Strategies for minimizing blood loss in orthopedic surgery

Strategies for Minimizing Blood Loss in Orthopedic Surgery Joseph D. Tobias Several major orthopedic surgical procedures including hip arthroplasty, femoral osteotomy, and spinal fusion may result in significant blood loss and the need for allogeneic blood transfusions. Due to the heightened awareness of the potential deleterious effects of allogeneic blood product administration, several techniques have been evaluated to determine their efficacy in limiting perioperative blood loss. The following article will discuss the options to limit the need for allogeneic blood product administration during orthopedic surgical procedures. These techniques include: general considerations, autologous transfusion therapy, intraoperative and postoperative blood salvage, pharmacologic manipulation of the coagulation cascade, and controlled hypotension. Undoubtedly, many of these techniques are effective alone; however, the goal of performing major orthopedic surgical procedures without the use of allogeneic blood products can only be accomplished by combining several of these techniques. Semin Hematol 41(suppl 1):145-156. © 2004 Elsevier Inc. All rights reserved.

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ERIOPERATIVE TRANSFUSIONS account for more than half of the estimated 20 million units of blood and blood products that are administered every year in the United States. Of the surgical procedures that are associated with significant blood loss, orthopedic procedures, especially those involving the hip, pelvis, and spine, lead the list with estimated losses that may exceed one half to an entire blood volume.19 During these procedures, as lost blood is replaced with allogeneic blood, blood loss may be exacerbated by the development of a coagulopathy related to the dilution of normal coagulation factors, alterations in acid-base status, hypothermia, or disseminated intravascular coagulation (DIC). Treatment of the coagulopathy includes reversal or elimination of the precipitating event, reversal or elimination of factors that further impair coagulation function (acid-base disturbances, hypothermia), and, when there is clinically significant or life-threatening bleeding, correction of coagulation function as guided by the coagulation profile including the prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), fibrinogen level, and platelet count by the administration of cryoprecipitate, fresh-frozen plasma (FFP), and/or platelet concentrates. Although in most circumstances the administration of blood and/or blood products including FFP, cryoprecipitate, and platelet concentrates can be used to effectively correct hemoglobin concentrations and coagulation function, there is a growing body of evidence that recognizes the potential adverse effects of allogeneic blood product administration. These adverse effects include the transmission of infectious diseases, immunosuppression, transfusion-related acute lung injury, transfusion reactions, and graftversus-host disease.16,39,45 Adverse outcomes from

blood and blood products are illustrated by several reports.7,8,52 For example, Taylor et al reviewed the potential impact of the administration of allogeneic blood products to 1,717 adult patients in intensive care.52 The nosocomial infection rates for the transfused versus the non-transfused groups were 15.38% and 2.92%, respectively (P ⬍ .005). They also described a dose-response curve that showed the more units of packed red blood cells administered, the greater the incidence of nosocomial infection. For each unit of packed red blood cells transfused, the odds of developing a nosocomial infection increased by a factor of 1.5. Furthermore, significant increases in mortality rates and length of hospitalization were observed in those patients who received packed red blood cell transfusions. Additional evidence for the potential deleterious effects of allogeneic blood transfusions is offered by Carson et al, who studied 9,598 consecutive patients undergoing surgery for hip fracture.7 They noted a 35% greater risk of serious bacterial infection, a 52% greater risk of pneumonia, and an overall increased cost of $14,000 in patients having a nosocomial infection. Potential problems also exist with the use of FFP, including the transmission of infectious diseases, volume overload, anaphylactoid reactions, and alterations in serum ionized calcium which may lead to From the Departments of Child Health and Anesthesiology, Division of Pediatric Critical Care/Pediatric Anesthesiology, University of Missouri, Columbia, MO. Address correspondence to Joseph D. Tobias, MD, Department of Anesthesiology, University of Missouri, 3W40H, One Hospital Dr, Columbia, MO 65212. © 2004 Elsevier Inc. All rights reserved. 0037-1963/04/4101-1024$30.00/0 doi:10.1053/j.seminhematol.2003.11.025

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hypotension, cardiovascular compromise, and even cardiac arrest.8 Cote et al evaluated the hemodynamic changes and alterations in ionized calcium levels during the administration of FFP.8 Their study was prompted by a retrospective review of 17 children with thermal injury who were undergoing burn debridement and who suffered intraoperative cardiovascular events, including hypotension and bradycardia, which were severe enough to require cardiopulmonary resuscitation in some cases. Eight of these events occurred during the administration of FFP. Their prospective study included 49 intraoperative infusions of FFP to 29 children undergoing burn debridement for thermal injury. The rate of FFP infusion was randomized at 1.0, 1.5, 2.0, or 2.5 mL/ kg/min and they noted statistically significant decreases in ionized calcium during each of the four infusion rates. The greatest decrease occurred at the most rapid infusion rate. Although they noted a significant reduction in mean arterial pressure (MAP) of ⱖ20% from baseline in five patients, this did not correlate with the magnitude of the drop in ionized calcium. They therefore concluded that clinically important decreases in MAP can occur with the administration of FFP and that these changes may be prevented by the administration of exogenous calcium. Given these and other concerns, there remains significant interest in avoiding or limiting the need for allogeneic blood products. The following is a review of several of the potential options for limiting allogeneic blood product use during orthopedic surgery. These techniques include: (1) general considerations such as optimization of preoperative coagulation function, intraoperative anesthetic technique, proper patient positioning, and maintenance of normothermia; (2) autologous transfusion therapy including preoperative donation with the use of erythropoietin and intraoperative collection using acute normovolemic hemodilution (ANH); (3) intraoperative and postoperative blood salvage; (4) pharmacologic manipulation of the coagulation cascade with epsilon-aminocaproic acid (EACA), tranexamic acid (TA), aprotinin, desmopressin (DDAVP), and recombinant factor VIIa (rFVIIa); and (5) controlled hypotension. Undoubtedly, many of these techniques are effective alone; however, the goal of performing major orthopedic surgical procedures without the use of allogeneic blood products can only be accomplished by combining several of these techniques.

General Considerations Effective preoperative evaluation and preparation of the patient are essential to limit allogeneic blood product use. Many of the patients presenting for major orthopedic surgery have chronic medical conditions that affect coagulation function. Many pedi-

atric patients with scoliosis presenting for posterior spinal fusion have associated cerebral palsy and static encephalopathy, which may be complicated by seizure disorders. The chronic administration of anticonvulsant agents including phenytoin and carbamazepine may adversely effect coagulation function. Additionally, in these patients and in chronically ill elderly patients, nutritional issues and poor intake of vitamin K may predispose to chronic low levels of vitamin K– dependent coagulation factors resulting in chronic coagulation dysfunction. Preoperative screening of coagulation function and simple measures such as the administration of vitamin K (oral or intramuscular) may alleviate such problems. Other medications such as nonsteroidal anti-inflammatory agents (NSAIDs) may also affect platelet function. These agents are frequently taken by patients with chronic orthopedic problems and pain. Acetylsalicylic acid irreversibly inhibits cyclo-oxygenase and platelet function for the life of the platelet; however, NSAIDs produce reversible inhibition of platelet function that is dependent on the plasma concentration and hence the half-life of the NSAID. Discontinuation of most NSAIDs for 2 to 5 days prior to surgery will result in a return of normal platelet function. Intraoperative issues can also impact on blood loss including choice of anesthetic technique (see below for a full discussion of controlled hypotension), fluid therapy, temperature control, and patient positioning. Although control of intraoperative blood pressure and the use of controlled hypotension is a significant factor in intraoperative blood loss, other aspects of the anesthetic technique may also influence the need for allogeneic blood transfusions. Gall et al evaluated the perioperative effects of intrathecal morphine, administered in the lumbar intrathecal space prior to the start of surgery, in 30 children (9 to 19 years of age) undergoing posterior spinal fusion for idiopathic scoliosis.15 In addition to improved analgesia, they also noted decreased blood loss with intrathecal morphine; estimated blood loss (mL/kg) was 41 ⫾ 23, 34 ⫾ 19, and 14 ⫾ 10 (P ⬍ .05 v the other two groups) in the patients receiving 0, 2, and 5 ␮g/kg of intrathecal morphine, respectively. Maintenance of normothermia is also of paramount importance in controlling blood loss in orthopedic surgery. Indeed, prospective trials have shown that the maintenance of normothermia is associated with reductions in blood loss, requirements for allogeneic blood products, postoperative infections, and hospital stay.31,44 Widman et al demonstrated the thermogenic effect of an amino acid solution infusion during hip arthroplasty in adults receiving spinal anesthesia.61 In those patients receiving the amino acid solution, the pre-anesthesia temperature increased by 0.4 ⫾ 0.2°C; it was unchanged in the

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control group. At the completion of the surgical procedure, temperature had decreased by 0.4 ⫾ 0.3°C in patients receiving the amino acid infusion and by 0.9 ⫾ 0.4°C in control patients. Blood loss was significantly greater in the controls (702 ⫾ 344 mL) than in the study patients (516 ⫾ 272 mL; P ⬍ .05). Although this technique is intriguing, it is also somewhat cumbersome and costly. In most anesthetic suites, maintenance of normothermia is provided by a combination of warming the room until the patient is anesthetized, positioned and draped, the use of forced air to warm blankets, and blood/fluid warmers. The choice of intraoperative fluid administration may affect coagulation function, thereby impacting on blood loss. During ANH (see below), blood (including red blood cells, coagulation factors, and platelets) is removed and replaced with crystalloids and/or colloids. One might therefore assume that coagulation would be adversely affected by this process of hemodilution. However, as the procedure results in the dilution of anticoagulatory proteins, such as antithrombin III, a hemodilution to a hematocrit of 25% to 30% actually exerts a procoagulant effect.41,42 Colloids used for volume expansion and blood replacement may adversely effect coagulation function. Several studies have demonstrated that medium or high molecular weight hydroxyethyl starches adversely effect coagulation function, in particular, platelet function, because of their effects on von Willebrand factor (vWF) when used in doses exceeding 10 to 15 mL/kg.28,41 When considering blood loss and orthopedic surgery, an additional factor is patient positioning. When using prone positioning for spinal surgery, padding under the chest and hips is important to prevent pressure on the abdomen, which can impede venous return and thereby increase venous pressure and bleeding from the venous system around the vertebral column.

Autologous Blood Transfusion Preoperative Donation Although preoperative donation of autologous blood was first suggested by Fantus in 1937 when he founded the first blood bank in the United States,11 it was not until the 1980s that the technique became popular. Advantages of this technique include reduction of exposure to allogeneic blood, the availability of blood for patients with rare phenotypes, reduction of blood shortages, avoidance of transfusion-induced immunosuppression, and the availability of blood to some patients who refuse transfusions based on religious beliefs. The criteria for autologous donation are

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less stringent than those for homologous donors,46 and patients with known malignancies and infections such as human immunodeficiency virus (HIV) or hepatitis may participate. Although earlier programs had age restrictions, many institutions now allow autologous donation in children below 2 years and adults older than 80 years.9 Additionally, there are no limitations with respect to a patient’s weight; patients weighing 50 kg or more are able to donate a standard unit of blood (450 ⫾ 50 mL), while those weighing less than 50 kg donate proportionately smaller volumes. Hematocrit should be checked prior to each donation and should be greater than 33%. Patients should receive iron supplementation upon initiation of donation and in some cases, the efficacy of red blood cell production can be augmented by the administration of erythropoietin (see below). Donations may be made every 3 days, but the usual practice is to donate 1 U per week. The last unit should be donated at least 5 to 7 days prior to surgery to allow plasma proteins to normalize and to restore intravascular volume. Blood is collected in bags with standard anticoagulants for blood storage including citrate phosphate dextrose with adenine (CPD-A), thus allowing a shelf-life of 35 days. Autologous donation and transfusion have few contraindications. The presence of bacteremia is an absolute contraindication due to the obvious concerns of reinfection during transfusion. Pregnancy (first or third trimester), severe or unstable angina, severe aortic stenosis, anemia, severe pulmonary diseases, hemodynamic instability, or limited cardiac reserve due to other lesions may also preclude preoperative donation. However, many of these potential contraindications have been challenged. Mann et al reported adverse effects in only 4% of preoperative donations in 342 “high-risk” patients, an incidence similar to that among healthy “low-risk” patients.33 All adverse effects were attributed to transient hypotension, which resulted in either light-headedness or temporary loss of consciousness. No episodes of clinically apparent myocardial ischemia were reported; however, electrocardiograms were not obtained during donation. Owings and investigators, who retrospectively reviewed the records of 291 consecutive patients undergoing elective cardiac surgery,37 reported that 36.8% of patients donated between 1 and 6 U of blood preoperatively; adverse reactions occurred in fewer than 1% of these patients. Autologous transfusion is frequently used in orthopedic surgery. For example, in one study, autologous blood accounted for 95% of the transfusion requirements in 1,672 patients, 60% of whom were older than 60 years, thus reinforcing the notion that age should not be considered a contraindication to autologous donation.17

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Often the limiting factor in autologous donation is persistent anemia despite iron supplementation. This has been attributed to inadequate erythropoietin levels; therefore, to facilitate donation, Goodnough and coworkers administered recombinant human erythropoietin to 47 patients.18 Significantly more units were donated by those who received erythropoietin (600 U/kg twice per week) (5.4 U) compared with the placebo group (4.1 U) leading the investigators to suggest that erythropoietin may be a useful adjunct in autologous donation. The reported adverse reaction rate associated with autologous donation ranges from 1.5% to 5%; this is similar to that reported among homologous donors. Most reactions are transient and hypotensive (vasovagal), requiring no treatment. Younger donors experience more reactions then elderly patients, which, again, is a situation similar to that found in homologous donation. The reaction rate is also higher among first-time donors and also among women. Autologous blood should not be given merely because it is available, but should comply with the same criteria as for the transfusion of allogeneic blood. It has, however, been suggested that a higher hemoglobin level should be used for the transfusion of autologous versus allogeneic blood. Because of the risks for incorrect identification and possible bacterial contamination, it is prudent to avoid transfusion unless absolutely indicated. Approximately 30% to 50% of all autologous blood is not transfused, which emphasizes that the technique, which can significantly increase patient costs, should not be used unless the surgical procedure has an anticipated blood loss of 30% to 50% of the patient’s estimated blood volume.

Acute Normovolemic Hemodilution ANH involves the removal of blood on the day of surgery, generally after the induction of anesthesia, and its replacement with crystalloid or colloid solutions. Blood is removed via a large bore intravenous cannula or a central line and replaced with an equal volume of colloid or threefold more crystalloid. The blood is collected in standard CPD-A blood bank bags and weighed to ensure that the appropriate amount of blood is removed. Close attention is paid to adequate volume replacement and the monitoring of vital signs is mandatory to avoid hypovolemia. Compensatory physiological mechanisms to maintain oxygen delivery to the tissues, despite a decrease in hematocrit, include a decrease in blood viscosity resulting in increased venous return, peripheral vasodilation, increased cardiac output, and rightward shift of the oxy-hemoglobin dissociation curve. As oxygen delivery declines, oxygen extraction at the tissue level can increase as an additional mechanism to maintain adequate oxygen delivery to tissues. In an animal model, van Woerkins et al demonstrated a

constant mixed venous oxygen saturation until an exchange of 50 mL/kg of blood was achieved, resulting in a post-ANH hematocrit of 9.3% ⫾ 0.3%.62 Fontana et al evaluated the effects of ANH in eight adolescents undergoing posterior spinal fusion for idiopathic scoliosis.13 In these patients, ANH was used to decrease the hemoglobin level from 10.0 ⫾ 1.6 g/dL to 3.0 ⫾ 0.8 g/dL. Oxygen delivery decreased from 532.1 ⫾ 138.1 mL/min/m2 to 262 ⫾ 57.1 mL/ min/m2 and the oxygen extraction ration increased from 17.3% ⫾ 6.2% to 44.4% ⫾ 5.9%. They also noted an increase in cardiac output, maintenance of a stable heart rate, and most importantly no detrimental decrease in the mixed venous oxygen saturation, which demonstrates the maintenance of adequate oxygen delivery to the tissues. Mixed venous oxygen saturation decreased from a baseline level of 90.8% ⫾ 5.4% to 72.3% ⫾ 7.8% after ANH. A significant advantage of ANH compared with the use of stored autologous blood is that since the blood is fresh, the coagulation factors and platelets are still active. As the hemoglobin level drops to the intraoperative transfusion trigger, the blood is infused in the opposite order that it was withdrawn, so that the units with the highest hematocrit are saved until the end of the procedure when there is the least amount of bleeding. Prospective randomized trials have demonstrated that ANH results in a decreased use of allogeneic blood products during various types of surgical procedures.21,26,53 ANH can be combined with other techniques such as intraoperative blood salvage or autologous donation. The preoperative administration of erythropoietin may be used to increase the hematocrit and thereby allow the removal of additional amounts of blood. This technique has been termed “augmented ANH.”

Intraoperative Blood Salvage The intraoperative collection and reinfusion of shed blood during a surgical procedure was first used in the 19th century. Initially used in cardiac surgery, the technique is now used during trauma, vascular, orthopedic and gynecologic surgery, as well as liver transplantation. There are three different techniques of intraoperative salvage. Semicontinuous flow devices were the first to be introduced and are the most complex to use. Examples include the Haemonetics Cell Saver (Haemonetics, Braintree, MA). The equipment consists of an aspiration and anticoagulation assembly, a reservoir with filter, a centrifuge bowl, a waste bag, and tubing. A double-line aspiration set includes an anticoagulation line that permits either heparin or citrate to be combined with the aspirated blood at a controlled rate. The anticoagulated blood is filtered into a disposable reservoir and is then pumped into a bowl, where it is centrifuged at ap-

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proximately 4,000 rpm, washed with saline, and pumped into a reinfusion bag. Most of the white blood cells, platelets, clotting factors, free plasma hemoglobin, and anticoagulant are removed in the washing process and eliminated in the waste bag. The entire process takes approximately 5 to 10 minutes and the red blood cell suspension has a hematocrit of approximately 45% to 60%. The second type of intraoperative salvage, otherwise known as the canister collection technique, uses a rigid canister with a sterile, disposable liner. Blood is aspirated from the wound and anticoagulant added in a manner similar to that of semicontinuous flow devices. The blood, which is collected in a rigid plastic reservoir containing a disposable liner, can either be washed prior to infusion or reinfused without washing. Functioning platelets and coagulation factors are present if the blood is left unwashed; however, there is an increased risk for adverse effects due to cellular debris, free hemoglobin, and fragmented blood components. The third type of collection is a single-use, selfcontained rigid plastic reservoir that collects the shed blood. Citrate is the anticoagulant and is placed in the container in a fixed quantity prior to use. Once the container is full, or every 4 hours, the blood is reinfused. This apparatus is most commonly used for postoperative blood collection and the surgical drains are connected to the canister. Coagulation factors and platelets are present in this blood and adverse effects may occur as a result of cell fragmentation and the release of free hemoglobin.60 Suggested indications for intraoperative blood salvage include anticipated loss of large volumes of blood (exceeding 20% of the patient’s blood volume) or a procedure associated with more than a 10% risk of transfusion being required. The technique is most cost-effective when large volumes of blood are harvested, such as in liver transplantation and major vascular surgery. Reported contraindications to the techniques are usually related to the contamination of the collected blood. For example, intraoperative blood salvage should not be used if there is a risk for bacterial contamination from bowel contents or an infected wound, since bacterial counts persist, despite washing. Aspiration of protamine or other hemostatic agents, such as thrombin, is not recommended because of the risks for initiating systemic coagulation. In addition, blood containing wound irrigants, debris, and amniotic fluid should not be salvaged since these agents may also initiate intravascular coagulation. Salvage of blood during cancer surgery is controversial, but recent innovations suggest that blood salvage can be used during cancer surgery with certain alterations in the technique, such as the irradiation of the blood prior to reinfusion. Other potential complications related to blood sal-

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vage include air embolism, fat embolism, coagulopathy, hemolysis, renal dysfunction, pulmonary dysfunction, hypocalcemia, and sepsis. Air embolism is uncommon except with improper use of the devices. Coagulopathy may occur related to the initiation of DIC, due to improper technique and the infusion of blood cell fragments or the infusion of residual anticoagulant after washing. Hemolysis may occur if the suction level is too high or if the aspiration method causes excessive mixing of air with blood. Free hemoglobin may be released during salvage and washing because of erythrocyte damage. When the levels of free hemoglobin exceed 100 to 150 mg/dL, hemoglobinuria and acute renal failure may develop, as free hemoglobin is filtered in the renal tubules. However, there are reports of free hemoglobin levels of 350 mg/dL in salvaged blood; in these cases mild creatinine elevations were observed, but acute renal failure has not been reported. If adequate diuresis is maintained, hemoglobin can be excreted in great quantities without adverse effects on renal function. Simple bedside monitoring for free hemoglobin in the urine is relatively quick and easy, as the urine will be positive for blood by dipstick, but will not contain red blood cells. Metabolic consequences of cell salvage may also be seen and include a metabolic acidosis and alterations in electrolytes such as magnesium, calcium, and potassium. These alterations may be lessened by using a balanced electrolyte solution instead of saline for washing the cells prior to reinfusion. Regardless of the technique, periodic measurement of electrolytes and acid-base status is suggested during blood salvage.

Pharmacologic Manipulation of the Coagulation Cascade Desamino-8-D-Arginine Vasopressin Desamino-8-D-arginine vasopressin (desmopressin or DDAVP) is a synthetic analog of vasopressin, and was initially used in the treatment of diabetes insipidus. It was developed by the deamination of homocysteine at position 1 of the natural hormone thereby protecting the molecule from peptidase degradation. A second modification involving D-arginine substitution for L-arginine at position 8, markedly decreases its pressor activity. These alterations resulted in a more potent and prolonged antidiuretic activity with V2 vasopressin receptor agonism and little or no activity at the V1 vasopressin receptor. As a result, there are no effects on the smooth muscle of the uterus or the gastrointestinal tract. The in vivo halflife of DDAVP is approximately 55 minutes. The mechanism of DDAVP in promoting hemostasis is based on its interaction with factor VIII

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(FVIII) and vWF.24,34 FVIII, a glycoprotein, in a complex with factor IX (FIX) accelerates the activation of factor X (FX). vWF binds FVIII (thus stabilizing it), transports FVIII around the circulation, and mediates platelet adhesion to the vascular subendothelium. Desmopressin exerts its effects on coagulation by increasing the release of both FVIII and vWF from endothelial storage sites. Anecdotal reports have demonstrated its efficacy in augmenting coagulation function in various acquired and congenital types of platelet dysfunction.30 The recommended dose of DDAVP is 0.15 to 0.3 ␮g/kg administered intravenously over 15 to 20 minutes prior to the start of the surgical procedure. Plasma levels of factor VIII and vWF increase to three to five times those of baseline. Administration over 20 to 30 minutes avoids systemic hypotension since the agent can cause systemic vasodilation. DDAVP may also be given subcutaneously or intranasally. Either route will increase the plasma levels of FVIII and vWF to levels equivalent to those seen with intravenous administration. Despite anecdotal reports of its successful use in qualitative and quantitative platelet disorders, the evidence for its efficacy in orthopedic surgical procedures in patients with normal baseline coagulation function is less than compelling. Although Kobrinsky et al found that DDAVP reduced blood loss by 32.5% and reduced the need for erythrocyte transfusion by 25.6% in patients undergoing posterior spinal fusion and Harrington rod placement,29 two more recent, prospective, randomized, controlled studies in patients undergoing posterior spinal fusion for scoliosis have failed to demonstrate any effect on blood loss.1,54 Untoward effects of DDAVP include decreased free water clearance from antidiuretic hormone activity, hypotension, and the potential for thrombotic events. Hyponatremia is uncommon following a single dose and is generally seen only when excessive free water is administered perioperatively.48 Hypotension results from endothelial cell release of prostacyclin during rapid DDAVP administration. Although anecdotal reports of arterial thrombosis have occurred, prospective studies have indicated no difference in the perioperative infarction rates following coronary artery bypass grafting between patients who received DDAVP and control groups.5,35,38

Epsilon-Aminocaproic Acid and Tranexamic Acid EACA and TA are gamma amino carboxylic acid analogs of lysine. These agents inhibit fibrinolysis by preventing the conversion of plasminogen to plasmin. Plasminogen is synthesized in the liver and circulates in the plasma bound to fibrinogen via ly-

sine-binding sites. Plasminogen is activated by tissue plasminogen activator or exogenous activator molecules (streptokinase, urokinase) to form plasmin. Plasmin acts to cleave fibrin (formed by thrombincleaving fibrinogen), thereby preventing the formation of the fibrin mesh and clot stabilization. This fibrinolytic system is a basic defense mechanism that prevents the excessive deposition of fibrin following the activation of the coagulation cascade. Plasmin can hydrolyze fibrinogen as well as activated coagulation factors (FV and FVIII). EACA and TA bind to the lysine group that binds plasminogen and plasmin to fibrinogen and displace these molecules from the fibrinogen surface, thus inhibiting fibrinolysis. EACA is given at an intravenous loading dose of 100 to 150 mg/kg followed by an infusion of 10 to 15 mg/kg/h; 90% is excreted in the urine within 4 to 6 hours of administration. TA is 7 to 10 times as potent as EACA and may be used at lower doses (loading dose of 10 mg/kg followed by an infusion of 1 mg/kg/h). Ninety percent of TA is excreted in the urine after approximately 24 hours. The benefits of both EACA and TA have been evaluated in various clinical scenarios, including cardiac surgery, prostrate surgery, liver transplantation, and following subarachnoid hemorrhage. All of these situations may involve activation of the fibrinolytic system because these tissues are high in tissue plasminogen activator. Florentino-Pineda et al evaluated the efficacy of EACA (100 mg/kg followed by 10 mg/kg/h) in 28 adolescents undergoing postoperative spinal fusion.12 The anesthetic technique, including the use of controlled hypotension, was constant between the two groups. Patients that received EACA had decreased intraoperative blood loss (988 ⫾ 411 mL v 1,405 ⫾ 670 mL; P ⫽ .024) and decreased transfusion requirements (1.2 ⫾ 1.1 U v 2.2 ⫾ 1.3 U; P ⫽ .003). Similar findings were reported by Neilipovitz et al in their study of 40 adolescents undergoing posterior spinal fusion.36 Patients who received TA (10 mg/kg followed by 1 mg/kg/h) had reduced total blood transfused (cell saver plus allogeneic packed red blood cells) of 1,253 ⫾ 884 mL versus 1,784 ⫾ 733 mL (P ⫽ .045), although the amount of allogeneic blood transfused was not statistically significant at 874 ⫾ 790 mL versus 1,254 ⫾ 542 mL (P ⫽ .08). Adverse effects of EACA or TA may be related to their effects on coagulation function and the route of excretion. As with any other agent that has procoagulant activity, the potential exists for thrombotic complications, although prospective, randomized trials have failed to show a higher incidence in patients receiving TA or EACA compared with control groups. Also, since these agents are cleared by the kidneys, thrombosis of the kidneys, ureters, or lower urinary tract may occur if urologic bleeding is present. Both EACA and TA may be associated with

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hypotension during rapid intravenous administration.

Aprotinin Aprotinin is considered under the broad heading of “antifibrinolytic” agents, although its mechanism of action is different from EACA and TA. Aprotinin is a naturally occurring serine protease inhibitor, which was first isolated from bovine lung in 1930. Aprotinin has at least two potential effects on coagulation function. It inhibits the enzymatic formation of several serine protease enzymes, including trypsin and plasma kallikrein, which convert plasminogen to plasmin. In addition, aprotinin preserves platelet adhesion by protecting membrane-bound glycoprotein receptors (vWF receptor) from degradation by plasmin. Aprotininisadministeredintravenouslyandundergoes rapid redistribution into the extracellular fluid, followed by accumulation in the renal tubular epithelium and subsequent lysosomal degradation. The dose is expressed as kallikrein-inhibitory units (KIU). Various dosing regimens have been used in the literature, which generally comprise high-dose (6 million units), intermediate-dose (2 to 6 million units), and low-dose regimens (⬍2 million units). Given its rapid renal accumulation and degradation, a continuous infusion is needed to maintain adequate plasma concentrations. To date, the majority of clinical experience with aprotinin remains in patients undergoing cardiovascular surgical procedures. A large meta-analysis of 45 trials involving a total of 5,805 patients clearly demonstrated a reduction in blood loss and decreased need for allogeneic transfusions.32,59 Odds ratio for the need for allogeneic transfusions were significantly reduced with all three dosing regimens (high, intermediate, and low) at 0.31 (range, 0.25 to 0.39; P ⬍ .0001), 0.35 (range, 0.22 to 0.58; P ⬍ .0001), and 0.49 (range, 0.33 to 0.73; P ⬍ .006) respectively. Several studies have also demonstrated the potential efficacy of aprotinin in patients undergoing orthopedic surgery procedures.2,6,25,58 Capdevila et al demonstrated beneficial effects of aprotinin in patients undergoing surgery of the hip, femur, or pelvis for infectious or malignant diseases.6 Aprotinin was administered as a bolus of 1 million KIU followed by 500,000 KIU per hour during the procedure. Patients who received aprotinin when compared with placebo had decreased intraoperative blood loss (median of 1,783 mL v 5,305 mL; P ⬍ .05) and decreased need for allogeneic blood (median of 3 U v 7 U; P ⬍ .05). Additionally, patients who received aprotinin had higher postoperative platelet counts. Urban et al prospectively evaluated the efficacy of aprotinin versus EACA in adult patients undergoing reconstructive procedures of the spine (anteroposte-

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rior spinal fusion).58 Sixty patients were randomized to placebo, EACA (5 g loading dose followed by 15 mg/kg/h), or aprotinin (1 million KIU followed by 0.25 million KIU/h). Intraoperative and total blood loss in the control, EACA, and aprotinin groups were: 3,556/5,181 mL, 2,929/4,056 mL, and 2,685/3,628 (P ⬍ .05), respectively. Units of packed red blood cells transfused in the three groups were 6 ⫾ 2, 5 ⫾ 2, and 4 ⫾ 1 and units of transfused FFP and platelets were 9/3, 3/1, and 0/0, respectively. In addition, there was a decreased incidence of respiratory complications in patients that received EACA or aprotinin compared with placebo (4 of 17, 1 of 20, and 9 of 18, respectively). Potential adverse effects of aprotinin include allergic reactions and renal toxicity. Anaphylactoid reactions have been reported and are more frequent in patients previously exposed to aprotinin. When there is no prior exposure, the incidence of anaphylaxis is less than 0.1%.43 With prior exposure within the previous 6 months, the reported incidence is 5% and decreases to 1% if the exposure is more than 6 months ago. Renal toxicity is postulated to be the result of aprotinin’s strong affinity for renal tissue and subsequent accumulation in proximal tubular epithelial cells or its inhibition of serine proteases (kallikrein-kinin system). Additional adverse effects include decreases in renal plasma flow, glomerular filtration rate, and electrolyte excretion. These effects are thought to be the result of the inhibition of intrarenal kallikrein activation and decreased prostaglandin synthesis. Conversely, it has been suggested that aprotinin may have a protective effect on renal function by reducing the excretion of enzymes that induce renal injury.

Recombinant Factor VIIa Recombinant DNA technology provides the means for producing pharmacologic quantities of various coagulation factors including activated FVII (FVIIa). In 1988, a patient with hemophilia and inhibitors against FVIII who was undergoing knee surgery, was the first patient to be treated with recombinant FVIIa (rFVIIa). To date, the majority of experience with rFVIIa in both adult and pediatric patients has been in the treatment of patients with hemophilia who have developed antibodies against FVIII (inhibitors) thereby making subsequent infusions of FVIII ineffective. In this scenario, rFVIIa has been shown to effectively control acute bleeding, and bleeding during surgery. Due to its efficacy in the hemophilia population, and its unique mechanism of action, there has been an increasing body of clinical experience with rFVIIa in the nonhemophiliac population with coagulation disturbances of various etiologies. In many cases, although anecdotal, rFVIIa has been used to control life-threatening hemorrhage even

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when other modalities have failed.27,56,57 To date, there is only one report regarding the use of rFVIIa in orthopedic surgical patients.55 Tobias reported the intraoperative administration of rFVIIa to two pediatric patients who had persistent intraoperative bleeding after FFP (20 to 30 mL/kg) failed to correct coagulation function. In both patients, rFVIIa subjectively controlled surgical bleeding. rFVIIa may potentially be considered when: the coagulopathy does not respond to FFP; time is not available to wait for blood typing, thawing, and administration of FFP; there are concerns regarding the potential hemodynamic effects of FFP; or religious issues preclude the use of blood products. rFVIIa can be quickly reconstituted from powder with a small volume of sterile water and administered intravenously over 2 to 3 minutes. As the action of rFVIIa is localized to the site of endovascular injury, the risk of excessive thrombogenesis might be limited. Since rFVIIa does not correct other factor deficiencies, there is the potential that the coagulopathy will recur once the rFVIIa is cleared, suggesting that other therapies are needed to ensure correction of coagulation function. These additional therapies may include repeat dosing of rFVIIa, administration of FFP or vitamin K. Dosing recommendations in pediatric patients in the intensive care unit and during the perioperative period have been extrapolated, in part, from the adult literature and supplemented by information from the pediatric hemophiliac population. Bolus doses have ranged from 40 to 100 ␮g/kg in nonhemophiliac, pediatric populations. With ongoing bleeding or risk for bleeding, repeated doses have been administered at 2- to 6-hour intervals. When compared with adults, the pharmacokinetics in pediatric patients demonstrate a shorter half-life and increased clearance.20 Given its potential therapeutic impact, rFVIIa warrants further investigation in the pediatric population. In addition to its effects on coagulation function, preliminary data report augmentation of platelet function, suggesting a potential role in patients with bleeding and qualitative platelet disorders.

Controlled Hypotension Controlled hypotension (also referred to as deliberate or induced hypotension) may be defined as a reduction of systolic blood pressure to 80 to 90 mm Hg, a reduction of mean arterial pressure (MAP) to 50 to 65 mm Hg, or a 30% reduction of baseline MAP. The latter is relevant for pediatric patients whose baseline MAP may lie between 50 to 65 mm Hg. Although the primary premise for the use of controlled hypotension is most commonly to limit intraoperative blood

loss, an additional benefit may be improved visualization of the surgical field. Controlled hypotension was first described by Cushing in 1917. Following the initial description, additional investigators offered variations of the technique. In 1947, Gardner described the use of arteriotomy and removal of 1,600 mL of blood to reduce systolic blood pressure and limit intraoperative blood loss. Gilles in 1948 described the first use of regional anesthesia (subarachnoid blockade) as an alternative to phlebotomy-induced hypotension. With the introduction of short-acting ganglionic blocking agents (1950) and continuous vasodilator infusions (1960), the popularity and feasibility of controlled hypotension continued to increased. Prior to advocating the use of controlled hypotension, important questions had to be answered including undeniable evidence of its efficacy. In 1966, Eckenhoff and Rich performed the first controlled study, demonstrating a 50% reduction in blood loss by lowering the MAP to 55 to 65 mm Hg.10 Other studies have provided additional convincing evidence that controlled hypotension is effective, especially during major orthopedic procedures including total hip arthroplasty and spine surgery, with reported reductions of intraoperative blood loss of up to 50%.50 Obviously the safety of this technique must also be demonstrated, as with any decrease in MAP, there is a concern for decreases in end-organ perfusion and tissue hypoxia. The theory behind controlled hypotension lies in the autoregulatory function of the arteriolar bed in end-organ tissues, such that perfusion and blood flow are maintained over the autoregulatory limits of the tissue, during MAP decrease. Although a full review of the literature and discussion of this matter is beyond the scope of this article, several studies have demonstrated the maintenance of end-organ perfusion and tissue oxygenation during controlled hypotension with several different pharmacologic agents.14,40,47,51 An additional question is whether it is the reduction in MAP or cardiac output that determines intraoperative blood loss during controlled hypotension. Sivarajan et al randomized patients to either sodium nitroprusside (SNP) or trimethaphan to achieve controlled hypotension.49 Although cardiac output and heart rate increased significantly more in patients receiving SNP, no difference in blood loss was noted between the two groups, thereby demonstrating that it is MAP not cardiac output that determines blood loss. Advances in drug therapy have provided the clinician with several pharmacologic options for controlled hypotension. While it is now generally accepted that it is the reduction in MAP and not cardiac output that is the primary determinant of intraoperative blood loss, there remains some controversy as to

Minimizing Blood Loss in Orthopedic Surgery

which of the many available agents is optimal for controlled hypotension. In fact, it is likely that any of a number of agents can be used. The agents available for controlled hypotension can be conveniently divided into those used by themselves (primary agents) and those used to limit the dose requirements and therefore the adverse effects of other agents (adjuncts or secondary agents). Primary agents include regional anesthetic techniques (spinal and epidural anesthesia), the inhalational anesthetic agents (halothane, isoflurane, sevoflurane), the nitrovasodilators (SNP and nitroglycerin), trimethaphan, prostaglandin E1 (PGE1), and adenosine. The calcium channel blockers and beta adrenergic antagonists have been used as both primary agents as well as adjuncts to other agents. The pharmacologic agents used primarily as adjuncts or secondary agents include the angiotensin-converting enzyme inhibitors and alpha adrenergic agonists such as clonidine. SNP is one of the most commonly used agents for controlled hypotension. It is a direct-acting, nonselective peripheral vasodilator that primarily dilates resistance vessels, leading to venous pooling and decreased systemic vascular resistance. It has a rapid onset of action (⬃30 seconds) and a peak hypotensive effect within 2 minutes; blood pressure returns to baseline values within 3 minutes of its discontinuation. SNP releases nitric oxide (formerly endothelial-derived relaxant factor), which activates guanylate cyclase leading to an increase in the intracellular concentration of cyclic guanosine monophosphate (cGMP). cGMP decreases the availability of intracellular calcium through one of two mechanisms: decreased release from the sarcoplasmic reticulum into smooth muscle or increased uptake by the sarcoplasmic reticulum. The net result is decreased free cytosolic calcium and vascular smooth muscle relaxation. Adverse effects include rebound hypertension, coronary steal, increased intracranial pressure, increased intrapulmonary shunt with ablation of hypoxic pulmonary vasoconstriction, platelet dysfunction, and cyanide toxicity. Direct peripheral vasodilation results in baroreceptor-mediated sympathetic responses with tachycardia and increased myocardial contractility. The renin-angiotensin system and sympathetic nervous system are also activated, leading to increased cardiac output, which may offset the initial drop in MAP. Plasma catecholamine and renin activity may remain elevated after the discontinuation of SNP resulting in rebound hypertension. An additional theoretical issue with SNP is the possibility of inducing coronary ischemia through a coronary steal phenomena. The dilatation of normal coronary arteries in non-ischemic areas of the myocardium may lead to an intracoronary steal with decreased oxygen delivery to the areas supplied by diseased vasculature, which is unable to vasodilate in

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response to SNP. Since myocardial oxygen extraction is already maximal, increased coronary blood flow from the accumulation of metabolic vasodilator substances is the primary mechanism responsible for meeting increased oxygen demands. As blood pressure decreases, coronary blood flow is maintained by vasodilatation of coronary vessels. In patients with coronary artery disease and stenosis, vasodilatation may be incomplete. Therefore, ischemia may occur with a decrease in MAP to 50 to 60 mm Hg. SNP is a direct cerebral vasodilator that may lead to increased cerebral blood flow and cerebral blood volume. Although the clinical consequences of this are minimal in patients with normal intracranial compliance, increased intracranial pressure may occur in patients with reduced intracranial compliance. A similar effect may be seen with any of the direct-acting vasodilating agents. SNP may also have deleterious effects on the pulmonary vasculature and respiratory function. Hypoxic pulmonary vasoconstriction (HPV) acts as a protective mechanism to shunt blood away from unventilated alveoli, thereby maintaining the matching of ventilation with perfusion. SNP may interfere with HPV, leading to increased pulmonary shunting. These effects may be further magnified by preoperative pulmonary parenchymal disease, intraoperative positioning, and positive pressure ventilation. Despite these effects, the clinical consequences are generally minimal in patients with normal preoperative respiratory function. Platelet function may be altered during SNP administration due to inhibition of thrombasthenin, a smooth muscle-like protein leading to a defect in platelet aggregation. Hines and Barash infused SNP in 19 cardiac surgery patients to maintain a MAP of 80 mm Hg prior to cardiopulmonary bypass.23 Infusion rates greater than 3 ␮g/kg/min (or a total dose of 16 mg in adults) decreased platelet aggregation with a prolongation of the bleeding time. Adenosine diphosphate (ADP)-aggregation studies demonstrated a 33% reduction in aggregation. Despite the alteration in laboratory evaluation of platelet function, clinical bleeding did not occur. Therefore, the clinical consequences of this phenomenon are thought to be minimal in patients with normal platelet function. Additional concerns with SNP administration are the possibility of cyanide and thiocyanate accumulation. Each molecule of SNP contains five molecules of cyanide and during metabolism by the rhodinase enzyme system of the liver, free cyanide is released. The plasma concentrations of both cyanide and thiocyanate are proportional to the total dose of SNP. Following metabolism of SNP, cyanide may either be converted to thiocyanate by the rhodinase system, combine with methemoglobin to produce cyanomethemoglobin, or bind with cytochrome oxidase. The latter may result in deleterious physiologic effects

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through the impairment of the electron transport system and oxidative phosphorylation. Cyanide has a high affinity for cytochrome oxidase and if conversion to thiocyanate is slow or inadequate, cellular hypoxia and metabolic acidosis may result. Clinical signs of cyanide toxicity include an elevated mixed venous oxygen tension or a significant increase in infusion requirements over time (tachyphylaxis). The risks of toxicity can be decreased by limiting the total dose of SNP as well as the duration of the infusion. Increased cyanide levels are more common with the acute administration of more than 5 to 8 ␮g/kg/min or prolonged (more than 24 hours) infusion rates greater than 2 ␮g/kg/min. As cyanide metabolism occurs primarily in the liver, patients with altered hepatic function may be at increased risk for toxicity. Toxicity is also more common in patients with dietary deficiency of vitamin B12 or sulfur. The latter compound is required for the hepatic conversion of cyanide to thiosulfate. Metabolism by the rhodinase system produces thiocyanate which is then excreted by the kidneys. Thiocyanate toxicity, which may occur in the presence of prolonged therapy or renal failure, may manifest as skeletal muscle weakness, mental confusion, seizures, and nausea. These symptoms generally occur with plasma concentrations greater than 10 mg/dL. Thiocyanate may also alter thyroid function, leading to hypothyroidism due to the inhibition of iodine uptake into the thyroid gland. Nicardipine is a dihydropyridine calcium channel block that vasodilates the systemic, cerebral, and coronary vasculature, but has limited effects on myocardial contractility and stroke volume. Unlike SNP, nicardipine does have some intrinsic negative chronotropic effects that may limit the rebound tachycardia. Like other direct-acting vasodilators, nicardipine and the other calcium channel antagonists may increase intracranial pressure. Bernard et al compared the efficacy of SNP versus nicardipine in 20 patients during isoflurane anesthesia for spinal surgery.3 An initial dose of nicardipine of 6.2 ⫾ 0.9 mg was required to achieve a MAP of 55 to 60 mm Hg. Infusion requirements varied from 3 to 5 mg/h to maintain a similar MAP. The decrease in MAP was associated with a decrease in pulmonary and systemic vascular resistance, increased cardiac output, and decreased arteriovenous oxygen content. Unlike SNP, no change in arterial oxygenation was seen with nicardipine, suggesting that it may have minimal effects on hypoxic pulmonary vasoconstriction. The efficacy of nicardipine compared favorably with that of SNP. One problem that was noted with nicardipine was that hypotension persisted for a mean of 43 minutes (range, 27 to 88 minutes) following discontinuation of the infusion, although no untoward consequences were noted. A follow-up study

of Bernard et al4 compared SNP and nicardipine for controlled hypotension during hip arthroplasty in 24 patients. Similar cardiovascular changes were noted with nicardipine, and again, hypotension persisted for 10 to 20 minutes following discontinuation of the infusion. Rebound hypertension was seen following discontinuation of the SNP infusion. Hersey et al compared SNP with nicardipine for controlled hypotension during posterior spinal fusion in 20 pediatric patients.22 Patients who received nicardipine had decreased blood loss when compared with the SNP group (761 ⫾ 199 mL v 1,297.5 ⫾ 264 mL; P ⬍ .05). Time to restoration of blood pressure back to baseline upon discontinuation of the infusion was significantly longer with nicardipine than with SNP (26.8 ⫾ 4.0 minutes v 7.3 ⫾ 1.1 minutes; P ⬍ .001).

Summary Increasing evidence has demonstrated the potential adverse effects of using allogeneic blood products. These effects may have significant deleterious effects on patients, which may impact on cost and length of hospitalization and in specific circumstances even on mortality. Many of the major orthopedic surgical procedures result in significant blood loss and the need for allogeneic blood transfusions. Therefore a series of options to limit the need for allogeneic blood product administration during orthopedic surgical procedures have been developed. These include general surgical considerations, autologous transfusion therapy, blood salvage, pharmacologic manipulation of the coagulation cascade, and controlled hypotension. Although many of these techniques are effective alone, the combination of several of these techniques can potentially lead us to the goal of performing major orthopedic surgical procedures without the use of allogeneic blood products. Autologous donation, ANH, and controlled hypotension have already been proven in several studies to be effective, but studies showing the efficacy of the various pharmacologic agents may not be as compelling; nevertheless, agents such as aprotinin seem promising in specific settings. Since the technology of artificial blood products, which may limit the need for allogeneic transfusion, may take years yet to perfect, use of the techniques described in this review should be considered to reduce the need for allogeneic products during orthopedic surgical procedures.

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54. Theroux MC, Corddry DH, Tietz AE, et al: A study of desmopressin and blood loss during spinal fusion for neuromuscular scoliosis: A randomized, controlled, double-blinded study. Anesthesiology 87:260-267, 1997 55. Tobias JD: Synthetic factor VIIa to treat dilutional coagulopathy during posterior spinal fusion in two children. Anesthesiology 96:1522-1525, 2002 56. Tobias JD, Berkenbosch JW: Synthetic factor VIIa concentrate to treat coagulopathy and gastrointestinal bleeding in an infant with end-stage liver disease. Clin Pediatr 41:613-616, 2002 57. Tobias JD, Groeper K, Berkenbosch JW: Preliminary experience with the use of recombinant factor VIIa to treat coagulation disturbances in pediatric patients. South Med J 96:1216, 2003 58. Urban MK, Beckman J, Gordon M, et al: The efficacy of antifibrinolytics in the reduction of blood loss during complex adult reconstructive spine surgery. Spine 26:1152-1156, 2001 59. Wells PS: Safety and efficacy of methods for reducing perioperative allogeneic transfusion: A critical review of the literature. Am J Ther 9:377-388, 2002 60. Wheeler TJ, Tobias JD: Complications of autotransfusion with salvaged blood. J Post Anesthesia Nurs 9:150-152, 1994 61. Widman J, Hammarqvist F, Sellden E: Amino acid infusion induces thermogenesis and reduces blood loss during hip arthroplasty under spinal anesthesia. Anesth Analg 95:17571762, 2002 62. van Woerkins EC, Trouwborst A, Duncker DJ, et al: Catecholamines and regional hemodynamics during isovolemic hemodilution in anesthetized pigs. J Appl Physiol 72:760769, 1992