of debate. One prospective study of 173 patients treated with PCC found that 4.6% of patients had a thrombotic event, but the investigators attributed these adverse events to cessation of anticoagulant therapy for underlying and ongoing risks of thrombosis.184 A study in a pig model of coagulopathy with blunt liver injury found that although 35 International Units/kg PCC improved coagulation and attenuated blood loss, increased doses (50 International Units/kg) of PCC therapy appeared to increase the risk of thromboembolism and DIC.185 Thrombogenicity has been a recognized problem for patients,186,187 in part related to the presence of activated clotting factors (for which heparin and antithrombin III have been added to some preparations) and in part because of the presence of other preexisting thromboembolic risk factors that resulted in initiation of warfarin therapy in these patients (e.g., venous thrombosis, atrial fibrillation) or new, concurrent risk factors (e.g., trauma, head injury). We previously reported a patient who was initially successfully treated with rfVIIa for refractory, massive hemorrhage while on extracorporeal membrane oxygenation (ECMO) after cardiothoracic surgery but who suffered massive thrombosis after subsequently receiving an activated PCC.126 Another case of fatal intracardiac thrombosis
following rapid administration of activated PCC for urgent warfarin coagulation reversal was also reported.188 The reported incidence of thromboembolic events published between 1998 and 2008 ranged from 0% to 7% (overall weighted mean, 2.3%), with higher and repeated dosing potentially associated with higher risk.179 Multinational trials of patients receiving a four-factor PCC product at various infusion speeds for urgent vitamin K antagonist reversal supported the safety and efficacy of rapid infusion of PCC in these patients.189,190 However, the recommendation that “whenever possible, patients receiving PCCs should be under low dose heparin prophylaxis”181 underscores that the use of PCCs in this setting is accompanied by risks of thrombosis. One review of eight clinical studies identified a thromboembolic event rate of 0.9% associated with PCC therapy.191 Studies of optimal dosing strategies for PCC, including fixed versus variable (weight-based) dosage, provide a basis for future research.192 As pooled blood product derivatives, PCCs also have potential risks of transmitting infectious agents.193 Various processing methods such as nanofiltration, solvent detergent treatment, and vapor heating have been used to inactivate pathogens in commercially available PCCs and pooled plasma products.194 The cost effectiveness of such products with pathogen reduction technology is an area of current debate.195,196 Potential risks and limitations of PCC therapy compared with plasma therapy are summarized in Table 63-6.
INDICATIONS FOR PLATELET TRANSFUSION The Joint Commission developed a performance indicator for prophylactic platelet transfusions in patients with malignant hematologic diseases or in patients who undergo stem cell transplantation, in which a platelet count threshold of 10,000/mm3 is appropriate for prophylactic platelet transfusions.197 Current guidelines from the European Union and United States recommend a transfusion trigger of 10 × 109/L for platelets transfused prophylactically.158,198 These guidelines are based on outcomes from four randomized clinical trials that compared prophylactic triggers of 10 × 109/L versus 20 × 109/L in patients with acute leukemia and in autologous and allogeneic hematopoietic stem cell transplant recipients.197,199-202 Two additional prospective studies also demonstrated safety with the lower threshold
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of 10 × 109/L for prophylactic platelet transfusions.203,204 The impact of these thresholds on numbers of platelet and blood transfusions is variable; however, one study demonstrated a 36% and 16% reduction in platelet and blood transfusions, respectively,204 whereas another showed no differences.203 Another trial demonstrated that “low-dose” prophylactic platelet transfusions are as effective as “standarddose” or “high-dose” transfusions.205 For therapeutic platelet transfusions, algorithms based on point-of-care testing have demonstrated promise in patients who have
TABLE 63-6 POTENTIAL RISKS AND LIMITATIONS OF PLASMA AND PROTHROMBIN COMPLEX CONCENTRATE THERAPY Product
Risks and Limitations
.Longer time to administer 1 2.Volume constraints 3.Transmissible disease, known/unknown 4.Allergic reactions 5.Transfusion-related acute lung injury (TRALI) 1.Limited availability 2.Some preparations lack factor VII 3.Donor pools: 3,000 to 20,000 4.Transmissible disease, known or unknown (for nonenveloped pathogens) 5.Thrombogenicity
II.Prothrombin complex concentrates
From Goodnough LT: A reappraisal of plasma, prothrombin complex concentrates, and recombinant factor VIIa in patient blood management, Crit Care Clin 28:413, 2012 with permission.
platelet-derived bleeding, such as in cardiothoracic surgery13,206 and in trauma.207 As for the evidence-based literature for plasma therapy, additional studies in platelet transfusion are needed (see also Chapter 61).208
BLOODLESS MEDICINE Some patients object to receiving blood or blood products as part of their medical treatment. Many of these individuals are Jehovah’s Witnesses and refuse the transfusion of another person’s blood based on strict interpretations of both Old and New Testament texts that refer to the sanctity of blood.209 This religious group currently has more than 6 million active and 14 million associated followers worldwide, and its publications are translated into more than 200 different languages. In the 1980s, bloodless medicine programs were started at the request of Jehovah’s Witness patients who wanted hospitals where they could receive the best medical care and have their desire to avoid allogeneic blood transfusions respected.209 Many people in the United States, regardless of their religious background, have voiced concern about the safety of blood transfusions. A telephone survey found that only 61% of the respondents believed the blood supply in the United States to be safe, and 33% said that they would refuse blood transfusions if hospitalized.22 Since 2000, public concerns about problems with the blood supply and shortages in the availability of volunteer blood donors have also led to the development of bloodless medicine centers.
Patient Blood Management
Optimize erythropoiesis • Identify, evaluate, and treat underlying anemia • Preoperative autologous blood donation • Consider erythropoiesis-stimulating agents (ESA) if nutritional anemias ruled out/treated • Refer for further evaluation if necessary • Time surgery with optimization of erythrocyte mass (note: unmanaged anemia is a contraindication for elective surgery)
• Manage nutritional/correctable anemia (e.g., avoid folate deficiency, iron-restricted erythropoiesis) • ESA therapy if appropriate • Be aware of drug interactions that can cause anemia (e.g., ACE inhibitor)
Minimize blood loss
• Identify and manage bleeding risk (past/family history) • Review medications (antiplatelet, anticoagulation therapy) • Minimize iatrogenic blood loss • Procedure planning and rehearsal
• Compare estimated blood loss with patient specific tolerable blood loss • Assess/optimize patient’s physiologic reserve (e.g., pulmonary and cardiac function) • Formulate patient-specific management plan using appropriate blood conservation modalities to manage anemia
Figure 63-2. Patient blood management. These principles applied in the perisurgical period enable treating physicians to have the time and tools to provide patient-centered evidenced-based patient blood mangement to minimize allogeneic blood transfusions. (From Goodnough LT, Shander A: Patient blood management, Anesthesiology 116:1367-1376, 2012.)
Chapter 63: Patient Blood Management
Bloodless medicine and surgery are defined as a team approach “that reduces blood loss and uses the best available alternatives to allogeneic transfusion therapy while focusing on the provision of the best possible medical care to all patients.”16 The objectives of a bloodless medicine program should include “providing leadership within an institution for bloodless medicine and being the advocate for patients not accepting transfusion.”210 All clinicians should realize that a philosophy of blood management that incorporates avoidance of unnecessary blood transfusions in all patients is appropriate even if a bloodless medicine center does not exist at their institutions.16 The principles of patient blood management can serve to achieve a goal of minimizing allogeneic blood transfusions, not only for Jehovah’s Witness patients, but also for all patients (Fig. 63-2).6
CONCLUSION Blood transfusions carry risks, they are costly, and the supply of blood is limited (see also Chapter 61). Blood transfusion outcomes are therefore undergoing renewed scrutiny by health care institutions to reduce blood use. In addition to accreditation organizations, professional societies are also well positioned to incorporate blood transfusion outcomes as quality indicators in their own guidelines and recommendations.211 The foundations of patient blood management in the perisurgical period are illustrated in Figure 63-2: (1) optimize erythropoiesis, (2) minimize blood loss, and (3) manage anemia. Strategies begin with preoperative preadmission testing and extend throughout the intraoperative and postoperative intervals, thus enabling treating physicians to minimize allogeneic blood transfusions while delivering safe and effective health care. Physicians and hospital quality or clinical effectiveness departments should incorporate the principles of patient blood management into hospital-based process improvement initiatives that enhance patient safety and clinical outcomes. Complete references available online at expertconsult.com
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References 191.Franchini M, Lippi G: Prothrombin complex concentrates: an update, Blood Transfus 8:149-154, 2010. 192.Khorsand N, Veeger NJ, Muller M, et al: Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy, Transfus Med 21:116-123, 2011. 193.Ratnoff OD: Some complications of the therapy of classic hemophilia, J Lab Clin Med 103:653-659, 1984. 194.Heger A, Svae TE, Neisser-Svae A, et al: Biochemical quality of the pharmaceutically licensed plasma OctaplasLG after implementation of a novel prion protein (PrPSc) removal technology and reduction of the solvent/detergent (S/D) process time, Vox Sang 97:219-225, 2009. 195.Custer B, Agapova M, Martinez RH: The cost-effectiveness of pathogen reduction technology as assessed using a multiple risk reduction model, Transfusion 50:2461-2473, 2010. 196.Toner RW, Pizzi L, Leas B, et al: Costs to hospitals of acquiring and processing blood in the US: a survey of hospital-based blood banks and transfusion services, Appl Health Econ Health Policy 9:29-37, 2011. 197.Rebulla P, Finazzi G, Marangoni F, et al: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia: Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto, N Engl J Med 337:1870-1875, 1997. 198.Schiffer CA, Anderson KC, Bennett CL, et al: Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology, J Clin Oncol 19:1519-1538, 2001. 199.Wandt H, Frank M, Ehninger G, et al: Safety and cost effectiveness of a 10 × 10(9)/L trigger for prophylactic platelet transfusions compared with the traditional 20 × 10(9)/L trigger: a prospective comparative trial in 105 patients with acute myeloid leukemia, Blood 91:3601-3606, 1998. 200.Heckman KD, Weiner GJ, Davis CS, et al: Randomized study of prophylactic platelet transfusion threshold during induction therapy for adult acute leukemia: 10,000/microL versus 20,000/ microL, J Clin Oncol 15:1143-1149, 1997.
201.Zumberg MS, del Rosario ML, Nejame CF, et al: A prospective randomized trial of prophylactic platelet transfusion and bleeding incidence in hematopoietic stem cell transplant recipients: 10,000/L versus 20,000/microL trigger, Biol Blood Marrow Transplant 8:569-576, 2002. 202.Callow CR, Swindell R, Randall W, Chopra R: The frequency of bleeding complications in patients with haematological malignancy following the introduction of a stringent prophylactic platelet transfusion policy, Br J Haematol 118:677-682, 2002. 203.Nevo S, Fuller AK, Hartley E, et al: Acute bleeding complications in patients after hematopoietic stem cell transplantation with prophylactic platelet transfusion triggers of 10 × 10(9) and 20 × 10(9) per L, Transfusion 47:801-812, 2007. 204.Buhrkuhl DC: An update on platelet transfusion in hematooncology supportive care, Transfusion 50:2266-2276, 2010. 205.Slichter SJ, Kaufman RM, Assmann SF, et al: Dose of prophylactic platelet transfusions and prevention of hemorrhage, N Engl J Med 362:600-613, 2010. 206.Nuttall GA, Oliver WC, Santrach PJ, et al: Efficacy of a simple intraoperative transfusion algorithm for nonerythrocyte component utilization after cardiopulmonary bypass, Anesthesiology 94:773-781, 2001. 207.Young PP, Cotton BA, Goodnough LT: Massive transfusion protocols for patients with substantial hemorrhage, Transfus Med Rev 25:293-303, 2011. 208.Delaney M, Meyer E, Cserti-Gazdewich C, et al: A systematic assessment of the quality of reporting for platelet transfusion studies, Transfusion 50:2135-2144, 2010. 209.Rosencrantz D, Shander A, Ozawa S, Spence RK: Establishing a bloodless medicine and surgery center. In Transfusion medicine and alternatives to blood transfusion, Paris, France, R&J Editions Medicales, 2000. 210.Goodnough LT, et al: Why “bloodless medicine” and how should we do it? Transfusion 43:668-676, 2003. 211.Shander AS, Goodnough LT: Blood transfusion as a quality indicator in cardiac surgery, JAMA 304:1610-1611, 2010.
Anesthesia and Treatment of Chronic Pain CHRISTOPH STEIN • ANDREAS KOPF
Key Points •The normal physiology of neuronal function, receptors, and ion channels, is altered by persistent pain. •Because of the large number of sources and manifestation of chronic pain, classification must include cancer-related, neuropathic, inflammatory, arthritis, and musculoskeletal pain. •Interdisciplinary management of chronic pain must include specialists in psychology, physical therapy, occupational therapy, neurology, and anesthesiology. •Drugs used for chronic pain are multiple and include opioids, nonsteroidal antiinflammatory drugs and antipyretic analgesics, serotonin receptor ligands, antiepileptics, antidepressants, topical analgesics (e.g., nonsteroidal antiinflammatory drugs, capsaicin, local anesthetics, opioids), and adjuvants such as local anesthetics, α2-agonists, baclofen, botulinum toxin, antiemetics, laxatives, novel drugs such as cannabinoids, and ion channel blockers. •Interventional management of chronic pain includes the use of diagnostic blocks, therapeutic blocks, continuous catheter techniques (peripheral, epidural, intrathecal), and stimulation techniques such as acupuncture, transcutaneous electrical nerve stimulation, and spinal cord stimulation. •Perioperative management of patients with chronic pain involves the following: the use of opioid and nonopioid analgesics; evaluation for dependence, addiction, and pseudoaddiction; and practical considerations.
PHYSIOLOGIC CHANGES IN PERSISTENT PAIN EXCITATORY MECHANISMS Pain may be roughly divided into two broad categories: physiologic and pathologic pain. Physiologic (acute, nociceptive) pain is an essential early warning sign that usually elicits reflex withdrawal and thereby promotes survival by protecting the organism from further injury. In contrast, pathologic (e.g., neuropathic) pain is an expression of the maladaptive operation of the nervous system; it is pain as a disease.1 Physiologic pain is mediated by a sensory system consisting of primary afferent neurons, spinal interneurons and ascending tracts, and several supraspinal areas. Trigeminal and dorsal root ganglia (DRGs) give rise to high-threshold Aδ and C fibers innervating peripheral tissues (skin, muscles, joints, viscera). These specialized primary afferent neurons, also called nociceptors, transduce noxious stimuli into action potentials and conduct them to the dorsal horn of the spinal cord (Fig. 64-1). When peripheral tissue is damaged,
primary afferent neurons are sensitized or directly activated, or both, by a variety of thermal, mechanical, and/ or chemical stimuli. Examples are protons, sympathetic amines, adenosine triphosphate (ATP), glutamate, neuropeptides (calcitonin gene–related peptide, substance P), nerve growth factor, prostanoids, bradykinin, proinflammatory cytokines, and chemokines.2,3 Many of these agents lead to opening (gating) of cation channels in the neuronal membrane. Such channels include the capsaicin-, proton-, and heat-sensitive transient receptor potential vanilloid 1 (TRPV1), or the ATP-gated purinergic P2X3 receptor. Gating produces an inward current of sodium (Na+) and calcium (Ca2+) ions into the peripheral nociceptor terminal. If this depolarizing current is sufficient to activate voltage-gated Na+ channels (e.g., Nav1.8), they too will open, further depolarizing the membrane and initiating a burst of action potentials that are then conducted along the sensory axon to the dorsal horn of the spinal cord.3,4 Thereafter, these impulses are transmitted to spinal neurons, brainstem, thalamus, and cortex.5,6
Chapter 64: Anesthesia and Treatment of Chronic Pain
Transmission of input from nociceptors to spinal neurons that project to the brain is mediated by direct monosynaptic contact or through multiple excitatory or inhibitory interneurons. The central terminals of nociceptors contain excitatory transmitters such as glutamate, substance P, and neurotrophic factors that activate postsynaptic N-methyl-d-aspartate (NMDA), neurokinin (NK1), and tyrosine kinase receptors, respectively. Repeated nociceptor stimulation can sensitize both peripheral and central neurons (activity-dependent plasticity). In spinal neurons, such a progressive increase of output in response to persistent nociceptor excitation has been termed wind-up. Later, sensitization can be sustained by transcriptional changes in the expression of genes coding for various neuropeptides, transmitters, ion channels, receptors, and signaling molecules (transcription-dependent plasticity) in both nociceptors and spinal neurons. Important examples include the NMDA receptor, cyclooxygenase-2 (COX-2), Ca2+ and Na+ channels, cytokines, and chemokines expressed by neurons and/or glial cells.7,8 In addition, physical rearrangement of neuronal circuits by apoptosis, nerve growth, and sprouting occurs in the peripheral and central nervous systems.1,5
Figure 64-1. Nociceptive pathways. For details see text. (Modified from Brack A, Stein C, Schaible HG: Periphere und zentrale Mechanismen des Entzündungsschmerzes. In Straub RH, editor: Lehrbuch der klinischen Pathophysiologie komplexer chronischer Erkrankungen, vol 1, Göttingen, Germany, 2006, Vandenhoeck & Ruprecht, pp 183-192.)
INHIBITORY MECHANISMS Concurrent with the events just described, powerful endogenous mechanisms counteracting pain unfold both in the periphery and in the central nervous system. In injured tissue, this process results from interactions between leukocyte-derived opioid peptides and peripheral nociceptor terminals carrying opioid receptors9,10 and/or by antiinflammatory cytokines.2 Inflammation of peripheral tissue leads to increased expression, axonal transport, and enhanced G-protein coupling of opioid receptors in DRG neurons as well as enhanced permeability of the perineurium. These phenomena depend on sensory neuron electrical activity, the production of proinflammatory cytokines, and the presence of nerve growth factor within the inflamed tissue. In parallel, opioid peptide–containing immune cells extravasate and accumulate in the inflamed tissue.10 These cells up-regulate the gene expression of opioid precursors and the enzymatic machinery for their processing into functionally active peptides.11,12 In response to stress, catecholamines, corticotropin-releasing factor, cytokines, chemokines, or bacteria, leukocytes secrete opioids. The latter activate peripheral opioid receptors and produce analgesia by inhibiting the excitability
Figure 64-2. Endogenous antinociceptive mechanisms within peripheral injured tissue. Opioid peptide-containing circulating leukocytes extravasate upon activation of adhesion molecules and chemotaxis by chemokines. Subsequently, these leukocytes are stimulated by stress or releasing agents to secrete opioid peptides. For example, corticotropin-releasing factor (CRF), interleukin-1β (IL-1) and norepinephrine (noradrenaline [NA], released from postganglionic sympathetic neurons) can elicit opioid release by activating their respective CRF receptors (CRFR), IL-1 receptors (IL-1R), and adrenergic receptors (AR) on leukocytes. Exogenous opioids (EO) or endogenous opioid peptides (OP, green triangles) bind to opioid receptors (OR) that are synthesized in dorsal root ganglia and are transported along intraaxonal microtubules to peripheral (and central) terminals of sensory neurons. The subsequent inhibition of ion channels (e.g., TRPV1, Ca2+) (see Fig. 64-3 and text) and of substance P (sP) release results in antinociceptive effects. cAMP, Cyclic adenosine monophosphate. (Modified from Stein C, Machelska H: Modulation of peripheral sensory neurons by the immune system: implications for pain therapy, Pharmacol Rev 63:860-881, 2011.)
of nociceptors, the release of excitatory neuropeptides, or both10,13 (Fig. 64-2). The clinical relevance of these mechanisms was shown in studies demonstrating that patients with knee joint inflammation expressed opioid peptides in immune cells and opioid receptors on sensory nerve terminals within synovial tissue.14 After knee surgery, pain and analgesic consumption were enhanced by blocking the interaction between the endogenous opioids and their receptors with intraarticular naloxone15 and diminished by stimulating opioid secretion.16 In the spinal cord, inhibition is mediated by the release of opioids, γ-aminobutyric acid (GABA), or glycine from interneurons, which activate presynaptic opioid or GABA receptors, or both, on central nociceptor terminals to reduce excitatory transmitter release. In addition, the opening of postsynaptic potassium (K+) or chloride (Cl−) channels by opioids or GABA, respectively, evokes hyperpolarizing inhibitory potentials in dorsal horn neurons. During ongoing nociceptive stimulation, spinal interneurons up-regulate gene expression and the production of opioid peptides.17,18 Powerful descending inhibitory
pathways from the brainstem also become active by operating mostly through noradrenergic, serotonergic, and opioid systems. A key region is the periaqueductal gray, which projects to the rostral ventromedial medulla, which then projects along the dorsolateral funiculus to the dorsal horn.19 The integration of signals from excitatory and inhibitory neurotransmitters with cognitive, emotional, and environmental factors (see later) eventually results in the central perception of pain. When the intricate balance of biologic, psychological, and social factors becomes disturbed, chronic pain can develop.
TRANSLATION OF BASIC RESEARCH Basic research on pain continues at a rapid pace, but translation into clinical applications has been difficult.20 Animal studies are indispensable. However, for ethical reasons these studies are restricted to days or weeks, whereas human chronic pain can last for months or years. Therefore, animal models do not mirror the truly chronic clinical situation and should be more cautiously termed
Chapter 64: Anesthesia and Treatment of Chronic Pain
reflections of persistent pain.21,22 Brain imaging is an area of intense research, and numerous studies have investigated changes in patients with various pain syndromes. However, such studies have not yet provided reproducible findings specific for a disease or a pathophysiologic basis for individual syndromes.21 Neuroimaging can detect only alterations associated with nociceptive processes, whereas clinical pain encompasses a much more complex subjective experience that critically relies on self-evaluation. Thus, imaging cannot provide an objective proxy, biomarker, or predictor for pain23 (see also the next section). Similarly, although basic research has produced some evidence for genetic control of pain, such findings are not expected to serve as a guide to individualized (personalized) clinical pain therapy any time soon.21,24
CLINICAL DEFINITIONS, PREVALENCE, AND CLASSIFICATION OF CHRONIC PAIN DEFINITIONS The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”25,26 This classification further states that pain is always subjective and that it is a sensation in parts of the body. At the same time, pain is unpleasant and therefore also has an emotional component. Aside from malignant disease, many people report pain in the absence of tissue damage or any likely pathophysiologic cause. Usually, no way exists to distinguish their experience from a condition resulting from tissue damage. If patients regard their experience as pain or if they report it in the same ways as pain caused by tissue damage, it should be accepted as pain. This definition avoids tying pain to a stimulus. Nociception is neurophysiologic activity in peripheral sensory neurons (nociceptors) and higher nociceptive pathways and is defined by the IASP as the “neural process of encoding noxious stimuli.” Nociception is not synonymous with pain. Pain is always a psychological state, even though it often has a proximate physical cause. Chronic pain is defined by the American Society of Anesthesiologists as “extending in duration beyond the expected temporal boundary of tissue injury and normal healing, and adversely affecting the function or well-being of the individual.”27 The IASP subcommittee on taxonomy defined it in 1986 as “pain without apparent biological value that has persisted beyond the normal tissue healing time usually taken to be three months.” The presence or extent of chronic pain often does not correlate with the documented tissue disorder.
PREVALENCE Beyond these general definitions, no common understanding exists about the characteristics of the patient with chronic pain. This may be one reason that estimates of pain prevalence differ greatly from one publication to another. Heterogeneous populations, the occurrence of undetected comorbidity, different definitions of chronic pain, and different approaches to data collection have
resulted in estimates of 20% to 60%. Some surveys indicate a more frequent prevalence among women and older adults. Chronic pain has enormous socioeconomic costs. In the United States alone, annual expenditures amount to more than $600 billion for health care, disability compensation, lost work days, and related expenses. Similar figures have been reported by other countries.28,29
CLASSIFICATION Traditionally, a distinction is made between malignant (related to cancer and its treatment) and nonmalignant (e.g., neuropathic, musculoskeletal, inflammatory) chronic pain. To separate somatic and psychological mechanisms is probably not warranted. Patients with cancer tend to have more serious health restrictions than do patients with chronic nonmalignant pain. Patients with nonmalignant pain may report higher pain scores and expect more pain relief than do patients with cancer.30 Nonmalignant chronic pain is frequently classified into inflammatory pain (e.g., arthritic), musculoskeletal pain (e.g., low back pain), headaches, and neuropathic pain (e.g., postherpetic neuralgia, phantom pain, complex regional pain syndrome, diabetic neuropathy, human immunodeficiency virus–associated neuropathy). Frequent symptoms of neuropathic pain include the following: spontaneous lancinating, shooting, or burning pain; hyperalgesia; and allodynia; or any combination of such pain.31 Cancer pain can originate from invasion of the tumor into tissues innervated by primary afferent neurons (e.g., pleura, peritoneum) or directly into a peripheral nerve plexus. In the latter situation, neuropathic symptoms may be predominant. A problem in the treatment of cancer pain is the lack of correlation between the patient’s selfreporting and the assessment of clinical staff. Pain may be underestimated by medical staff and family members, thus resulting in poor pain control.29 Many treatments for cancer are associated with severe pain. For example, cytoreductive radiation therapy or chemotherapy frequently causes painful oral mucositis, especially in patients undergoing bone marrow transplantation.32
BIOPSYCHOSOCIAL CONCEPT OF CHRONIC PAIN Patients with chronic pain who have cancer or nonmalignant diseases have in common the complex influences of biologic (tissue damage), cognitive (memory, expectations), emotional (anxiety, depression), and environmental factors (reinforcement, conditioning). Many patients present with limited mobility, lack of motivation, depression, anger, anxiety, and fear of reinjury, all of which hamper the return to normal work or recreational activities. Such patients may become preoccupied with pain and somatic processes, which may disrupt sleep, cause irritability, and social withdrawal. Other cognitive factors such as patients’ expectations or beliefs (e.g., perceived inability to control the pain) influence psychosocial and physical functioning. Pain behavior such as limping, medication intake, or avoidance of activity is subject to operant conditioning; that is, it responds to reward and punishment. For example, pain behavior may be positively reinforced by attention from a spouse or health