1. TRIPICU Trial: Implications for Cardiac Patients 10 th International Conference, The Pediatric Cardiac Intensive Care Society, Miami, December 13, 2014 Jacques Lacroix

2. Financial support Relationship with a commercial interest: none.

3. Financial support Relationship with a commercial interest: none. Academic funding: – CIHR grant #177453. – NHLBI. – PHRC #12.01, 2011. – Établissement français du sang. – Health Technology Assessment, National Institute for Health Research (United Kingdom). – Sanquin (Netherland) – Research program (blood products): FRSQ #24460 Programme Hospitalier de Recherche Clinique (PHRC, France)

4. 4 Acknowledgement Study managers: Lucy Clayton, Nicole Poitras. Thank you to Ann Thompson and members of the PALISI Network. Thank you to Paul Hébert, John Marshall, Deborah Cook and members of the Canadian Critical Care Trials Group. Thank you to Phil Spinella and Marisa Tucci.

5. Transfusion Requirements In PICU (TRIPICU) study TRIPICU study: a large international randomized controlled trials. 5

6. TRIPICU study Hypothesis of the TRIPICU study: in stable critically ill children, the risk of adverse outcome in a restrictive strategy group (7.0 g/dL) will not be higher than the risk in a liberal strategy group (9.5 g/dL) when pre- storage leukocyte-reduced packed red blood cell units are used. Patients: stable or stabilized critically ill children. – Cyanotic and cardiac surgery patients younger than 28 days were excluded. Primary outcome: new or progressive MODS after randomization, including death.

7. Definition of “stable/stabilized” patients in TRIPICU study Definition: – 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 in the last 2 hours. Respiratory and neurological status were not taken into account in this definition. 7

8. Basic design of TRIPICU study Liberal group: transfusion if Hb ≤ 9.5 g/dL Restrictive group: transfusion if Hb ≤ 7.0 g/dL Targetted post- transfusion Hb: 11.0-12.0 g/dL Targetted post- transfusion Hb: 8.5-9.5 g/dL Only pre-storage leukocyte-reduced red cell units were used Eligibility: Hb ≤ 9.5 g/dL (95 g/L) within 7 days post entry into PICU

9. TRIPICU study: most frequent reasons for non enrollment of eligible cases Cardiac children < 28 days of age or cyanotic were excluded

10. TRIPICU study: primary outcome Threshold Hb (g/dL)7.09.5 Total number of patients (n)320317 New/progressive MODS (n)*3839 Deaths (n)14 * New or progressive MODS (multiple organ dysfunction syndrome) was the primary outcome measure of the TRIPICU trial. All deaths were considered cases of progressive MODS. Can we apply these results to subgroups of patients enrolled in TRIPICU, including cardiac patients?

11. TRIPICU study: statistical analysis of subgroups TRIPICU subgroupPlanned?# Absolute risk reduction (95%CI) p All patients in TRIPICU Yes6370.4% (–4.6 to +5.5)NI* Severity of illness (PRISM score) 0 (1 st IQR) Yes128 +1.5% (–6.3 to +9.4)1.00 1-4 (2 nd IQR) Yes239 –0.3% (–7.9 to +7.4)0.94 5-7 (3 rd IQR) Yes121 –2.2% (–13.0 to +8.7)0.69 ≥ 8 (4 th IQR) Yes149 +1.5% (–6.3 to +9.4)1.00 *NI: statistically significant non inferiority (TRIPICU was a non-inferiority trial). These data suggest that there is no justification to give more RBC transfusions to stable critically ill children even when their severity of illness is higher.

12. TRIPICU study: statistical analysis of subgroups TRIPICU subgroupPlanned?# Absolute risk reduction (95%CI) p All patients in TRIPICU Yes6370.4% (–4.6 to +5.5)NI Severity of illness (PRISM score) 0 (1 st IQR) Yes128 +1.5% (–6.3 to +9.4)1.00 1-4 (2 nd IQR) Yes239 –0.3% (–7.9 to +7.4)0.94 5-7 (3 rd IQR) Yes121 –2.2% (–13.0 to +8.7)0.69 ≥ 8 (4 th IQR) Yes149 +1.5% (–6.3 to +9.4)1.00 Cases of sepsis *Yes137+0.3% (–12 to +14)NS Non cardiac surgery †Yes124+1.0% (–9 to +11)NS * Karam et al. Pediatr Crit Care Med 2011;12:512-8. † Rouette et al. Ann Surg 2010;251:412-7. What did we find in the subgroup analysis of 125 pediatric cardiac patients?

13. Cardiac cases in TRIPICU: data at PICU entry Restrictive (n = 63)Liberal (n = 62) PRISM score at PICU entry (this score measures severity of illness) (x ± SD) 3.4 ± 3.53.2 ± 3.2 PELOD score (this score estimates severity of multiple organ dysfunction) (x ± SD) 4.1 ± 5.03.7 ± 5.2 Mechanical ventilation: n (%) 39 (62%)37 (60%) Blood lactate (mmol/L) (x ± SD) 1.9 ± 1.51.7 ± 0.9 Patients were similar at PICU entry.

14. Cardiac cases in TRIPICU: subgroup analysis* RACHS Score-1Restrictive (n = 63)Liberal (n = 62) 1109 22125 32715 459 500 600 Other04 * Jenkins et al. 2002. Restrictive vs liberal (X 2 ): p value = 0.06. Willems et al. Crit Care Med 2010;38:649-56.

15. Intervention (RBC): did the research protocol make a difference? Total number of RBC transfusions: Restrictive: 13 Liberal: 82 (p < 0.0001) No RBC transfusion post-randomization: 52 patients (82.5%) (restrictive) vs 0 (liberal) (p < 0.001) Average length of storage (days): 16.7±9.3 vs 13.2±10.9 (p = 0.13)

16. Intervention (RBC): did the research protocol make a difference? Lowest daily Hb level post-randomization Average difference: 2.1 ± 0.21 g/dL (p < 0.0001)

17. TRIPICU: outcomes in non-cyanotic cardiac cases > 28 day of age Threshold Hb (g/dL)7.09.5P-value Patients (n)6362 New/progressive MODS (n)840.36 28 th day mortality (n)220.98 Worst daily PELOD score7.0 ± 10.66.7 ± 7.3NS Median blood lactate (mmol/L)1.6 ± 1.01.5 ± 0.9NS Nosocomial infections (n)12 (19%) NS Length of mechanical ventilation (days)4.6 ± 3.14.7 ± 4.6NS Length of PICU stay7.0 ± 5.07.4 ± 6.4NS MODS: multiple organ dysfunction syndrome.

18. TRIPICU study: statistical analysis of subgroups TRIPICU subgroupPlanned?# Absolute risk reduction (95%CI) p All patients in TRIPICU Yes6370.4% (–4.6 to +5.5)NI Severity of illness (PRISM score) 0 (1 st IQR) Yes128 +1.5% (–6.3 to +9.4)1.00 1-4 (2 nd IQR) Yes239 –0.3% (–7.9 to +7.4)0.94 5-7 (3 rd IQR) Yes121 –2.2% (–13.0 to +8.7)0.69 ≥ 8 (4 th IQR) Yes149 +1.5% (–6.3 to +9.4)1.00 Cases of sepsisYes137+0.3% (–12 to +14)NS Non cardiac surgeryYes124+1.0% (–9 to +11)NS Cardiac surgery ( non cyanotic )Yes125+6.2% (–7.6 to +10.4)0.36

19. TRIPICU study: statistical analysis of subgroups TRIPICU subgroupPlanned?# Absolute risk reduction (95%CI) p All patients in TRIPICU Yes6370.4% (–4.6 to +5.5)NI Severity of illness (PRISM score) 0 (1 st IQR) Yes128 +1.5% (–6.3 to +9.4)1.00 1-4 (2 nd IQR) Yes239 –0.3% (–7.9 to +7.4)0.94 5-7 (3 rd IQR) Yes121 –2.2% (–13.0 to +8.7)0.69 ≥ 8 (4 th IQR) Yes149 +1.5% (–6.3 to +9.4)1.00 Cases of sepsisYes137+0.3% (–12 to +14)NS Non cardiac surgeryYes124+1.0% (–9 to +11)NS Cardiac surgery ( non cyanotic )Yes125+6.2% (–7.6 to +10.4)0.36 Respiratory dysfunctionNo480+0.1%NS ALI in TRIPICUNo73–6.3%NS ARDS in TRIPICUNo48–2.8%NS Neurological dysfunctionNo40–10.6%NS Head trauma in TRIPICUNo30+2.3%NS

20. CONCLUSION In pediatric cardiac surgery patients, a restrictive RBC transfusion strategy may be as safe (ie not- inferior) as a liberal strategy with respect to the incidence and severity of multiple organ dysfunction and 28-day all-cause mortality when pre-storage leukocyte reduced packed RBC units are used. A restrictive RBC transfusion strategy decreases significantly the number of RBC transfusions and exposure to blood products.

21. Conclusion: generalizability Meta-analysis on RBC transfusion and PICU mortality. – Risk ratio (95%CI): 0.98 (0.23, 4.25) – No heterogeneity at all (I 2 = 0%). Randomized controlled trial by de Gast-Bakker et al: – 8.0 vs 10.8 g/dL: 0/53 vs 0/54. – De Gast-Bakker et al. Intensive Care Med 2013;39:2011-9. The meta-analysis and the trial suggest that a restrictive transfusion strategy is safe in cardiac surgery PICU patients. Curley et al Crit Care Med 2014;42:2611-24

22. Conclusion: application If there is no difference in the outcomes of patients allocated in the restrictive and liberal RBC transfusion strategy of TRIPICU, why not using a liberal transfusion strategy? – Even though transfusions are safer than ever, they are not innocuous in ICU patients. A transfusion might be a 2 nd hit in ICU patients. There is a strong association between RBC transfusion and mortality in cardiac patients. – Primum non nocere. If there is no problem, do not fix it.

23. The great consistency of results in all planned and unplanned subgroup analyses and in all secondary outcomes of TRIPICU suggests that the response to RBC transfusion is similar in all stable/stabilized PICU patients, whatever their basic disease. – There is no evidence that the cardiac patient described above is different then the children enrolled in TRIPICU Data of TRIPICU show that this transfusion would be useless on a short-term basis. – We do not know for long-term outcomes, like neurological development. A non cyanotic post-surgery cardiac children (> 28 days post- term) is stable; someone prescribes a RBC transfusion even though the Hb level is 9.2 g/dL because s/he believes the child is different than those enrolled in TRIPICU. Conclusion: applicability

24. Conclusion: recommendation Non-cyanotic cardiac children older than 28 days post-term do not need a RBC transfusion… – If they are stable/stabilized – and if their Hb level is > 7.0 g/dL. Should we apply this recommendation on a mandatory basis? – Not yet: we do not have good data on long-term outcomes.

25. Conclusion: future direction “Further randomized controlled trials are necessary to determine the optimal transfusion strategy for patients undergoing cardiovascular surgery” Curley et al. Crit Care Med 2014;42:2611-24. Other studies in transfusion medicine most be done in the field of pediatric cardiac surgery.

26. Other studies on transfusion in PICU cardiac patients. – Unstable patients? – Processed RBC units: washed, irradiated, leucoreduced… – Goal-directed RBC transfusion therapy (ScvO 2, NIRS, etc). – Role of anemia and RBC transfusion on long-term outcomes. – Length of storage: the Age Blood in Children in PICU (ABC-PICU) study is on-going. – Studies on plasma and platelets transfusion. 26 (Phil Spinella, Marisa Tucci) Conclusion: future direction