Three decades of transfusion - Critical Care Canada Forum€¦ · ABC-PICU: CIHR, NIH. Programme Hospitalier de Recherche Clinique (PHRC, France) 3 . Objective This lecture is devoted

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)

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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.

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Anemia To maintain hemoglobin level in normal range

Main safety issues


Transfusion-transmitted infectious diseases (TTID)


Finding measures that decrease risk of TTID

Landmark studies

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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

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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.



To improve O2 delivery (DO2)

Main safety issues



Is it safe to give less RBC trans-fusions?



Can we tolerate anemia in critically ill patients?

Landmark studies

TRIPICU

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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 .

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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.

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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?

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* 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

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Data from TRIPICU study show great consistency of results in all planned and

unplanned subgroup analyses.




To improve DO2 and to prevent NISHOT

Main safety issues




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

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




To improve DO2 and to prevent NISHOT

To improve O2 consumption (VO2) & prevent NISHOT

Main safety issues




Length of storage of RBC units (up to 42 days)

Can we produce safer RBC units?




- 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.

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(Phil Spinella, Marisa Tucci)

Conclusion: future direction

Documents

Three decades of transfusion - Critical Care Canada Forum€¦ · ABC-PICU: CIHR, NIH. Programme Hospitalier de Recherche Clinique (PHRC, France) 3 . Objective This lecture is devoted