Pretransfusion testing of patients before red

TRANSFUSION COMPLICATIONS Risks and adverse outcomes associated with emergency-release red blood cell transfusion Sudhanshu B. Mulay, Elizabeth A. Jaben, Pamela Johnson, Karafa Badjie, and James R. Stubbs BACKGROUND: Group O red blood cell (RBC) units are used for emergency transfusions and are often uncrossmatched when transfused. We sought to determine the risk of alloimmunization and identify acute adverse outcomes of this practice. STUDY DESIGN AND METHODS: The transfusion medicine database was searched for emergencyrelease transfusion (ERT) episodes from January 2006 through December 2010. The data collected included age and sex of the recipient, blood bank history, survival after the ERT episode, antibody screen results, antibody identifications, and compatibility of released units. RESULTS: A total of 1444 ERT episodes took place involving 1407 patients. A total of 4144 RBC units were released. Of the 129 positive antibody screens, 34 had no antibody on further work-up, 14 had autoantibodies, 48 had a single antibody specificity, and 25 had multiple antibody specificities. Seven patients developed an antibody that could be attributed to the ERT episode, and 15 patients developed an antibody after ERT and additional RBC transfusions. There were 32 reported suspected transfusion reactions. No acute hemolytic transfusion reactions were reported. Seven patients were given a total of 10 incompatible RBC units. Of these patients, one developed a delayed serologic transfusion reaction. The rate of alloimmunization attributable to ERT was 3%. Overall, the rate of incompatible transfusion was less than 0.3% and the rate of a delayed hemolytic transfusion reaction was approximately 0.02%. CONCLUSION: There is minimal risk associated with the release of emergency uncrossmatched blood in the setting of an acutely bleeding patient. [Correction statement added after online publication 15-Oct-2012: the number of patients with autoantibodies, single antibody specificity and multiple antibody specificity has been update.] Pretransfusion testing of patients before red blood cell (RBC) transfusion is necessary to prevent immune-mediated hemolysis during or after transfusion. However, certain emergencies, trauma and nontrauma, do not allow adequate time to perform the required pretransfusion testing before initiation of transfusion. In such situations transfusion of uncrossmatched RBC units is widely accepted to meet the patients immediate need for oxygen-carrying capacity. ABO group specific (based on prior history) or group O RBC units, either D+ or D, depending on the institutional policy, are typically utilized for emergency release to avoid ABO blood group related acute intravascular hemolysis. The safety of transfusing group O RBC units has been studied in civilian and military settings. 1-5 The majority of these data are focused on trauma. In the military setting, the population studied was mostly young and otherwise healthy men, which differs significantly from a typical civilian population. This is particularly true with regard to alloimmunization, which tends to be infrequent in healthy, young men and higher in older men with comorbidities, multiparous women, or previously transfused patients. 6 The use of uncrossmatched group O RBC transfusion as a lifesaving measure eliminates the risk of acute intra- ABBREVIATIONS: ERT(s) = emergency-release transfusion(s); ICU = intensive care unit. From the Division of Hematology-Oncology, University of Connecticut Health Center, Farmington, Connecticut; the Division of Clinical Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, Arizona; and the Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Address reprint requests to: James R. Stubbs, MD, Department of Laboratory Medicine and Pathology, Division of Transfusion Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905; e-mail: stubbs.james@mayo.edu. Received for publication May 3, 2012; revision received August 29, 2012, and accepted August 29, 2012. doi: 10.1111/j.1537-2995.2012.03922.x TRANSFUSION 2013;53:1416-1420. 1416 TRANSFUSION Volume 53, July 2013

RISK OF EMERGENCY RELEASE vascular hemolysis due to anti-a and anti-b isoagglutinins, but still carries a risk of alloimmunization to non- ABO RBC antigens and subsequent delayed hemolysis. In a retrospective study conducted by Saverimuttu and colleagues 7 on 27,968 antibody screens, the prevalence of clinically significant antibodies was shown to be 1.9%. The authors estimated the rate of alloimmunization to be 0.5% to 4.0%. More recently, a retrospective analysis of 1002 emergency-release RBC transfusions involving 265 episodes by Goodell and coworkers 8 found clinically significant alloantibodies in 6.4% of the total episodes studied. Among these episodes, 15 antigen-incompatible RBC units were transfused to seven recipients. In the same study, the authors found only one transfusion (0.4%) associated with a hemolytic transfusion reaction. 8 These results, however, should be interpreted with caution as there might be underestimation of the true incidence of hemolytic transfusion reactions due to a high mortality rate. There continues to be a paucity of data regarding the safety of transfusing uncrossmatched emergency-release RBC units. Thus, we performed this retrospective study to analyze the incidence of alloimmunization secondary to uncrossmatched emergency-release transfusions (ERTs). In addition, we sought to evaluate the adverse outcomes of ERT, including hemolytic (due to prior alloimmunization to non-abo RBC antigens) and nonhemolytic transfusion reactions. MATERIALS AND METHODS After approval from human studies review (institutional review board) was obtained, a review of the transfusion medicine database from January 2006 through December 2010 was conducted to identify transfusion episodes involving emergency-release units. Emergency-release units were defined as RBC units released before completion of ABO/Rh typing, antibody screen, antibody identification when appropriate, and crossmatch utilizing an in-date recipient sample. Samples were considered in date if they were collected up to 56 days before the date of the intended transfusion and the recipients were documented to not have been pregnant and/or not have received a transfusion in the 3 months before sample collection or in the period since sample collection. For recipients not meeting these criteria, or if the history could not be confirmed, then the sample was considered in date if drawn within 3 days of the time of the intended transfusion. In cases of ERT recipients who were known to have previously identified clinically significant RBC alloantibodies, group O uncrossmatched units negative for the corresponding non-abo RBC antigen were given based on the historical data whenever possible. During the study period, the policy at our institution was to provide D- units to all patients for the first 6 RBC units (with four O- RBC units in a monitored refrigerator located in the trauma room). After the initial 6 units, males over the age of 18 and females over the age of 55 could be switched to D+ RBC units at the discretion of the transfusion medicine physician in consultation with the transfusing clinical service. Once the necessary testing was completed, recipients were issued antigen-negative, crossmatchcompatible (electronic or serologic as appropriate) RBC units based on the results of the testing. Retrospective serologic crossmatch was performed on units that were emergently released for patients identified as having clinically significant alloantibodies. Plasma, platelets (PLTs; single-donor apheresis), and cryoprecipitate were provided as ordered. Data obtained from the transfusion medicine database included the number of emergency-release episodes and number of units released. Additional recipient information collected included age, sex, history of prior transfusions, survival after the episode of ERT, service requesting ERT units, ABO type, antibody screen results, specificities of any antibodies identified, compatibility of transfused units, and transfusion reactions reported. Antibodies were considered clinically significant if they had been documented to be associated with hemolytic disease of the newborn, hemolytic transfusion reactions, or decreased RBC survival. 9 Based on this definition, antibodies to the following blood group antigens were considered clinically significant: Rh, Kell, Duffy, Kidd, Ss, lowincidence antigens (for example, Wr a ), MN, and anti-a1 if reactive at 37 C. Since antibodies to Lewis, P1, and Lutheran have doubtful clinical significance, they were considered not significant for the purpose of this study. RESULTS Analysis of data from January 2006 through December 2010 revealed 1444 ERT episodes for 1407 patients. There was a slight predominance of male patients (n = 774, 54%). Although age of the patients ranged from 0 to 98 years almost half (n = 663) of the episodes involved patients more than 65 years of age. Women with childbearing potential (<55 years old) accounted for 258 ERT episodes. Basic demographics are shown in Table 1. A total of 4144 RBC units were released with a mean of 2.87 RBC units per episode (range, 1-28 units). In addition to the ERT RBC units, a mean of 9.71 RBC units (range, 0-74 units) were utilized during or within 24 hours after the 1444 ERT episodes. Similarly, 2.03 units of single-donor PLTs (range, 0-17 units), 8.74 units of plasma (range, 0-70 units), and 1.51 units of cryoprecipitate (range, 0-16 units) were utilized during or within 24 hours after the ERT episode. The most common patient blood group was O+ (496 episodes). In 23 episodes (1.59%), the patients died of causes unrelated to transfusion before receipt of the sample for compatibility testing and in one episode Volume 53, July 2013 TRANSFUSION 1417

MULAY ET AL. the patient s blood group could not be determined (see Table 1). We categorized the ERT episodes based on the ordering service. The emergency and trauma unit involved the most number of ERT episodes (n = 664) followed by intensive care unit (ICU, n = 437), while the obstetric service had only one episode of ERT. The all-cause mortality on Day 45 after ERT episodes was 476. The highest mortality TABLE 1. Demographics for the patient populations studied including sex, age, responsible hospital service, and blood type Demographic Male Female Sex 774 670 Age (years) <18 37 39 18-54 231 219 55-65 148 107 >65 358 305 Ordering service Medicine 83 94 Surgery 83 82 ICU 243 194 ETU 365 299 OB NA 1 ABO and D type A+ 261 213 A- 55 49 B+ 62 56 B- 9 11 AB+ 23 16 AB- 9 5 O+ 261 235 O- 82 73 Patient died before test completion 12 11 Unable to determine 1 ETU = emergency trauma unit; OB = obstetrics. Fig. 1. The responsible hospital service or location for the emergency transfusions and distribution of 45-day all-cause mortality. ETU = emergency trauma unit; OB = obstetrics. ( ) Day 45 mortality; ( ) episodes. involved ERT episodes from the ICU (216 episodes) followed by patients in the emergency and trauma unit (186 episodes; see Fig. 1). The antibody screen was positive in 129 (10%) patients in the first sample that arrived at the time of ERT. A historical antibody was known in 43 episodes based on the information available prior to the necessary testing on the day of ERT. Further serologic work-up (extended antibody panels) did not reveal any antibody specificity in 34 episodes. Autoantibodies (without underlying alloantibodies) were identified in 12 episodes. Of those with antibodies identified in the first sample, 48 had a single antibody specificity with the most common specificity of anti-k (n = 12) followed by anti-e (n = 9). Interestingly, in eight episodes the antibody identified was passive in nature (due to RhIG in seven patients and passive anti-a in one patient). In 25 ERT episodes, antibodies with two or more antigen specificities were identified (median, 3 antigen specificities; range, 2-8). [Correction statement added after online publication 15-Oct-2012: The number of patients with single antibody specificity and the number of ERT episodes has been updated.] Of the 1256 patients with a negative antibody screen on initial testing, a subsequent antibody screen more than 14 days after the ERT episode was available on 232 patients. Seven patients without any history of transfusion or pregnancy before the ERT episode and no transfusion after the ERT episode acquired clinically significant alloantibodies (anti-k, two patients; anti-e, two patients; anti-jk a, one patient; anti-d and anti-k, one patient; antibody to a low-incidence antigen, one patient). An additional 15 patients with transfusions after the ERT episode also developed alloantibodies. These patients had a negative antibody screen on the day of ERT and no prior history of blood transfusion. There were 15 additional patients with a history of transfusion and/or a positive screen, who received additional transfusions after ERT and went on to develop additional antibodies. [Correction added after online publication 15-Oct-2012: The previous sentence has been added.] Including only those patients with an antibody screen more than 14 days after the ERT episode (to allow for the development of a new alloantibody), the alloimmunization rate attributable to ERT episodes was 3%, and the overall alloimmunization rate, including those patients with additional RBC transfusions, was 9.5%. These alloimmunization rates were calculated using 232 as the denominator. Of the patients who developed an 1418 TRANSFUSION Volume 53, July 2013

RISK OF EMERGENCY RELEASE TABLE 2. Characteristics of adverse reactions during ERT episodes or subsequent transfusions Type of adverse reaction (-) Ab screen (+) Ab screen Previous TXN Total Not related to transfusion 10 4 14 14 Febrile nonhemolytic 6 0 6 6 Circulatory overload 2 0 1 2 Allergic 3 2 4 6 DHTR or DSTR 2 2 3 4 Ab = antibody; DHTR = delayed hemolytic transfusion reaction; DSTR = delayed serologic transfusion reaction; TXN = transfusions. alloantibody, 11 were blood group O (receiving ABOidentical RBC components). Two patients with a positive antibody screen at the time of the ERT went on to develop a new antibody 14 days after the ERT. In total, 145 patients had antibodies that were either historically present or identified during or after the ERT episode, for an overall prevalence of alloantibodies of 10%. [Correction statement added after online publication 15-Oct- 2012: total number and percentage of patients with antibodies has been updated.] Thirty-two patients were reported to have an adverse reaction during ERT or the subsequent transfusions (Table 2). Many of these (n = 14, 44%) were subsequently determined (by review of the medical records) to be unrelated to the RBC transfusion. One female patient with a history of prior transfusions, who was found to have anti-c and anti-e alloantibodies, developed a delayed hemolytic transfusion reaction. Three patients developed delayed serologic transfusion reactions, defined as rapid development of alloantibody (e.g., 3-21 days after the implicated RBC transfusion) in the absence of laboratory evidence of hemolysis. 9 Seven patients received a total of 10 crossmatchincompatible RBC units (found during retrospective crossmatch after the release of the RBC units). Two of these patients died within 24 hours of the episode of causes unrelated to the transfusion. No acute transfusion reactions (hemolytic or nonhemolytic) occurred in these patients. One patient had evidence of a delayed serologic transfusion reaction (included above), but no clinical sequelae. DISCUSSION Hemorrhagic shock due to trauma or in a nontrauma setting can have devastating outcomes, which is largely due to failure of adequate tissue oxygen delivery particularly to vital body organs. RBC transfusions play a major role in the management of hemorrhagic shock. Early RBC transfusion helps to restore cardiac output and increases oxygen-carrying capacity. In such bleeding emergencies, the need to rapidly provide RBC units for transfusion often precludes completion of necessary pretransfusion testing, such as the ABO/Rh type, antibody screen, and crossmatch procedures. Except in extremely rare circumstances, the use of uncrossmatched blood group O RBC units lacking A and B RBC antigens during emergency transfusions avoids the possibility of acute intravascular hemolysis due to isoagglutinins. However, recipients of ERT are at risk of developing alloimmunization due to non-abo antigens and can also develop hemolysis due to preexisting non-abo alloantibodies. With this study, we add data on a large and diverse population of patients who received RBC transfusion in an emergent setting, before the completion of pretransfusion testing. We report 1444 episodes for patients including men, women, and children and trauma, medical, surgical, critical care, and obstetric patients. Additionally, follow-up information, including subsequent antibody screens, was available on a large number of patients. This information contributes to and expands the existing information in the civilian and military populations and supports the safety of this practice. In addition, most of the literature regarding uncrossmatched blood transfusion has focused on a military setting composed of a healthy and young population. However, in our study almost half of the patient population was more than 65 years in age thus providing a valuable insight into the practice of uncrossmatched blood transfusion in this population. According to the published data, the prevalence of alloantibodies ranges from 2% to 7%. 7,8,10 The incidence of alloimmunization in this study after the ERT episode (previous negative antibody screen) was 3% directly attributed to the ERT episode and 9.5% overall, for those patients with an antibody screen more than 14 days after the episode. The prevalence of alloantibodies in our population was 10%. These figures may be underestimates of the rate of alloimmunization because of the high 45-day all-cause mortality. Also, the retrospective nature of this study may have skewed our data analysis. A prospective study will allow a more accurate calculation of incidence. Overall, the benefits of the use of ERT outweigh the risks. This has been shown time and time again in the military setting. 6 Although the military population is unique in that it is almost exclusively (especially historically) composed of young, healthy men, the conclusion that this is a safe practice has been extrapolated into the civilian population. A recent study from a large tertiary care center reported a rate of non-abo hemolytic transfusion reactions of 0.4% with the use of uncrossmatched O RBC transfusion and the risk of receiving antigenincompatible RBC units as 2.6%. 8 Our findings of an Volume 53, July 2013 TRANSFUSION 1419

MULAY ET AL. incompatible transfusion rate of less than 0.3% and a hemolytic transfusion reactions rate of approximately 0.02% support the safety of the practice of emergency release of RBC units for transfusion to an acutely bleeding patient. Additionally, we did not identify a single acute hemolytic transfusion reaction in our study population. Reports of acute hemolytic reactions in the military studies were often due to isoagglutinins in group O whole blood or due to clerical errors and the use of type-specific blood. 6 In conclusion, group O RBCs can continue to be used safely in cases of emergency transfusion, which precludes pretransfusion compatibility testing in all patient populations. CONFLICT OF INTEREST The authors declare that they have no conflict of interest relevant to the manuscript submitted to TRANSFUSION. REFERENCES 1. Blumberg N, Bove JR. Un-cross-matched blood for emergency transfusion. One year s experience in a civilian setting. JAMA 1978;240:2057-9. 2. Dutton RP, Shih D, Edelman BB, Hess J, Scalea TM. Safety of uncrossmatched type-o red cells for resuscitation from hemorrhagic shock. J Trauma 2005;59:1445-9. 3. Schwab CW, Shayne JP, Turner J. Immediate trauma resuscitation with type O uncrossmatched blood: a two-year prospective experience. J Trauma 1986;26:897-902. 4. Barnes A, Jr, Allen TE. Transfusions subsequent to administration of universal donor blood in Vietnam. JAMA 1968; 204:695-7. 5. Lefebre J, McLellan BA, Coovadia AS. Seven years experience with group O unmatched packed red blood cells in a regional trauma unit. Ann Emerg Med 1987;16:1344-9. 6. Barnes A, Jr. Status of the use of universal donor blood transfusion. CRC Crit Rev Clin Lab Sci 1973;4:147-60. 7. Saverimuttu J, Greenfield T, Rotenko I, Crozier J, Jalaludin B, Harvey M. Implications for urgent transfusion of uncrossmatched blood in the emergency department: the prevalence of clinically significant red cell antibodies within different patient groups. Emerg Med (Fremantle) 2003;15:239-43. 8. Goodell PP, Uhl L, Mohammed M, Powers AA. Risk of hemolytic transfusion reactions following emergencyrelease RBC transfusion. Am J Clin Pathol 2010;134:202-6. 9. Roback JD, Grossman BJ, Harris T, Hillyer CD. Technical manual. 17th ed. Bethesda, MD: American Association of Blood Banks; 2011. p. 457-8, 577-8. 10. Unkle D, Smejkal R, Snyder R, Lessig M, Ross SE. Blood antibodies and uncrossmatched type O blood. Heart Lung 1991;20:284-6. 1420 TRANSFUSION Volume 53, July 2013