Current Concepts Transfusion Morbidity & Mortality St. Charles Health System Grand Rounds, Bend, Oregon. Agenda. Serious Consequences of Transfusion

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1 Current Concepts Transfusion Morbidity & Mortality St Charles Health System Grand Rounds, Bend, Oregon February 22, 2013 Mark A Popovsky, MD Associate Clinical Professor, Harvard Medical School Vice President & Chief Medical Officer, Haemonetics Corporation Agenda Overview of life-threatening transfusion reactions TACO Reportable events Transfusion complications within the context of blood management 2 Context Serious Consequences of Transfusion Transfusion Therapy: Previously viewed as a matter of compatibility, transfusion reaction avoidance and workup Today patient blood management Avoid unnecessary transfusions 4 rights Right product Right time Right patient Right dose 3 4 Transfusion-Associated Circulatory Overload (TACO) TACO: Clinical Profile (textbook) Definition/Mechanism Pulmonary edema due to transfusion Too much blood +/- non-sanguineous fluid Transfused too rapidly Cardiogenic Role of cytokines? Risk Factors Onset Symptoms Signs Very young/old < 2 hours of transfusion Respiratory distress BP; systolic > diastolic; Tachycardia 5 6

2 TACO: Presentation Clinical Acute dyspnea Tachycardia Orthopnea Systolic pressure Cyanosis Pulse pressure 0 2 desaturation Pedal edema PAOP >18mm Hg; CVP>12 Jugular venous distension TACO: Presentation Radiographic CT ratio > 053 and vascular pedicle width >65 mm 1:50 AM 9:15AM 12:05 AM EKG: New ST segment and T wave changes Acknowledgement: M Looney 7 8 Most Frequent Presentation Dyspnea (77%) Hypertension (43%) 0 2 desaturation (36%) Diagnostic Criteria #1 Hypoxemia: Pa0 2 /Fi0 2 <90% on room air Bilateral infiltrates on CXR in presence of clinically evident left atrial hypertension During or within 6 hours of transfusion #2 Pulmonary edema within 6 hours New onset or exacerbation of at least 3 symptoms/signs Robillard et al Transfusion Medicine 2009;19:280 References: Toy et al Critical Care Medicine 2005;33:721-6 NHSN Biovigilance Component Incidence of TACO Investigator Year Population Incidence/ Patient Popovsky 1996 THA/TKA 1% Bierbaum 1999 THA/TKA 8% Finlay 2005 General 1% Demographics of TACO Quebec Hemovigilance System: Age Distribution % % % % % % Robillard et al Transfusion 2008;48:204A 11 12

3 Clinical Impact of TACO Increases morbidity 21% of cases life-threatening (Robillard) Increases ICU stay (Li, 2009) Increases hospital length of stay (Popovsky 1996) in orthopedic surgery 1 RBC is sufficient to trigger the reaction! 20 53% of cases Importance of TACO: FDA Mortality Data % of Fatalities FY05 FY06 FY07 FY09 47% 56% 65% 30% TACO 2% 13% 10% 27% (Popovsky 1985 & 1996, Robillard 2008) Mortality Case Fatality % French Hemovigilance 37 Quebec Hemovigilance 14 UPMC 83 Risk Factors Setting Volume Flow rate David Vox Sang 2002 Robillard et al Transfusion 2008;48:204 Narick et al Transfusion 2011;51:127A Risk Factors: ICU Patients Medical ICU 6% incidence Risk factors Positive fluid balance (14 vs 08L) Faster rate of transfusion (225 ml/hr vs 168 ml/hr) LV dysfunction Risk Factors: General Hospital Setting OR Female gender 21 Past CHF 56 Hx hemodialysis 35 Recent surgery 23 Mechanical Ventilation 27 Recent vasopressors 97 Positive fluid balance 12 Li et al Transfusion 2011;51:338 Murphy E Transfusion 2010;50:127A-128A 17 18

4 TACO: Role of RBC Volume Quebec Hemovigilance System Age # RBC/Case Mean 211 Transfusion Flow Rate: RBC Requirements/Recommendations Circular of Information (USA): As patient can tolerate, but in less than 4 hours AABB Technical Manual, 17 th Edition 240 ml/hr (adults) 4 ml/min P Robillard (personal communication) Flow Rate: RBC Problem No accounting of recipient weight (blood volume) No accounting of the patient s underlying cardiac reserve Flow Rate: RBC (cont) Problem: Flow rate is poorly controlled 2005 study: 47 cases of TACO Mean: 45 ml/min (270 ml/hr) Range: ml/min Implications: TACO occurs with low flow rates as low as 09 ml/min Need better quality control of infusion process Need data for better nursing transfusion guidelines Andrzejewski C (personal communication) Popovsky MA Transfusion Reactions, Flow Rate: FFP & Platelets Plasma Transfusion and TACO AABB Appropriate Recommendation FFP 300 ml/hr? Platelets 300 ml/hr? University of Pittsburgh Medical Center Retrospective: Prevalence 1:1566 (1:2564 1:1014) patients Prospective: 84 patients 272 units FFP - Prevalence: 48%! - None reported to blood bank - 14/24 patients in ICU had TACO 23 Ref: 17 th Edition AABB Technical Manual, Narick et al Transfusion 2011;51s:127A global leader in blood management solutions for our customers 2011 Haemonetics Corp

5 Preventing TACO Pre-transfusion risk assessment (non-emergent transfusions) Intravascular volume and/or fluid balance assessment Respiratory, cardiac & renal function Slower rate of transfusion Pre-emptive diuretics One unit at a time Good nursing transfusion supervision Summary TACO is frequent TACO is a serious clinical problem We are beginning to understand the risk profile : The First Definition Transfusion-related acute lung injury Acute respiratory distress Hypoxemia: Pa0 2 of torr Bilateral pulmonary edema: rapid onset Hypotension: moderate; unresponsive to fluids Fever (1-2ºC) Occurs within 6 hours of a plasma-containing transfusion Popovsky & Moore: 1983 & 1985 (Transfusion & Amer Rev Resp Disease) Laboratory Findings 1980 s Mayo Clinic Studies Leukopenia in 10 Reference Findings 1983 (N = 5) HLA Class I donor antibodies in 4/5 Leukoagglutinating Antibodies in 5/5 Antibody/Antigen correspondence in 3/ (N = 36) Donor HLA/leukoagglutinating in 89% Aby/Ag correspondence in 59% Recipient antibody in 6% White Blood Cells (cells/ mm 3 ) Hours Looney et al Chest 2004;126:

6 Clinical Features Timeline: Symptoms from onset of transfusion >90% of cases within 1-2 hours 100% of cases within 6 hours Plasma-containing transfusions Classic : CXR MA Popovsky & SB Moore Transfusion 1985;25: Immediately after transfusion Looney et al Chest 2004;126:249 1 day later : Which Components? Plasma Content Fresh Frozen Plasma ml Apheresis platelets ml Red Blood Cells ml Platelet concentrates ml Stem cells Variable Clinical Course Morbidity N % Required oxygen support Required mechanical ventilation Pulmonary infiltrates Rapid resolution ( 96 hrs) Slow resolution (> 7 days) 6 17 Mortality 2 6 Long-term sequelae 0 Popovsky & Moore, Transfusion 1985;25: ARDS vs ARDS Clinical: -like ARDS-like Risk Factors: Septicemia Aspiration Multiple transfusions DIC Drug overdose Fracture of long bones Toxic inhalation Infection Inflammation Multiple transfusions End-stage liver disease Morbidity 100% ventilation % ventilation Long-Term Survival in Mayo Clinic Nested case-control (74 ; 74 control) Evaluated in-hospital, 1 & 2 year mortality Mortality, % Hospital 1 Year 2 Years P Controls Mortality 30-40% 5-20% Long-term injury: Yes No? G Li et al Chest (in press) 35 36

7 : % Transfusion-Associated Deaths % of All Deaths % % % % % Source: US FDA, CBER 2009 : Incidence Period Investigators Incidence Popovsky 1:5000 Late 1990 s Wallis 1: Silliman 1: Finlay 1: NBS (SHOT) RBC 1:520,000 FFP/Cryo 1:58,000 Platelets 1:75, : Under-reported & Under-recognized Risk Factors for in Critical Care Patients Mary FFP 36 Patients Mild/Moderate (17%) Severe (22%) 2 Repeat Reactions 2 reported to transfusion service! Investigator N Design Key Factors Jia 789 Retrospective Multivariate analysis Gajic 901 Prospective cohort Plasma transfusions Sepsis Female plasma Donor pregnancies Anti-granulocyte pos units Odds Ratio P Kopko et al JAMA 2002;287: References: Chest 2008;133: AJRCCM 2007;176: Pathogenesis of Antibody-Mediated Pulmonary Edema Increased Microvascular Permeability Blood Component Antibody PMN O 2 - Enzymes Edema & Leukocyte Antibodies (Antibody-mediated) Other Mediators 2-event Model Priming Activation Sequestration Aggregation Activation Adapted from Y Fung & C Silliman Trans Med Rev 2009;23:

8 Intravascular 2-Event Model 1 Underlying Condition 2 3 Who Develops? Predisposing Condition (1 st Event) - Priming Recent surgery Trauma Active infection or inflammation Liver disease Hematologic disease Extra Vascular Edema Gender and age are not factors Bux et al Brit J Haem 2007;136: Gajic et al Amer J Resp Crit Med 2007;176: Y Fung & C Silliman Trans Med Rev 2009;23: Distribution of HLA/HNA Antibodies in as Percent of Transfusion Deaths: FDA Reports Severe Presentation N = 36 Fatal 60% HNA-3 & HLA-A2 All (%) FFP-related (%) NA HLA Class II (47%) Class I/II (8%) HNA (33%) Class I (11%) 45 Reil et al Vox Sang 2008;95: Summary Pulmonary complications - & TACO - are the most serious transfusion complications today TACO can be prevented with better fluid management and TACO are underrecognized & underreported Pathogenesis of is more clearly understood but not completely Diverting female plasma has saved lives FDA-Reportable Transfusion Reactions CFR Any fatality (suspected or proven) As soon as possible Written report within 7 days 47 48

9 Blood Management Pillars Evidence-based transfusions Autologous transfusion Avoid Preoperative autologous donation Intra or postoperative cell salvage Hemostasis management Managing pre-operative anemia Questions?