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BMJ Clin Evid. 2007; 2007: 0320.
Published online 2007 November 7.
PMCID: PMC2943784

Perinatal asphyxia

William McGuire, Associate Professor

Abstract

Introduction

In resource-rich countries, the incidence of severe perinatal asphyxia (causing death or severe neurological impairment) is about 1/1000 live births. In resource-poor countries, perinatal asphyxia is probably much more common. Data from hospital-based studies in such settings suggest an incidence of 5–10/1000 live births.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions in term or near-term newborns with perinatal asphyxia? We searched: Medline, Embase, The Cochrane Library and other important databases up to June 2006 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticonvulsants (prophylactic), antioxidants, calcium channel blockers, corticosteroids, fluid restriction, head and/or whole body hypothermia, hyperbaric oxygen treatment, hyperventilation, inotrope support, magnesium sulphate, mannitol, opiate antagonists, and resuscitation (in air versus higher concentrations of oxygen).

Key Points

Estimates of the incidence of perinatal asphyxia vary. In resource-rich countries, severe perinatal asphyxia (causing death or severe neurological impairment) is 1/1000 live births; in resource-poor countries, studies suggest an incidence of 5–10/1000 live births.

Limited evidence from three small, weak RCTs suggests that mortality may be lower in infants treated with antioxidants compared with placebo.

There is limited evidence that hypothermia reduces mortality and neurodevelopmental disability in infants with perinatal asphyxia.

Limited evidence from one small RCT suggests that a magnesium sulphate/dopamine combination may be more effective than no treatment in reducing a combined outcome of mortality, abnormal scans, and failure to feed.

Small RCTs with flawed methods suggest that anticonvulsants are of no benefit in reducing mortality or improving neurodevelopmental outcomes in term infants with perinatal asphyxia.

Resuscitation in air lowered mortality in infants with perinatal asphyxia compared with resuscitation in 100% oxygen. However, current clinical practice is to use 100% oxygen.

Limited evidence from a systematic review that reported problems with publication bias in the RCTs it identified suggests that hyperbaric oxygen treatment lowers rates of mortality and adverse neurological outcomes in infants with perinatal asphyxia and hypoxic–ischaemic encephalopathy. This treatment, although widely used in China, is not standard practice in other countries.

We don't know whether calcium channel blockers, corticosteroids, fluid restriction, hyperventilation, inotrope support, mannitol, or opiate antagonists are helpful in infants with perinatal asphyxia.

About this condition

Definition

The clinical diagnosis of perinatal asphyxia is based on several criteria, the two main ones being evidence of cardiorespiratory and neurological depression (defined as an Apgar score remaining less than 7 at 5 minutes after birth) and evidence of acute hypoxic compromise with acidaemia (defined as an arterial blood pH of less than 7 or base excess greater than 12 mmol/L). In many settings, especially resource-poor countries, it may be impossible to assess fetal or neonatal acidaemia. In the immediate postpartum period when resuscitation is being undertaken, it may not be possible to determine whether the neurological and cardiorespiratory depression is secondary to hypoxia–ischaemia, or to another condition such as feto-maternal infection, or metabolic disease. Consequently, resuscitation and early management will often be of suspected rather than confirmed perinatal asphyxia. This review deals with perinatal asphyxia in term and near-term newborns.

Incidence/ Prevalence

Estimates of the incidence of perinatal asphyxia vary depending on the definitions used. In resource-rich countries, the incidence of severe perinatal asphyxia (causing death or severe neurological impairment) is about 1/1000 live births. In resource-poor countries, perinatal asphyxia is probably much more common. Data from hospital-based studies in such settings suggest an incidence of 5–10/1000 live births. However, this probably represents an underestimate of the true community incidence of perinatal asphyxia in resource-poor countries.

Aetiology/ Risk factors

Perinatal asphyxia may occur in utero, during labour and delivery, or in the immediate postnatal period. There are numerous causes, including placental abruption, cord compression, transplacental anaesthetic or narcotic administration, intrauterine pneumonia, severe meconium aspiration, congenital cardiac or pulmonary anomalies, and birth trauma. Postnatal asphyxia can be caused by an obstructed airway, maternal opiates — which can cause respiratory depression — or congenital sepsis.

Prognosis

Worldwide, perinatal asphyxia is a major cause of death and of acquired brain damage in newborn infants. The prognosis depends on the severity of the asphyxia. Only a minority of infants with severe encephalopathy after perinatal asphyxia survive without handicap. However, there are limited population-based data on long-term outcomes after perinatal asphyxia, such as cerebral palsy, developmental delay, visual and hearing impairment, and learning and behavioural problems. After an asphyxial event, there may be an opportunity to intervene to minimise brain damage. The first phase of brain damage — early cell death — results from primary exhaustion of the cellular energy stores. Early cell death can occur within minutes. Immediate resuscitation to restore oxygen supply and blood circulation aims to limit the extent of this damage. A secondary phase of neuronal injury may occur several hours after the initial insult. The mechanisms believed to be important in this process include oxygen free radical production, intracellular calcium entry, and apoptosis. Treatments during the postresuscitation phase aim to block these processes, thereby limiting secondary cell damage and minimising the extent of any brain damage.

Aims of intervention

To minimise mortality, and brain and other organ damage, with minimal adverse effects.

Outcomes

Mortality: treatment failure measured by rates of death before hospital discharge. Neurological impairment: includes incidence of neurodevelopmental disability assessed at greater than 12 months of age using a validated tool, and severity of hypoxic–ischaemic encephalopathy assessed using a validated tool.

Methods

Clinical Evidence search and appraisal March 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to March 2007, Embase 1980 to March 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and the National Institute of Health and Clinical Excellence (NICE). Abstracts of studies retrieved from the initial search were assessed independently by two information specialists. Predetermined criteria were used to identify relevant studies. Study design criteria for inclusion in this review were: systematic reviews, RCTs, and quasi-randomised studies. Open trials were included because blinding was not possible for all interventions; however, those assessing neurological deficit were blind to treatment group. Small trials (fewer than 20 people) and trials with less than 80% follow-up were included. There was no minimum length of follow-up. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table
GRADE Evaluation of interventions for Perinatal asphyxia.

Glossary

Apgar score
Quantitative score, usually measured at 1, 5, and 10 minutes after birth. The infant's heart rate, respiratory effort, muscle tone, response to stimulation (usually pharyngeal suctioning), and colour are assessed. For each of these five components, assessors award a maximum of 2 points for normal, 1 point for poor, and 0 points for bad. An Apgar score of less than 7 indicates moderate neuro/cardiorespiratory depression, and a score of less than 3 indicates severe depression. The Apgar score is less reliable in premature infants, in whom it directly correlates with gestation.
High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Hypoxic–ischaemic encephalopathy (neonatal encephalopathy)
An abnormal neurobehavioural state in newborn infants, which is described clinically by stages. Stage 1 (mild): hyperalertness, hyper-reflexia, dilated pupils, tachycardia, and absence of seizures. Stage 2 (moderate): lethargy, hyper-reflexia, contraction of the pupils, bradycardia, seizures, hypotonia with weak suck, and Moro reflex. Stage 3 (severe): stupor, flaccidity, seizures, small pupils that react poorly to light, decreased stretch reflexes, hypothermia, and absent Moro reflex.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate vision loss
Loss of three or more lines of distance vision measured on a special eye chart, corresponding to a doubling of the visual angle.
Near term
Greater than 34 completed weeks' gestation and less than 37 weeks' gestation. (i.e. 35 and 36 weeks' gestation)
Neurodevelopmental disability
Defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay, auditory and visual impairment.
Term
Greater than 36 completed weeks' gestation.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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2007; 2007: 0320.
Published online 2007 November 7.

Antioxidants

Summary

Limited evidence from three small, weak RCTs suggests that mortality may be lower in infants treated with antioxidants compared with placebo.

Benefits and harms

Allopurinol versus placebo or no drug treatment:

We found one systematic review (search date not reported) that identified one small RCT, and we found two subsequent RCTs.

Mortality

Allopurinol compared with placebo Allopurinol seems more effective than placebo at reducing mortality in infants with perinatal asphyxia (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality

RCT
22 term neonates with asphyxia
In review
Death
2/11 (18%) with allopurinol (40 mg/kg)
6/11 (55%) with no drug treatment

RR 0.73
95% CI 0.26 to 2.09
Not significant

RCT
22 term neonates with asphyxia
In review
Rates of death or developmental delay (method of assessment not reported)
4/11 (36%) with allopurinol (40 mg/kg)
7/11 (64%) with no drug treatment

RR 0.57
95% CI 0.23 to 1.41
Not significant

RCT
32 term neonates with severe asphyxia Death
13/17 (77%) with allopurinol (iv 40 mg/kg; 2 doses)
10/15 (67%) with placebo

RR 1.15
95% CI 0.74 to 1.79
Not significant

RCT
60 term neonates with mild, moderate, or severe asphyxia Death
3/30 (10%) with allopurinol (40 mg/kg/day for 3 days)
3/30 (10%) with placebo

RR 1.00
95% CI 0.22 to 4.56
Not significant

Neurological impairment

Allopurinol compared with placebo Allopurinol may be no more effective than placebo at reducing the risk of neurological impairment in infants with perinatal asphyxia (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Neurological impairment

RCT
60 term neonates with mild, moderate, or severe asphyxia Incidence of severe neurological impairment >12 months after birth
38/27 (30%) with allopurinol (40 mg/kg/day for 3 days)
12/27 (44%) with placebo

RR 0.67
95% CI 0.33 to 1.37
Not significant

Adverse effects

No data from the following reference on this outcome.

Miltiorrhizae versus citicoline (cytidine diphosphate choline):

We found one systematic review (search date not reported), which identified one small RCT comparing two antioxidants versus each other. The RCT compared miltiorrhizae (a Chinese herb with antioxidant properties) versus citicoline (also an antioxidant).

Mortality

Miltiorrhizae compared with citicoline (cytidine diphosphate choline) Miltiorrhizae (a Chinese herb with antioxidant properties) may be more effective than citicoline at reducing the rate of a composite outcome of death and neurological development in infants with perinatal asphyxia (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality

RCT
63 neonates with perinatal asphyxia, unclear if near term or term
In review
Mortality or neurological abnormality
6/35 (17%) with miltiorrhizae
13/28 (46%) with citicoline

R 0.37
95% CI 0.16 to 0.81
Moderate effect sizemiltiorrhizae

Neurological impairment

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

The systematic review cautioned that both of the RCTs it identified gave insufficient information on allocation concealment, method of randomisation, and blinding of assessors to determine trial quality and validity of the findings.

Comment

Clinical guide:

Free radicals are recognised as an important cause of brain damage in infants who have suffered an asphyxial injury. In theory, antioxidants might therefore prevent free radical neuronal damage after perinatal asphyxia.

Substantive changes

Antioxidants One RCT comparing allopurinol versus placebo added, which found no significant difference in mortality between groups. However, there remains insufficient evidence to draw conclusions about the effects of antioxidants in infants with perinatal asphyxia, so categorisation unchanged (Unknown effectiveness).

2007; 2007: 0320.
Published online 2007 November 7.

Calcium channel blockers

Summary

We don't know whether calcium channel blockers are helpful in infants with perinatal asphyxia.

The use of calcium channel blockers has been associated with clinically important hypotension in severely asphyxiated newborn infants.

Benefits and harms

Calcium channel blockers:

We found no systematic review or RCTs.

Further information on studies

Comment

Clinical guide:

The use of calcium channel blockers has been associated with clinically important hypotension in severely asphyxiated newborn infants. In one small case series, four term infants with asphyxia received a continuous infusion of nicardipine. The heart rate increased in all four infants, and mean arterial blood pressure fell in three. Two infants had a sudden and marked fall in blood pressure, together with severe impairment of skin blood flow and a concurrent fall in cerebral blood flow.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Corticosteroids

Summary

We found no direct information about the effects of corticosteroids in the treatment of infants with perinatal asphyxia.

We don't know whether corticosteroids are helpful in infants with perinatal asphyxia.

Benefits and harms

Corticosteroids:

We found no systematic review or RCTs.

Further information on studies

Comment

Clinical guide:

Although corticosteroids may reduce cerebral oedema, data from studies in older children or adults with cerebral hypoxia, and from animal studies, suggest that corticosteroids do not improve neurological outcomes. In a small case series of newborn infants with birth asphyxia treated with dexamethasone, there was no evidence of an effect on cerebral perfusion pressure.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Fluid restriction

Summary

We found no direct information about the effects of fluid restriction in the treatment of infants with perinatal asphyxia.

We don't know whether fluid restriction is helpful in infants with perinatal asphyxia.

Benefits and harms

Fluid restriction:

We found one systematic review (search date 2004), which identified no RCTs assessing the effects of fluid restriction in term newborns with perinatal asphyxia.

Further information on studies

Comment

Clinical guide:

Current recommendations to restrict fluid input are based mainly on data from the treatment of adults and older children, or from animal models of cerebral hypoxia. The rationale is that fluid restriction may limit cerebral oedema, which may be important in the pathogenesis of brain damage after perinatal asphyxia. However, there is concern that excessive fluid restriction may cause dehydration and hypotension, resulting in decreased cerebral perfusion and further brain damage.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Head and/or whole-body hypothermia

Summary

There is limited evidence that hypothermia reduces mortality and neurodevelopmental disability in infants with perinatal asphyxia.

Benefits and harms

Head, and whole-body, hypothermia versus normothermia:

We found one systematic review (search date 2003, 2 RCTs) and three subsequent RCTs.

Mortality

Head, and whole-body, hypothermia compared with normothermia Head, and whole-body, hypothermia seems more effective than normothermia at reducing mortality or composite outcomes of death and severe disability in infants with perinatal asphyxia (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality

Systematic review
50 term infants with moderate/severe neonatal encephalopathy and evidence of intrapartum asphyxia
2 RCTs in this analysis
Mortality
5/27 (19%) with hypothermia
6/23 (26%) with normothermia

RR 0.73
95% CI 0.26 to 2.09
Not significant

RCT
67 term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Mortality
10/32 (31%) with systemic hypothermia
14/33 (42%) with normothermia

RR 0.74
95% CI 0.38 to 1.41
Not significant

RCT
234 newborn infants with clinical and electroencephalographic evidence of moderate or severe neonatal (hypoxic–ischaemic) encephalopathy Death at 18 months
36/108 (33%) with therapeutic cooling of the infant's head and mild systemic hypothermia
42/110 (38%) with normothermia

RR 0.87
95% CI 0.61 to 1.25
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Mortality
24/102 (24%) with whole-body cooling
37/106 (35%) with normothermia

RR 0.68
95% CI 0.44 to 1.05
Not significant

Systematic review
23 term infants with moderate/severe neonatal encephalopathy and evidence of intrapartum asphyxia
Data from 1 RCT
Combined outcome of death or major neurodevelopmental disability
7/18 (39%) with hypothermia
4/13 (31%) with normothermia

RR 1.26
95% CI 0.46 to 3.44
Not significant

RCT
234 newborn infants with clinical and electroencephalographic evidence of moderate or severe neonatal (hypoxic–ischaemic) encephalopathy Combined outcome of death or severe disability at 18 months
59/108 (55%) with therapeutic cooling of the infant's head and mild systemic hypothermia
73/110 (66%) with normothermia

RR 0.82
95% CI 0.66 to 1.02
Not significant

RCT
Subgroup analysis of 46 infants with severe amplitude-integrated electroencephalographic findings at enrollment
Subgroup analysis
Combined outcome of death or severe disability at 18 months
19/24 (79%) with therapeutic cooling of the infant's head and mild systemic hypothermia
15/22 (68%) with normothermia

RR 1.16
95% CI 0.82 to 1.65
Not significant

RCT
Subgroup analysis of 172 infants with intermediate amplitude integrated electroencephalographic changes
Subgroup analysis
Combined outcome of death or severe disability at 18 months
40/84 (48%) with therapeutic cooling of the infant's head and mild systemic hypothermia
58/88 (66%) with normothermia

RR 0.72
95% CI 0.55 to 0.95
NNT 6
95% CI 3 to 25
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Death or moderate/severe disability at 18–24 months
45/102 (44%) with whole-body cooling
64/106 (60%) with normothermia

RR 0.73
95% CI 0.56 to 0.95
NNT 6
95% CI 3 to 33
Small effect sizehypothermia

Neurological impairment

Head, and whole-body, hypothermia compared with normothermia Head, and whole-body, hypothermia is no more effective than normothermia at reducing in neurological impairment in infants with perinatal asphyxia (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Neurological impairment

Systematic review
23 term infants with moderate/severe neonatal encephalopathy and evidence of intrapartum asphyxia
Data from 1 RCT
Major neurodevelopmental disability
4/13 (31%) with hypothermia
1/10 (10%) with normothermia

RR 3.08
95% CI 0.40 to 23.44
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Rate of moderate or severe disability in survivors
21/78 (27%) with whole-body cooling
26/68 (38%) with normothermia

RR 0.70
95% CI 0.44 to 1.13
Not significant

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
31 infants
Data from 1 RCT
Sinus bradycardia
with hypothermia
with normothermia
Absolute results not reported

RR 2.21
95% CI 0.1 to 50.3
Not significant

Systematic review
31 infants
2 RCTs in this analysis
Need for inotrope support
with hypothermia
with normothermia
Absolute results not reported

RR 2.41
95% CI 0.82 to 7.08
Not significant

Systematic review
31 infants
Data from 1 RCT
Anaemia requiring blood transfusion
with hypothermia
with normothermia
Absolute results not reported

RR 3.68
95% CI 0.19 to 70.9
Not significant

Systematic review
31 infants
Data from 1 RCT
Hypokalaemia
with hypothermia
with normothermia
Absolute results not reported

RR 1.16
95% CI 0.49 to 2.73
Not significant

Systematic review
31 infants
Data from 1 RCT
Oliguria
with hypothermia
with normothermia
Absolute results not reported

RR 0.67
95% CI 0.22 to 2.03
Not significant

Systematic review
31 infants
Data from 1 RCT
Coagulopathy resulting in major thrombosis or haemorrhage
with hypothermia
with normothermia
Absolute results not reported

RR 3.68
95% CI 0.19 to 70.9
Not significant

Systematic review
31 infants
Data from 1 RCT
Culture-proven sepsis
with hypothermia
with normothermia
Absolute results not reported

RR 0.72
95% CI 0.05 to 10.52
Not significant

RCT
67 term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Bradycardia
11/31 (35%) with systemic hypothermia
2/31 (6%) with normothermia

RR 5.5
95% CI 1.33 to 22.8
Large effect sizenormothermia

RCT
67 term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Plasma transfusions for coagulopathy
23/31 (74%) with systemic hypothermia
11/31 (35%) with normothermia

RR 2.09
95% CI 1.25 to 3.51
Moderate effect sizenormothermia

RCT
67 term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Mean duration of inotrope support
5 days with systemic hypothermia
2 days with normothermia

P = 0.02
Effect size not calculatednormothermia

RCT
234 newborn infants with clinical and electroencephalographic evidence of moderate or severe neonatal (hypoxic–ischaemic) encephalopathy Sinus bradycardia
10/112 (9%) with therapeutic cooling of the infant's head and mild systemic hypothermia
1/118 (1%) with normothermia

RR 10.5
95% CI 1.37 to 80.97
Large effect sizenormothermia

RCT
234 newborn infants with clinical and electroencephalographic evidence of moderate or severe hypoxic–ischaemic encephalopathy Hypotension
62/112 (55%) with therapeutic cooling of the infant's head and mild systemic hypothermia
61/118 (52%) with normothermia

RR 1.07
95% CI 0.84 to 1.36
Not significant

RCT
234 newborn infants with clinical and electroencephalographic evidence of moderate or severe hypoxic–ischaemic encephalopathy Coagulopathy
21/112 (19%) with therapeutic cooling of the infant's head and mild systemic hypothermia
17/118 (14%) with normothermia

RR 1.30
95% CI 0.73 to 2.34
Not significant

RCT
234 newborn infants with clinical and electroencephalographic evidence of moderate or severe hypoxic–ischaemic encephalopathy Renal impairment
73/112 (65%) with therapeutic cooling of the infant's head and mild systemic hypothermia
83/118 (70%) with normothermia

RR 0.93
95% CI 0.77 to 1.11
Not significant

RCT
234 newborn infants with clinical and electroencephalographic evidence of moderate or severe hypoxic–ischaemic encephalopathy Hypoglycaemia
14/112 (13%) with therapeutic cooling of the infant's head and mild systemic hypothermia
20/118 (17%) with normothermia

RR 0.74
95% CI 0.39 to 1.39
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Hypotension treated with vasopressors
42/112 (38%) with whole-body cooling
35/118 (30%) with normothermia

RR 1.26
95% CI 0.88 to 1.82
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Cardiac arrhythmia
2/112 (2%) with whole-body cooling
1/118 (1%) with normothermia

RR 2.11
95% CI 0.19 to 22.9
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Persistent pulmonary hypertension
25/112 (22%) with whole-body cooling
23/118 (19%) with normothermia

RR 1.15
95% CI 0.69 to 1.90
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Renal impairment
22/112 (20%) with whole-body cooling
27/118 (23%) with normothermia

RR 0.86
95% CI 0.52 to 1.42
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Hypoglycaemia
12/112 (11%) with whole-body cooling
16/118 (14%) with normothermia

RR 0.79
95% CI 0.39 to 1.60
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Hypocalcaemia
28/112 (25%) with whole-body cooling
20/118 (17%) with normothermia

RR 1.47
95% CI 0.88 to 2.46
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Hepatic dysfunction
20/112 (18%) with whole-body cooling
16/118 (14%) with normothermia

RR 1.32
95% CI 0.72 to 2.41
Not significant

RCT
208 term or near-term infants with moderate/severe neonatal encephalopathy after perinatal asphyxia Disseminated intravascular coagulopathy
18/112 (16%) with whole-body cooling
12/118 (10%) with normothermia

RR 1.58
95% CI 0.80 to 3.13
Not significant

Further information on studies

Although the RCT evaluated neurodevelopmental disability as an outcome, we have not included these data, because 23% of surviving infants did not have neurodevelopmental assessment owing to loss to follow-up.

Comment

Clinical guide:

The possibility that therapeutic cooling of the encephalopathic newborn infant's brain may limit delayed neuronal death has been considered for more than 40 years. Experimental studies using animal models have shown that lowering the core temperature by about 3°C after a hypoxic–ischaemic insult reduces the neuronal metabolic rate and the level of secondary cellular energy failure. In addition to the recently completed trials mentioned above, several large RCTs of therapeutic hypothermia for newborn infants with hypoxic–ischaemic encephalopathy are currently in progress. They investigate the effect of direct head cooling (plus moderate systemic hypothermia), or whole-body cooling sufficient to lower brain core temperature by about 3°C. Once these data are available, a systematic review and meta-analysis (if appropriate) may provide a more precise estimate of treatment effect. Currently, head and/or whole-body hypothermia is not recommended outside the context of controlled clinical trials.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Hyperbaric oxygen treatment

Summary

Limited evidence, from a systematic review that reported problems with publication bias in the RCTs it identified, suggests that hyperbaric oxygen treatment lowers rates of mortality and adverse neurological outcomes in infants with perinatal asphyxia and hypoxic–ischaemic encephalopathy. This treatment, although widely used in China, is not standard practice in other countries.

Benefits and harms

Hyperbaric oxygen treatment:

We found one systematic review (search date 2004, 20 RCTs and quasi-RCTs, all undertaken in China and reported in the Chinese medical literature).

Mortality

Hyperbaric oxygen treatment compared with control Hyberbaric oxygen treatment may be more effective than control at reducing mortality in infants with perinatal asphyxia and hypoxic–ischaemic encephalopathy (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality

Systematic review
675 infants with evidence of perinatal asphyxia and hypoxic–ischaemic encephalopathy
7 RCTs in this analysis
Mortality
15/348 (4%) with hyperbaric oxygen
51/327 (16%) with control

OR 0.26
95% CI 0.14 to 0.46
Moderate effect sizehyperbaric oxygen

Neurological impairment

Hyperbaric oxygen treatment compared with control Hyberbaric oxygen treatment may be more effective than control at reducing neurological impairment (developmental delay, epilepsy, mental retardation, cerebral palsy, or a combination) in infants with perinatal asphyxia and hypoxic–ischaemic encephalopathy (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Neurological impairment

Systematic review
675 infants with evidence of perinatal asphyxia and hypoxic–ischaemic encephalopathy
7 RCTs in this analysis
Rate of adverse neurological sequelae
43/332 (13%) with hyperbaric oxygen
84/317 (26%) with control

OR 0.41
95% CI 0.27 to 0.61
Moderate effect sizehyperbaric oxygen

Adverse effects

No data from the following reference on this outcome.

Further information on studies

The findings should be interpreted with caution. The weaknesses in the trial methods included quasi-randomisation, lack of allocation concealment or blinding of outcome measurement, incompleteness, and short length of follow-up. It is also possible that publication bias resulted from selective publication of trials indicating that hyperbaric oxygen therapy improves outcomes.

Comment

Clinical guide:

Hyperbaric oxygen is widely used for treating infants with hypoxic–ischaemic encephalopathy in China, but is not a standard practice in other countries.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Hyperventilation

Summary

We found no direct information from RCTs about the effects of hyperventilation in the treatment of infants with perinatal asphyxia.

We don't know whether hyperventilation is helpful in infants with perinatal asphyxia.

Benefits and harms

Hyperventilation:

We found no systematic review or RCTs.

Further information on studies

Comment

Clinical guide:

Hyperventilation-induced hypocapnia causes cerebral vasoconstriction. Although this might be associated with a compensatory increase in oxygen extraction in the brain, vasoconstriction may potentially worsen regional cerebral ischaemia.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Inotrope support

Summary

We don't know whether inotrope support is helpful in infants with perinatal asphyxia.

Benefits and harms

Inotrope support versus placebo:

We found one systematic review (search date 2002), which found no RCTs of sufficient size to assess the effects of dopamine or other inotropic agents in infants with perinatal asphyxia.

Inotrope support plus magnesium sulphate:

See option on magnesium sulphate

Further information on studies

Comment

Clinical guide:

More research is needed on the effect of inotrope support for infants who are hypotensive after perinatal asphyxia.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Magnesium sulphate

Summary

Limited evidence from one small RCT suggests that a magnesium sulphate/dopamine combination may be more effective than no treatment in reducing a combined outcome of mortality, abnormal scans, and failure to feed.

Benefits and harms

Magnesium sulphate :

We found one systematic review (search date not reported), which identified no RCTs.

Magnesium sulphate plus inotrope support versus no drug treatment:

We found one small RCT which compared magnesium sulphate infusion 250 mg/kg daily plus dopamine 5 micrograms/kg/minute infusion versus no drug treatment for 3 days.

Mortality

Magnesium sulphate plus inotrope support compared with no drug treatment Magnesium sulphate plus dopamine is no more effective at reducing mortality at three days, but may be more effective at reducing a composite adverse outcome of death, abnormal cranial computerised tomography and electroencephalography results, and the failure to establish oral feeding at three days in infants with severe birth asphyxia, compared with no drug treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality

RCT
33 near-term or term infants with severe birth asphyxia Mortality
2/17 (12%) with magnesium sulphate (250 mg/kg daily) plus dopamine (5 micrograms/kg/minute)
1/16 (6%) with no drug treatment

RR 1.88
95% CI 0.19 to 18.8
Not significant

RCT
33 near-term or term infants with severe birth asphyxia Incidence of a composite adverse outcome
5/17 (29%) with magnesium sulphate (250 mg/kg daily) plus dopamine (5 micrograms/kg/minute)
11/16 (69%) with no drug treatment

RR 0.43
95% CI 0.19 to 0.96
NNT 2.6
95% CI 1.4 to 12.5
Moderate effect sizemagnesium sulphate plus dopamine

Neurological impairment

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Mannitol

Summary

We don't know whether mannitol is helpful in infants with perinatal asphyxia.

Benefits and harms

Mannitol versus no drug treatment:

We found one small RCT, which compared mannitol (a single dose of 1 g/kg) versus no drug treatment.

Mortality

Mannitol compared with no drug treatment A single dose of mannitol seems no more effective than no treatment at reducing mortality rates in neonates with asphyxia (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality

RCT
25 term neonates with asphyxia Mortality
4/12 (33%) with mannitol (single dose 1 g/kg)
4/13 (31%) with no drug treatment

RR 1.08
95% CI 0.35 to 3.40
Not significant

Neurological impairment

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Opiate antagonists

Summary

We don't know whether opiate antagonists are helpful in infants with perinatal asphyxia.

Benefits and harms

Opiate antagonists:

We found one systematic review (search date 2003), which identified no RCTs assessing the outcomes of interest.

Further information on studies

Comment

The systematic review identified one RCT (193 term infants with 1-minute Apgar scores 6 or lower), which compared intramuscular naloxone (about 0.4 mg/kg) versus placebo (saline solution injection) but did not assess mortality or neurodevelopmental outcomes. It found no significant difference between treatments in respiratory rate and heart rate at 24 hours after birth (significance assessment not reported). However, it found that naloxone improved active muscle tone of upper and lower limbs compared with placebo (data reported graphically, at 5 minutes: P <0.05). The RCT gave no information on adverse effects.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Resuscitation in air versus pure oxygen

Summary

Resuscitation in air lowered mortality in infants with perinatal asphyxia compared with resuscitation in 100% oxygen. However, current clinical practice is to use 100% oxygen.

Benefits and harms

Resuscitation in air versus pure oxygen:

We found one systematic review (5 RCTs) comparing resuscitation in air versus resuscitation using 100% oxygen.

Mortality

Resuscitation in air compared with 100% oxygen Resuscitation in air may be more effective than 100% oxygen at reducing mortality in infants (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality

Systematic review
1737 term and preterm infants with low Apgar scores at birth
5 RCTs in this analysis
Mortality
69/881 (8%) with air
111/856 (13%) with 100% oxygen

OR 0.59
95% CI 0.48 to 0.74
See further information on studies regarding interpretation of this result
Small effect sizeair

Systematic review
1502 term infants with low Apgar scores at birth
5 RCTs in this analysis
Subgroup analysis
Mortality
44/762 (6%) with air
70/740 (9%) with 100% oxygen

OR 0.59
95% CI 0.40 to 0.87
P = 0.008
See further information on studies regarding interpretation of this result
Small effect sizeair

Neurological impairment

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

These findings should be interpreted with caution because of weaknesses in the methods used in some of the original trials — such as quasi-randomisation, lack of allocation concealment or blinding of outcome measurement, incompleteness, and short length of follow-up.

Comment

Clinical guide:

Current standard practice is to resuscitate infants with neurological and cardiorespiratory depression using 100% oxygen, with the aim of reversing hypoxia rapidly. However, there is some evidence from preclinical and animal studies to suggest that resuscitating infants using lower inspired oxygen concentrations (including air) may be as effective as 100% oxygen. There is also some evidence that using lower concentrations of oxygen limits oxidative stress and secondary neuronal death. Although the above systematic reviews indicate that mortality is lower if air rather than 100% oxygen is used, these findings should be interpreted with caution because of weaknesses in the methods used in some of the original trials — such as quasi-randomisation, lack of allocation concealment or blinding of outcome measurement, incompleteness, and short length of follow-up.

Substantive changes

No new evidence

2007; 2007: 0320.
Published online 2007 November 7.

Anticonvulsants (prophylactic)

Summary

Small RCTs with flawed methods suggest that anticonvulsants are of no benefit in reducing mortality or improving neurodevelopmental outcomes in term infants with perinatal asphyxia.

Benefits and harms

Prophylactic anticonvulsants versus no drug treatment:

We found one systematic review (search date 2001, 3 RCTs) and one subsequent RCT.

Mortality

Prophylactic anticonvulsants compared with no drug treatment Thiopental or phenobarbital may be no more effective than no drug treatment at reducing mortality in term infants with perinatal asphyxia, and in near-term infants with hypoxic–ischaemic encephalopathy (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality

Systematic review
110 term infants
3 RCTs in this analysis
Mortality
12/58 (21%) with barbiturate (thiopental or phenobarbital)
10/52 (19%) with no drug treatment

RR 1.06
95% CI 0.50 to 2.27
Not significant

RCT
45 asphyxiated neonates (gestational age 34 weeks and over) manifesting hypoxic–ischaemic encephalopathy in the first 6 hours of life Mortality
5/25 (20%) with prophylactic phenobarbital (20 mg/kg given within 6 hours after birth
3/20 (15%) with standard treatment

RR 1.33
95% CI 0.36 to 4.92
Not significant

Neurological impairment

Prophylactic anticonvulsants compared with no drug treatment We don’t know whether thiopental or phenobarbital are more effective than no treatment at reducing neurological disabilities in term infants with perinatal asphyxia. Phenobarbital may be more effective at reducing the risk of seizures in near-term infants with hypoxic–ischaemic encephalopathy (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Neurological impairment

Systematic review
77 surviving term infants
3 RCTs in this analysis
Rates of severe neurodevelopmental disability
9/40 (23%) with barbiturate (thiopental or phenobarbital)
14/37 (38%) with no drug treatment

RR 0.61
95% CI 0.30 to 1.22
Not significant

RCT
45 asphyxiated neonates (gestational age 34 weeks and over) manifesting hypoxic–ischaemic encephalopathy in the first 6 hours of life Proportion of infants who developed seizures
2/25 (8%) with prophylactic phenobarbital (20 mg/kg given within 6 hours after birth)
8/20 (40%) with standard treatment

RR 0.20
95% CI 0.05 to 0.84
NNT 3.1
95% CI 1.8 to 12.5
Moderate effect sizephenobarbital

Adverse effects

No data from the following reference on this outcome.

Further information on studies

The RCTs identified in the systematic review were small and used weak methods, including lack of allocation concealment, lack of blinding, and lack of placebo control.

Comment

Clinical guide:

Although prophylactic anticonvulsant therapy may reduce the frequency of seizures in infants following perinatal asphyxia, there is no evidence that mortality or longer-term neurodevelopmental outcomes are affected.

Substantive changes

No new evidence


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