Neonatal ECMO Study of
Temperature
NEST
Basic ECMO circuit
ECMO Study follow-up at four
Recruited
185
ECMO
Conventional
93
92
Deaths
31
Lost to
follow-up 1
Assessed at four
61
Deaths
54
Lost to
follow-up 3
Assessed at four
35
Outcome classification
Normal
Impairment
No functional loss
Disability
Mild
Little or no support
Moderate
Needs aids or assistance
Severe
Constant supervision
Results – Cognitive
80
70
60
50
% 40
30
20
10
0
ECMO
Conventional
85+
84 - 70
69 - 50
General Conceptual Ability Score
< 50
Results – Cognitive
70
%
60
ECMO
50
Conventional
40
30
20
10
0
normal
impaired
mild
moderate severe
disability disability disability
Results - Neuromotor
60
ECMO
50
Conventional
40
% 30
20
10
0
normal
impaired
mild
moderate severe
disability disability disability
Results – General health
70
60
ECMO
50
Conventional
% 40
30
20
10
0
normal
impaired
mild
moderate severe
disability disability disability
Results – Behaviour
60
50
ECMO
40
Conventional
% 30
20
10
0
normal
impaired
mild
moderate
disability disability
severe
disability
Results – Hearing
100
ECMO
80
Conventional
60
%
40
20
0
normal
impaired
mild
moderate severe
disability disability disability
Outcome at four years of age
ECMO
60 %
Conventional
35 %
Normal
12
20
4
11
Impairment
18
30
9
26
Mild disability
18
30
12
34
Moderate disability
9
15
10
29
Severe disability
3
5
0
Results – Overall
60
ECMO
50
Conventional
40
% 30
20
10
0
normal
impaired
mild
moderate severe
disability disability disability
Overall outcome
100
90
80
70
60
n 50
40
30
20
10
0
Lost
No disability
Mod/mild disability
Severe disability
Died
ECMO
Conventional
“Concept”
• Infants receiving ECMO represent a high
risk group for cerebral injury
• Mild hypothermia appears to be a promising
means of offering neuroprotection following
hypoxic ischaemic injury
Pilot Study Progress
Stage I: 1998 -1999
Twenty neonates recruited
Cooled for first 12 hours of ECMO
No significant problems found.
Stage II: 2000 -2001
Twenty neonates recruited
Cooled for the first 24 hours of ECMO
Stage III: 2001
Five neonates recruited
Cooled to 340c core temperature for the
first 48 hours of ECMO
Methods
25 consecutive neonates referred for ECMO
(n = 5 per group)
Group 1 (Control): Core temp at 370c for five days
Group 2: 360c for 24 hours
Group 3: 350c for 24 hours
Group 4: 340c for 24 hours
Group 5: 340c for 48 hours
Method
Protocol: Blood Sampling Points
ECMO Cannulation (VA or VV-DLC)
Cooling
Baseline
2H
12 H
37 0C
24 H 36 H 48 H Day 3
Day 4
Infants were carefully assessed clinically and biologically
Blood Samples were drawn from the ECMO circuit
sampling port at the times shown
Day 5
Measurements
Serum Assays
Cytokines: IL6 and IL8
Molecular Markers of Coagulation:
Thrombin-Antithrombin III, Antithrombin III, Plasmin
2 plasminogen
Complement: C3a
Measurements
Heparin and Platelet Transfusion Requirements
Oxygenator resistance: calculated 2, 12 and 24
hourly thereafter using the formula:
Pre-oxygenator pressure - post-oxygenator pressure(mmHg)
circuit blood flow (ml/min)
Summary of Demographic Data for Study Groups
Group 1
(370C)
Gestation in
weeks
Age at ECMO
in hours
Birth weight
(Kg)
Oxygenation
Index at Referral
40
(33,40)
24
(22,37)
2.6
(2.4,3.7)
50
(35-70)
Group 2
(360C for
24 hours)
40
(38,40)
30
(25,432)
3.7
(3.2, 4.3)
48
(27-89)
Group 3
(350C for
24 hours)
40
(38,41)
24
(16,94)
3.4
(2.8-4.7)
40
(28-90)
Group 4
(340C for
24 hours)
38
(37,40)
50
(6,384)
3.7
(2.7-4.4)
31
(20-52)
Group 5
(340C for
48 hours)
40
(39,41)
22
(12,26)
3.4
(3.1-4.3)
40
(31-55)
3
4
2
4
1
1
Primary diagnoses
MAS/PPHN
3
Sepsis
1
RDS
1
CDH
TAPVD †
Inborn Error of
Metabolism ‡
1
1
1
1
1
*Comparison of groups by Kruskal-Wallis test (df = 4) values are median (range)
p*
0.2
0.1
0.4
0.5
Median Group Core Temperature During Study Period
37.5
37.0
Rectal Temperature ('C)
36.5
36.0
Study Group
35.5
5
35.0
4
34.5
3
34.0
2
*
33.5
0
20
1
40
60
80
100
120
Time on ECMO (hours)
*Comparing groups 1-5, median rectal temperature SD at 24 hours
(Kruskal-Wallis chi-squared = 23.3, df = 4, p<0.001)
Progress and Complications During the Study
Number of
Patients
Group 1
(370C)
Group 2
(360C for
24 hrs)
Group 3
(350C for
24 hrs)
4
3
5
80
(68-176)
128
(60-451)
70
(43-122)
Bleeding
0
1†
0
0
0
Circuit
Dysfunction
0
0
0
0
0
No of Deaths
0
1
0
3
0
Venovenous
Cannulation
Median
(range) time
on ECMO in
hours *
* Comparison of groups by Kruskal-Wallis (df = 4)
† Bleeding at cannula site due to heparin bolus
Group 4 Group 5
(340C for (340C for
24 hrs)
48 hrs)
3
2
p
- 3.1
0.5
5
97
96
(60-218) (62-164)
Cardiovascular Data During Cooling and Rewarming
Group 1
(370C)
Group 2
(360C for
24 hours)
Group 3
(350C for
24 hours)
Group 4
(340C for
24 hours)
Group 5
(340C for
48 hours)
Heart rate prior to
cooling
(beats/minute)
165
(150-176)
170
(132-188)
149
(130-214)
165
(130-201)
168
(126-178)
Heart rate during
cooling
(beats/minute)
136*
(85-200)
129
(78-188)
103
(68-214)
127
(74-201)
108
(82-187)
MABP during
cooling (mmHg)
52*
(34-83)
56
(36-90)
54
(36-82)
51
(27-77)
50
(33-87)
MABP when
rewarmed
(mmHg)
52
(38-75)
59
(36-81)
53
(35-86)
53
(39-76)
52
(38-73)
*Denotes patients not cooled
Values are median (range)
Results
No systemic difference between groups for:
– Molecular markers of coagulation
– Complement C3a
– Cytokines IL6 and IL8
– Platelet transfusion requirements
– Oygenator resistance
Mean IL6 (Temperature Groups)
400
300
Group
5
200
4
3
100
2
0
1
0
24
48
72
Time on ECMO (hours)
96
120
Mean C3a (Temperature Groups)
3000
2000
Group
5
1000
4
3
2
0
1
0
24
48
Time on ECMO (hours)
72
96
120
Conclusions
• Applying mild hypothermia (340C) for 24 or
48 hours of neonatal ECMO appears
feasible and safe
• No major complications related to mild
hypothermia were observed in this study.
The next steps
A randomised controlled trial
Trial outline
• Research question to be addressed:
Does cooling neonates (neonate: less than or
equal to 28 days of age) requiring ECMO to
34oC for the first 48 to 72 hours of their
ECMO run result in improved Bayley scores
at 2 years of age?
• Trial design: Pragmatic multi-centre
randomised controlled trial.
Trial outline
• Eligibility
– Meeting standard ECMO criteria but no
congenital diaphragmatic hernias and no
post cardiac ECMO
Trial outline
• Blinding
• Randomisation
• Consent
Trial outline
• Minimisation by approach to ECMO
(VV or VA).
Trial outline
• ECMO management
• Organisation
Trial outline
• Trial end points
– Primary outcome: MDI of the Bayley scales
(34) at age of 2 years (24 - 27 months).
– Note: Where the MDI cannot be assessed
because of severe disability or death, a score
of either 40 or 0 will be recorded respectively.
Trial outline
Secondary outcomes:
• Death
• Outcome of a structured neurological
assessment
• Results of simple questionnaire completed by
parents about their child’s health at two years
of age.
• PDI of the Bayley scales
• Visuospatial assessment
• Testers rating of child behaviour
Trial Size
Assumed
mean
Bayley
scores of
the two
arms
85 & 95
85 & 95
90 & 95
Assumed SD
of Bayley
scores
Significance
Power to
detect
difference
between the
two arms
Sample size
Number
needed to be
recruited
assuming
80%survival to
2 years
5%
90
94
118
10
5%
90
42
53
10
5%
90
168
210
15
Analysis
• Intention-to-treat analysis
• Pre specified secondary analyses by
disease severity and diagnosis
Other issues
• Timescale
• aEEG
• MRI
Thank you