Blood Transfusion During Lower-Extremity Revascularization: NSQIP Database Outcome Analysis

Abstract

Background. Worse outcomes in transfused patients have been observed in various settings, but little is known about the significance of RBC transfusion in patients with peripheral arterial disease. We queried the NSQIP database to examine the effect of intraoperative blood transfusion on the morbidity and mortality in patients who underwent lower-extremity revascularization. Methods. We analyzed the data from the Participant Use Data File containing vascular surgical cases submitted to the ACS NSQIP in 2005, 2006 and 2007. CPT-4 codes were used to select lower-extremity revascularization procedures. Thirty-day outcomes analyzed were: 1) mortality; 2) composite morbidity; 3) graft/prosthesis failure; 4) return to the operating room for any reason within 30 days; 5) wound occurrences; 6) sepsis or septic shock; 7) pulmonary occurrences; and 8) renal insufficiency or failure. Outcome rates were compared between the transfused and non-transfused groups using the chi² test. Patients were ranked into five equal-sized groups (quintiles) based on their transfusion propensity. Results. The database contained 8,799 patients who underwent lower extremity revascularization between 2005 and 2007. Transfusion rates ranged from 4.4% in the lowest propensity quintile to 52.9% in the high propensity quintile. The mortality rate was significantly higher in transfused patients versus non-transfused (chi² Conclusion. In a large number of patients undergoing lower-extremity revascularization we have found that there is higher risk of postoperative mortality, pulmonary, renal and infectious complications after receiving intraoperative RBC transfusion. The risk for adverse outcomes increases with higher number of units transfused. Additional studies are necessary to better define transfusion triggers that balance the risk/benefit ratio for blood transfusion.

VASCULAR DISEASE MANAGEMENT 2010;7(7):E152–E156

Key words: lower limb; surgery; morbidity; mortality; chronic ischemia

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Introduction

Red blood cell (RBC) transfusion is a common event in the perioperative course of patients undergoing lower-extremity revascularization. Worse outcomes in transfused patients have been observed in various settings including critically ill patients, elderly patients, cardiac surgery, trauma patients, orthopedic surgical patients and patients with acute coronary syndrome. Allogeneic transfusions have been associated with a higher risk of intensive care unit (ICU) admission, longer hospital and ICU stays, a higher postoperative infection rates, a higher risk of developing adult respiratory distress syndrome (ARDS), longer time to ambulation, a higher incidence of atrial fibrillation and a higher risk of ischemic outcomes compared with nontransfused cohorts.^1–5 We queried the National Surgical Quality Improvement Program (NSQIP) database to examine the effect of intraoperative blood transfusion on the morbidity and mortality in patients who underwent lower-extremity revascularization.

Methods

The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) collects data on 135 variables including preoperative risk factors, intraoperative variables and 30-day postoperative morbidity and mortality outcomes for patients undergoing surgical procedures in both the inpatient and outpatient setting. We analyzed the data from the Participant Use Data File containing vascular surgical cases submitted to the ACS NSQIP in 2005, 2006 and 2007 by 173 hospitals throughout the United States. Primary procedure CPT-4® codes were used to select lower-extremity procedures, which were grouped into venous graft (CPT code 35533, 35541, 35546, 35556, 35558, 35565, 35566, 35571, 35583, 35585, or 35587); prosthetic graft (CPT code 35646, 35647, 35654, 35656, 35661, 35665, 35666, or 35671); or thromboendarterectomy (CPT code 35371, 35372 or 35381). Intraoperative transfusion of packed red blood cells was categorized as: none, 1–2 units and ≥ 3 units. Outcome rates were compared between the transfused and nontransfused groups using the chi² test. Thirty-day outcomes analyzed were: 1) mortality; 2) composite morbidity (one or more of 21 adverse events uniformly defined by the ACS NSQIP); 3) graft/prosthesis failure; 4) return to the operating room for any reason within 30 days; 5) wound occurrences; 6) sepsis or septic shock; 7) pulmonary occurrences; and 8) renal insufficiency or failure. The risk (propensity) of intraoperative transfusion in this patient population was calculated using logistic regression of over 55 ACS NSQIP patient risk factors in a forward stepwise fashion (p for entry 0.10) followed by addition of the procedure group and complexity (Work RVUs). Patients were ranked into five equal-sized groups (quintiles) based on their transfusion propensity. Within each quintile, the numbers of transfused and nontransfused patients were counted and the mortality rates were compared using chi2 tests. The odds ratios (OR) by transfusion category were calculated for each of the outcomes using logistic regression.

Results

The ACS NSQIP database contained 8,799 patients who underwent lower-extremity revascularization between 2005 and 2007. Their mean age was 66.8 ± 12.0 years, and 5,569 (63.3%) were male. Transfusion rates varied across procedure group, ranging from 14.5% in the thromboendarterectomy patients to 27.1% in the prosthetic bypass patients (chi² p 28% received intraoperative transfusion, suggesting that preoperative anemia was not the only indication for transfusion. Transfusion rates ranged from 4.4% in the lowest propensity quintile to 52.9% in the high propensity quintile (Table 2). The mortality rate was significantly higher in transfused patients versus nontransfused (chi² p 2 p Discussion The goal of blood product transfusion is to replace volume and to increase blood oxygen carrying capacity.⁶ During the last decades of the twentieth century, substantial attention was focused on infectious risks including transfusion-associated hepatitis B and C, HIV, West Nile Virus and Variant Creutzfeldt-Jakob disease. With donor screening and antibody, antigen and/or nucleic acid testing, many of the concerns regarding transfusion transmission of infectious diseases have been well addressed and largely mitigated. The risk of acquiring HIV or hepatitis C virus has fallen by approximately 99.99% in developed countries, likely approaching a residual risk for transfusion-transmitted HIV of 1 in 5–8 million screening units (United States).^7,8 These dramatic improvements in infectious risk have led to new and increased focus on the other serious hazards of transfusion such as multiple-system organ failure associated with cytokine release, bacterial contamination, sepsis, metabolic disturbances, circulatory overload, hemolytic reactions and risk of old blood. Studies on cardiac surgery patients who received blood transfusions showed an increased mortality rate, a higher incidence of postoperative infection, prolonged respiratory support, a higher risk of postoperative infection and a higher risk of renal failure.^9,10 Similarly, in critical-care patients, transfusion has been associated with increased overall and ICU 14-day mortality rates, a higher 28-day mortality rate, longer length of stay, a higher risk of developing ARDS and a higher incidence of bloodstream infections.^11–15 We focused on the risks of blood transfusion in patients following peripheral vascular operations, and using the NSQIP database, examined 30-day morbidity and mortality. Our data suggest that after risk adjustment, patients receiving intraoperative transfusion are at higher risk of developing morbidity and mortality. More units of transfused RBCs were associated with increased mortality and morbidity (as manifested by renal, pulmonary and septic complications) in a dose-dependent manner. After removal from the body and with the added effect of storage, RBCs undergo changes (many irreversible) that adversely affect their viability and function. These adverse changes include oxidation and rearrangement of lipids, loss of proteins and depletion of ATP and 2, 3-diphosphoglycerate. In storage, RBCs continuously lose their membrane through shedding vesicles and become rigid. Moreover, during storage, bioactive byproducts and ions (hemoglobin, lipids and potassium) — some with proinflammatory effects — are released from RBCs and accumulate in blood units, whereby they can cause adverse reactions in a recipient. These changes are collectively called “storage lesion.” Transfusion of blood that is stored for prolonged periods (but still within the currently accepted maximum allowed storage time of 42 days) has been linked to an increased risk of complications and reduced survival in patients undergoing cardiac surgery and in other patient populations.^16–20 Renal complications were also more frequent in transfused patients in our study. Koch et al reported that each unit of RBCs transfused was associated with a > 100% increased odds for postoperative renal morbidity.²¹ We also determined that the risk of renal morbidity was almost double for patients who received ≥ 3 units compared to 1–2 units. Transfusion-associated lung injury (TRALI) is a well recognized complication and is considered to be the second leading cause of mortality from transfusion.^22,23 In our population there was almost a three-fold overall increase in the incidence of pulmonary complications in transfused patients; transfusion of 3 or more units carried an even higher risk as compared to 1–2 units. The pathophysiologic mechanisms of TRALI are incompletely understood and have been described as antibody-mediated and nonantibody-mediated. In both cases, activation of neutrophils plays a causal role, and these activated cells are thought to locally mediate pulmonary injury.^24,25 The threshold at which a patient receives a blood transfusion is arbitrary, depending on the institution’s protocol. The optimal range of hematocrit values that balances the associated complications of blood transfusion with complications related to anemia is unknown. Habib et al²⁶ reported that the lowest hematocrit value on cardiopulmonary bypass (27 described a benefit for RBC transfusion in patients who were elderly and had low admission hematocrit values (28 reported similar overall 30-day mortality rates for a restrictive transfusion strategy (hemoglobin levels maintained between 7 and 9 g/dL) versus a more liberal strategy (hemoglobin levels maintained between 10 and 12 g/dL). Although mortality was similar in the two groups, it was significantly lower with the restrictive strategy among patients who were less acutely ill. Because we found that transfusion was not limited to patients with low Hct in our population, we carried out a propensity risk assessment based on preoperative Hct, procedure type and complexity, ASA class, emergent status, age and 18 other risk factors versus whether or not the patient received a transfusion intraoperatively. The propensity regression showed that mortality is significantly higher in transfused versus nontransfused patients within groups matched by their preoperative risk (propensity) of intraoperative transfusion, even for low- and medium-propensity patients. The immunologic effects of blood transfusion may be responsible for the observed increase in risk of infection in blood-transfused patients. Blood transfusions have been shown to be an independent risk factor for infection.^29,30 Transfusion-related immunomodulation (TRIM) includes both alloimmunization of the host and immune activation as well as tolerance manifested as cancer recurrence, improved allograft survival and higher rates of postoperative infections.^31,32 Leukoreduction may decrease postoperative infections,³³ and today, most RBC transfusions in the U.S. are leukoreduced, however, the cost effectiveness of leukoreduction has yet to be proven, especially in low-risk populations.³⁴ The risk of graft failure was higher for transfused versus nontransfused patients, although this did not reach statistical significance after adjusting for transfusion propensity. Disorders of coagulation after transfusion are often associated with bleeding, but an increased risk for venous thromboembolism has been described.³⁵ Increased thrombotic risk may be related to dilution of anticoagulant factors or formation of microaggregates, which are composed primarily of degenerating platelets along with granulocyte debris and fibrin strands and measure somewhat larger than 40 microns in diameter. They form rapidly during blood storage, with an increasing number and size of microaggregates over time.³⁶

Conclusion

To conclude, our study in a large number of patients undergoing lower-extremity revascularization indicates that allogenic intraoperative transfusion is associated with higher postoperative morbidity and mortality. This finding is true after adjusting for propensity for transfusion, thus, the reason that transfused patients do poorly is not because they have a lower preoperative hematocrit. When do the risks of anemia outweigh the hazards of transfusion? In the Absence of acute bleeding, hemoglobin levels consistent with the TRICC trial (7.0–9.0 g/dL) are well tolerated.37 There is little evidence that RBC transfusion in the nonbleeding patient with a hemoglobin concentration > 7.0 g/dL leads to improved outcome. Clinicians should use hemodynamic and physiologic parameters such as blood pressure, heart rate, urine output, in conjunction with hemoglobin levels, to decide whether a patient needs to be transfused. Additional prospective, randomized studies are required to determine the risk-to-benefit of RBC transfusion in various disease states, the optimal transfusion trigger and the effects of blood storage time and leukodepletion on clinical outcomes.

Acknowledgement. The American College of Surgeons National Surgical Quality Improvement Program and the hospitals participating in the ACS NSQIP are the source of the data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions.

Complete Figure 2 legend: Mortality is significantly higher in transfused versus non-transfused patients within groups matched by their preoperative risk (propensity§) of intraoperative transfusion. *Chi² p

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From the Vascular Surgery Department, University of Kentucky, Lexington, Kentucky. The authors report no conflicts of interest regarding the content herein. Manuscript submitted December 23, 2009, provisional acceptance given March 11, 2010, final version accepted March 31, 2010. Address for correspondence: Eleftherios S. Xenos, MD, University of Kentucky, Vascular Surgery, 800 Rose Street, Lexington, KY 40536. E-mail: esxeno2@email.uky.edu