Intraoperative blood loss is a common problem that can be encountered, especially, in multilevel spine fusion procedures. Currently, there is no apparent definition for significant hemorrhage in spine surgery, and there are no clear reports on consequences associated with major blood loss under these circumstances. Major blood loss may lead to blood, platelet, and factor transfusions. Although blood screening has improved the safety considerably over the years, there are still known risks of transfusion, including potential transfusion reactions and alloimmunization as well as infectious risks, such as hepatitis, human immunodeficiency virus, cytomegalovirus, and transfusion-associated bacterial sepsis. Furthermore, there is emerging data suggesting that blood transfusion may be associated with an increased risk of postoperative infections. Additionally, the costs of blood replacement must be considered. In a recent cost-benefit analysis, the average cost for cell saver (CS) was $512 per patient, autotransfusion was $270 per individual, and allogeneic blood replacement was $250 per unit transfused.1
Coagulopathy (also called clotting disorder and bleeding disorder) is a defect in the body's mechanism for blood clotting, causing bleeding diathesis. This may happen during spine surgery if the patient develops severe hemorrhage that requires massive blood transfusion. Massive transfusion is defined as the replacement by transfusion of 1 volume of a patient's blood (60 mL/kg in adult) in 24 hours. Several preoperative and intraoperative techniques are currently available to reduce blood loss and transfusion requirements, such as preoperative autologous blood donation, CS, recombinant factor VIIa (FVIIa), and perioperative antifibrinolytic agents, such as aprotinin, tranexamic acid, and ε-aminocaproic acid.
The purposes of this study are to conduct an evidence-based systematic review of the published literature to address the following clinical questions:
- How do we define significant hemorrhage in adult spine fusion surgery, and what is the incidence of this complication?
- Are there effective measures to decrease hemorrhage in adult spine fusion surgery?
Materials and Methods
Electronic Literature Database
The literature search is outlined in detail elsewhere.1a We conducted a systematic search in Medline, EMBASE, and the Cochrane Collaboration Library for literature published from January 1990 through April 2009. We limited our results to humans and to articles published in the English language. Reference lists of key articles were also systematically checked. We excluded studies evaluating surgical interventions that did not involve spinal fusion, and those involving tumors, trauma, or pediatric cases. For our first study question, we attempted to identify studies specifically designed to characterize the threshold, incidence, or frequency of significant hemorrhage. To determine effective preventive measures to decrease hemorrhage (study question no. 2), we attempted to identify studies that measured the effect of an intervention or prevention strategy. We excluded editorials, review articles without quantitative data, case reports, studies with sample size <10, and non-English-written studies (Figure 1).
Each retrieved citation was reviewed by 2 independently working reviewers (J.R.D. and D.J.F.). Most articles were excluded on the basis of information provided by the title or abstract. Citations that seemed to be appropriate or those that could not be excluded unequivocally from the title and abstract were identified, and the corresponding full-text reports were reviewed by the 2 reviewers. Any disagreement between them was resolved by consensus. From the included articles, the following data were extracted: study design, patient demographics, surgical treatment rendered, rate or number of documented events of significant hemorrhage, volume of blood loss and blood transfused, measures used to prevent or decrease significant hemorrhage, and potential complications arising from using those preventive measures.
Level of evidence ratings were assigned to each article independently by the 2 reviewers using criteria set by The Journal of Bone and Joint Surgery. American Volume (J Bone Joint Surg Am) for therapeutic and prognostic studies, and modified to delineate criteria associated with methodologic quality and described elsewhere (See Supplemental Digital Content 1, individual study ratings, tables, individual study ratings, available at: https://links.lww.com/BRS/A420).2
The risk of transfusion was reported as the proportion of patients receiving a transfusion and underwent adult spine fusion. Volume of blood loss or blood transfused was recorded as means with standard deviations when available. Complications from strategies to prevent or reduce major hemorrhage were reported as the proportion of patients experiencing the complication or the mean number of days spent in the intensive care unit (ICU). Data were summarized in the tables, and qualitative analysis was performed considering the following 3 domains: quality of studies (level of evidence), quantity of studies (the number of published studies similar in patient population, condition treated, and outcome assessed), and consistency of results across studies (whether the results of the different studies lead to a similar conclusion).3 We judged whether the body of literature represented a minimum standard for each of the 3 domains using the following criteria: for study quality, at least 80% of the studies reported needed to be rated as a level of evidence I or II; for study quantity, at least 3 published studies were needed, which were adequately powered to answer the study question; for study consistency, at least 70% of the studies had to have consistent results. The overall strength of the body of literature was expressed in terms of the impact that further research may have on the results. An overall strength of “high” means that further research is very unlikely to change our confidence in the estimate of effect. The overall strength of “moderate” is interpreted as further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. A grade of “low” means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate, whereas “very low” means that any estimate of effect is very uncertain.1a
We identified 90 articles or reports from our literature search reporting on significant hemorrhage. From these potential articles or reports, we judged 33 to undergo full-text review. After full-text review, we excluded 15 for the following reasons: 12 studies did not meet the inclusion criteria (included nonspinal fusion, pediatric, tumor, or trauma patients) and 3 studies did not report on outcomes of interest (Figure 2) (Supplemental Digital Content, available at: https://links.lww.com/BRS/A420; more information on excluded articles can be found in Table 1). Of the remaining 18 articles, 9 provided information on the incidence of major hemorrhage requiring transfusions. Five were retrospective cohort studies, 1 graded as level of evidence II and 4 graded level of evidence III,1,4–7 3 were retrospective case-series studies graded as level of evidence IV,8–10 and 1 was a registry study graded as level of evidence IV.11 We found 9 articles evaluating measures to prevent or reduce the major hemorrhage. Of these, 5 were randomized controlled trials (RCTs), 1 graded as level of evidence I,12 and 4 graded level of evidence II13–16; 1 was a prospective and retrospective cohort, graded as level of evidence III17; and 3 retrospective cohort studies graded as level of evidence III18–20 (Supplemental Digital Content, available at: https://links.lww.com/BRS/A420; further details with respect to level of evidence for each study can be found in Table 2).
Question 1. How Do We Define Significant Hemorrhage in Adult Spine Fusion Surgery and What Is the Incidence of This Complication?
We found no studies that attempted to define significant hemorrhage in spine surgery, nor did we identify any study that assessed whether blood hemorrhage volume predicts complications after spine fusion surgery. In general, studies of spine fusion reported the proportion of patients requiring transfusion and the average volume of blood loss for a given population. Among patients who did not receive preventative strategies to reduce hemorrhage, the proportion requiring transfusion in 6 studies ranged from 50% to 81% and the mean blood loss ranged from 650 to 2839 mL per patient (Table 1).1,4–7,12 Four studies included patients who received instrumentation,1,6,7,12 1 study did not report whether instrumentation was used,5 and 1 included patients in which some received instrumentation and others did not.4 In the Cha et al4 study, noninstrumented patients had nearly half the blood loss of those who were instrumented (1041 vs. 2026 mL) and a lower proportion requiring transfusion (69% vs. 87%; relative risk [RR], 0.80; 95% CI, 0.65–0.99).
Question 2. Are There Effective Measures to Decrease Hemorrhage in Adult Spine Fusion Surgery?
We identified 11 comparative studies that evaluated 5 strategies to decrease hemorrhage (Table 2).
The effectiveness of antifibrinolytic agents was evaluated in 4 RCTs12,13,15,16 and 2 retrospective cohort studies.19,20 In 1 RCT, Lentschener et al12 assessed the efficacy of aprotinin in 72 consecutive patients who underwent elective lumbar interbody spine fusion through a posterior approach. Patients were randomized in a double-blinded fashion, stratified by the number of levels fused, to receive 2 × 106 kallikrein-inhibitor units (KIU) of aprotinin followed by 5 × 105 KIU/h until skin closure (n = 35) or an equivalent volume of 0.9% saline solution (placebo; n = 37). Intraoperative blood loss was measured via the volume of blood in suction bottles and weight of sponges, whereas postoperative blood loss was measured via drainage tubes for 24 hours after surgery. The target hematocrit value for packed red blood cells (RBCs) transfusion was 26%, except in patients aged >60 years or those with preexisting heart or lung disease. There was a significant reduction in perioperative blood loss in the aprotinin group compared with the controls (1935 ± 873 mL vs. 2809 ± 973 mL, respectively; P = 0.007). Further, the number of perioperative packed RBCs transfused was significantly lower in the aprotinin compared with the placebo group (6 U vs. 19 U, respectively; P = 0.001). No adverse drug effects, such as circulatory disturbances, deep venous thrombosis, or alteration of serum creatinine were detected.
Urban et al15 assessed the efficacy of antifibrinolytics in 60 patients who underwent same-day anteroposterior spinal fusion. Patients were randomly assigned to receive (1) Amicar 5-g load over 30 minutes followed by 15 mg/kg/h, (2) aprotinin 1 million KIU load over 30 minutes followed by 0.25 million KIU/h, or (3) neither. Intraoperative blood loss was estimated by weighing surgical sponges, measuring blood collected by drainage and suction canisters, and subtracting all irrigation fluids added to the surgical field. Patients received transfusions to maintain a hemoglobin level >8 g/dL (hematocrit, 25%–28%). Patients were monitored for at least 24 hours in an ICU and 2 to 3 days in a “step-down” ICU. Postoperative blood loss was estimated from drainage from the surgical wounds and chest tube. Fifty-five patients completed the study, and total blood loss was greatest for the control group (5181 mL; n = 18), followed by the Amicar group (4056 mL; n = 17), and was least for the aprotinin group (3628 mL; n = 20). However, only the aprotinin patients demonstrated a significant difference from the control. Aprotinin patients were transfused significantly less units of RBCs compared with controls (aprotinin 4 ± 1 U, Amicar 5 ± 2 U, and control 6 ± 2 U).
Wong et al16 assessed the efficacy of tranexamic acid in 151 patients who underwent elective posterior thoracic or lumbar instrumented spinal fusions. Patients were randomly assigned, stratified by surgeon and number of levels fused, to receive either tranexamic acid 10 mg/kg intravenously before the surgical incision followed by 1 mg/kg/h until skin closure or an equivalent volume of normal saline (placebo). Perioperative blood loss was measured by adding the volume of blood in suction bottles, CS, and weight of the sponges intraoperatively as well as wound drainage of the surgical drain for the first 24 hours after surgery. Packed RBCs were given 1 U at a time to maintain a hemoglobin concentration of >7 g/dL or at a higher hemoglobin concentration if continuing blood loss was occurring or signs or symptoms of anemia developed. Seventy-three patients in the tranexamic acid group and 74 in the placebo group completed the study. Perioperative blood loss was significantly less in the tranexamic acid versus placebo group (3079 ± 2558 mL vs. 4363 ± 3030 mL, respectively; P = 0.017). There was no difference in the amounts of blood products transfused between the 2 groups.
Krohn et al13 evaluated the efficacy of topical use of tranexamic acid given to the surgical wound in patients who underwent fixation surgery of the lumbar spine. Thirty consecutive patients were randomized to 500 mg tranexamic acid added to the irrigation solution during wound closure (n = 16) or saline irrigation solution alone (n = 14). Postoperative blood loss through the wound drainage tube was measured in a collection unit for autologous transfusion for 18 hours after surgery. Postoperative blood loss was significantly reduced in the tranexamic acid irrigation group compared with the control group (252 mL vs. 525 mL, respectively; P = 0.02).
Recombinant Factor VIIa
One RCT14 conducted a multicenter, randomized, double-blinded placebo-controlled dose-escalation trial in which patients who underwent elective spinal fusion surgery of 3 or more motions segments by posterior approach were eligible to participate. Three consecutive cohorts of 16 to 17 patients (16 patients for the first 2 cohorts and 17 patients for the third cohort) were randomized to treatment with 3 doses of rFVIIa (n = 12 × 3 cohorts) or placebo (n = 4 for the first 2 cohorts and n = 5 for the third cohort) administered when 10% of estimated blood volume had been reached and then 2 hours and 4 hours after the initial dose. The rFVIIa doses were 3 × 30 μg/kg for the first cohort with escalation to 3 × 60 μg/kg and then 3 × 120 μg/kg for the next 2 cohorts. Patients were not randomized to treatment until 10% loss of estimated blood volume had been reached, with a total expected loss of at least 20% of estimated blood volume before the end of surgery. Blood loss was calculated by measuring the volume of blood in the CS, suction container, and blood-soaked gauze and swabs. RBCs were administered during and after surgery when hemoglobin was <9 g/dL. Mean adjusted surgical blood loss was as follows: 2536 mL for placebo and 1120, 400, and 823 mL for 3 × 30, 3 × 60, and 3 × 120 μg/kg rFVIIa, respectively. The transfusion volume for all blood products was not significantly different between the rFVIIa groups and placebo (89–287 mL rFVIIa groups, 1488 mL placebo). In the rFVIIa group, 1 (2.7%) patient suffered from a thromboembolic stroke and died, whereas there were no reported thromboembolism events reported among the 13 patients receiving placebo.
Platelet Cell Growth Factor
Castro et al18 retrospectively studied a consecutive series of patients who underwent 1- or 2-level bilateral transforaminal lumbar interbody fusion with instrumentation and autologous iliac crest bone graft procedures. The theoretical primary benefit of the platelet cell growth factor was to stimulate graft consolidation into a fusion mass. The hypothetical secondary benefit was to decrease the postoperative blood loss by stimulating clot formation. In 22 “cases,” activated growth factor (AGF) platelet gel was added to the autologous bone graft, whereas a consecutive series of 62 historical controls did not receive AGF platelet gel. The postoperative transfusion rate was not significant between the 2 groups, 23% (5 of 22) in the AGF group and 37% (23 of 62 in the control group).
Three retrospective cohort studies evaluated the effectiveness of CS in preventing significant hemorrhage. These studies reported varied results with respect to the effectiveness of the CS technique.
Gause et al6 assessed the efficacy of intraoperative CS in a retrospective cohort of 188 patients who underwent elective instrumented posterior lumbar spinal arthrodesis for degenerative disease. CS was used in 75% (141 of 188) of the patients, and 25% (47 of 188) did not receive CS. Estimated blood loss was determined based on the amount of blood in suction canisters, CS canister, and weight of sponges. Indications for transfusion were hemoglobin concentration ≤7 g/dL and hematocrit ≤21% or symptomatic anemia. The amount of blood lost in the CS group was statistically greater than in the non-CS group (1476 mL vs. 766 mL, respectively). The transfusion rate was 87.2% (123 of 141) in CS patients and 76.6% (36 of 47) in the non-CS group. Patients in the CS group received an average of 1.2 U of autologous and 1.6 U of allogeneic blood compared with 0.73 U of autologous and 0.87 U of allogeneic blood in the non-CS group (P = 0.028 and <0.001, respectively). A potential bias was identified for the CS group in the possibility that the operative team was aware that CS was being used, and therefore, was less meticulous about hemostasis throughout the case. In addition, the CS blood that was reinfused may have contained products that adversely affected coagulation, and thus, may have increased bleeding. Furthermore, a selection bias might have influenced the results because the authors might have selected patients with expected lower blood loss to be in the non-CS group. Conversely, Behrman and Keim17 found that CS reduced the need for homologous and prebanked autologous blood by 35% compared with no blood salvage, and a group that received CS and Solcotrans (R) after surgery reduced the need by 68% compared with no blood salvage.
Finally, in a retrospective study by Reitman et al,1 the CS group required fewer postoperative transfusions (1 U to 36% of patients in the CS group vs. 1 U to 50% of patients in the control group). However, the authors concluded that the difference was less than expected and that the use of CS was not cost-effective during most elective lumbar procedures.
Normovolemic Hemodilution, Hypotensive Anesthesia, and Staged Procedures
No comparative studies evaluating normovolemic hemodilution, hypotensive anesthesia, or staged procedures in adult spine surgery were found. One retrospective study used the perspective comparative database to evaluate the blood service cost and utilization associated with allogeneic blood transfusions during and after spine surgery.11 The perspective comparative database is a large database created and maintained by Premier Inc., Charlotte, NC, for the purposes of quality improvement. It contains patient-level data, including demographic, disease state, and billing data representing from over 700 hospitals in the United States. A sample of 42,029 spinal fusion surgeries served as the study population. Total cost was calculated by summing direct costs plus overhead. Direct costs represented items used by the patients and itemized in the hospital accounting system. Overhead costs were costs associated with facility and personnel. The authors performed multivariate analysis and reported that patients receiving hypotensive anesthesia (odds ratio (OR) = 1.61; 95% CI, 1.47–1.77), a volume expander (OR = 1.95; 95% CI, 1.75–2.18), or an erythropoietic agent (OR = 1.64; 95% CI, 1.27–2.12) had a higher risk of allogeneic blood transfusion. Patients who received cell salvage had a lower risk of transfusion (OR = 0.40; 95% CI, 0.32–0.50). They concluded that most blood avoidance techniques have low utilization or do not reduce the burden of transfusion associated with spinal fusion. One case series evaluated the utility of normovolemic hemodilution in limiting the need for postoperative allergenic blood transfusions in 68 patients undergoing 3- to 6-level lumbar laminectomies with 1- to 2-level instrumented fusions. Postoperative allogeneic transfusions were required by 23.5% of patients, with a mean of 1.9 U required per individual.9
There is very low evidence to support a definition of significant hemorrhage in spine fusion surgery, or to link blood hemorrhage volume with increased complications. There is high evidence that the rate of transfusion in adult spine fusion surgery ranges from 50% to 81%. There is high evidence that antifibrinolytic agents as a class reduce blood loss and the need of transfusion in adult spine fusion surgery. However, there is very low evidence for the safety of the antifibrinolytics. Very low evidence exists for the safety or effectiveness of rFVIIa, AGF platelet gel, CS, normovolemic hemodilution, hypotensive anesthesia, or staged procedures as strategies to decrease hemorrhage in adult spine fusion surgery (Table 3).
We found no studies that attempted to define significant hemorrhage in spine surgery. Nevertheless, the definitions in the anesthesiology literature regarding terms such as “major” or “massive” blood loss remain somewhat arbitrary, but it is commonly accepted that loss of 1 volume of the patient's total blood (60 mL/kg in adults) in <24 hours constitutes major blood loss. Most spinal surgery studies reported the amount of surgical blood loss that required transfusion, and those blood loss numbers range from 650 to 2839 mL per case. The literature also suggests that those patients who are going to have spinal instrumentation may have an increased risk of major blood loss as well as requiring transfusion when compared with those having noninstrumented spinal surgery. This information allows physicians to appropriately counsel their patients on the potential need for blood replacement during their procedure as well as before surgery plan for the surgical blood needs both intraoperatively and after surgery.
The safety profile of the antifibrinolytic agents has been reported in RCTs and large observational studies and in cardiac patients. Earlier meta-analysis of RCTs compared the safety of aprotinin with no treatment or with placebo and found no increase in mortality or vascular thrombosis.21,22 Meta-analyses of RCTs comparing aprotinin with lysine analogs (tranexamic acid and ε-aminocaproic acid) also reported no difference in the risk of adverse events among the 3 agents.21,23 Observational studies, however, began to show an increase in the risk of adverse events with the use of aprotinin compared with tranexamic acid and ε-aminocaproic acid. Okubadejo et al19 reported that aprotinin increased the risk of acute renal failure, especially in women aged >60. Mangano et al,24 in 2006, conducted a multicenter observational study that looked at the risk associated with aprotinin use in coronary artery bypass surgery. This study involved 4374 patients who received revascularization. They prospectively compared 3 agents, aprotinin (n = 1295), aminocaproic acid (n = 883), and tranexamic acid (n = 822), with no agent (n = 1374) with respect to serious outcomes using propensity scores and multivariable methods. They found that aprotinin use was associated with a 2.5-fold increased risk of renal failure requiring dialysis (OR = 2.59; 95% CI, 1.36–4.95), a 55% increased risk of myocardial infarction or heart failure (P < 0.001), and a 181% increased risk of stroke or encephalopathy (P = 0.001). Neither aminocaproic acid nor tranexamic acid was associated with an increased risk of renal, cardiac, or cerebral events. They concluded that the association between aprotinin and serious end organ damage indicates that continued use is not prudent and that the less-expensive generic medications, aminocaproic acid and tranexamic acid, are safe alternatives. In 2008, the Blood Conservation Using Antifibrinolytics in a Randomized Trial study,25 a large RCT comparing aprotinin and lysine analogs in high-risk cardiac surgical patients, was stopped prematurely because of an increased number of deaths in the aprotinin group (RR = 1.53; 95% CI, 1.06–2.22).
Following the reporting of these studies, 2 meta-analyses were published assessing the safety of aprotinin in cardiac surgery, 1 involving RCTs by Henry et al26 from the Cochrane Collaboration and 1 by Gagne et al27 involving observational studies. In the meta-analysis by Henry et al,26 the risk of death was higher comparing aprotinin with tranexamic acid (RR = 1.43; 95% CI, 0.98–2.08) or with ε-aminocaproic acid (RR = 1.49; 95% CI, 0.98–2.28). The Gagne et al study included 11 observational studies, 7 reporting on death as the outcome and 10 reporting on renal dysfunction. They found that aprotinin was associated with long-term mortality (hazard ratio = 1.22; 95% CI, 1.08–1.39) and renal dysfunction (RR = 1.42; 95% CI, 1.13–1.79) compared with no aprotinin (the comparison group could have included a mix of ε-aminocaproic acid, tranexamic acid, or no antifibrinolytic therapy). They concluded that the totality of the epidemiologic evidence indicates an increased risk of long-term mortality and renal dysfunction associated with aprotinin compared with other antifibrinolytic agents.
The use of rFVIIa in a dose escalation trial has not been shown to decrease the need for blood products transfusion. AGF platelet gel has also not been shown to decrease the need for transfusion using evidence based literature. The theoretical advantage of hypotensive anesthesia is lower blood loss and its disadvantage is organ hypoperfusion. The hypothetical advantage of staged procedure is to lower the risk of coagulopathy, and disadvantages are possible increase risk of infection and longer stay in the hospital. Having said that, no comparative studies evaluating hypotensive anesthesia or staged procedures in adult spine surgery were found.
The CS technology has been used for many years in joint arthroplasty and spinal deformity surgery. Results evaluating its effect during spine surgery were mixed from 3 retrospective studies, all suffering from poor methodologic quality. On the basis of the current literature, there is little to support its cost or effective use during routine elective spinal surgery. No studies were found to support the use of normovolemic hemodilution, hypotensive anesthesia, or staged procedures to reduce the chance of major hemorrhage in adults undergoing spinal surgery.
The field of studies on intraoperative blood loss in spine surgery has remained challenging for a number of reasons; among them are technical difficulties and a rather large number of variables as well as lack of reproducible threshold parameters for application of study medications. Some of the studies that have been included in this systemic review are retrospective. One has to consider the inherent limitations of a retrospective study, which includes selection bias. In particular, the surgeon's decision regarding the use of perioperative antifibrinolytic agents or CS because it is likely that the surgeons elected their use in cases in which greater blood loss was anticipated versus neither methods in the control group in which lower blood loss was expected.
Despite its efficacy in RCTs, there are concerns related to the use of aprotinin on the basis of increased risks of complications such that we do not recommend its use in spine surgery. With respect to the antifibrinolytics of the lysine analog class (tranexamic acid and aminocaproic acid), on the basis of the available efficacy and safety data, we recommend that they be considered as possible agents to help reduce major hemorrhage in adult spine surgery. On the basis of the current literature, there is no support for routine use of CS during elective spinal surgery.
- There is no clear definition of significant hemorrhage in spine fusion surgery, nor is the incidence of this complication documented.
- There is high level of evidence that the rate of transfusion in adult spine fusion surgery ranges from 50% to 81%.
- The current literature provides little controlled evidence to support effective measures to decrease massive hemorrhage in major spine surgery. As a class, the antifibrinolytic agents seem to reduce blood loss and the need of transfusion in adult spine fusion surgery; however, the safety profile for these agents in this population is not fully known. In particular, the use of aprotinin is not recommended on the basis of the safety data in the cardiac literature.
- There is little or no evidence to support the use of recombinant factor VIIa, activated growth factor platelet gel, CS technology, normovolemic hemodilution, hypotensive anesthesia, or staged procedures to reduce the chance of major hemorrhage in adults undergoing spinal surgery.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.spinejournal.com).
The authors thank Ms. Nancy Holmes, RN, for her administrative assistance, and Ms. Erika Ecker, BS, for her assistance in searching the literature, abstracting data, and proofing.
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