- Email: [email protected]
Transfusion in surgery and trauma
Crit Care Clin 20 (2004) 281 – 297
Transfusion in surgery and trauma Carl I. Schulman, MD, Stephen M. Cohn, MD, FACS* Division of Trauma and Critical Care, University of Miami, 1800 NW 10th Avenue, Miami, FL 33136, USA
Beal stated ‘‘blood transfusion is like marriage. . .it should not be entered upon lightly, unadvisedly or wantonly. . .or more often than is absolutely necessary’’ [1]. Approximately 40% of 11 million units of blood transfused in the United States each year are used for emergency resuscitation, and two thirds of all transfusions occur perioperatively. The supply of blood is limited, so clinicians need to understand the issues related to transfusion. In this review, blood transfusion as it relates to the surgical and trauma patient is discussed.
History of transfusion in surgery In 1667, the first animal-to-human transfusion was performed by Denis (Paris) and Lower (London) [2]. A footnote in a medical journal credits Philadelphia physician Philip Syng Physick with performing the first human-to-human blood transfusion in 1795. The real history of modern transfusion, however, begins on the battlefield. Although millions were wounded in World War I, only a few hundred transfusions were performed. During the war, Dr. Keynes described the phenomenon of giving a blood transfusion to a patient in shock as ‘‘pulling men back from the jaws of death’’ [3]. Most of these transfusions, however, were from living donors directly into the recipient. In the 1930s Dr. Norman Bethune, a Canadian surgeon, transported blood to the wounded at the front lines during the Spanish Civil War [3]. This began the modern practice of transfusion. The magnitude of the injury problem in modern times is such that in 1996 there were 173,900 traumatic deaths in the United States with 2,782,400 injury admissions.
* Corresponding author. E-mail address: [email protected] (S.M. Cohn). 0749-0704/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2003.12.005
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Of these, nearly 15% of patients were in shock and potentially in need of a lifesaving transfusion.
Blood use in surgery—bloody operations Elective surgery is also affected by the supply and demand of blood. In 1997, 8.6% of hospitals cancelled some elective surgery due to blood shortage [4]. Fig. 1 shows the types of surgeries performed that required between 2 and 4 units of blood based on surgical specialties for the years 1997 and 2000. For the year 2000, orthopedic surgeries topped the list followed by cardiothoracic and general surgery. Fig. 2 shows transfusion practices in United States patients and the amount of blood transfused per patient.
Blood use in trauma and military issues The issues relating to the use of blood in civilian and military casualty situations concern the rapidity with which blood is available, the amount of blood available, and the need to store and transport blood in the field. In urban trauma centers, uncrossmatched blood is used emergently in patients with hemorrhagic shock. Currently, shortages in the blood supply have forced clinicians to be even more judicious in their use of transfusions and use techniques to conserve and recover blood perioperatively and intraoperatively. The military situation differs in that the wounded soldier is unable to be evacuated quickly and may need transfusion on the front lines. The inability to
Fig. 1. Types of surgeries performed that required between 2 and 4 units of blood based on surgical specialties for the years 1997 and 2000.
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Fig. 2. Transfusion practices in US patients and the amount of blood transfused per patient. Data from Stover & Associates, LLC. Transfusion practices in US patients. Stanford, Connecticut; 1996.
store and transport blood is another major obstacle to treating the bleeding soldier. The military uses hypertonic saline to stabilize bleeding patients until they can be evacuated and treated in a facility capable of providing transfusions. In this arena, the use of blood substitutes may play an important role in the future.
Transfusion in surgery The modern era of transfusion in surgery was ushered in by Dr. Alexis Carrel who in 1908 performed the first modern transfusion by suturing the vein of a baby’s leg to an artery in her father’s arm [3]. This was followed by the use of the semi-direct transfusion method permitting the transfer of blood to individuals remote from the donor and facilitating the development of blood banks. Since then, clinicians have continued to improve the techniques for transfusion and attempted to elucidate the proper indications for transfusion of the critically ill and bleeding patient.
Critical care In 1993, Groeger et al [5] surveyed 2876 intensive care units (ICUs) in 1706 hospitals (40% of hospitals in the United States) for a 1-day ‘‘snapshot’’ of ICU care. They found that 17% of patients were in the ICU for > 2 weeks and 14% of patients had been transfused. In another study looking at 609 patients admitted to the ICU, 142 (23%) stayed in the ICU for > 1 week and 121 (20%) were transfused a mean of 9.5 units [6]. Vincent et al [7] recently reported a survey of more than 4000 patients in European ICUs and found a transfusion rate of 37% with patients averaging 41.1 ± 39.7 mL of blood removed per day. Historical transfusion triggers were based on anecdotal and observational data. In 1942, Adams and Lundy [8] wrote ‘‘When the concentration of hemoglobin is
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less than 8 to 10 g per mL of whole blood it is wise to give a blood transfusion before operation.’’ Hebert and colleagues [9] focused on transfusion thresholds in the critically ill patient. They randomized 838 patients to a restrictive (hemoglobin [Hgb] 7 to 9 g/dL) or a liberal (Hgb 10 to12 g/dL) transfusion strategy and found a decrease in mortality for those patients in the restrictive group with an Acute Physiology and Chronic Health Evaluation (APACHE) < 20 and for those less than 55 years of age. This suggests that a more restrictive transfusion strategy may confer a survival benefit in ICU patients.
Elective surgery Guidelines from the National Institutes of Health consensus conference in 1998 on perioperative transfusion of red cells recommended a threshold for transfusion at a hemoglobin level of 7 to 8 g/dL [10]. A recent randomized small pilot study in elderly orthopedic hip surgery patients evaluated perioperative transfusion using two different transfusion triggers. Patients were transfused for hemoglobin levels < 10 or were transfused when ‘‘symptomatic’’ (or Hgb less than 8 g/dL). The ‘‘symptomatic’’ group demonstrated a higher mortality at 60 days when compared with those transfused to 10 g/dL (11.9 versus 4.8%) [11]. Similarly, a study of elderly patients undergoing elective surgery found intraoperative or postoperative myocardial ischemia was more frequent in patients with hematocrits < 28% [12]. These studies underscore the fact that elderly patients and those with pre-existing cardiac disease may represent a unique subset of patients and therefore broad generalizations should be made with caution regarding the threshold for transfusion in these patients.
Emergency surgery/trauma The trauma patient requires special attention when discussing the utility of transfusions. Severe hemorrhage is the second leading cause of traumatic death (40%), exceeded only by traumatic brain injury [13]. Unlike medical or elective surgical patients, the trauma patient is suffering from severe, acute, hemorrhagic shock until proven otherwise. These patients are often hypothermic and acidotic, adding to their risk of coagulopathy. Hypothermia-related coagulopathy requires both rewarming and clotting-factor repletion [14,15]. The most severely injured may require massive transfusions, resulting in a dilutional coagulopathy. Massive blood transfusion is defined as > 10 units of blood (1 blood volume or 5000 mL) [16]. Transfusion of > 10 units of blood causes thrombocytopenia, low fibrinogen, and prolonged prothrombin time. Transfusion of > 20 units of blood causes coagulation defects in 70% of patients, with thrombocytopenia being most common [17]. Since these patients exhibit a massive systemic inflammatory response, the concept of damage control surgery has evolved to
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minimize the initial insult and mitigate the need for continued transfusions. In the 1970s the mortality rate was 93% for patients requiring > 25 units of blood in < 24 hours. Currently, the survival rate of these patients is approximately 50% [18]. Modern techniques in anesthesia coupled with surgical concepts such as damage control surgery have undoubtedly increased the survival rate for these patients [19]. In the trauma setting, it is sometimes not possible to wait the 30 to 60 minutes required for typing and crossmatching of blood. In these circumstances, the use of type-specific or universal donor (O negative) blood is used. Approximately 200,000 units of O-negative blood are used each year in emergency situations. The use of universal donor blood avoids major transfusion reactions due to the A, B, and Rh surface antigens, but minor reactions due to less common antigens are still possible. In an effort to facilitate the care of the severely bleeding patient, many trauma centers now have massive transfusion protocols. These protocols define procedures and responsibilities for members of the trauma team and blood bank personnel. Guidelines are put into place for the use of component therapy, blood bank inventories, and transportation of blood to the patient areas. In trauma patients, a correlation has been shown between low initial hemoglobin level and mortality [20]. A similar linear correlation has been demonstrated between survival and the number of units of transfused blood [21]. The absolute level at which to transfuse trauma patients remains controversial. However, transfusion remains a mainstay of therapy in the hypotensive, unstable trauma patient. The clinician must determine the likelihood for further blood loss and take into account the physiologic reserve of the patient to determine the need for transfusion. Trauma patients now have lower hemoglobin concentrations during their hospital stays and appear to have more frequent complete crossmatching of transfused blood [22].
Effects of transfusion in surgery/trauma patients Effect on infection/mortality The immune consequences of transfusion in the surgical patient have been extensively studied. Koval and colleagues [23] prospectively studied 687 geriatric patients undergoing open reduction and internal fixation of a hip fracture. The rate of postoperative infection was 27% in those transfused versus 15% in those not transfused (P = 0.001). Houbiers et al [24] looked prospectively at 697 patients undergoing surgery for colorectal cancer. They found the rate of bacterial infection was 39% in those transfused versus 24% (P < 0.01) in those not transfused. The relative risk of infection was 1.6 for those receiving 1 to 3 units, which increased to 3.6 for > 3 units transfused. In vitro, the function of peripheral blood mononuclear cells was assessed during culture with autologous and allogeneic stored blood. Co-incubation with stored autologous or allogeneic whole blood resulted in significant TNF-a depression and IL-10 induction,
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suggesting an immunosuppressive effect [25]. Transfusion of blood components has been associated with impairment of natural killer cells and decreases in helper-suppressor cell ratios as well as effects on B lymphocytes and increased production of certain cytokines. Once again, there appears to be a linear correlation between the degree of immune impairment and the amount of blood transfused [26]. In vivo, levels of IL-6 and bactericidal permeability increasing protein were higher in cardiac surgery patients after transfusion with packed red blood cells (PRBCs) compared with those who did not receive transfusion [27]. These patients also had worse postoperative performance. In the trauma setting, a 3-year cohort study (1 year retrospective, 2 years prospective) revealed that transfusion of > 6 units of blood in the first 12 hours after admission was an independent predictor of multiple organ failure [28]. The immune consequences of transfusion in the surgical patient are not fully elucidated. The clinician should be aware of the harmful effects of transfusion and be wary of unnecessary use. Obviously, patients transfused in these retrospective studies may have had more complex operations or more significant underlying disease contributing to their worse outcomes. This variability in study populations makes cause and effect relationships between transfusion and patient outcomes much less clear.
Effect of age of blood The FDA requires that a unit of packed red blood cells must be discarded after 42 days, and therefore the oldest typed unit of blood is provided by the blood bank. Because of blood bank inventory limitations of this precious resource, the typical unit of packed cells transfused in the United States is 21 days old [29]. The clinical consequences of transfusing these bioreactive substances in aged blood are uncertain but may have significant adverse effects, particularly in the multiply injured trauma patient and the critically ill. In an animal model of transfusion, old stored rat blood demonstrates a decreased ability to improve tissue oxygen consumption when compared with fresh cells or other blood substitutes [30,31]. The transfusion of rat blood stored under standard blood bank conditions for 28 days increased hemoglobin concentration but failed to correct tissue hypoxia when compared with fresh rat blood (< 5 days) or a red cell substitute. Deterioration in oxygen transport has been noted even after relatively short storage periods (5 to 7 days). It remains to be determined if the observed effects of transfusing old stored blood were due to corpuscular changes within the red blood cells (RBCs) or associated with bioactive substances in plasma supernatant of stored RBC concentrates. Furthermore, the magnitude of the effect of prolonged blood storage and its clinical consequences has yet to be established. For example, direct measurements of gastric mucosal pH (pHi), an indicator of gut oxygenation or splanchnic ischemia has been related to the age of blood in critically ill patients after transfusion [32,33]. Retrospective clinical studies
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have tested the association between the age of transfused blood and length of stay in the ICU [34] or mortality [35]. A recently published study evaluating the effect of length of storage on postoperative pneumonia in 416 consecutive patients undergoing coronary artery bypass grafting noted an adjusted increase of 1% in the risk of postoperative pneumonia per day of average increase in the length of storage of RBCs [36]. Zallen et al [37] have also shown that the age of transfused blood is an independent risk factor for postinjury multiple organ failure. Certainly, the sicker patients are more likely to be transfused. These studies suggest that magnitude of transfusion is an independent risk factor for subsequent complications. Although there is no prospective clinical trial data, accumulating evidence shows that the age of blood may play a role in the alterations in immune function that occur after transfusion. Regulatory agencies have been forced to increase storage times to maintain an adequate supply of red cells. The results of recent clinical and laboratory studies comparing old and fresh RBCs suggest that further clinical trials documenting the risks and benefits of prolonged RBC storage must be performed. We therefore performed a prospective randomized pilot study, with prior institutional review board (IRB) approval, comparing the outcome of patients transfused with blood stored for varying time periods [38]. We sought to determine the logistic feasibility of performing this study considering our limited inventory of blood. All patients admitted to our Level I Trauma Center between August 2000 and July 2001 were potential study participants. Patients were randomized to receive leukocyte-depleted type-specific ‘‘young’’ (< 11-day-old) blood or ‘‘old’’ (> 20-day-old) blood during the first 24 hours of their hospitalization. Patients were only randomized if the blood bank had at least 15 units of both young and old blood available. Due to availability of blood types found during an inventory of our blood bank, it was predetermined that only patients with type A blood would be studied (approximately 40% of the United States population). We have no old type O blood and type B is uncommon. Patients were considered for analysis if 2 or more units of type-specific blood were transfused. Data on infectious complications, respiratory failure, and outcome were collected. More than 8000 injuries were evaluated at Jackson Memorial Hospital during the year with more than 3600 severe injuries seen at the Ryder Trauma Center (more than 1200 had injury severity score [ISS] > 15). Only 24 of those presenting to the trauma center could be randomized due to blood bank inventory limitations. Of these, 17 patients were transfused 2 or more units of type-specific blood. Eight patients were randomized to the ‘‘young’’ blood group and nine patients to the ‘‘old’’ blood group. The ‘‘young’’ group received 9.3 ± 1.9 units of blood. The ‘‘old’’ group received 10.6 ± 3.35 units of blood. No statistically significant differences in complications between these two small patient groups were found. This pilot study demonstrated the limitations of our blood bank inventory to provide adequate inventory for a randomized trial focusing on the age of transfused blood. Due to these logistical restraints, a multicenter trial will likely be required to study the impact of the age of transfused blood on trauma patients.
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Adjuncts to transfusion/conservation methods Epogen The body’s stimulus for RBC production is endogenous erythropoietin (EPO), which is produced in response to tissue hypoxia caused by anemia, hypoxemia, and ischemia. EPO acts to stimulate progenitor cells and accelerate the marrow transit time [39]. Because its effects are not realized for 5 to 7 days, it is not a solution to acute blood loss in the trauma and surgical patient. EPO may be effective, however, in preoperative preparation of the anemic patient and in the care of the postoperative or critically ill ICU population. To be maximally effective, EPO must be administered with adequate iron available to aid in RBC production. A recent large prospective, multicenter 30-day observational study was performed in ICU patients. It consisted of 4892 patients in 284 ICUs at 213 US hospitals. They found that 44% of patients were transfused a mean of 4.6 ± 4.9 units of blood (median 3 units) and had a mean pretransfusion hemoglobin of 8.6 ± 1.7 [40]. A phase III trial of epogen consisting of 1302 patients (75% surgical) showed a statistically significant reduction (20%) in the need for transfusion, but the actual number of units saved was only 0.6 per patient [41]. Thus, it is unclear whether this overall savings of 0.6 units per patient is beneficial or cost effective. Too few hospitals may be using EPO in the preoperative preparation of the surgical patient. In a survey of United States hospitals, Hutchinson et al [42] found that only 2% of hospitals routinely used EPO for their preoperative
Table 1 Comparison of techniques for blood conservation and bloodless surgery
Erythropoietin Indications
Advantages
EBL 2 – 5 units Hgb 10 – 13 g/dL Surgery in 2 – 4 weeks No infectious or immunologic risk
Disadvantages Not applicable to acute blood loss 5 – 7 day lag time
Preoperative autologous donation Similar to EPO
Acute normovolemic hemodilution
EBL > 20% HGB > 10 g/dL No severe myocardial disease No transfusion? time transmitted disease ? cost No alloimmunization ? clerical error ? contamination Bacterial contamination Need preop Hct Volume overload < 20 % Clerical error (incompatibility) Costs Possibly wasteful
Intraoperative blood recovery EBL > 20% > 10% patients require transfusion Transfusion > 1 unit Rapid availability Cost effectiveness
Relative contraindications: Enteric contamination Hemostatic agents Malignancy
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preparation in efforts to reduce allogeneic blood transfusions. A new outpatient regimen for the administration of EPO has been described consisting of three weekly injections followed by a dose just before surgery. In orthopedic patients, this has reduced the number of patients requiring transfusion and increased the postoperative hemoglobin while minimizing the cost of EPO treatment [43]. A recent meta-analysis examined 21 trials of erythropoietin use in patients undergoing orthopedic or cardiac procedures. It demonstrated a significant relative risk reduction in the need for transfusion in patients undergoing orthopedic surgery (relative risk [RR] 0.36 for orthopedic surgery, P < 0.0001; RR 0.25 for cardiac surgery, P = 0.06) [44]. The currently accepted indications for preoperative use of EPO are anticipated blood loss of 2 to 5 units, preoperative hemoglobin level between 10 g/dL and 13 g/dL, and elective surgery scheduled in the next 2 to 4 weeks (Table 1). Surgeons will have to select patients most likely to benefit from preoperative EPO to maximize the benefits of decreased transfusions while minimizing the costs of therapy.
Blood substitutes Blood substitutes have been undergoing extensive evaluation as a potential alternative to the use of allogeneic blood in emergent and elective surgery. Unfortunately, research and development efforts at Baxter and Alliance have led to limited success with their products (tetramerized human hemoglobin; second generation perflurocarbons, respectively), despite extensive investigations. Fortunately, three companies have recently completed or have ongoing major clinical trials demonstrating potentially efficacious oxygen-carrying therapeutic agents. Northfield Laboratories (Evanston, Illinois) undertook a prospective, randomized trial of its product Polyheme (a chemically modified hemoglobin derived from human blood) in 44 trauma patients (ISS mean 21 ± 10). Patients received either PRBCs or up to 6 units of Polyheme. Study patients received a mean of 4.4 ± 2 units of Polyheme with no adverse events. The transfusion requirements were 6.8 ± 3.9 units in the Polyheme group, and 10.4 + 4.2 units in the control group (P < 0.05) with no difference at 48 hours [45]. There were no significant adverse effects, suggesting Polyheme might be a clinically useful blood substitute. Biopure (Cambridge, Massachusetts) conducted a phase III trial of its product Hemopure (purified hemoglobin from refined cow’s blood). They studied 693 elective orthopedic surgery patients and found a 59% transfusion avoidance in the Hemopure group at 42 days. The only adverse effects were a slight rise in the systolic blood pressure (maximum 14 mm Hg) [Anesthesia Res Society Poster 2002]. A 27% avoidance rate was seen in patients undergoing infrarenal aortic reconstruction [46], and a 34% reduction was seen in cardiac surgery patients [47]. Hemosol (Mississauga, Ontario, Canada) sought to evaluate the efficacy of Hemolink (o-raffinose cross-linked human hemoglobin) in a Phase III trial looking at avoidance of RBC transfusion or the reduction in the number of RBC units transfused in coronary artery bypass graft (CABG) surgery patients. The
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incidence of jaundice (36%) and hypertension (66% versus 33% in controls) was higher in the Hemolink arm. These were expected results of the metabolism of hemoglobin and the nitric oxide-binding properties of Hemolink. A higher rate of avoidance of RBC transfusion was observed in subjects who received Hemolink (17% transfused) than in subjects who received Pentaspan (27% transfused). The first transfusion occurred at an average of 41.5 hours post-treatment in the Hemolink arm compared with an average of 24.1 hours post-treatment in the control arm. Overall, a lower number of RBC units were transfused in the Hemolink arm (49 units) compared with the control arm (104 units). Additional clinical trials with Hemolink focusing upon transfusion avoidance are being initiated in North America [48]. These and other ongoing trials suggest that a safe and viable blood substitute is a future reality that should revolutionize the practice of transfusion.
Bloodless surgery Preoperative autologous donation Although possible for many decades, the use of preoperative autologous blood donation was not widespread. Currently, with the threat of HIV and other viruses, it has gained increased attention. In the last 15 years it has risen from < 5% of eligible patients to 50% to 75% of patients for certain elective surgeries [49,50]. Unfortunately, up to half of the autologous blood collected is discarded [51] because its use in patients other than the donor is not recommended [52]. Although preoperative autologous donation prevents transfusion-transmitted disease and avoids red cell alloimmunization, it is not without adverse consequences. It does not eliminate the risk of bacterial contamination or volume overload or the risk of administrative error resulting in ABO incompatibility. It costs more than allogeneic blood donation and could be considered wasteful if the blood is discarded [53]. It has been suggested that patients who donate 2 to 4 units of preoperative autologous blood require transfusion after a smaller volume of blood loss due to their decreased hematocrit [54]. In certain circumstances, however, preoperative autologous blood donation remains an excellent option.
Acute normovolemic hemodilution Acute normovolemic hemodilution (ANH) is another way to decrease the need for allogeneic transfusion in elective surgery. The technique consists of removing 2 to 4 units of the patients’ own blood immediately preoperatively and replacing this volume with crystalloid to maintain an isovolemic state, albeit with a markedly diminished circulating hematocrit. The operation is then performed
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normally. The actual RBC loss during the procedure is minimized because the shed blood has a lower hematocrit. After the procedure the patient is given back his/her own blood to restore the volume and hematocrit. Recommendations for the use of hemodilution are expected blood loss > 20%, a preoperative hemoglobin of greater than 10 g/dL, and the absence of severe myocardial disease (see Table 1) [55]. The clinical utility of hemodilution may not become apparent unless the preoperative hematocrit is reduced to < 20% [56]. A prospective study of patients undergoing radical prostatectomy found that 21% of patients received allogeneic blood despite preoperative hemodilution [57]. However, a retrospective case-control study of 800 patients who underwent total joint arthroplasty found that ANH reduced the need for allogeneic transfusion [58]. The advantages of hemodilution versus preoperative donation are savings in time, cost, and a smaller likelihood of clerical error or contamination. A metaanalysis of 24 trials (containing a total of 1218 patients) showed that ANH reduced the likelihood of exposure to allogeneic blood (odds ratio [OR] 0.31, 95% CI 0.15 to 0.62) and reduced the total units of allogeneic blood transfused. However, closer examination suggested the reductions in blood exposure may have been due to flawed study design [59]. Overall, it appears that ANH and preoperative autologous blood transfusion have similar rates of success and efficacy [60]. A survey of Canadian hospitals found ANH and EPO were used in 45% and 25% of cardiac centers, respectively [61]. The preferred techniques will likely depend on local resources and expertise.
Intraoperative blood recovery More and more surgeons are using intraoperative blood recovery techniques to minimize the need for transfusion. The most commonly used technique is the cell saver machine (Haemonetics Corp., Natick, Massachusetts). The cell saver collects shed blood throughout the procedure and then spins and washes the blood, which is returned to the patient during or after the procedure. It has been used extensively in cardiac surgery and is now becoming more common in high blood loss elective general surgery procedures and in trauma. Some machines can process the equivalent of up to 10 units of blood per hour. RBC viability is similar to that from a transfusion of stored PRBCs [62]. The processing of the blood, however, removes platelets and plasma proteins contributing to a dilutional coagulopathy. The washing process can lead to hemolysis and the ‘‘salvaged blood syndrome.’’ Retained platelet-leukocyte deposits produce procoagulant leukotactic substances and may increase the risk of the development of disseminated intravascular coagulation (DIC) [15]. The general indications for cell saver are anticipated blood loss > 20% total blood volume, that > 10% of patients undergoing the same procedure require transfusion, and that the mean transfusion requirement exceeds 1 unit (see Table 1). Some relative limitations are that it may not be optimal if there is a
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large amount of enteric contamination or if hemostatic agents such as thrombin have been used. However, a study in 11 patients with thoracoabdominal trauma who received contaminated shed blood showed no significant increase in infectious complications [63]. Its use in the presence of malignancy and possible contamination with malignant cells is also a relative contraindication. Whether the use of intraoperative blood recovery actually reduces the need for allogeneic transfusion is not clear. Previous studies have suggested decreased transfusion requirements for patients undergoing cardiac or orthopedic surgeries. On the other hand, in a prospective, randomized trial of patients undergoing repair of an abdominal aortic aneurysm, its use did not decrease the need or amount of allogeneic transfusion [64]. Instead of decreasing the number of transfusions in procedures with large blood loss, the availability and cost effectiveness of cell salvage may be of greater significance. A retrospective review of 126 patients with abdominal trauma in which the cell saver was used showed an average recovery of 6.9 units of blood per patient with a cost savings of almost 50% compared with allogeneic blood transfusion [65]. Clearly, further studies will need to be performed to better define the role of cell salvage techniques in different types of surgical situations.
‘‘Less-blood surgery’’ Hemostatic and pharmacologic techniques In addition to the techniques for bloodless surgery, several surgical techniques and perioperative pharmacologic therapies are used to minimize blood loss and thus minimize transfusions. Some of these techniques include meticulous primary hemostasis, the use of hemostatic substances such as fibrin glue or gelfoam and thrombin, or pharmacologic agents such as aprotinin, desmopressin, aminocaproic acid, and tranexamic acid. Special circumstances such as operations for isolated extremity injuries may even include the temporary use of pneumatic tourniquets to minimize blood loss. Fibrin sealant has been used in a wide variety of surgical procedures from liver resections to major vascular reconstructions. In burn surgery, where the duration of operation is often limited by the amount of blood loss, fibrin sealant has been shown to decrease the time to achieve hemostasis of the donor sites [66]. A systematic review of 12 trials examining the use of fibrin sealant as a method to minimize perioperative blood transfusion showed a reduced rate of allogeneic blood transfusions (RR 0.40, 95% CI 0.26 to 0.61) coinciding with reduced blood loss [67,68]. The overall use of these technologies was studied in a survey of Canadian hospitals under the auspices of the International Study of Peri-Operative Transfusion (ISPOT). They found the majority of techniques was used primarily in cardiac surgery (70% of centers) and included aprotinin, tranexamic acid, aminocaproic acid, and desmopressin [61]. A survey of Israeli hospitals showed similar
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results. They found most techniques were primarily used by cardiac surgery and orthopedic departments [69]. These surveys suggest the techniques to minimize allogeneic transfusions are underused by most clinicians.
Damage control surgery Lastly, the technique of abbreviated surgery (damage control) must be discussed. This represents the concept of identifying that continued operative intervention will lead to continued blood loss without hope of achieving primary hemostasis. When the patient has massive blood loss, becomes hypothermic and acidotic, and begins to suffer from a severe coagulopathy, further attempts in the operating room at achieving primary hemostasis are futile. The patient is packed and some temporary closure of the operative site is performed. The patient is then taken to the intensive care unit where he or she can continue to be resuscitated. Not until the hypothermia, acidosis, and coagulopathy have been corrected is the patient returned to the operating room for definitive surgical treatment.
Bloodless surgery centers The culmination of all types of blood conservation and avoidance can be found in bloodless surgery programs. They epitomize the use of these and other techniques to provide care to those who refuse transfusions for whatever reasons. A recent review of such a program and its effectiveness in major versus minor surgeries in 51 Jehovah’s Witnesses demonstrated significant decreases in postoperative blood loss and improved hemoglobin values [70]. This emphasizes the need for teamwork between surgeons, anesthesiologists, and other support personnel to maximize resources, decrease blood loss, and minimize transfusions. The University of Miami has one of the foremost Centers for Bloodless Medicine and Surgery. Founded in 1994, it includes 145 clinicians who specialize in providing all types of medical care while avoiding the use of blood transfusions. It has grown from as few as 200 admissions and outpatient visits in the early 1990s to almost 3000 patients seen in 2001. Its patient base continues to grow, and patient satisfaction is > 90%. The death rate in 4286 patients between 1995 and 2001 was only 2.1%, and only 0.3% of patients died due to refusal of blood [71].
Summary The role of transfusion in surgery and trauma continues to evolve with our greater understanding of the true indications for and effects of transfusion. The potential adverse immune consequences and end-organ effects of blood transfusion must be weighed against the need for replacement of blood volume and oxygen-carrying capacity. The techniques to conserve blood and avoid transfu-
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sion play an important role in caring for the bleeding surgical patient. The future holds great promise for the possibility of redefining the art of blood transfusion and perhaps one day replacing it entirely.
References [1] Beal RW. The rational use of blood. Aust NZ J Surg 1976;46(4):309 – 13. [2] History of blood transfusion medicine. Available at: http://www.bloodbook.com/trans-history. html. Accessed: February 16, 2004. [3] Starr D. Blood: an epic history of medicine and commerce. 1st edition. New York: Alfred A. Knopf; 1999. [4] National blood data resource center. Available at: http://www.nbdrc.org. Accessed: February 16, 2004. [5] Groeger JS, et al. Descriptive analysis of critical care units in the United States: patient characteristics and intensive care unit utilization. Crit Care Med 1993;21(2):279 – 91. [6] Corwin HL, Parsonnet KC, Gettinger A. RBC transfusion in the ICU. Is there a reason? Chest 1995;108(3):767 – 71. [7] Vincent JL, et al. Anemia and blood transfusion in critically ill patients. JAMA 2002;288(12): 1499 – 507. [8] Adams RC, Lundy JS. Anesthesia in cases of poor risk. Some suggestions for decreasing the risk. Surg Gynecol Obstet 1942;74:1011. [9] He´bert PC, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion requirements in critical care investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340(6):409 – 17. [10] Consensus conference. Perioperative red blood cell transfusion. JAMA 1988;260(18):2700 – 3. [11] Carson JL, et al. A pilot randomized trial comparing symptomatic vs. hemoglobin-level-driven red blood cell transfusions following hip fracture. Transfusion 1998;38(6):522 – 9. [12] Hogue Jr CW, Goodnough LT, Monk TG. Perioperative myocardial ischemic episodes are related to hematocrit level in patients undergoing radical prostatectomy. Transfusion 1998; 38(10):924 – 31. [13] Sauaia A, et al. Epidemiology of trauma deaths: a reassessment. J Trauma 1995;38(2):185 – 93. [14] Gubler KD, et al. The impact of hypothermia on dilutional coagulopathy. J Trauma 1994;36(6): 847 – 51. [15] Orlinsky M, et al. Current controversies in shock and resuscitation. Surg Clin North Am 2001; 81(6):1217 – 62 [xi – xii]. [16] Donaldson MD, Seaman MJ, Park GR. Massive blood transfusion. Br J Anaesth 1992;69(6): 621 – 30. [17] Faringer PD, et al. Blood component supplementation during massive transfusion of AS-1 red cells in trauma patients. J Trauma 1993;34(4):481 – 5 [discussion: 485 – 7]. [18] Dennis J. Blood replacement, massive transfusion, and hemostasis in hemorrhagic shock. Trauma Q 1992;8:62 – 8. [19] Whitten CS, Giesecke AH, et al. An analysis of survival in patients with traumatic injuries who received transfusions of forty units or more. Anesthesiology 1995;83:A218. [20] Knottenbelt JD. Low initial hemoglobin levels in trauma patients: an important indicator of ongoing hemorrhage. J Trauma 1991;31(10):1396 – 9. [21] Miller SE, Lim RC, Pearl TCY, et al. Massive blood transfusion in trauma patients: a study of factors effecting survival. J Trauma 1982;22:630. [22] Farion KJ, et al. Changes in red cell transfusion practice among adult trauma victims. J Trauma 1998;44(4):583 – 7. [23] Koval KJ, et al. Does blood transfusion increase the risk of infection after hip fracture? J Orthop Trauma 1997;11(4):260 – 5 [discussion: 265 – 6].
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[24] Houbiers JG, et al. Transfusion of red cells is associated with increased incidence of bacterial infection after colorectal surgery: a prospective study. Transfusion 1997;37(2):126 – 34. [25] Biedler AE, et al. Impact of alloantigens and storage-associated factors on stimulated cytokine response in an in vitro model of blood transfusion. Anesthesiology 2002;97(5):1102 – 9. [26] Landers DF, Dullye KK. Vascular access and fluid resuscitation in trauma: issues of blood and blood products. Anesth Clin N Am 1999;17(1):125 – 40. [27] Fransen E, et al. Impact of blood transfusions on inflammatory mediator release in patients undergoing cardiac surgery. Chest 1999;116(5):1233 – 9. [28] Sauaia A, et al. Early predictors of postinjury multiple organ failure. Arch Surg 1994;129(1): 39 – 45. [29] Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: anemia and blood transfusion in the critically ill—current clinical practice in the United States. Crit Care Med 2004;32(1): 39 – 52. [30] Fitzgerald RD, et al. Transfusing red blood cells stored in citrate phosphate dextrose adenine-1 for 28 days fails to improve tissue oxygenation in rats. Crit Care Med 1997;25(5):726 – 32. [31] Sielenkamper A, White M, Martin CM, Sibbald WJ, Chin-Yee I. Diaspirin crosslinked hemoglobin (DCLHb) increases oxygen uptake in septic, oxygen supply-dependent rats. 1996: American Thoracic Society 1996 International Conference. [32] Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993;269(23):3024 – 9. [33] Silverman HJ, Tuma P. Gastric tonometry in patients with sepsis. Effects of dobutamine infusions and packed red blood cell transfusions. Chest 1992;102(1):184 – 8. [34] Martin CM, Lu X, Hebert P, Schweitzer I. Age of transfused red blood cells is associated with ICU length of stay. Clin Invest Med 1994;17:124. [35] Purdy FR, Tweeddale MG, Merrick PM. Association of mortality with age of blood transfused in septic ICU patients. Can J Anaesth 1997;44(12):1256 – 61. [36] Vamvakas EC, Carven JH. Transfusion and postoperative pneumonia in coronary artery bypass graft surgery: effect of the length of storage of transfused red cells. Transfusion 1999;39(7): 701 – 10. [37] Zallen G, et al. Age of transfused blood is an independent risk factor for postinjury multiple organ failure. Am J Surg 1999;178(6):570 – 2. [38] Schulman CI, et al. Impact of age of transfused blood in the trauma patient. J Trauma 2002; 52(6):1224 – 5. [39] O’Leary PJ. The physiologic basis of surgery. Philadelphia: Williams & Wilkins; 1993. [40] Corwin HL, Surgenor SD, Gettinger A. Transfusion practice in the critically ill. Crit Care Med 2003;31(12):S668 – 71. [41] Corwin HL, et al. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002;288(22):2827 – 35. [42] Hutchinson AB, et al. Utilization of technologies to reduce allogeneic blood transfusion in the United States. Transfus Med 2001;11(2):79 – 85. [43] Goldberg MA. Perioperative epoetin alfa increases red blood cell mass and reduces exposure to transfusions: results of randomized clinical trials. Semin Hematol 1997;34(3 Suppl 2):41 – 7. [44] Laupacis A, Fergusson D. Erythropoietin to minimize perioperative blood transfusion: a systematic review of randomized trials. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Transfus Med 1998;8(4):309 – 17. [45] Gould SA, et al. The first randomized trial of human polymerized hemoglobin as a blood substitute in acute trauma and emergent surgery. J Am Coll Surg 1998;187(2):113 – 20 [discussion: 120 – 2]. [46] LaMuraglia GM, et al. The reduction of the allogenic transfusion requirement in aortic surgery with a hemoglobin-based solution. J Vasc Surg 2000;31(2):299 – 308. [47] Levy JH, et al. Polymerized bovine hemoglobin solution as a replacement for allogeneic red blood cell transfusion after cardiac surgery: results of a randomized, double-blind trial. J Thorac Cardiovasc Surg 2002;124(1):35 – 42.
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[48] Cheng DC. Safety and efficacy of o-raffinose cross-linked human hemoglobin (Hemolink) in cardiac surgery. Can J Anaesth 2001;48(4 Suppl):S41 – 8. [49] Goodnough LT, Monk TG, Brecher ME. Autologous blood procurement in the surgical setting: lessons learned in the last 10 years. Vox Sang 1996;71(3):133 – 41. [50] Toy PT, et al. Predeposited autologous blood for elective surgery. A national multicenter study. N Engl J Med 1987;316(9):517 – 20. [51] Renner SW, Howanitz PJ, Bachner P. Preoperative autologous blood donation in 612 hospitals. A College of American Pathologists’ Q-Probes study of quality issues in transfusion practice. Arch Pathol Lab Med 1992;116(6):613 – 9. [52] Blum LN, et al. Crossover use of donated blood for autologous transfusion: report of the Council on Scientific Affairs, American Medical Association. Transfusion 1998;38(9):891 – 5. [53] Goodnough LT, et al. Transfusion medicine. Second of two parts – blood conservation. N Engl J Med 1999;340(7):525 – 33. [54] Cohen JA, Brecher ME. Preoperative autologous blood donation: benefit or detriment? A mathematical analysis. Transfusion 1995;35(8):640 – 4. [55] Napier JA, et al. Guidelines for autologous transfusion. II. Perioperative haemodilution and cell salvage. British Committee for Standards in Haematology Blood Transfusion Task Force. Autologous Transfusion Working Party. Br J Anaesth 1997;78(6):768 – 71. [56] Brecher ME, Rosenfeld M. Mathematical and computer modeling of acute normovolemic hemodilution. Transfusion 1994;34(2):176 – 9. [57] Monk TG, et al. Acute normovolemic hemodilution can replace preoperative autologous blood donation as a standard of care for autologous blood procurement in radical prostatectomy. Anesth Analg 1997;85(5):953 – 8. [58] Schmied H, et al. The effects of red-cell scavenging, hemodilution, and active warming on allogenic blood requirements in patients undergoing hip or knee arthroplasty. Anesth Analg 1998;86(2):387 – 91. [59] Bryson GL, Laupacis A, Wells GA. Does acute normovolemic hemodilution reduce perioperative allogeneic transfusion? A meta-analysis. The International Study of Perioperative Transfusion. Anesth Analg 1998;86(1):9 – 15. [60] Goodnough LT, et al. A randomized trial of acute normovolemic hemodilution compared to preoperative autologous blood donation in total knee arthroplasty. Vox Sang 1999;77(1):11 – 6. [61] Graham ID, et al. The use of technologies to minimize exposure to perioperative allogeneic blood transfusion in elective surgery. A survey of Canadian hospitals. Int J Technol Assess Health Care 2000;16(1):228 – 41. [62] Williamson KR, Taswell HF. Intraoperative blood salvage: a review. Transfusion 1991;31(7): 662 – 75. [63] Timberlake GA, McSwain Jr NE. Autotransfusion of blood contaminated by enteric contents: a potentially life-saving measure in the massively hemorrhaging trauma patient? J Trauma 1988; 28(6):855 – 7. [64] Clagett GP, et al. A randomized trial of intraoperative autotransfusion during aortic surgery. J Vasc Surg 1999;29(1):22 – 30 [discussion: 30 – 1]. [65] Smith LA, Barker DE, Burns RP. Autotransfusion utilization in abdominal trauma. Am Surg 1997;63(1):47 – 9. [66] Nervi C, et al. A multicenter clinical trial to evaluate the topical hemostatic efficacy of fibrin sealant in burn patients. J Burn Care Rehabil 2001;22(2):99 – 103. [67] Carless PA, Anthony DM, Henry DA. Systematic review of the use of fibrin sealant to minimize perioperative allogeneic blood transfusion. Br J Surg 2002;89(6):695 – 703. [68] Lopez PP, Rashid QN, Cohn SM. Chapter 33: Fibrin glue use in surgery. In: Lewandrowski K, Wise DL, Trantolo DJ, Gresser JD, Yaszemski MJ, Altobelli DE, editors. Tissue engineering and biodegradable equivalents: scientific and clinical applications. New York: Marcel Dekker Inc.; 2002. p. 665 – 80. [69] Katz E, et al. The use of technologies to decrease peri-operative allogenic blood transfusion: results of practice variation in Israel. Isr Med Assoc J 2001;3(11):809 – 12.
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[70] Proposito D, et al. [Objectives of a bloodless surgery program. A comparative study (major surgery vs. minor-medium surgery) in 51 Jehova’s Witnesses patients]. Ann Ital Chir 2002;73(2): 197 – 209 [discussion: 209 – 10]. [71] Mitchell D. Annual report: Center for Bloodless Medicine & Surgery at the University of Miami/ Jackson Memorial Medical Center. Miami, FL: University of Miami; 2001.
Transfusion in surgery and trauma Carl I. Schulman, MD, Stephen M. Cohn, MD, FACS* Division of Trauma and Critical Care, University of Miami, 1800 NW 10th Avenue, Miami, FL 33136, USA
Beal stated ‘‘blood transfusion is like marriage. . .it should not be entered upon lightly, unadvisedly or wantonly. . .or more often than is absolutely necessary’’ [1]. Approximately 40% of 11 million units of blood transfused in the United States each year are used for emergency resuscitation, and two thirds of all transfusions occur perioperatively. The supply of blood is limited, so clinicians need to understand the issues related to transfusion. In this review, blood transfusion as it relates to the surgical and trauma patient is discussed.
History of transfusion in surgery In 1667, the first animal-to-human transfusion was performed by Denis (Paris) and Lower (London) [2]. A footnote in a medical journal credits Philadelphia physician Philip Syng Physick with performing the first human-to-human blood transfusion in 1795. The real history of modern transfusion, however, begins on the battlefield. Although millions were wounded in World War I, only a few hundred transfusions were performed. During the war, Dr. Keynes described the phenomenon of giving a blood transfusion to a patient in shock as ‘‘pulling men back from the jaws of death’’ [3]. Most of these transfusions, however, were from living donors directly into the recipient. In the 1930s Dr. Norman Bethune, a Canadian surgeon, transported blood to the wounded at the front lines during the Spanish Civil War [3]. This began the modern practice of transfusion. The magnitude of the injury problem in modern times is such that in 1996 there were 173,900 traumatic deaths in the United States with 2,782,400 injury admissions.
* Corresponding author. E-mail address: [email protected] (S.M. Cohn). 0749-0704/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2003.12.005
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Of these, nearly 15% of patients were in shock and potentially in need of a lifesaving transfusion.
Blood use in surgery—bloody operations Elective surgery is also affected by the supply and demand of blood. In 1997, 8.6% of hospitals cancelled some elective surgery due to blood shortage [4]. Fig. 1 shows the types of surgeries performed that required between 2 and 4 units of blood based on surgical specialties for the years 1997 and 2000. For the year 2000, orthopedic surgeries topped the list followed by cardiothoracic and general surgery. Fig. 2 shows transfusion practices in United States patients and the amount of blood transfused per patient.
Blood use in trauma and military issues The issues relating to the use of blood in civilian and military casualty situations concern the rapidity with which blood is available, the amount of blood available, and the need to store and transport blood in the field. In urban trauma centers, uncrossmatched blood is used emergently in patients with hemorrhagic shock. Currently, shortages in the blood supply have forced clinicians to be even more judicious in their use of transfusions and use techniques to conserve and recover blood perioperatively and intraoperatively. The military situation differs in that the wounded soldier is unable to be evacuated quickly and may need transfusion on the front lines. The inability to
Fig. 1. Types of surgeries performed that required between 2 and 4 units of blood based on surgical specialties for the years 1997 and 2000.
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Fig. 2. Transfusion practices in US patients and the amount of blood transfused per patient. Data from Stover & Associates, LLC. Transfusion practices in US patients. Stanford, Connecticut; 1996.
store and transport blood is another major obstacle to treating the bleeding soldier. The military uses hypertonic saline to stabilize bleeding patients until they can be evacuated and treated in a facility capable of providing transfusions. In this arena, the use of blood substitutes may play an important role in the future.
Transfusion in surgery The modern era of transfusion in surgery was ushered in by Dr. Alexis Carrel who in 1908 performed the first modern transfusion by suturing the vein of a baby’s leg to an artery in her father’s arm [3]. This was followed by the use of the semi-direct transfusion method permitting the transfer of blood to individuals remote from the donor and facilitating the development of blood banks. Since then, clinicians have continued to improve the techniques for transfusion and attempted to elucidate the proper indications for transfusion of the critically ill and bleeding patient.
Critical care In 1993, Groeger et al [5] surveyed 2876 intensive care units (ICUs) in 1706 hospitals (40% of hospitals in the United States) for a 1-day ‘‘snapshot’’ of ICU care. They found that 17% of patients were in the ICU for > 2 weeks and 14% of patients had been transfused. In another study looking at 609 patients admitted to the ICU, 142 (23%) stayed in the ICU for > 1 week and 121 (20%) were transfused a mean of 9.5 units [6]. Vincent et al [7] recently reported a survey of more than 4000 patients in European ICUs and found a transfusion rate of 37% with patients averaging 41.1 ± 39.7 mL of blood removed per day. Historical transfusion triggers were based on anecdotal and observational data. In 1942, Adams and Lundy [8] wrote ‘‘When the concentration of hemoglobin is
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less than 8 to 10 g per mL of whole blood it is wise to give a blood transfusion before operation.’’ Hebert and colleagues [9] focused on transfusion thresholds in the critically ill patient. They randomized 838 patients to a restrictive (hemoglobin [Hgb] 7 to 9 g/dL) or a liberal (Hgb 10 to12 g/dL) transfusion strategy and found a decrease in mortality for those patients in the restrictive group with an Acute Physiology and Chronic Health Evaluation (APACHE) < 20 and for those less than 55 years of age. This suggests that a more restrictive transfusion strategy may confer a survival benefit in ICU patients.
Elective surgery Guidelines from the National Institutes of Health consensus conference in 1998 on perioperative transfusion of red cells recommended a threshold for transfusion at a hemoglobin level of 7 to 8 g/dL [10]. A recent randomized small pilot study in elderly orthopedic hip surgery patients evaluated perioperative transfusion using two different transfusion triggers. Patients were transfused for hemoglobin levels < 10 or were transfused when ‘‘symptomatic’’ (or Hgb less than 8 g/dL). The ‘‘symptomatic’’ group demonstrated a higher mortality at 60 days when compared with those transfused to 10 g/dL (11.9 versus 4.8%) [11]. Similarly, a study of elderly patients undergoing elective surgery found intraoperative or postoperative myocardial ischemia was more frequent in patients with hematocrits < 28% [12]. These studies underscore the fact that elderly patients and those with pre-existing cardiac disease may represent a unique subset of patients and therefore broad generalizations should be made with caution regarding the threshold for transfusion in these patients.
Emergency surgery/trauma The trauma patient requires special attention when discussing the utility of transfusions. Severe hemorrhage is the second leading cause of traumatic death (40%), exceeded only by traumatic brain injury [13]. Unlike medical or elective surgical patients, the trauma patient is suffering from severe, acute, hemorrhagic shock until proven otherwise. These patients are often hypothermic and acidotic, adding to their risk of coagulopathy. Hypothermia-related coagulopathy requires both rewarming and clotting-factor repletion [14,15]. The most severely injured may require massive transfusions, resulting in a dilutional coagulopathy. Massive blood transfusion is defined as > 10 units of blood (1 blood volume or 5000 mL) [16]. Transfusion of > 10 units of blood causes thrombocytopenia, low fibrinogen, and prolonged prothrombin time. Transfusion of > 20 units of blood causes coagulation defects in 70% of patients, with thrombocytopenia being most common [17]. Since these patients exhibit a massive systemic inflammatory response, the concept of damage control surgery has evolved to
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minimize the initial insult and mitigate the need for continued transfusions. In the 1970s the mortality rate was 93% for patients requiring > 25 units of blood in < 24 hours. Currently, the survival rate of these patients is approximately 50% [18]. Modern techniques in anesthesia coupled with surgical concepts such as damage control surgery have undoubtedly increased the survival rate for these patients [19]. In the trauma setting, it is sometimes not possible to wait the 30 to 60 minutes required for typing and crossmatching of blood. In these circumstances, the use of type-specific or universal donor (O negative) blood is used. Approximately 200,000 units of O-negative blood are used each year in emergency situations. The use of universal donor blood avoids major transfusion reactions due to the A, B, and Rh surface antigens, but minor reactions due to less common antigens are still possible. In an effort to facilitate the care of the severely bleeding patient, many trauma centers now have massive transfusion protocols. These protocols define procedures and responsibilities for members of the trauma team and blood bank personnel. Guidelines are put into place for the use of component therapy, blood bank inventories, and transportation of blood to the patient areas. In trauma patients, a correlation has been shown between low initial hemoglobin level and mortality [20]. A similar linear correlation has been demonstrated between survival and the number of units of transfused blood [21]. The absolute level at which to transfuse trauma patients remains controversial. However, transfusion remains a mainstay of therapy in the hypotensive, unstable trauma patient. The clinician must determine the likelihood for further blood loss and take into account the physiologic reserve of the patient to determine the need for transfusion. Trauma patients now have lower hemoglobin concentrations during their hospital stays and appear to have more frequent complete crossmatching of transfused blood [22].
Effects of transfusion in surgery/trauma patients Effect on infection/mortality The immune consequences of transfusion in the surgical patient have been extensively studied. Koval and colleagues [23] prospectively studied 687 geriatric patients undergoing open reduction and internal fixation of a hip fracture. The rate of postoperative infection was 27% in those transfused versus 15% in those not transfused (P = 0.001). Houbiers et al [24] looked prospectively at 697 patients undergoing surgery for colorectal cancer. They found the rate of bacterial infection was 39% in those transfused versus 24% (P < 0.01) in those not transfused. The relative risk of infection was 1.6 for those receiving 1 to 3 units, which increased to 3.6 for > 3 units transfused. In vitro, the function of peripheral blood mononuclear cells was assessed during culture with autologous and allogeneic stored blood. Co-incubation with stored autologous or allogeneic whole blood resulted in significant TNF-a depression and IL-10 induction,
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suggesting an immunosuppressive effect [25]. Transfusion of blood components has been associated with impairment of natural killer cells and decreases in helper-suppressor cell ratios as well as effects on B lymphocytes and increased production of certain cytokines. Once again, there appears to be a linear correlation between the degree of immune impairment and the amount of blood transfused [26]. In vivo, levels of IL-6 and bactericidal permeability increasing protein were higher in cardiac surgery patients after transfusion with packed red blood cells (PRBCs) compared with those who did not receive transfusion [27]. These patients also had worse postoperative performance. In the trauma setting, a 3-year cohort study (1 year retrospective, 2 years prospective) revealed that transfusion of > 6 units of blood in the first 12 hours after admission was an independent predictor of multiple organ failure [28]. The immune consequences of transfusion in the surgical patient are not fully elucidated. The clinician should be aware of the harmful effects of transfusion and be wary of unnecessary use. Obviously, patients transfused in these retrospective studies may have had more complex operations or more significant underlying disease contributing to their worse outcomes. This variability in study populations makes cause and effect relationships between transfusion and patient outcomes much less clear.
Effect of age of blood The FDA requires that a unit of packed red blood cells must be discarded after 42 days, and therefore the oldest typed unit of blood is provided by the blood bank. Because of blood bank inventory limitations of this precious resource, the typical unit of packed cells transfused in the United States is 21 days old [29]. The clinical consequences of transfusing these bioreactive substances in aged blood are uncertain but may have significant adverse effects, particularly in the multiply injured trauma patient and the critically ill. In an animal model of transfusion, old stored rat blood demonstrates a decreased ability to improve tissue oxygen consumption when compared with fresh cells or other blood substitutes [30,31]. The transfusion of rat blood stored under standard blood bank conditions for 28 days increased hemoglobin concentration but failed to correct tissue hypoxia when compared with fresh rat blood (< 5 days) or a red cell substitute. Deterioration in oxygen transport has been noted even after relatively short storage periods (5 to 7 days). It remains to be determined if the observed effects of transfusing old stored blood were due to corpuscular changes within the red blood cells (RBCs) or associated with bioactive substances in plasma supernatant of stored RBC concentrates. Furthermore, the magnitude of the effect of prolonged blood storage and its clinical consequences has yet to be established. For example, direct measurements of gastric mucosal pH (pHi), an indicator of gut oxygenation or splanchnic ischemia has been related to the age of blood in critically ill patients after transfusion [32,33]. Retrospective clinical studies
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have tested the association between the age of transfused blood and length of stay in the ICU [34] or mortality [35]. A recently published study evaluating the effect of length of storage on postoperative pneumonia in 416 consecutive patients undergoing coronary artery bypass grafting noted an adjusted increase of 1% in the risk of postoperative pneumonia per day of average increase in the length of storage of RBCs [36]. Zallen et al [37] have also shown that the age of transfused blood is an independent risk factor for postinjury multiple organ failure. Certainly, the sicker patients are more likely to be transfused. These studies suggest that magnitude of transfusion is an independent risk factor for subsequent complications. Although there is no prospective clinical trial data, accumulating evidence shows that the age of blood may play a role in the alterations in immune function that occur after transfusion. Regulatory agencies have been forced to increase storage times to maintain an adequate supply of red cells. The results of recent clinical and laboratory studies comparing old and fresh RBCs suggest that further clinical trials documenting the risks and benefits of prolonged RBC storage must be performed. We therefore performed a prospective randomized pilot study, with prior institutional review board (IRB) approval, comparing the outcome of patients transfused with blood stored for varying time periods [38]. We sought to determine the logistic feasibility of performing this study considering our limited inventory of blood. All patients admitted to our Level I Trauma Center between August 2000 and July 2001 were potential study participants. Patients were randomized to receive leukocyte-depleted type-specific ‘‘young’’ (< 11-day-old) blood or ‘‘old’’ (> 20-day-old) blood during the first 24 hours of their hospitalization. Patients were only randomized if the blood bank had at least 15 units of both young and old blood available. Due to availability of blood types found during an inventory of our blood bank, it was predetermined that only patients with type A blood would be studied (approximately 40% of the United States population). We have no old type O blood and type B is uncommon. Patients were considered for analysis if 2 or more units of type-specific blood were transfused. Data on infectious complications, respiratory failure, and outcome were collected. More than 8000 injuries were evaluated at Jackson Memorial Hospital during the year with more than 3600 severe injuries seen at the Ryder Trauma Center (more than 1200 had injury severity score [ISS] > 15). Only 24 of those presenting to the trauma center could be randomized due to blood bank inventory limitations. Of these, 17 patients were transfused 2 or more units of type-specific blood. Eight patients were randomized to the ‘‘young’’ blood group and nine patients to the ‘‘old’’ blood group. The ‘‘young’’ group received 9.3 ± 1.9 units of blood. The ‘‘old’’ group received 10.6 ± 3.35 units of blood. No statistically significant differences in complications between these two small patient groups were found. This pilot study demonstrated the limitations of our blood bank inventory to provide adequate inventory for a randomized trial focusing on the age of transfused blood. Due to these logistical restraints, a multicenter trial will likely be required to study the impact of the age of transfused blood on trauma patients.
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Adjuncts to transfusion/conservation methods Epogen The body’s stimulus for RBC production is endogenous erythropoietin (EPO), which is produced in response to tissue hypoxia caused by anemia, hypoxemia, and ischemia. EPO acts to stimulate progenitor cells and accelerate the marrow transit time [39]. Because its effects are not realized for 5 to 7 days, it is not a solution to acute blood loss in the trauma and surgical patient. EPO may be effective, however, in preoperative preparation of the anemic patient and in the care of the postoperative or critically ill ICU population. To be maximally effective, EPO must be administered with adequate iron available to aid in RBC production. A recent large prospective, multicenter 30-day observational study was performed in ICU patients. It consisted of 4892 patients in 284 ICUs at 213 US hospitals. They found that 44% of patients were transfused a mean of 4.6 ± 4.9 units of blood (median 3 units) and had a mean pretransfusion hemoglobin of 8.6 ± 1.7 [40]. A phase III trial of epogen consisting of 1302 patients (75% surgical) showed a statistically significant reduction (20%) in the need for transfusion, but the actual number of units saved was only 0.6 per patient [41]. Thus, it is unclear whether this overall savings of 0.6 units per patient is beneficial or cost effective. Too few hospitals may be using EPO in the preoperative preparation of the surgical patient. In a survey of United States hospitals, Hutchinson et al [42] found that only 2% of hospitals routinely used EPO for their preoperative
Table 1 Comparison of techniques for blood conservation and bloodless surgery
Erythropoietin Indications
Advantages
EBL 2 – 5 units Hgb 10 – 13 g/dL Surgery in 2 – 4 weeks No infectious or immunologic risk
Disadvantages Not applicable to acute blood loss 5 – 7 day lag time
Preoperative autologous donation Similar to EPO
Acute normovolemic hemodilution
EBL > 20% HGB > 10 g/dL No severe myocardial disease No transfusion? time transmitted disease ? cost No alloimmunization ? clerical error ? contamination Bacterial contamination Need preop Hct Volume overload < 20 % Clerical error (incompatibility) Costs Possibly wasteful
Intraoperative blood recovery EBL > 20% > 10% patients require transfusion Transfusion > 1 unit Rapid availability Cost effectiveness
Relative contraindications: Enteric contamination Hemostatic agents Malignancy
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preparation in efforts to reduce allogeneic blood transfusions. A new outpatient regimen for the administration of EPO has been described consisting of three weekly injections followed by a dose just before surgery. In orthopedic patients, this has reduced the number of patients requiring transfusion and increased the postoperative hemoglobin while minimizing the cost of EPO treatment [43]. A recent meta-analysis examined 21 trials of erythropoietin use in patients undergoing orthopedic or cardiac procedures. It demonstrated a significant relative risk reduction in the need for transfusion in patients undergoing orthopedic surgery (relative risk [RR] 0.36 for orthopedic surgery, P < 0.0001; RR 0.25 for cardiac surgery, P = 0.06) [44]. The currently accepted indications for preoperative use of EPO are anticipated blood loss of 2 to 5 units, preoperative hemoglobin level between 10 g/dL and 13 g/dL, and elective surgery scheduled in the next 2 to 4 weeks (Table 1). Surgeons will have to select patients most likely to benefit from preoperative EPO to maximize the benefits of decreased transfusions while minimizing the costs of therapy.
Blood substitutes Blood substitutes have been undergoing extensive evaluation as a potential alternative to the use of allogeneic blood in emergent and elective surgery. Unfortunately, research and development efforts at Baxter and Alliance have led to limited success with their products (tetramerized human hemoglobin; second generation perflurocarbons, respectively), despite extensive investigations. Fortunately, three companies have recently completed or have ongoing major clinical trials demonstrating potentially efficacious oxygen-carrying therapeutic agents. Northfield Laboratories (Evanston, Illinois) undertook a prospective, randomized trial of its product Polyheme (a chemically modified hemoglobin derived from human blood) in 44 trauma patients (ISS mean 21 ± 10). Patients received either PRBCs or up to 6 units of Polyheme. Study patients received a mean of 4.4 ± 2 units of Polyheme with no adverse events. The transfusion requirements were 6.8 ± 3.9 units in the Polyheme group, and 10.4 + 4.2 units in the control group (P < 0.05) with no difference at 48 hours [45]. There were no significant adverse effects, suggesting Polyheme might be a clinically useful blood substitute. Biopure (Cambridge, Massachusetts) conducted a phase III trial of its product Hemopure (purified hemoglobin from refined cow’s blood). They studied 693 elective orthopedic surgery patients and found a 59% transfusion avoidance in the Hemopure group at 42 days. The only adverse effects were a slight rise in the systolic blood pressure (maximum 14 mm Hg) [Anesthesia Res Society Poster 2002]. A 27% avoidance rate was seen in patients undergoing infrarenal aortic reconstruction [46], and a 34% reduction was seen in cardiac surgery patients [47]. Hemosol (Mississauga, Ontario, Canada) sought to evaluate the efficacy of Hemolink (o-raffinose cross-linked human hemoglobin) in a Phase III trial looking at avoidance of RBC transfusion or the reduction in the number of RBC units transfused in coronary artery bypass graft (CABG) surgery patients. The
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incidence of jaundice (36%) and hypertension (66% versus 33% in controls) was higher in the Hemolink arm. These were expected results of the metabolism of hemoglobin and the nitric oxide-binding properties of Hemolink. A higher rate of avoidance of RBC transfusion was observed in subjects who received Hemolink (17% transfused) than in subjects who received Pentaspan (27% transfused). The first transfusion occurred at an average of 41.5 hours post-treatment in the Hemolink arm compared with an average of 24.1 hours post-treatment in the control arm. Overall, a lower number of RBC units were transfused in the Hemolink arm (49 units) compared with the control arm (104 units). Additional clinical trials with Hemolink focusing upon transfusion avoidance are being initiated in North America [48]. These and other ongoing trials suggest that a safe and viable blood substitute is a future reality that should revolutionize the practice of transfusion.
Bloodless surgery Preoperative autologous donation Although possible for many decades, the use of preoperative autologous blood donation was not widespread. Currently, with the threat of HIV and other viruses, it has gained increased attention. In the last 15 years it has risen from < 5% of eligible patients to 50% to 75% of patients for certain elective surgeries [49,50]. Unfortunately, up to half of the autologous blood collected is discarded [51] because its use in patients other than the donor is not recommended [52]. Although preoperative autologous donation prevents transfusion-transmitted disease and avoids red cell alloimmunization, it is not without adverse consequences. It does not eliminate the risk of bacterial contamination or volume overload or the risk of administrative error resulting in ABO incompatibility. It costs more than allogeneic blood donation and could be considered wasteful if the blood is discarded [53]. It has been suggested that patients who donate 2 to 4 units of preoperative autologous blood require transfusion after a smaller volume of blood loss due to their decreased hematocrit [54]. In certain circumstances, however, preoperative autologous blood donation remains an excellent option.
Acute normovolemic hemodilution Acute normovolemic hemodilution (ANH) is another way to decrease the need for allogeneic transfusion in elective surgery. The technique consists of removing 2 to 4 units of the patients’ own blood immediately preoperatively and replacing this volume with crystalloid to maintain an isovolemic state, albeit with a markedly diminished circulating hematocrit. The operation is then performed
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normally. The actual RBC loss during the procedure is minimized because the shed blood has a lower hematocrit. After the procedure the patient is given back his/her own blood to restore the volume and hematocrit. Recommendations for the use of hemodilution are expected blood loss > 20%, a preoperative hemoglobin of greater than 10 g/dL, and the absence of severe myocardial disease (see Table 1) [55]. The clinical utility of hemodilution may not become apparent unless the preoperative hematocrit is reduced to < 20% [56]. A prospective study of patients undergoing radical prostatectomy found that 21% of patients received allogeneic blood despite preoperative hemodilution [57]. However, a retrospective case-control study of 800 patients who underwent total joint arthroplasty found that ANH reduced the need for allogeneic transfusion [58]. The advantages of hemodilution versus preoperative donation are savings in time, cost, and a smaller likelihood of clerical error or contamination. A metaanalysis of 24 trials (containing a total of 1218 patients) showed that ANH reduced the likelihood of exposure to allogeneic blood (odds ratio [OR] 0.31, 95% CI 0.15 to 0.62) and reduced the total units of allogeneic blood transfused. However, closer examination suggested the reductions in blood exposure may have been due to flawed study design [59]. Overall, it appears that ANH and preoperative autologous blood transfusion have similar rates of success and efficacy [60]. A survey of Canadian hospitals found ANH and EPO were used in 45% and 25% of cardiac centers, respectively [61]. The preferred techniques will likely depend on local resources and expertise.
Intraoperative blood recovery More and more surgeons are using intraoperative blood recovery techniques to minimize the need for transfusion. The most commonly used technique is the cell saver machine (Haemonetics Corp., Natick, Massachusetts). The cell saver collects shed blood throughout the procedure and then spins and washes the blood, which is returned to the patient during or after the procedure. It has been used extensively in cardiac surgery and is now becoming more common in high blood loss elective general surgery procedures and in trauma. Some machines can process the equivalent of up to 10 units of blood per hour. RBC viability is similar to that from a transfusion of stored PRBCs [62]. The processing of the blood, however, removes platelets and plasma proteins contributing to a dilutional coagulopathy. The washing process can lead to hemolysis and the ‘‘salvaged blood syndrome.’’ Retained platelet-leukocyte deposits produce procoagulant leukotactic substances and may increase the risk of the development of disseminated intravascular coagulation (DIC) [15]. The general indications for cell saver are anticipated blood loss > 20% total blood volume, that > 10% of patients undergoing the same procedure require transfusion, and that the mean transfusion requirement exceeds 1 unit (see Table 1). Some relative limitations are that it may not be optimal if there is a
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large amount of enteric contamination or if hemostatic agents such as thrombin have been used. However, a study in 11 patients with thoracoabdominal trauma who received contaminated shed blood showed no significant increase in infectious complications [63]. Its use in the presence of malignancy and possible contamination with malignant cells is also a relative contraindication. Whether the use of intraoperative blood recovery actually reduces the need for allogeneic transfusion is not clear. Previous studies have suggested decreased transfusion requirements for patients undergoing cardiac or orthopedic surgeries. On the other hand, in a prospective, randomized trial of patients undergoing repair of an abdominal aortic aneurysm, its use did not decrease the need or amount of allogeneic transfusion [64]. Instead of decreasing the number of transfusions in procedures with large blood loss, the availability and cost effectiveness of cell salvage may be of greater significance. A retrospective review of 126 patients with abdominal trauma in which the cell saver was used showed an average recovery of 6.9 units of blood per patient with a cost savings of almost 50% compared with allogeneic blood transfusion [65]. Clearly, further studies will need to be performed to better define the role of cell salvage techniques in different types of surgical situations.
‘‘Less-blood surgery’’ Hemostatic and pharmacologic techniques In addition to the techniques for bloodless surgery, several surgical techniques and perioperative pharmacologic therapies are used to minimize blood loss and thus minimize transfusions. Some of these techniques include meticulous primary hemostasis, the use of hemostatic substances such as fibrin glue or gelfoam and thrombin, or pharmacologic agents such as aprotinin, desmopressin, aminocaproic acid, and tranexamic acid. Special circumstances such as operations for isolated extremity injuries may even include the temporary use of pneumatic tourniquets to minimize blood loss. Fibrin sealant has been used in a wide variety of surgical procedures from liver resections to major vascular reconstructions. In burn surgery, where the duration of operation is often limited by the amount of blood loss, fibrin sealant has been shown to decrease the time to achieve hemostasis of the donor sites [66]. A systematic review of 12 trials examining the use of fibrin sealant as a method to minimize perioperative blood transfusion showed a reduced rate of allogeneic blood transfusions (RR 0.40, 95% CI 0.26 to 0.61) coinciding with reduced blood loss [67,68]. The overall use of these technologies was studied in a survey of Canadian hospitals under the auspices of the International Study of Peri-Operative Transfusion (ISPOT). They found the majority of techniques was used primarily in cardiac surgery (70% of centers) and included aprotinin, tranexamic acid, aminocaproic acid, and desmopressin [61]. A survey of Israeli hospitals showed similar
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results. They found most techniques were primarily used by cardiac surgery and orthopedic departments [69]. These surveys suggest the techniques to minimize allogeneic transfusions are underused by most clinicians.
Damage control surgery Lastly, the technique of abbreviated surgery (damage control) must be discussed. This represents the concept of identifying that continued operative intervention will lead to continued blood loss without hope of achieving primary hemostasis. When the patient has massive blood loss, becomes hypothermic and acidotic, and begins to suffer from a severe coagulopathy, further attempts in the operating room at achieving primary hemostasis are futile. The patient is packed and some temporary closure of the operative site is performed. The patient is then taken to the intensive care unit where he or she can continue to be resuscitated. Not until the hypothermia, acidosis, and coagulopathy have been corrected is the patient returned to the operating room for definitive surgical treatment.
Bloodless surgery centers The culmination of all types of blood conservation and avoidance can be found in bloodless surgery programs. They epitomize the use of these and other techniques to provide care to those who refuse transfusions for whatever reasons. A recent review of such a program and its effectiveness in major versus minor surgeries in 51 Jehovah’s Witnesses demonstrated significant decreases in postoperative blood loss and improved hemoglobin values [70]. This emphasizes the need for teamwork between surgeons, anesthesiologists, and other support personnel to maximize resources, decrease blood loss, and minimize transfusions. The University of Miami has one of the foremost Centers for Bloodless Medicine and Surgery. Founded in 1994, it includes 145 clinicians who specialize in providing all types of medical care while avoiding the use of blood transfusions. It has grown from as few as 200 admissions and outpatient visits in the early 1990s to almost 3000 patients seen in 2001. Its patient base continues to grow, and patient satisfaction is > 90%. The death rate in 4286 patients between 1995 and 2001 was only 2.1%, and only 0.3% of patients died due to refusal of blood [71].
Summary The role of transfusion in surgery and trauma continues to evolve with our greater understanding of the true indications for and effects of transfusion. The potential adverse immune consequences and end-organ effects of blood transfusion must be weighed against the need for replacement of blood volume and oxygen-carrying capacity. The techniques to conserve blood and avoid transfu-
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sion play an important role in caring for the bleeding surgical patient. The future holds great promise for the possibility of redefining the art of blood transfusion and perhaps one day replacing it entirely.
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