Neonatal ECMO Study of Temperature

NEST

Basic ECMO circuit

ECMO Study follow-up at four

ECMO93

Conventional92

Deaths31

Deaths54

Lost to follow-up 1

Lost to follow-up 3

Assessed at four61

Assessed at four35

Recruited185

Outcome classification

Normal

Impairment No functional loss

Disability

Mild Little or no support

Moderate Needs aids or assistance

Severe Constant supervision

Results – Cognitive

0

10

20

30

40

50

60

70

80

85+ 84 - 70 69 - 50 < 50

General Conceptual Ability Score

ECMO

Conventional

Results – Cognitive

0

10

20

30

40

50

60

70

normal impaired milddisability

moderatedisability

severedisability

%

ECMO

Conventional

Results - Neuromotor

0

10

20

30

40

50

60

normal impaired milddisability

moderatedisability

severedisability

%

ECMO

Conventional

Results – General health

0

10

20

30

40

50

60

70

normal impaired milddisability

moderatedisability

severedisability

%

ECMO

Conventional

Results – Behaviour

0

10

20

30

40

50

60

normal impaired milddisability

moderatedisability

severedisability

%

ECMO

Conventional

Results – Hearing

0

20

40

60

80

100

normal impaired milddisability

moderatedisability

severedisability

%

ECMO

Conventional

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

0

10

20

30

40

50

60

normal impaired milddisability

moderatedisability

severedisability

%

ECMO

Conventional

Overall outcome

0102030405060708090

100

ECMO Conventional

n

LostNo disabilityMod/mild disabilitySevere disabilityDied

“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 ProgressStage I: 1998 -1999

Twenty neonates recruited

Cooled for first 12 hours of ECMO

No significant problems found.

Stage II: 2000 -2001Twenty neonates recruited

Cooled for the first 24 hours of ECMO

Stage III: 2001Five 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

MethodProtocol: Blood Sampling Points

BaselineBaseline 2 H2 H 12 H12 H 24 H 48 H48 H Day 3Day 3 Day 4Day 4 Day 5Day 5

ECMO Cannulation (VA or VV-DLC)ECMO Cannulation (VA or VV-DLC)

CoolingCooling 37 37 00CC

Infants were carefully assessed clinically and biologicallyInfants were carefully assessed clinically and biologically

Blood Samples were drawn from the ECMO circuit Blood Samples were drawn from the ECMO circuit sampling port at the times shownsampling port at the times shown

36 H

Serum AssaysCytokines: IL6 and IL8

Molecular Markers of Coagulation: Thrombin-Antithrombin III, Antithrombin III, Plasmin 2 plasminogen

Complement: C3a

Measurements

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)

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)

p*

Gestation in weeks

40

(33,40)

40

(38,40)

40

(38,41)

38

(37,40)

40

(39,41)

0.2 Age at ECMO

in hours 24

(22,37)

30

(25,432)

24

(16,94)

50

(6,384)

22

(12,26)

0.1 Birth weight

(Kg) 2.6

(2.4,3.7)

3.7

(3.2, 4.3)

3.4

(2.8-4.7)

3.7

(2.7-4.4)

3.4

(3.1-4.3)

0.4 Oxygenation

Index at Referral 50

(35-70)

48

(27-89)

40

(28-90)

31

(20-52)

40

(31-55)

0.5 Primary diagnoses

MAS/PPHN 3 3 4 2 4

Sepsis 1 1 1

RDS 1 1

CDH

1 1

TAPVD †

1

Inborn Error of Metabolism ‡

1

Summary of Demographic Data for Study Groups

*Comparison of groups by Kruskal-Wallis test (df = 4) values are median (range)

Median Group Core Temperature During Study Period

*Comparing groups 1-5, median rectal temperature SD at 24 hours (Kruskal-Wallis chi-squared = 23.3, df = 4, p<0.001)

Time on ECMO (hours)

120100806040200

Re

cta

l Te

mp

era

ture

('C

)37.5

37.0

36.5

36.0

35.5

35.0

34.5

34.0

33.5

Study Group

5

4

3

2

1*

Number of Patients

Group 1 (370C)

Group 2 (360C for 24 hrs)

Group 3 (350C for 24 hrs)

Group 4 (340C for

24 hrs)

Group 5 (340C for 48 hrs)

2 p

Venovenous Cannulation

4

3

5

3

5

Median (range) time on ECMO in hours *

80 (68-176)

128 (60-451)

70 (43-122)

97 (60-218)

96 (62-164)

- 3.1

0.5

Bleeding

0 1† 0 0 0

Circuit Dysfunction

0

0

0

0

0

No of Deaths 0 1 0 3 0

Progress and Complications During the Study

* Comparison of groups by Kruskal-Wallis (df = 4)† Bleeding at cannula site due to heparin bolus

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) MABP when rewarmed (mmHg)

52* (34-83) 52 (38-75)

56 (36-90) 59 (36-81)

54 (36-82) 53 (35-86)

51 (27-77) 53 (39-76)

50 (33-87) 52 (38-73)

Cardiovascular Data During Cooling and Rewarming

*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

Time on ECMO (hours)

120967248240

IL6

(m

cg/L

)400

300

200

100

0

Group

5

4

3

2

1

Mean IL6 (Temperature Groups)

Time on ECMO (hours)

120967248240

Com

plem

ent

(C3a

) n

g/m

l

3000

2000

1000

0

Group

5

4

3

2

1

Mean C3a (Temperature Groups)

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

Assumed mean Bayley scores of the two arms

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

85 & 95 15 5% 90 94 118

85 & 95 10 5% 90 42 53

90 & 95 10 5% 90 168 210

Trial Size

Analysis

• Intention-to-treat analysis

• Pre specified secondary analyses by disease severity and diagnosis

Other issues

• Timescale

• aEEG

• MRI

Thank you