TRIPICU Trial: Implications for
Cardiac Patients
10th International Conference, The
Pediatric Cardiac Intensive Care
Society, Miami, December 13, 2014
Jacques Lacroix
Financial support
• Relationship with a
commercial interest: none.
Acknowledgement
Thank you to Paul Hébert, John
Marshall, Deborah Cook and
members of the Canadian
Critical Care Trials Group.
Study managers: Lucy Clayton,
Nicole Poitras.
Thank you to Ann Thompson
and members of the PALISI
Network.
Thank you to Phil Spinella and
Marisa Tucci.
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Transfusion Requirements In PICU
(TRIPICU) study
• TRIPICU study: a large international randomized
controlled trials.
5
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 prestorage 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.
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.
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Basic design of TRIPICU study
Liberal group:
transfusion if
Hb ≤ 9.5 g/dL
Eligibility: Hb ≤ 9.5 g/dL
(95 g/L) within 7 days
post entry into PICU
Restrictive group:
transfusion if Hb
≤ 7.0 g/dL
Targetted posttransfusion Hb:
11.0-12.0 g/dL
Only pre-storage
leukocyte-reduced red
cell units were used
Targetted posttransfusion Hb:
8.5-9.5 g/dL
TRIPICU study: most frequent reasons for non
enrollment of eligible cases
Cardiac children < 28 days of
age or cyanotic were excluded
TRIPICU study: primary outcome
Threshold Hb (g/dL)
Total number of patients (n)
New/progressive MODS (n)*
Deaths (n)
7.0
320
38
14
9.5
317
39
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?
TRIPICU study: statistical analysis of subgroups
TRIPICU subgroup
All patients in TRIPICU
0 (1st IQR)
Severity
of illness 1-4 (2nd IQR)
(PRISM
5-7 (3rd IQR)
score)
≥ 8 (4th IQR)
Planned?
#
Absolute risk reduction
(95%CI)
p
Yes
637
0.4% (–4.6 to +5.5)
NI*
Yes
128
+1.5% (–6.3 to +9.4)
1.00
Yes
239
–0.3% (–7.9 to +7.4)
0.94
Yes
121
–2.2% (–13.0 to +8.7)
0.69
Yes
149
+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.
TRIPICU study: statistical analysis of subgroups
Planned?
#
Absolute risk reduction
(95%CI)
p
Yes
637
0.4% (–4.6 to +5.5)
NI
Yes
128
+1.5% (–6.3 to +9.4)
1.00
Yes
239
–0.3% (–7.9 to +7.4)
0.94
Yes
121
–2.2% (–13.0 to +8.7)
0.69
Yes
149
+1.5% (–6.3 to +9.4)
1.00
Cases of sepsis *
Yes
137
+0.3% (–12 to +14)
NS
Non cardiac surgery †
Yes
124
+1.0% (–9 to +11)
NS
TRIPICU subgroup
All patients in TRIPICU
0 (1st IQR)
Severity
of illness 1-4 (2nd IQR)
(PRISM
5-7 (3rd IQR)
score)
≥ 8 (4th IQR)
* 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?
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 ± 3.5
3.2 ± 3.2
PELOD score (this score
estimates severity of multiple
organ dysfunction) (x ± SD)
4.1 ± 5.0
3.7 ± 5.2
39 (62%)
1.9 ± 1.5
37 (60%)
1.7 ± 0.9
Mechanical ventilation: n (%)
Blood lactate (mmol/L) (x ± SD)
Patients were similar at PICU entry.
Cardiac cases in TRIPICU:
subgroup analysis*
RACHS Score-1
Restrictive (n = 63)
Liberal (n = 62)
1
2
3
4
10
21
27
5
9
25
15
9
5
6
Other
0
0
0
0
0
4
* Jenkins et al. 2002.
Restrictive vs liberal (X2): p value = 0.06.
Willems et al. Crit Care Med 2010;38:649-56.
Intervention (RBC): did the research
protocol make a difference?
60
Total number of RBC transfusions:
• Restrictive: 13
• Liberal: 82 (p < 0.0001)
50
40
Cases
30
20
10
0
Restrictive
Liberal
0
52
0
1
9
46
2
2
12
3
0
0
Number of RBC transfusions/patient
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)
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)
TRIPICU: outcomes in non-cyanotic
cardiac cases > 28 day of age
Threshold Hb (g/dL)
7.0
9.5
Patients (n)
63
62
New/progressive MODS (n)
8
4
0.36
28th day mortality (n)
2
2
0.98
7.0 ±
10.6
6.7 ± 7.3
NS
Median blood lactate (mmol/L)
1.6 ± 1.0 1.5 ± 0.9
NS
Nosocomial infections (n)
12 (19%)
12 (19%)
NS
Length of mechanical ventilation (days)
4.6 ± 3.1 4.7 ± 4.6
NS
Length of PICU stay
7.0 ± 5.0 7.4 ± 6.4
NS
Worst daily PELOD score
P-value
MODS: multiple organ dysfunction syndrome.
TRIPICU study: statistical analysis of subgroups
Planned?
#
Absolute risk reduction
(95%CI)
p
Yes
637
0.4% (–4.6 to +5.5)
NI
Yes
128
+1.5% (–6.3 to +9.4)
1.00
Yes
239
–0.3% (–7.9 to +7.4)
0.94
Yes
121
–2.2% (–13.0 to +8.7)
0.69
Yes
149
+1.5% (–6.3 to +9.4)
1.00
Cases of sepsis
Yes
137
+0.3% (–12 to +14)
NS
Non cardiac surgery
Yes
124
+1.0% (–9 to +11)
NS
Cardiac surgery (non cyanotic)
Yes
125
+6.2% (–7.6 to +10.4)
0.36
TRIPICU subgroup
All patients in TRIPICU
0 (1st IQR)
Severity
of illness 1-4 (2nd IQR)
(PRISM
5-7 (3rd IQR)
score)
≥ 8 (4th IQR)
TRIPICU study: statistical analysis of subgroups
Planned?
#
Absolute risk reduction
(95%CI)
p
Yes
637
0.4% (–4.6 to +5.5)
NI
Yes
128
+1.5% (–6.3 to +9.4)
1.00
Yes
239
–0.3% (–7.9 to +7.4)
0.94
Yes
121
–2.2% (–13.0 to +8.7)
0.69
Yes
149
+1.5% (–6.3 to +9.4)
1.00
Cases of sepsis
Yes
137
+0.3% (–12 to +14)
NS
Non cardiac surgery
Yes
124
+1.0% (–9 to +11)
NS
Cardiac surgery (non cyanotic)
Yes
125
+6.2% (–7.6 to +10.4)
0.36
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 subgroup
All patients in TRIPICU
0 (1st IQR)
Severity
of illness 1-4 (2nd IQR)
(PRISM
5-7 (3rd IQR)
score)
≥ 8 (4th IQR)
CONCLUSION
• In pediatric cardiac surgery patients, a restrictive
RBC transfusion strategy may be as safe (ie notinferior) 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.
Conclusion: generalizability
• Meta-analysis on RBC transfusion and PICU mortality.
– Risk ratio (95%CI): 0.98 (0.23, 4.25)
– No heterogeneity at all (I2 = 0%).
Curley et al Crit Care Med
2014;42:2611-24
• 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.
Conclusion: applicability
A non cyanotic post-surgery cardiac children (> 28 days postterm) 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.
• 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.
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.
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.
Conclusion: future direction
• Other studies on transfusion in PICU cardiac patients.
– Unstable patients?
– Processed RBC units: washed, irradiated, leucoreduced…
– Goal-directed RBC transfusion therapy (ScvO2, 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.
(Phil Spinella,
Marisa Tucci)
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