Treatment options for preterm infants with cardiovascular compromise include inotropes, volume expansion and corticosteroids. Inotropes that have the potential for use in preterm infants include adrenaline, dobutamine, dopamine, isoprenaline and noradrenaline. These inotropes have varying pharmacological effects which include increased myocardial contractility and heart rate (via beta receptors), and reduced (via beta receptors) or increased (via alpha receptors) vascular resistance. The mechanism of action is often dose dependent and also depends on which receptors are stimulated.
Adrenaline infusions are most frequently used in neonates for the treatment of hypotension and pulmonary hypertension (Perkin 1982; Zaritsky 1984). Adrenaline has both alpha and beta receptor agonist effects (Seri 1995; Zaritsky 1984). At low dose it is a potent inotrope, chronotrope and systemic and pulmonary vasodilator. At higher doses it has differential effects on the systemic and pulmonary circulations, increasing systemic pressure more than pulmonary pressure (Barrington 1993; Barrington 1995). Animal studies have demonstrated improvement in cardiac output (Barrington 1993; Cheung 1997), myocardial perfusion (Barrington 1995) and increased mesenteric vascular resistance (Cheung 1997). Reported adverse effects of adrenaline infusion in the neonate include increases in peripheral vascular resistance leading to decreased cardiac output and tissue perfusion, hypertension, tachycardia and severe tissue necrosis with extravasation of the infusate (Perkin 1982; Seri 2001). There is a paucity of published studies regarding the circulatory effects of adrenaline infusion in the neonate (Seri 1998a; Campbell 1998) and there is no systematic review of the use of adrenaline in preterm infants with cardiovascular compromise.
Dopamine has been used extensively in neonates for treatment of hypotension and also has dose dependent actions. Low infusion rates (0.5 to 5 microgram/kg/min) are used to improve renal function. Medium ranges (6 to 10 microgram/kg/min) are used for treatment of heart failure. With doses up to 10 microgram/kg/min there is an increase in blood pressure (Osborn 2002b; Padbury 1987) and possibly cardiac output (Lundstrom 2000; Osborn 2002b; Padbury 1987). However, there is concern that higher doses may only increase blood pressure with no improvement in cardiac function or output (Osborn 2002b; Roze 1993). The usual justification of using dopamine in hypotensive preterm infants is to increase cerebral perfusion and avoid ischaemic injury. However, there is no evidence yet that cerebral blood flow is increased by the use of dopamine (Lundstrom 2000; Seri 1998b; Barrington 1995; Osborn 2002b). In the neonate, dopamine has no significant effect on mesenteric blood flow (Seri 1998b; Cheung 1997) or coronary blood flow (Barrington 1995). Reported adverse effects of dopamine in the neonate include severe vasoconstriction, local tissue necrosis if extravasation occurs, tachyarrhythmia (Seri 1995) and hepatic injury after inappropriately placed umbilical venous catheter (Venkataraman 1984).
Dobutamine, an inotrope with predominantly beta receptor effects, has been used in asphyxiated hypotensive preterm infants with myocardial dysfunction (Perkin 1982; Seri 2001), and has been compared to dopamine in several randomised trials in preterm infants with hypotension (Subhedar 2002) or low blood flow (Osborn 2002b). The dose range used to increase cardiac output has been up to 20 micrograms/kg/min (Osborn 2002b). Potential adverse effects are similar to the other inotropes and include tachyarrhythmia and hypertension (Seri 2001), although hypertension is unusual (Osborn 2002b). The effects of dopamine versus dobutamine have been examined in a systematic review (Subhedar 2002). Dopamine was more effective than dobutamine for treatment of systemic hypotension in the short term. However, there was insufficient evidence concerning long term benefits and safety to give firm recommendations on the choice of drug to treat neonatal hypotension. Noradrenaline has both alpha and beta activity, producing greater increases in vascular resistance than the other inotropes (Zaritsky 1984). The adverse side effects are similar to adrenaline. There is a paucity of studies with noradrenaline in the preterm population (Derleth 1997). Isoprenaline is a synthetic catecholamine with almost purely beta effects (Zaritsky 1984) with an important adverse effect being tachyarrhythmia.
This review will examine the evidence for the use of adrenaline compared to no treatment or other inotropes for the treatment of preterm infants with cardiovascular compromise. As preterm infants may have different underlying causes of cardiovascular compromise or have different clinical indications for inotrope treatment, subgroup analysis will examine the evidence for use of adrenaline depending on aetiology of compromise or clinical indication for inotrope. This review should be viewed in the context of other Cochrane reviews of cardiovascular interventions in preterm infants including those examining dopamine and dobutamine for hypotension (Subhedar 2002), corticosteroids for hypotension (Whitelaw 2002), and early volume expansion (Osborn 2002c; Osborn 2002d).
See: Cochrane Neonatal Group Search Strategy
The standard search method of the Cochrane Neonatal Group as described in the Cochrane Library was used. The following electronic databases were searched: MEDLINE (1966 - August 2003), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2003) and EMBASE (1980 - August 2003). In addition, recent abstracts, conferences and cited references from retrieved articles were hand searched. Unpublished studies were sought by hand searching the conference proceedings of the Society for Pediatric Research (1998-2003). Search strategies were developed using the following keywords/index terms: 'infant, pre term', 'hypotension', 'adrenaline or epinephrine', 'dopamine', 'dobutamine', 'isoproterenol', 'inotrope', 'sepsis', 'asphyxia' . Searches were limited to randomised controlled trials. There was no language restriction.
The standard search method of the Cochrane Neonatal Review Group (CNRG) as described in the Cochrane Collaboration Handbook was used to conduct this systematic review.
The pre-specified inclusion criteria regarding gestational age were adjusted after review of the studies. Phillipos 1996 included infants that were both term and preterm. It is not stated how many infants were term or preterm; however, as the mean gestational age was 36 weeks, a decision was made to include this study.
The methodological quality of studies was assessed as recommended by the CNRG. Two reviewers independently assessed and selected the studies to be included in the review. Studies were assessed for methodological quality using the following criteria: allocation concealment, blinding of randomisation, completeness of follow up and blinding of the outcome measure. Data were extracted independently by the reviewers. Additional information was requested from the study authors of the studies that were assessed to be eligible. Authors were contacted by e-mail for additional information regarding individual patient data for haemodynamic measures and any other outcomes. The author of one study (Phillipos 1996) provided a copy of conference proceedings but has not yet provided any further information. The authors of an ongoing study (Pellicer 2003) have provided information regarding the progress of the study to date.
Statistical analysis: When available, data will be analysed using the standard methods of the CNRG. Treatment effects will be analysed using relative risk (RR), risk difference (RD) and number needed to treat (NNT) for categorical outcomes, and mean difference (MD) and weighted mean difference (WMD) for continuous outcomes, with 95% confidence intervals where appropriate. Heterogeneity between studies will be examined. Meta-analysis will be performed for studies where treatments are used for similar patients and similar dosage schedules. A fixed effect model will be used for the meta analysis unless significant heterogeneity exists between studies, in which case the cause of the heterogeneity will be explored and if appropriate, a random effects model used. Sensitivity analysis will be performed including only studies of good methodology (adequate randomisation and allocation concealment and <10% post randomisation losses).
Subgroup analysis were to be performed according to trials that enrolled
infants on the basis of :
1. Aetiology of cardiovascular compromise
Infants: Phillipos 1996 enrolled hypotensive newborn infants <24 hours age with a mean BP one SD below mean for weight (using data from Versmold 1981) and indwelling arterial line. Infants were stratified into three groups of 20 infants: 750-1250g, 1251-1750g and >1750g. Infants with congenital heart disease were excluded. For infants >1750g, the dopamine group had a mean gestation of 34 (range 30-34) weeks and birth weight 2471g; the adrenaline group had a mean gestation 36 (range 34-41) weeks and mean birthweight 2642g. Seven infants in each group had a patent ductus arteriosus. For infants <=1750g, only 16 of the anticipated 40 infants are reported. Clarification as to whether this is an ongoing or completed study has been sought from the author. This review will only report outcomes for infants >1750g. Infants <1750g were not included in the current review as we are awaiting clarification from the authors regarding the completion status of the study. When these data become available, it is intended that they be included in a future update of this review.
Interventions: Phillipos 1996 allocated infants to dopamine or adrenaline. Dopamine was started at 5 and then increased to 10, 15 and 20 micrograms/kg/min every 20 minutes, and adrenaline was started at 0.125 and increased 0.25, 0.375 and 0.5 micrograms/kg/min every 20 minutes till desired mean BP was achieved for at least one hour. If the desired BP was not achieved, the other drug was added.
Measurement: Phillipos 1996 used invasive
BP monitoring of all infants and used 2-D echocardiography to determine left
and right ventricular output, left and right stroke volume index, and mean
pulmonary artery pressure.
No other clinical outcomes were reported.
One study (Phillipos 1996) enrolling a
total of 20 infants >1750g met eligibility criteria and was included in
this systematic review. No outcome data were able to be entered into the analysis
tables, so all treatment effects are reported in text.
Primary clinical outcomes
Effects on mortality, neurodevelopmental outcome, periventricular or
intraventricular haemorrhage (any grade of severity), and periventricular
leukomalacia were not reported.
Secondary outcomes: Short term haemodynamic changes
Failure to correct systemic hypotension or failure to correct low systemic
or organ blood flow was not reported. For infants >1750g, Phillipos 1996 reported a significant increase
in mean heart rate and mean BP at the highest dose reached, and at the study
endpoint, for both adrenaline and dopamine. The significance of the difference
between the two inotropes was not reported. Neither inotrope produced a statistically
significant change in left or right ventricular outputs. Dopamine produced
a significant fall in left ventricular stroke volume compared to baseline.
Whether this was statistically different to the effect of adrenaline was
not reported.
Secondary outcomes: Drug side effects
Tachyarrhythmias, extravasation of infusate and hepatic injury were not
reported.
Secondary outcomes: Short term neonatal outcomes
Patent ductus arteriosus, gastrointestinal complications (perforation, necrotising
enterocolitis), chronic lung disease, duration of ventilation and respiratory
support, duration of hospital stay and renal complications not reported.
Subgroup analyses
The available trial enrolled predominately preterm infants with hypotension.
There is inadequate information in the reported abstracts to determine the
aetiology of the cardiovascular compromise although as infants were enrolled
in the first day of life it is likely a substantial number had problems with
the transitional circulation. The dose ranges used for both adrenaline and
dopamine incorporated all prespecified subgroup analyses. No sensitivity analysis
was performed as the methodological quality of the included study is unclear.
This review found evidence from one small randomised study (Phillipos 1996), reporting outcomes in 20 hypotensive infants >1750g in the first 24 hours after birth, that both dopamine and adrenaline increased heart rate and mean blood pressure but did not have a statistically significant effect on left or right ventricular outputs. Outcomes from this trial for infants born <=1750g were excluded from this review as it is unclear whether the reported infants represent a preliminary report of an incomplete study or a study that was stopped early. The available study was of unclear methodological quality as it has been published in abstract form only and methods of randomisation, allocation concealment and blinding were not reported. The study was reported as being randomised and double blinded. No study reported any other clinically important outcomes including mortality and neurodevelopmental outcome. No study enrolled infants with low systemic or organ blood flow or reported incidence of low blood flow.
The limitations of this review include the lack of published reports including methodology and data, and the small numbers of infants enrolled in the included trial. Publication of existing data is important.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Phillipos 1996 | Single centre trial, Canada. Blinding of randomisation: unclear. Blinding of intervention: yes, but method not reported. Blinding of outcome assessment: yes, but method not reported. Follow up: infants >1750g: 2/20 (10%) not included in analysis. Infants <=1750g: 16 infants reported in abstract (?ongoing study). |
Newborn infants <24 hours age, hypotensive with mean BP 1SD
below mean for weight and indwelling arterial line. Stratified into 3 groups
of 20 infants: 750-1250g, 1251-1750g and >1750g. For infants >1750g, n =20, Dopamine group: n = 10, mean gestation 34 weeks, mean BW 2471g. Adrenaline group: n = 10, mean gestation 36 weeks, mean BW 2642g. Exclusions: congenital heart disease
|
1. Dopamine titrated [5, 10, 15, 20 mcg/kg/min] every 20 minutes
till desired mean BP achieved for 1 hour. 2. Adrenaline titrated [0.125, 0.25, 0.375, 0.5 mcg/kg/min] every 20 minutes till desired mean BP achieved for 1 hour. If the desired BP was not achieved, the other drug was added. |
Primary outcomes: effects on mean BP, mean pulmonary artery pressure,
left and right ventricular cardiac indices and stroke volumes. Outcomes: heart rate; invasive mean blood pressure; study endpoint was stable desired mean BP for 1 hour; echocardiographically measured left and right ventricular output, left and right stroke volume index, and mean pulmonary artery pressure. No other clinical outcomes reported. |
The number of infants who received both inotropes or did not achieve
primary end point not reported. Highest infusion rate to obtain desired mean BP not reported. Randomised, blinded study of dopamine vs adrenaline in hypotensive predominately preterm infants. For infants <=1750g: only 16 of the anticipated 40 infants were reported, possibly incomplete study. Authors contacted, awaiting reply. |
B |
| Study | Trial name or title | Participants | Interventions | Outcomes | Starting date | Contact information | Notes |
| Pellicer 2003 | Randomised blinded controlled trial on the effects on brain haemodynamics of dopamine v epinephrine for inotropic support in preterm infants. | Preterm infants < 31 weeks GA or < 1501 gram with systemic hypotension (MBP mmHg < GA) within the first 24h of age | Dopamine 2.5, 5, 7.5, 10 mcg/kg/min or epinephrine 0.125, 0.25, 0.375, 0.5 mcg/kg/min increasing every 20 minutes until a desired MAP is achieved and maintained. If this was not achieved the other drug was added. | Changes in cerebral blood volume, cerebral oxyhaemoglobin and deoxyhaemoglobin Mean arterial pressure Heart rate Transcutaneous pCO2 Peripheral oxygen saturations |
May 2002 | Adelina Pellicer apellicer.hulp@salud.madrid.org |
Sample size required: 60 Currently 51 infants enrolled |
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| This review is published as a Cochrane review in
The Cochrane Library 2004, Issue 1, 2004 (see www.CochraneLibrary.net for
information). Cochrane reviews are regularly updated as new evidence emerges
and in response to comments and criticisms, and The Cochrane Library should
be consulted for the most recent version of the Review. |