It is widely accepted that epinephrine should have a place in the resuscitation of the apparently stillborn or extremely bradycardic infant. Formal guidelines sanctioning its use are in existence and include the position statement formulated at the International Guidelines 2000 Conference on Cardiopulmonary Resuscitation and Emergency Cardiac Care (AAP 2000). This position statement, based on a consensus of experts, specifically advises that epinephrine be used when the heart rate remains less than sixty after at least thirty seconds of adequate ventilation and chest compressions. Furthermore, it considers this to be a Class 1 recommendation, where class 1 indicates a practice that is "always acceptable, proven safe and definitely useful". However, a recent review concluded that there is in fact very little scientific evidence in support of these recommendations, and that the existing evidence is largely derived from animal research and the human adult literature (Wyckoff 2001). The use of epinephrine is also endorsed in the resuscitation texts and courses of the American Academy of Pediatrics (AAP Kattwinkel 2000) and the European Resuscitation Council (ALSG 2000) but again without reference to any supporting scientific data. It is also acknowledged that significant hazards may be associated with the use of epinephrine. These include the possibility that the caregiver may be distracted from giving priority to ventilatory support, and a possible predisposition to major organ injury such as renal failure, necrotising enterocolitis and intraventricular haemorrhage/infarction (ECNI 1992).
In animal models, epinephrine has been shown to exert its benefits through the combination of beta-1 effects which stimulate the heart and, more importantly, the alpha effect of increasing non-cerebral peripheral resistance. As a function of the latter, cerebral and myocardial blood flow are increased (Berkowitz 1991). Beta-1 effects, however, may also impede post resuscitation recovery by increasing myocardial oxygen demand (Vincent 1997).
In humans, there are no data on the ontogeny of adrenergic receptors or on the time course of myocardial sympathetic innervation (Zaritsky 1984). Studies which examined age-related effects of catecholamines in piglets and lambs have, however, demonstrated that responses in cardiac contractility and vascular reflexes are diminished in the newborn animal (Buckley 1979; Manders 1979).
Many questions also remain unanswered with regard to both the dosage and route of administration of epinephrine. The current recommendation regarding dose is to use 0.1 - 0.3 ml/kg of a 1:10 000 solution, by the intravenous or endotracheal route, repeated every three to five minutes as indicated. Higher doses have been used in children (Goetting 1991) and adults (Paradis 1991) but there are no data addressing this issue in the neonatal population. Meta-analysis of studies comparing high versus low dose epinephrine in adults did not show any benefit with the higher dose (Vandyke 2000). A randomised, blinded trial of high versus standard dose epinephrine in a swine model showed that the higher dose did not improve survival rate or neurological outcome. Furthermore, the higher dose was associated with severe tachycardia and hypertension, and a higher mortality rate immediately after resuscitation (Berg 1996). Lucas showed that after endotracheal administration, comparable plasma levels of epinephrine can be achieved despite the low pulmonary blood flow seen in a newborn lamb model of cardio-pulmonary resuscitation (Lucas 1994). However, on the basis of data derived from a dog model (Orlowski 1990) and from a human adult study (Quinton 1987), other authors have suggested that the endotracheal route is unreliable. Dosage considerations are also clouded by the finding in newborn lambs that the extent of metabolic acidosis can significantly attenuate the haemodynamic response to epinephrine (Preziosi 1993).
Whether the use of epinephrine in infants with extreme prematurity poses specific risks remains unclear. The hypothesis that the pre-term infant may be vulnerable to haemodynamic fluctuations of the type induced by epinephrine has been investigated in a beagle puppy model (Pasternak 1983). This study showed that acute onset cerebral hypertension, as may be seen in response to catecholamines, is a likely significant risk factor for intraventricular haemorrhage. Antenatal factors predisposing to premature birth pose independent risks for cerebral injury, as may post-natal ischaemia/hypoxia (Graziani 1996). Given these considerations, it would be valuable to undertake a sub-group analysis of available data on the use of epinephrine by gestational age.
Finally, perhaps one of the most compelling reasons to closely examine the evidence for the use of epinephrine is that when administered to very pre-term infants, there may be a very high rate of death and disability (Sims 1994, O'Donnell 1998).
Objectives
Primary objective:
• To determine if the administration of epinephrine to apparently stillborn
and extremely bradycardic newborns reduces mortality and morbidity
Secondary objectives:
• To determine the effect of intravenous versus endotracheal administration
on mortality and morbidity
• To determine the effect of high dose versus standard dose epinephrine
on mortality and morbidity, where high dose is defined as any dose greater
than the current recommended standard dose of 0.1 to 0.3ml/kg of a 1:10,000
solution of epinephrine
• To determine whether the effect of epinephrine on mortality and morbidity
varies with gestational age, i.e. term (greater than or equal to 37 weeks)
versus pre-term (less than 37 weeks)
Criteria for considering studies for this review
Types of studies
Randomised and quasi-randomised controlled trials.
The unit of randomisation may be the individual or a cluster (e.g. allocation
by time period or hospital).
Types of participants
Newborns, both preterm and term, receiving resuscitation for unexpected
apparent stillbirth* or extreme bradycardia (heart rate less than 60 beats
per minute after a minimum of 30 seconds of ventilation and chest compressions).
*apparent stillbirth being defined as the baby identified as asystolic immediately
after birth, a heart rate having been recognised intra-partum.
Types of interventions
a) epinephrine administration vs placebo or no epinephrine administration.
b) high dose (as defined above) vs standard dose epinephrine.
c) Intravenous vs endotracheal administration.
Types of outcome measures
Primary:
• Mortality - before 28 days, at discharge and at 12 and 24 months, and
5 yrs
• Severe disability at follow-up at 12, 24 months and 5 yrs on, defined
as any of blindness, deafness, cerebral palsy or cognitive delay (score more
than 2 standard deviations below the mean for a recognised psychometric test,
e.g. Bayley Scales)
• Death or severe disability at 12 and 24 months, and 5 yrs
Secondary:
• Any intraventricular haemorrhage
• Severe intraventricular haemorrhage (IVH) i.e. Papile grades three and
four
• Periventricular leukomalacia (PVL)
• Cognitive delay (as above)
• Cerebral palsy at 12 and 24 months, and 5 yrs
• Blindness
• Deafness
• Any supplemental oxygen requirement at 28 days
• Any supplemental oxygen requirement at 36 weeks corrected age
• Any supplemental oxygen requirement at discharge home
• Days of mechanical ventilation (via endotracheal tube or nasal continuous
positive airway pressure)
• Days of supplemental oxygen therapy
• Necrotising enterocolitis
• Elevated serum creatinine
• Days of intensive care
• Days in hospital
Search strategy for identification of studies
RCTs were to be identified from MEDLINE (from 1966 to the present) using
the MeSH heading 'epinephrine' OR the textwords 'adrenaline' OR 'adrenalin',
AND the MeSH heading 'infant, newborn', AND the MeSH headings 'resuscitation'
OR 'asphyxia neonatorum' OR the textwords 'stillborn' OR 'stillbirth' or
'asystole' OR 'asystolic'.
Other databases, including CINAHL (from 1982), Current Contents back to 1998, EMBASE, and the current CCTR (The Cochrane Library, Issue 4, 2002) were searched using a similar strategy. Bibliographies of published trials and conference proceedings were to be reviewed. No language restrictions were applied. Unpublished studies were sought by hand searching the conference proceedings of the Society for Pediatric Research and the European Society for Pediatric Research from 1993 to 2002.
Criteria and methods used to assess the methodological quality of the trials: standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Two of the three reviewers worked independently to search for and assess trials for inclusion and methodological quality. Eligible studies were to be assessed using the following key criteria: allocation concealment (blinding of randomisation), blinding of intervention, completeness of follow up and blinding of outcome measurement. The reviewers were to extract data independently. Differences were to be resolved by discussion. Study investigators were to be contacted for additional information or data as required.
Weighted mean differences (WMD) were to be reported for continuous variables such as duration of oxygen therapy. For categorical outcomes such as mortality, the relative risks (RR) and 95% confidence intervals were to be reported. For significant findings, the risk difference (RD) and number needed to treat (NNT) were also to be reported. Each comparison was to be tested for heterogeneity to determine suitability for pooling of results in a meta-analysis. The fixed effects model was to be used for meta-analysis.
The following sub-group analyses were planned:
1. Epinephrine versus no epinephrine/placebo: Four sub-groups on the basis
of dose and route of administration, i.e., standard dose/i.v., high dose/i.v.,
standard dose/ETT, high dose/ETT.
2. Intravenous versus endotracheal route of administration: Three sub-groups
on the basis of dose, i.e., standard dose equal in both groups, high dose
equal in both groups, and differing doses.
3. Standard dose versus high dose: Identified trials were to be placed
in two sub-groups on the basis of route of administration, i.e., intravenous
and endotracheal.
A sensitivity analysis was planned, including only trials of highest methodological quality (i.e. truly randomised).
Description of studies
No studies were found meeting the inclusion criteria for this review.
Three case series were identified by the search strategy. Sims et al (Sims 1994) retrospectively examined data for 105 infants who received epinephrine and/or atropine for resuscitation in the delivery room and/or nursery settings. Of the 25 survivors, nine were severely handicapped at follow up. The factors associated with a worse outcome were: gestation less than 28 weeks, need for early repeated resuscitation, asystole, and collapse without a clear precipitant. O'Donnell et al (O'Donnell 1998) attempted to evaluate mortality and morbidity for 78 infants requiring epinephrine as part of resuscitation at birth, with follow up after at least one year. 40 infants survived, with significantly more term survivors (67%) compared to preterm (42%). Of the babies below 29 weeks gestation, 78% either died or showed evidence of neurodevelopmental disability. These findings are very different to those of Jankov et al (Jankov 2000) who retrospectively examined outcomes for babies of birthweight less than 750 grams. In this study, of 16 babies who received CPR, 12 also received epinephrine. Nine of the 16 babies survived and eight of these showed no disability at a median follow up age of two years. In addition, the use of epinephrine was not statistically associated with an adverse outcome in this study.
Methodological quality of included studies
No studies were found meeting the inclusion criteria for this review.
Results
No studies were found meeting the inclusion criteria for this review.
Discussion
Given that we found no randomised controlled trials which address the use
of epinephrine in neonatal resuscitation, this systematic review does not
establish if the administration of epinephrine to the apparently stillborn
or extremely bradycardic newborn reduces mortality and morbidity. This confirms
that the current recommendations for the use of epinephrine in this context
are based only on evidence derived from animal models and the human adult
literature.
The search strategy used for this review did identify three case series, but no clinical trial data. These retrospective studies, while highlighting the possible long term dangers and benefits associated with the use of epinephrine, cannot be used to reaffirm or modify current guidelines. Given that epinephrine may be hazardous to the resuscitated newborn, it would be valuable for future trials to compare epinephrine not only with placebo/no drug, but also with other drugs. The neonatal literature does not currently recognise an immediately eligible alternative drug, but other vasopressor agents, such as norepinephrine, are theoretically plausible in providing powerful alpha effects without potentially harmful beta effects.
Reviewers' conclusions
Implications for practice
We found no randomised, controlled trials to support or refute that the
administration of epinephrine to the apparently stillborn or extremely bradycardic
newborn infant reduces mortality and morbidity. Similarly, we found no randomised,
controlled trials which addressed the issues of optimum dosage and route of
administration of epinephrine.
Implications for research
There is an urgent need for randomised, controlled trials to establish if
the administration of epinephrine to the apparently stillborn or extremely
bradycardic newborn affects mortality and morbidity.
Acknowledgements
Potential conflict of interest
None
| Study | Reason for exclusion |
| Jankov 2000 | Retrospective study; not a randomised controlled trial. |
| O'Donnell 1998 | Retrospective study; not a randomised controlled trial. |
| Sims 1994 | Retrospective study; not a randomised controlled trial. |
Jankov RP, Asztalos EV, Skidmore MB. Favourable neurological outcomes following delivery room cardiopulmonary resuscitation of infants <=750g at birth. J Paediatr Child Health 2000;36:19-22.
O'Donnell 1998 {published data only}
O'Donnell AI, Gray PH, Rogers YM. Mortality and neurodevelopmental outcome for infants receiving adrenaline in neonatal resuscitation. J Paediatr Child Health 1998;34:551-556.
Sims 1994 {published data only}
Sims DG, Heal CA, Bartle SM. Use of adrenaline and atropine in neonatal resuscitation. Arch Dis Child 1994;70:F3-F10.
* indicates the primary reference for the study
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Dr Peter G Davis, MD, MBBS
Consultant Paediatrician
Division of Paediatrics
Royal Women's Hospital
132 Grattan St
Melbourne
Victoria AUSTRALIA
3053
Telephone 1: +61 3 93442000 extension: 2130
Facsimile: +61 3 93471761
E-mail: pgd@unimelb.edu.au