1. Transfusions and ALI Resident research conference July 31, 2012 Elizabeth Nowlis, MD

2. Acute lung injury is bad Incidence from 10% to over 40% of critically ill patients Mortality up to 40-50% Long-term sequelae for survivors Cost $$$$$

3.  ALI/ARDS: risk factors Trauma Injury severity Fractures, spine surgery Aspiration/Pneumonitis Pneumonia Pulmonary contusion Transfusion Transplant (lung, HSCT) Genetic factors?

4. Transfusion as a risk factor Gong 2005

5. Transfusion as a risk factor Silverboard 2005

6. Pathophysiology of ALI ? ? ? ?

7. PRBC processing Leukoreduced Irradiated Washed etc plasma platelets (optional) whole blood (for now) PRBCs plus a teeny bit of plasma plasma (storage lesion?)

8. Hypothesis 1: HLA Ab/Ag matching Transfusions & ALI

9. Hypothesis 2: “inflammatory mediators” Transfusions & ALI Cell becomes fragile: storage lesion? mechanical trauma?

10. Trauma Injury severity Fractures, spine surgery Aspiration/Pneumonit is Pneumonia Pulmonary contusion Transfusion Transplant (lung, HSCT) Genetic factors? Recipient risk factors: Parity Female sex (=parity) Certain antibodies ____? Donor risk factors:

11. Aging and RBCs Altered lipid composition of membranes Increased glycosylation Increased “packing susceptibility” Increased viscosity Altered morphology Shortened lifespan? Vulnerability to oxidative stress Impact on storage lesion???

12. Does RBC donor age affect transfusion recipient outcome?

13. Study design

14. Subjects Recruitment: Feb 2003 – Aug 2004 Adult trauma patients presenting to HMC expected to receive transfusions within 24h Exclusion criteria: expected survival <48h received blood products active infection already Incarcerated <18 yo required CMV- or rare blood type, alloantibodies prehospital hypertonic saline study

15. Recipient (subject) ALI/ARDS: Diagnostic criteria: P/F ratio CXR non-cardiogenic by chart review Early ( 72h, <28d) Exposure variable ≥ 1 unit from a donor > median age any hospital day prior to development of ALI Multivariate logistical regression adjusted for: patient age; injury severity score; APACHE II score; highest ED lactate; hemorrhagic shock; lowest ED Hematocrit; blunt injury mechanism; leukoreduced blood; storage time of RBC units; amount of crystalloid and other blood products infused while at-risk for ALI Analysis

16. Results 1,511 units PRBCs transfused while subjects “at risk” for ALI 103 (49%) subjects developed ALI 48% received ≥1 unit from a donor older than the median age -higher transfusion requirements -worse measures of hemorrhage

17. Results OutcomeOdds Ratio (95% CI)P-value ALI (28-day)0.98 (0.50, 1.89)0.941 Early ALI (<72h)1.14 (0.53, 2.49)0.732 Late ALI (>72h, <28d)0.86 (0.37, 1.96)0.712

18. Results No significant correlation between age of oldest RBC donor and transfusion recipient ALI RBC storage time does not appear to be a significant interaction term

19. Strengths & Weaknesses Future directions Secondary analysis Low signal-to-noise Fairly large sample size Almost no studies exist! High incidence of ALI? More direct measures? - e.g. measure MPs directly Other donor variables

20. Thanks to: Tim WatkinsAvery Nathens Barbara Konkle Puget Sound Blood Center staffSteve Dinwiddie Ajmani RS, Rifkind JM (1998). Hemorheological Changes during Human Aging. Gerontology 44:111. Bowdler AJ, Foster AM (1987). The effect of donor age on the flow properties of blood. Exp Ger 22:155. Gajic O, Rana R, Winters JL, Yilmaz M, Mendez JL, Rickman OB, O'Byrne MM, Evenson LK, Malinchoc M, DeGoey SR, Afessa B, Hubmayr RD, Moore SB (2007). Transfusion-related Acute Lung Injury in the Critically Ill: Prospective Nested Case-Control Study. Am J Resp Crit Care Med 176:886. Gong et al.2005. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med 33(6):1191-8. Jozwiak Z, Jasnowska B (1985). Changes in oxygen-metabolizing enzymes and lipid peroxidation in human erythrocytes as a function of age of donor. Mech Age Dev 32:77. Judkiewicz L, Ciszewski R, Bartosz G (1988). The effect of donor age on the packing susceptibility of erythrocytes. Mech Age Dev 46:83. Mangalmurti NS, Chatterjee S, Cheng G, Andersen E, Mohammed A, Siegel DL, Schmidt AM, Albelda SM, Lee JS (2010). Advanced glycation end products on stored red blood cells increase endothelial reactive oxygen species generation through interaction with receptor for advanced glycation end products. Transfusion 50(11):2353. Nathens AB, Nester TA, Rubenfeld GD, Nirula R, Gernscheimer TB (2006). The effects of leukoreduced blood transfusion on infection risk following injury: a randomized controlled trial. Shock 26(4):342. Onaran I, Yalcin AS, Sultuybek G (1997). Effect of donor age on the susceptibility of erythrocytes and erythrocyte membranes to cumene hydroperoxide-induced oxidative stress. Mech Age Dev 98: 127. Prisco D, Rogasi PG, Paniccia R, Abbate R, Gensini GF (1991). Age-related changes in red blood cell lipids. Angiology 42(4):316. Silliman CC, Ambruso DR, Boshkov LK (2005). Transfusion-related acute lung injury. Blood 105:2266. Silverboard et al. 2005. The role of acute blood transfusion in the development of acute respiratory distress syndrome in patients with severe trauma. J Trauma 59(3):717-23. Watkins TR, Rubenfeld GD, Martin TR, Nester TA, Caldwell E, Billgren J, Ruzinski J, Nathens AB (2008). Effects of leukoreduced blood on acute lung injury arter trauma: a randomized controlled trial. Crit Care Med 36(5):1493. References