Three decades of transfusion Toronto, Critical Care Canada Forum, October 30, 2014.

Transcription

1 Three decades of transfusion Toronto, Critical Care Canada Forum, October 30, Jacques Lacroix For the Canadian Critical Care Trials Group and the PALISI Network Pediatric Intensive Care Unit Sainte-Justine Hospital Université de Montréal

2 Financial support Relationship with a commercial interest: none. ABLE study: CIHR grant # PHRC #12.01, EFS. Health Technology Assessment, National Institute for Health Research (United Kingdom). Sanquin (Netherland) Research program on blood products: FRSQ #24460 ABC-PICU: CIHR, NIH. Programme Hospitalier de Recherche Clinique (PHRC, France)

3 Objective This lecture is devoted to red blood cell (RBC) transfusions. Main topics: Safety issues. Transfusion-transmitted infectious diseases. Non-infectious serious hazards of transfusion (NISHOT). Limiting RBC transfusions. Length of storage of RBC units. 3

4 What is the problem? Anemia: Observed in 74% of critically ill children. Anemia in PICU is associated with mortality. Transfusion: Red blood cell transfusion is the only rapid way to restore hematocrit. Around 50% of critically ill children admitted to pediatric ICU in North-America reveive 1 red blood cell transfusion during their ICU stay. Red cell transfusions are not perfectly safe.

5 Years Future Justification of RBC transfusions Anemia Main safety issues Clinical research questions Blood incompatibility, hemolysis Landmark studies NISHOT: non infectious serious hazards of transfusion; RBC: red blood cells. 5

6 Years Future Justification of RBC transfusions Main safety issues Anemia Blood incompatibility, hemolysis To maintain hemoglobin level in normal range Transfusiontransmitted infectious diseases (TTID) Clinical research questions Finding measures that decrease risk of TTID Landmark studies 6

7 Transfusion-transmitted infections: a problem presently? Infection Rate per units transfused (2012, Canada) HIV 1/8,000,000 to 1/12,000,000 Hepatitis B 1/1,100,000 to 1/1,700,000 Hepatitis C 1/5,000,000 to 1/7,000,000 Bacteria (platelets) 1/47,000 to 1/105,000 CONCLUSION: red blood cell transfusions are pretty safe presently with respect to transfusion-transmitted infections. Concerns: In the last two decades, NISHOT became the Testing for HIV, hepatitis B and C is systematically performed in less than 45% most of members important of the World safety Health Organization. issue. Blood products providers will remain concern by emerging germs (babesiosis, Chagas disease, Dengue, Chikungunya, hepatatis E, etc). 7

8 Non-infectious serious hazards of transfusion (NISHOT) Early onset NISHOT: appear < 24 hours post-transfusion (mechanisms) MODS, TRALI, etc (TRIM, disturbed local O 2 delivery) Transfusion-associated circulatory overload (TACO: overtransfusion) Isolated hypotensive reaction (bradykinins) Major allergic reaction, anaphylaxis (allergy) Febrile non-hemolytic reaction Acute hemolytic transfusion reaction, ABO incompatibility Early onset complications of massive transfusion: coagulopathy, thrombocytopenia, hypothermia, hypocalcemia, etc Late onset NISHOT: Delayed hemolytic reaction Allo-immune thrombopenia, post-transfusion purpura Transfusion associated graft versus host disease (TA-GvHD) 8

9 Transfusion-associated respiratory complications (TARC) Critically ill children might be more prone than less severely ill children to contract NISHOT (2 nd hit theory). Some NISHOT are underreported in ICU patients, like TARC. Why? Some TARC are difficult to recognize (TACO). Hemovigilance systems record only new respiratory complications in patients who were asymptomatic before transfusion (classic TRALI). A significant proportion of transfused PICU patients already show some respiratory symptoms before they receive a transfusion. New respiratory complications cannot be detected in such patients. We looked for new and progressive TARC in a prospective cohort of 136 consecutive critically ill children transfused in the PICU of Sainte-Justine hospital. At least one TARC was observed in 71 patients (52%). 9

10 TARC in 136 transfused PICU patients TARC New Progressive Respiratory dysfunction associated with transfusion 9 49 Transfusion-associated acute lung injury (TRALI) Certain/probable classic TRALI 2 0 Delayed TRALI (TRALI that appeared 20 5 > 6 hrs post-transfusion) Transfusion-associated circulatory TBD TBD overload (TACO) Transfusion-associated dyspnea (TAD) 0 0 Kleiber et al. Réanimation 2012;21: S

11 Years Future Justification of RBC transfusions Main safety issues Anemia Blood incompatibility, hemolysis To maintain hemoglobin level in normal range Transfusiontransmitted infectious diseases (TTID) To improve O 2 delivery (DO 2 ) Is it safe to give less RBC transfusions? Clinical research questions Finding measures that decrease risk of TTID Can we tolerate anemia in critically ill patients? Landmark studies TRIPICU 11

12 Is it safe to give less red cell transfusion to PICU patients? The Transfusion Requirements In PICU (TRIPICU) study provides most available data on the risk/benefit ratio of RBC transfusion in PICU. However, only stable or stabilized PICU patients were included in this randomized clinical trial. 12

13 Stable/stabilized patients Definition in TRIPICU study. The mean arterial pressure is not less than 2 standard deviations below normal mean for age and the cardiovascular support (pressors/inotropes and fluids) has not been increased for at least 2 hours. Please, note that respiratory and neurological status were not taken into account in this definition. 13

14 Basic design of TRIPICU study Liberal group: transfusion if Hb 95 g/l Eligible: Hb 95 g/l (9.5 g/dl) within 7 days post entry into PICU Restrictive group: transfusion if Hb 70 g/l Targetted Hb post-transfusion: g/l Only pre-storage leukocyte-reduced packed RBC units were used Targetted Hb post-transfusion: g/l

15 RCT: threshold hemoglobin in PICU cases (TRIPICU study) Threshold hemoglobin (g/l) Total number of patients (n) New/progressive MODS (n)* Deaths (n) * New/progressive MODS (multiple organ dysfunction syndrome) was the primary outcome measure of the TRIPICU study; all deaths were considered cases of progressive MODS. From: Lacroix et al. N Engl J Med 2007;356: Can we apply these results to subgroups of patients enrolled in TRIPICU? 15

16 TRIPICU subgroups TRIPICU subgroups Planned? # Absolute risk reduction (95%CI) p All patients in TRIPICU Yes % ( 4.6 to +5.5) NI PRISM score Data from TRIPICU study show great consistency of results in all planned and unplanned subgroup analyses. 0 (1 st IQR) Yes % ( 6.3 to +9.4) (2 nd IQR) Yes % ( 7.9 to +7.4) (3 rd IQR) Yes % ( 13.0 to +8.7) (4 th IQR) Yes % ( 6.3 to +9.4) 1.00 Sepsis, severe sepsis, shock Yes % ( 12 to +14) NS Non cardiac surgery Yes % ( 9 to +11) NS Cardiac surg. (non cyanotic) Yes % ( 4 to +16.5) NS Respiratory dysfunction No % NS ALI in TRIPICU No % NS ARDS in TRIPICU No % NS Neurological dysfunction No % NS Head trauma in TRIPICU No % NS 16

17 Years Future Justification of RBC transfusions Main safety issues Clinical research questions Anemia Blood incompatibility, hemolysis To maintain hemoglobin level in normal range Transfusiontransmitted infectious diseases (TTID) Finding measures that decrease risk of TTID To improve O 2 delivery (DO 2 ) Is it safe to give less RBC transfusions? Can we tolerate anemia in critically ill patients? To improve DO 2 and to prevent NISHOT Length of storage of RBC units (up to 42 days) - Older RBC units: harm? - Fresher RBC units: benefit? Landmark studies TRIPICU ARIPI ABC-PICU NISHOT: non infectious serious hazards of transfusion; RBC: red blood cells. Studies in adults on age of blood: ABLE, INFORM, RECESS, TRANSFUSE. 17

18 Background: length of storage of red blood cell (RBC) units Determination of the upper limit of RBC shelf life (maximum length of storage) (FDA, AABB): Based upon an hemolysis < 1% (0.8% in Europe) and Having 75% of RBC still alive in circulation of healthy volunteers 24 hours post-transfusion. Criteria advocated in the 40s (Mollison & Young. Quart J Exp Physiol 1942;31:359-92). The upper limit of RBC shelf life is not based upon Laboratory or clinical efficacy evaluations. Potential adverse effects of time from storage process. It is presently unknown if the efficacy and safety of older RBC units are similar to fresher blood.

19 RCT: Age of red blood cell in premature infants (ARIPI) Principal investigator: Dean Fergusson, Ottawa. Basic design: double-blind multicenter effectiveness RCT. Patients: 377 prematures < 1250 g birth weight, in neonatal ICU and requiring one or more RBC transfusions (multiple consecutive RBC transfusions is frequent in these patients). Intervention: Experimental: blood stored 7 days (these patients will be exposed to fresh RBC units, but to multiple donors). Control (usual care): Pedi-packs (these patients will be exposed to older RBC units, but to less donors). Primary (composite) outcome: mortality, retinopathy, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage. Conclusion: no difference in any outcome. Fergusson et al. JAMA 2012;308:

20 Length of storage: ongoing trials 1. ABLE study (ISRCTN ). 2. RECESS (NCT ; M Steiner, NIH 1. Patients: 1600 cases of coranoplasty with cardiopulmonary bypass. 2. Primary outcome measure: MODS score. 3. Red Cell Storage Duration and Outcomes in Cardiac Surgery (NCT ): Koch et al, Cleveland. 1. Patients: 2800 adults. 2. Outcome: morbidity post-surgery. 4. INFORM: > 24,000 hospitalized adults. 5. TRANSFUSE: 6000 adults in ICU. 6. ABC-PICU study: children (Tucci, Spinella).

21 RECESS trial RBC transfusions 10 days (n=538) 21 days (n=560) P value Median unit/patient 4.0 (2.0, (2.0, 6.0) 0.30 Perfect adherence: % subjects 478 (89%) 468 (87%) 0.35 Median storage time (days) 7 (5, 9) 29 (24, 33) < Primary and secondary outcomes MODS score (1 st outcome) 8.48 ± ± With 1 serious adverse event 283 (5.3%) 288 (6.1%) 0.72 Median SAE/subject 1 (0, 2) 1 (0, 2) 0.75 All cause mortality 23 (4%) 29 (5%) 0.51 Steiner ME, Triuzi DJ, Assinavy SY, Slonin SR, Delaney M, Blajchman MA, Granger S, D'Andrea PA, Pukinsbek S, Szowell CP, for the Transfusion Medicine/Homeostasis Network. Randomized trial results: Red Cell Storage Age is not associated with a significant difference in multiple organ dysfunction score or mortality in transfused cardiac surgery patients. Transfusion 2014;54:15A

22 CONCLUSION

23 Conclusion: optimal RBC tranfusion practice Severe anemia (Hb < g/l) is frequent and it is associated with mortality in severely ill patients. RBC transfusions are also associated with mortality. There is evidence that too many RBC transfusions are given to critically ill children. What determinants should drive practitioners to prescribe RBC transfusion to critically ill children is unclear, but hemoglobin concentration is always in the picture. More attention must be put on NISHOT and on transfusionassociated respiratory complications (TARC). We do not know if fresh blood is better than old blood. 23

24 Years Future Justification of RBC transfusions Main safety issues Clinical research questions Landmark studies Anemia Blood incompatibility, hemolysis To maintain hemoglobin level in normal range Transfusiontransmitted infectious diseases (TTID) Finding measures that decrease risk of TTID To improve O 2 delivery (DO 2 ) Is it safe to give less RBC transfusions? Can we tolerate anemia in critically ill patients? TRIPICU To improve DO 2 and to prevent NISHOT Length of storage of RBC units (up to 42 days) - Older RBC units: harm? - Fresher RBC units: benefit? ARIPI ABC-PICU NISHOT: non infectious serious hazards of transfusion; RBC: red blood cells. Studies in adults on age of blood: ABLE, INFORM, RECESS, TRANSFUSE. To improve O 2 consumption (VO 2 ) & prevent NISHOT Can we produce safer RBC units? - Cost/benefit analysis in specific subpopulation - Knowledge application 24

25 Conclusion: future direction More studies must be done on RBC transfusion. Examples: RBC transfusion in cases of hemorrhagic shock, in unstable patients, in the operating room, in cardiac patients, etc. Goal-directed RBC transfusion therapy (ScvO 2, NIRS, etc). Processed RBC units: washing, irradiation, leucoreduction, etc. Knowledge transfer in transfusion medicine. Length of storage: Age of Blood in Children in PICU (ABC-PICU) More studies must be done on plasma and platelets transfusion. (Phil Spinella, Marisa Tucci) 25