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Perinatal asphyxia: Pathophysiology and therapy

Peter Davis Melbourne

Australia

With thanks to Dr Sue Jacobs

Moderate or severe HIE

• Complicates ~1/1000 term live births: –Mortality: >25%

–Major neurological sequelae: >25% • Cerebral palsy, intellectual impairment, seizures

–Cognitive impairments at school-age, even without neuromotor deficits • Associated behavioural & educational

difficulties

A Little Basic Science

• Neuronal death occurs in 2 phases

• Severe insult

–Immediate neuronal death – cellular hypoxia and primary energy failure

–Delayed neuronal death – occurs at least 6 hours later i.e. allows a therapeutic window

A Little Basic Science

• Secondary phase – accounts for a major proportion of cell loss

–Pathology - hyperemia, cytotoxic oedema, mitochondrial failure, accumulation of cytotoxins, apoptosis, nitric oxide synthesis, free radical damage

–Clinically – encephalopathy, increased seizure activity

Mechanism of protection by hypothermia

• Survival of cells otherwise destined to die through apoptosis

• Reduced metabolic rate

• Reduced release of excitatory amino acids (glutamate, dopamine)

• Lower production of nitric oxide and free radicals

Methods of cooling newborns

• Selective head cooling with mild systemic hypothermia

– Rationale: ‘Cool brain more than body’

• Newborn brain produces 70% of total body heat

• Minimise adverse effects of systemic cooling

• Whole-body hypothermia

– Rationale: ‘Reduce systemic temperature to achieve deep brain cooling’

• Core body temperature & deep brain temperature are similar

• Mathematic modeling supports this

Potential Adverse Effects of Cooling

Heart

– ↓Contractility, BP

– Bradycardia

– Arrhythmias

– PPHN

Lungs

– Pulmonary oedema

– Hypoxia

Gastrointestinal

– NEC

Hematological

– Coagulopathy & platelet dysfunction

Metabolic

– Acidosis

– O2 dissociation curve to left

– Hypokalaemia

– Hypoglycaemia

Immunological

– Sepsis

Randomised Trials of Cooling for HIE

All RCTs included

• Term or near-term newborns < 6 hours of age with:

– Moderate or severe encephalopathy • aEEG

– Peripartum hypoxia-ischaemia: e.g • Apgar score < 5 at 10 minutes, and/or

• Mechanical ventilation or resuscitaiton at 10 minutes, and/or

• Cord pH < 7.1 or arterial pH < 7.1 or base deficit of 12 or more within 60 minutes of birth

– No congenital abnormality or active bleeding and not ‘in extremis’

RCTs Intervention

Therapeutic hypothermia (whole body or selective head cooling)

Or

No cooling (standard care)

Active (device) and/or Passive cooling

RCTs Outcomes

• Primary: –death or long-term (>18 months) major

neurodevelopmental disability

• Secondary: –Death, major neurodevelopmental

disability, CP, neuromotor delay, intellectual impairment, blindness, deafness

–Adverse effects of cooling: CVS, FBC, coagulation, hypoglycaemia, renal, culture proven sepsis

‘Larger’ published RCTs

CoolCap

2005

NICHD

2005

TOBY

2009

Number 234 205 325

aEEG Yes No Yes

Method Selective head Systemic Systemic

Primary

outcome

Death or severe

disability at 18

months

Death or

moderate/severe

disability at 18

months

Death or severe

disability at 18

months

‘Larger’ published RCTs

Zhou

2010

Simbruner

2010

ICE

2011

Number 194 129 221

aEEG No Yes No

Method Selective head Systemic Systemic

Primary

outcome

Death or severe

disability at 18

months

Survival free of

handicap at 18

months

Death or severe

disability at 24

months

The ‘ICE’ randomized trial of whole body hypothermia for hypoxic-ischemic

encephalopathy (HIE)

Sue Jacobs Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, Wright IMR, Kirpalani HM, Darlow BA, Doyle LW and The ICE Collaboration

Arch Pediatr Adolesc Med. 2011 Aug;165(8):692-700.

Background

Most infants with moderate-to-severe HIE are born in non-tertiary settings

Hypothermia should be started immediately after the insult for maximum benefit

Gunn, 2000

Aim: To determine the effectiveness and safety of whole body hypothermia to 33.5C for 72 hours in term and near term newborns with moderate-to-severe HIE using: clinical eligibility criteria

a simple method of hypothermia

initiated within 6 hours of birth at the birth hospital by dedicated neonatal retrieval teams

Prospective, multicenter, international, randomized controlled trial

‘Infant Cooling Evaluation’ trial ICE ICE

Inclusion criteria

1. Near term (> 35 weeks)

2. Encephalopathy (moderate or severe)

3. Peripartum hypoxia/ ischemia i.e., two of:

a) Apgar score < 5 at 10 minutes

b) Need for ventilation at 10 minutes

c) Metabolic acidosis (pH <7.00 or BE >-12) within 1 hour of birth

4. Treatment at, or transport to, one of the participating centers

Exclusion criteria 1. Hypothermia unable to be started within 6

hours of birth 2. Birth weight <2 kg 3. Major congenital abnormalities:

a) Suspected neuromuscular disorders b) Suspected chromosomal abnormalities c) Life threatening CVS or respiratory abnormalities d) Suspected coagulopathy e) Imperforate anus

4. Severe respiratory distress (FiO2 >80%) 5. ‘In extremis’: hypotension or severe acidosis

unresponsive to treatment 6. Any active cooling before consent

Methods

All infants assessed for eligibility at birth hospital:

Inborn infants by study investigator

Outborn infants by retrieval team Obtained informed parental consent

Randomized

Initiated the intervention

Continued the same hypothermia and monitoring protocol during transport to NICU as for inborns

Methods

‘Control’ 36.8 - 37.3°C (PR)

‘Cool’ 33.0 - 34.0°C (PR) for 72 hours

Hypothermia protocol: ‘Passive’ at ambient environmental temperature

Radiant warmer turned off

‘Active’ with 2 refrigerated gel packs placed:

Under head + shoulders

Over chest + abdomen

Rewarm at < 0.5°C every 2 hours

Assessed for eligibility

(n = 542)

Randomized (n = 221)

Excluded (n = 321) Not meeting inclusion criteria

(n=207)

Refused (n=33)

Not approached (n=80)

Consented, not randomised

(n=1)

Cool (n = 110) Control (n = 111)

Lost to follow-up (n=3)

Unable to contact (n=2)

Refused (n=1)

Died (n=27)

Survivors assessed (n=80)

Lost to follow-up (n=10)

Withdrew, unable to contact (n=2)

Refused (n=8)

Died (n=42)

Survivors assessed (n=59)

Analyzed (n = 107) Analyzed (n = 101)

Neonatal baseline characteristics (1)

Cool (n=110) Control (n=111)

Gestation (weeks) - mean 39 39

Birth weight (g) - mean 3348 3515

Male 55% 60%

Outborn 62% 60%

Age at randomization

(hours) - mean

4.0 3.9

Temperature at

randomization (°C) -

mean

36.3 36.6

Neonatal baseline characteristics (1) Cool (n=110) Control (n=111)

Gestation (weeks) - mean 39 39

Birth weight (g) - mean 3348 3515

Male 55% 60%

Outborn 62% 60%

Age at randomization

(hours) - mean

4.0 3.9

Temperature at

randomization (°C) - mean

36.3 36.6

Neonatal baseline characteristics (2) Cool (n=110) Control (n=111)

Apgar score (median)

1 minute

5 minutes

10 minutes

1

3

4

1

3

4

Resuscitation

Ventilation

Chest compressions

Adrenaline

100%

63%

39%

100%

62%

45%

Neonatal baseline characteristics (3)

Cool (n=110) Control (n=111)

Peripartum hypoxia/ischaemia

Apgar 5 at 10 mins

Ventilation 10 mins

Cord/gas within 1 hr (mean)

pH

Base excess

82%

96%

6.9

-20.4

86%

96%

6.9

-19.0

Assessment encephalopathy

Mild

Moderate

Severe

15%

57%

27%

23%

50%

27%

Clinical seizures 33% 34%

Primary outcome

Reported for 94% (208/221)

Hypothermia significantly reduced death or major sensorineural disability at 2 years of age:

Cool Control Risk Ratio

(95% CI)

P

value

Death or major

disability

51% 66% 0.77 (0.62, 0.98) 0.03

Absolute reduction 15%

NNT 7 (95%CI 4, 59)

Secondary outcomes: Mortality

Hypothermia significantly reduced mortality

Cool Control Risk Ratio (95%

CI)

P

value

Death 25% 39% 0.65 (0.43, 0.97) 0.04

Absolute reduction 14%

NNT 7

Adverse effects of hypothermia

6 infants discontinued intervention

3 overt bleeding

1 parental request; 2 by clinicians

Cool Control P-value

Arrhythmia requiring treatment 0 0

Hypoxia in 100% oxygen 0 0

Overt bleeding 3% 0 0.25

Death during intervention 12% 17% 0.26

Other effects of hypothermia Cool Control P-value

Hypotension treated with

inotropes

46% 47% 0.94

Treated coagulopathy 18% 11% 0.13

Thrombocytopaenia <150 x

109/L

51% 45% 0.45

Oliguria 34% 27% 0.30

Hepatic dysfunction 35% 45% 0.14

Seizures (any) 77% 79% 0.94

Sepsis 5% 7% 0.59

Strengths of ICE

Whole body therapeutic hypothermia is beneficial No major adverse effects Results consistent with other RCTs &

meta-analyses Only ‘larger’ RCT to report safety &

outcomes of hypothermia initiated at the birth hospital, continued during retrieval & transport to the tertiary NICU

ICE Conclusions

ICE method is effective, safe and widely applicable: Identifies infants with HIE at risk of

adverse outcome soon after birth Uses a simple, inexpensive method of

whole body hypothermia Could be used in non-tertiary settings

whilst awaiting retrieval and during transport to the regional NICU

Systematic reviews & meta-analyses

• 7 reviews published

• Cochrane review ‘Cooling for newborns with HIE’ updated July 2007

• Today updated to include 12 RCT’s & 1504 term newborns with moderate or severe HIE

– 7 trials of whole-body cooling

– 5 trials of selective head cooling

Death or major disability in survivors (8 studies, n=1344)

Study or Subgroup

1.2.1 Selective head cooling with mild systemic hypothermia

Gunn 1998

Gluckman 2005

Zhou 2010

Subtotal (95% CI)

Total events

Heterogeneity: Chi² = 2.46, df = 2 (P = 0.29); I² = 19%

Test for overall effect: Z = 2.78 (P = 0.005)

1.2.2 Whole body cooling

Eicher 2005

Shankaran 2005

Azzopardi 2009

Simbruner 2010

Jacobs 2002

Subtotal (95% CI)

Total events


Test for overall effect: Z = 4.80 (P < 0.00001)

Total (95% CI)

Total events


Test for overall effect: Z = 5.53 (P < 0.00001)

Events

7

59

31

97

14

45

74

27

55

215

312

Total

18

108

100

226

27

102

163

53

107

452

678

Events

4

73

46

123

21

64

86

48

67

286

409

Total

13

110

94

217

25

103

162

58

101

449

666

Weight

1.1%

17.6%

11.5%

30.3%

5.3%

15.5%

21.0%

11.2%

16.8%

69.7%

100.0%

M-H, Fixed, 95% CI

1.26 [0.46, 3.44]

0.82 [0.66, 1.02]

0.63 [0.44, 0.91]

0.77 [0.64, 0.92]

0.62 [0.41, 0.92]

0.71 [0.54, 0.93]

0.86 [0.68, 1.07]

0.62 [0.46, 0.82]

0.77 [0.62, 0.98]

0.75 [0.66, 0.84]

0.75 [0.68, 0.83]

Hypothermia Standard care Risk Ratio Risk Ratio

M-H, Fixed, 95% CI

0.2 0.5 1 2 5

Favors hypothermia Favors standard care

Mortality (12 studies, n=963)

Disability in survivors assessed (8 studies, n=917)

Infants with severe encephalopathy: Death or major disability

Outcome Hypothermia

(%)

Standard

(%)

RR

(95% CI)

NNT

p-value

Death or major

disability in survivors

46% 61% 0.77

(0.66,0.90)

7

0.0001

Mortality 25% 34% 0.77

(0.66,0.90)

11

0.001

Major disability 19% 25% 0.78

(0.64,0.96)

16

0.02

Major disability in

survivors

26% 39% 0.67

(0.55,0.80)

14

0.001

Outcome in survivors Hypothermia

(%)

Standard

(%)

RR

(95% CI)

NNT

p-value

Cerebral palsy 23% 35% 0.66

(0.54, 0.82)

8

0.0001

Neuromotor delay

(BSID PDI <70)

26% 35% 0.75

(0.59, 0.94)

11

0.01

Developmental delay

(BSID MDI <70)

22% 34% 0.65

(0.53, 0.81)

8

0.0001

Blindness 6% 10% 0.62

(0.38, 1.01)

0.06

Deafness 4% 6% 0.66

(0.35, 1.26)

0.21

Cochrane review summary

• When used within strict protocols in tertiary NICUs, therapeutic hypothermia is beneficial to near-term newborns with moderate or severe HIE. – Cooling reduces mortality and major disability.

– The benefits of cooling on survival and neurodevelopment outweigh the short term adverse effects (sinus bradycardia, thrombocytopaenia).

– Whole-body and selective head cooling both effective.

In 1997….

‘Hypothermia is the most promising option for a clinically feasible neural rescue therapy in encephalopathic newborns following acute perinatal asphyxia’

Thoresen and Wyatt. Acta Paediatr 1997;86:1029-33

In 2014

• Therapeutic hypothermia improves outcome after moderate or severe HIE. – But, 46% of cooled infants still die or survive with

major disability.

• Further strategies are needed: – Regional guidelines to facilitate earlier induction

of cooling

– Refinement of current hypothermia methods

– Synergistic neuroprotective therapies

ILCOR 2010 Treatment Recommendation

• Term and near-term with moderate to severe HIE should be offered cooling

• Whole body and selective head cooling are both appropriate

• Cooling should be initiated and conducted in neonatal intensive care facilities using the protocols used in the RCTS (begin within 6 hours of birth, continue for 72 hours after birth, and rewarm over at least 4 hours).

• Monitor for adverse effects: thrombocytopenia and hypotension

• All treated infants should be followed up longitudinally

http://www.healthynewbornnetwork.org/

Gaps in newborn resuscitation in resource-limited settings

Gaps in the evidence

Cord clamping

Timing

Positive pressure ventilation

Best interface

Optimal ventilation parameters

Others

Simple ways to administer blended oxygen

Thermal management of asphyxiated infant

Problems and solutions

• Most of the burden of illness occurs in resource limited settings

• Most of the evidence comes from the developed world

So ...

• Should facilitate/support research in the developing world

• Community based interventions are very important – But once NMR < 25-30 per 1000 live births

hospital based therapies are required to gain further improvements

• Small part of the puzzle – use what we know to improve their outcomes

Barriers to application in resource limited settings

• Lack of suitable cooling equipment ($)

• Lack of skilled personnel

• Higher rates of sepsis (neutrophil function)

• Lack of facilities for disabled children

• Lack of ventilatory support

Effectiveness vs efficacy

• Can accurate/reliable cooling be achieved with ice packs and passive cooling?

• Does this method of cooling improve long term outcomes?

• Is it safe?

– Infection

– Coagulopathy

– ...

What is “resource limited”?

• A continuous rather than dichotomous variable e.g. China, South Africa ...

• Self defined?

• All of us?

• What resources are needed to safely cool?

Evidence pertinent to resource limited settings

• 4 RCTs

– ICE Trial: gel packs, advanced setting

– Bharadwaj (2012) India: gel packs

– Thayyil (2013) India: phase changing material mattress

– Robertson (2011, 2008) Uganda: water bottles

Rectal temperature: Bharadwaj

Rectal temperature: Thayyil

Simple whole body cooling: Death

Death or disability

Disability

*Bharadwaj – assessed at 6 months

Results

• Simple cooling delivers reasonably precise and accurate whole body hypothermia

• The technique reduces death (and death or disability) in a developed world setting (ICE)

• No evidence of benefit or harm (mortality) in resource limited setting

Conclusions

• Insufficient evidence for effectiveness or safety in resource limited settings -- therefore cooling not recommended outside RCT

• (opportunity cost=money spent on cooling could be spent better on prevention)

Conclusions

• The treatment is efficacious and safe(ish). No evidence of harm, small trials underpowered, therefore cool and audit the results.

Conclusions

• Define the resources required to safely cool and let units decide where they fit – Intravenous fluids

– Supplemental oxygen

– Anticonvulsants

– Antibiotics

– Adequate trained staff

– Pathology: glucose, electrolytes, coagulation studies

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