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Three decades of transfusion
Toronto, Critical Care Canada Forum, October 30, 2014.
Jacques Lacroix For the Canadian Critical Care
Trials Group and the PALISI Network
Pediatric Intensive Care Unit Sainte-Justine Hospital Université de Montréal
Financial support Relationship with a
commercial interest: none.
ABLE study: CIHR grant #177453. PHRC #12.01, 2011. 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.
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.
Years 1970-9 1980-9 1990-0 2000-9 Future Justification of RBC transfusions
Anemia
Main safety issues
Blood in-compati-bility, hemolysis
Clinical research questions
Landmark studies NISHOT: non infectious serious hazards of transfusion; RBC: red blood cells.
5
Years 1970-9 1980-9 1990-0 2000-9 Future Justification of RBC transfusions
Anemia To maintain hemoglobin level in normal range
Main safety issues
Blood in-compati-bility, hemolysis
Transfusion-transmitted infectious diseases (TTID)
Clinical research questions
Finding measures that decrease risk of TTID
Landmark studies
6
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
7
CONCLUSION: red blood cell transfusions are pretty safe presently with respect to transfusion-transmitted infections.
Concerns: Testing for HIV, hepatitis B and C is systematically performed in less
than 45% of members of the World Health Organization. Blood products providers will remain concern by emerging germs
(babesiosis, Chagas disease, Dengue, Chikungunya, hepatatis E, etc).
In the last two decades, NISHOT became the most important safety issue.
Non-infectious serious hazards of transfusion (NISHOT)
www.nishot.uk.org Early onset NISHOT: appear < 24 hours post-transfusion
(mechanisms) MODS, TRALI, etc (TRIM, disturbed local O2 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
Transfusion-associated respi-ratory complications (TARC)
Critically ill children might be more prone than less severely ill children to contract NISHOT (2nd 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
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
> 6 hrs post-transfusion) 20 5
Transfusion-associated circulatory overload (TACO)
TBD TBD
Transfusion-associated dyspnea (TAD) 0 0
10 Kleiber et al. Réanimation 2012;21: S131.
Years 1970-9 1980-9 1990-0 2000-9 Future Justification of RBC transfusions
Anemia To maintain hemoglobin level in normal range
To improve O2 delivery (DO2)
Main safety issues
Blood in-compati-bility, hemolysis
Transfusion-transmitted infectious diseases (TTID)
Is it safe to give less RBC trans-fusions?
Clinical research questions
Finding measures that decrease risk of TTID
Can we tolerate anemia in critically ill patients?
Landmark studies
TRIPICU
11
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
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
Basic design of TRIPICU study
Eligible: Hb ≤ 95 g/L (9.5 g/dL) within 7 days
post entry into PICU
Targetted Hb post-transfusion: 110-120 g/L
Targetted Hb post-transfusion: 85-95 g/L
Liberal group: transfusion if Hb ≤ 95 g/L
Restrictive group: transfusion if Hb ≤ 70 g/L
Only pre-storage leukocyte-reduced packed
RBC units were used
RCT: threshold hemoglobin in PICU cases (TRIPICU study)
Threshold hemoglobin (g/L) 70 95 Total number of patients (n) 320 317 New/progressive MODS (n)* 38 39 Deaths (n) 14 14
Can we apply these results to subgroups of patients enrolled in TRIPICU?
15
* 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;356:1609-19.
TRIPICU subgroups Planned? # Absolute risk reduction (95%CI) p All patients in TRIPICU Yes 637 0.4% (–4.6 to +5.5) NI
PRISM score
0 (1st IQR) Yes 128 +1.5% (–6.3 to +9.4) 1.00 1-4 (2nd IQR) Yes 239 –0.3% (–7.9 to +7.4) 0.94 5-7 (3rd IQR) Yes 121 –2.2% (–13.0 to +8.7) 0.69 ≥ 8 (4th IQR) Yes 149 +1.5% (–6.3 to +9.4) 1.00
Sepsis, severe sepsis, shock Yes 137 +0.3% (–12 to +14) NS Non cardiac surgery Yes 124 +1.0% (–9 to +11) NS Cardiac surg. (non cyanotic) Yes 125 +6.3% (–4 to +16.5) NS Respiratory dysfunction No 480 +0.1% NS ALI in TRIPICU No 73 –6.3% NS ARDS in TRIPICU No 48 –2.8% NS Neurological dysfunction No 40 –10.6% NS Head trauma in TRIPICU No 30 +2.3% NS
TRIPICU subgroups
16
Data from TRIPICU study show great consistency of results in all planned and
unplanned subgroup analyses.
Years 1970-9 1980-9 1990-0 2000-9 Future Justification of RBC transfusions
Anemia To maintain hemoglobin level in normal range
To improve O2 delivery (DO2)
To improve DO2 and to prevent NISHOT
Main safety issues
Blood in-compati-bility, hemolysis
Transfusion-transmitted infectious diseases (TTID)
Is it safe to give less RBC trans-fusions?
Length of storage of RBC units (up to 42 days)
Clinical research questions
Finding measures that decrease risk of TTID
Can we tolerate anemia in critically ill patients?
- 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
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.
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;308:1443-51
Length of storage: ongoing trials 1. ABLE study (ISRCTN44878718). 2. RECESS (NCT00991341; M Steiner, NIH
1. Patients: 1600 cases of coranoplasty with cardio-pulmonary bypass.
2. Primary outcome measure: MODS score.
3. “Red Cell Storage Duration and Outcomes in Cardiac Surgery” (NCT00458783): 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).
RECESS trial ≤ 10 days (n=538) ≥ 21 days (n=560) P value
RBC transfusions Median unit/patient 4.0 (2.0, 5.0 3.0 (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) < 0.001 Primary and secondary outcomes MODS score (1st outcome) 8.48 ±3.62 8.66 ±3.66 0.43 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
CONCLUSION
Conclusion: optimal RBC tranfusion practice
Severe anemia (Hb < 40-50 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 transfusion-associated respiratory complications (TARC).
We do not know if fresh blood is better than old blood. 23
Years 1970-9 1980-9 1990-0 2000-9 Future Justification of RBC transfusions
Anemia To maintain hemoglobin level in normal range
To improve O2 delivery (DO2)
To improve DO2 and to prevent NISHOT
To improve O2 consumption (VO2) & prevent NISHOT
Main safety issues
Blood in-compati-bility, hemolysis
Transfusion-transmitted infectious diseases (TTID)
Is it safe to give less RBC trans-fusions?
Length of storage of RBC units (up to 42 days)
Can we produce safer RBC units?
Clinical research questions
Finding measures that decrease risk of TTID
Can we tolerate anemia in critically ill patients?
- Older RBC units: harm? - Fresher RBC units: benefit?
- Cost/benefit analysis in specific subpopulation - Knowledge application
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. 24
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 (ScvO2, 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.
25
(Phil Spinella, Marisa Tucci)
Conclusion: future direction