The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow

Osborn DA, Paradisis M, Evans N

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Date edited: 15/11/2006
Date of last substantive update: 16/10/2006
Date of last minor update: / /
Date next stage expected / /
Protocol first published: Issue 1, 2005
Review first published: Issue 1, 2007

Contact reviewer

Dr David A Osborn
Neonatologist
RPA Newborn Care
Royal Prince Alfred Hospital
Missenden Road
Camperdown
New South Wales AUSTRALIA
2050
Telephone 1: +61 2 95158363
Facsimile: +61 2 95504375
E-mail: david.osborn@email.cs.nsw.gov.au

Contribution of reviewers

DO wrote the protocol and review. All reviewers independently assessed studies for eligibility, assessed study quality and extracted data. All reviewers contributed to the writing of the final version.

Internal sources of support

RPA Newborn Care, Royal Prince Alfred Hospital, AUSTRALIA

External sources of support

Centre for Perinatal Health Services Research, University of Sydney, AUSTRALIA

What's new

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Low systemic blood flow is common in extremely premature infants and has been associated with brain and intestinal injury, death and developmental impairment. It is unclear what is the best strategy to prevent or treat this.

The usual strategy for supporting the cardiovascular system of the preterm infant is to treat infants with low blood pressure with agents (inotropes) aimed at increasing blood pressure. However, many of infants with low blood flow have normal blood pressure. One trial was found that examined the effect of inotropes in infants with low systemic blood flow. The trial found that many infants failed to respond to the two commonly used inotropes (dobutamine and dopamine) and neither was better at improving outcomes of very preterm babies. Further research is needed to determine the best strategy for preventing or treating low systemic or organ blood flow in these very immature babies.

Abstract

Background

Low systemic blood flow (SBF) is common in extremely premature infants in the first day after birth and has been associated with peri / intraventricular haemorrhage (PIVH), necrotising enterocolitis (NEC), mortality and developmental impairment.

Objectives

To determine the effect of specific inotropes on morbidity and mortality in preterm infants with low systemic blood flow

Search strategy

Searches were made of The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006 ), MEDLINE (1966 - April 2006), EMBASE (1980 - April 2006) and CINAHL (1982 - April 2006), supplemented by searches of abstracts of conference proceedings, citations of reviews and expert informants.

Selection criteria

Random and quasi-random controlled trials of inotropes enrolling preterm infants with low systemic or organ blood flow in the neonatal period.

Data collection & analysis

Independent assessment of trial eligibility, quality and data extraction by each review author. Synthesis of data using relative risk (RR) and weighted mean difference (WMD) using standard methods of the Cochrane Collaboration.

Main results

No studies that compared an inotrope to no treatment in preterm infants with low SBF were found. One study (Osborn 2002a) was found that compared dobutamine versus dopamine. The study was of adequate methodology. It enrolled 42 infants < 30 weeks gestation and < 12 hours after birth with low SVC flow. The trial compared the effect of dobutamine versus dopamine titrated 10 to 20 μg/kg/min with the goal of increasing and maintaining SVC flow > 40 ml/kg/min. No significant difference was reported in mortality to discharge (RR 1.41, 95% CI 0.79, 2.52), PIVH (RR 1.01, 95% 0.52, 1.97), grade 3 or 4 PIVH (RR 0.39, 95% CI 0.12, 1.31) or NEC. At three years, there was no significant difference in cerebral palsy, deafness, Developmental quotient > 2 sd below norm or combined disability (RR 0.10, 95% CI 0.01, 1.56). Surviving infants treated with dobutamine had a significantly higher development quotient (MD 35.00, 95% CI 17.68, 52.32). There was no significant difference in death or disability at the latest time reported (RR 0.95, 95% CI 0.66, 1.38). For secondary outcomes, there was no significant difference in periventricular leucomalacia, renal impairment, pulmonary haemorrhage, retinopathy of prematurity or CLD at 36 weeks. There was no significant difference in treatment failure. Dobutamine produced a significantly greater increase in SVC flow at the highest dose reached (MD 13.10, 95% CI 2.87, 23.33), whereas dopamine produced a significantly greater increase in mean BP at 10 and 20 μg/kg/min and at the highest dose reached (MD -7.20, 95% CI -11.41, -2.99).

Reviewers' conclusions

In preterm infants with low systemic blood flow, there is some evidence that dobutamine is better than dopamine at increasing and maintaining systemic blood flow. The only eligible trial did not demonstrate any consistent differences in clinical outcomes. However, this study was not sufficiently powered to prove or disprove effects on clinical outcomes. It is unclear what is the most effective strategy for improving the cardiovascular status of immature infants in the first day. Further trials are needed to determine effective strategies for preventing and improving low systemic and organ blood flow.

Background

Cardiovascular interventions have most frequently been given to preterm infants on the basis of hypotension, poor peripheral tissue perfusion as measured by increased capillary refill time, or evidence of a developing acidosis or renal impairment. Commonly used criteria for hypotension and cardiovascular intervention have included a mean blood pressure (BP) ≤ 30 mm Hg, which was associated with increased mortality and cerebral injury in a cohort study (Miall-Allen 1987). Other studies have defined hypotension as below the range (usually the 10^th centile) seen in population studies of preterm infants. A commonly used bedside approximation of the 10^th centile is a mean BP less than the gestational age in weeks or a systolic BP ≤ 40 mmHg (Subhedar 2003). However, there are several substantial limitations to using hypotension as the criteria for cardiovascular support in preterm infants. There is a poor correlation between BP and systemic blood flow (SBF) in the first days after birth (Kluckow 1996; Osborn 2004a). This is because BP is the product of blood flow and systemic vascular resistance. Using hypotension as a criteria for cardiovascular intervention in the first day after birth results in a considerable delay in treatment of many infants, with many infants with low SBF not receiving treatment for many hours or missing treatment altogether (Kluckow 2000). Infants who have persisting inotrope requirements because of hypotension after the first days after birth frequently have normal or high SBF pointing to low systemic vascular resistance as the problem. Finally, studies of cardiovascular support in preterm infants that have used hypotension as the criterion for treatment and correction of hypotension as the goal of treatment are yet to demonstrate any improvements in morbidity or mortality (Subhedar 2003).

Low systemic and/or organ blood flow occurs in a variety of situations in preterm infants including extremely preterm infants in the first day after birth (Kluckow 2000; Osborn 2002a), infants with perinatal asphyxia, severe respiratory problems and pulmonary hypertension (Evans 1996), sepsis or necrotising enterocolitis. Low SBF is common in the first day after birth and is associated with decreasing gestation, mechanical ventilation, a large diameter ductus arteriosus, high pulmonary and systemic vascular resistances (Kluckow 2000; Osborn 2002a) and poor myocardial contractility (Osborn 2002b). Normally, SBF is measured using echocardiographic measurements of ventricular outputs. However, in the first day after birth, large shunts across the ductus arteriosus and foramen ovale are common and result in the ventricular outputs overestimating SBF by up to 100% (Evans 1996). Alternatives include using echocardiography to measure ventricular inputs such as superior vena cava (SVC) flow (Kluckow 2000b) or using techniques such as near infrared spectroscopy (NIRS) or xenon clearance to measure organ blood flows, particularly cerebral blood flow. In analyses adjusted for potential perinatal confounders, low SVC (Kluckow 2000; Osborn 2002a) and low cerebral blood flows (Meek 1999) in the first day after birth have been independently shown to precede intraventricular haemorrhage in preterm infants. Infants with early low SVC flows are also at increased risk of low urine output and hyperkalaemia (Kluckow 2001), mortality (Osborn 2002a) and poor neurodevelopmental outcome (Hunt 2001).

Strategies that have been used to provide cardiovascular support to preterm infants have included the use of volume expansion (see Cochrane reviews: Osborn 2004c; Osborn 2001), inotropes, nitric oxide and corticosteroids. Most studies comparing these interventions enrolled infants with hypotension, not with documented low systemic or organ blood flow. This review will focus on the use of inotropes to provide cardiovascular support for infants with demonstrated low systemic and/or organ blood flows. Inotropes used in preterm infants have included dopamine, dobutamine, isoprenaline (isoproterenol), adrenaline (epinephrine), noradrenaline (norepinephrine) and milrinone. In selecting an inotrope for treatment in preterm infants, it is likely to be important to consider the underlying pathophysiology of the cardiovascular compromise as well as the pharmacokinetics and pharmacodynamics of the inotrope (for reviews see Osborn 2004b; Seri 2001). Dopamine at low doses stimulates dopamine and beta-adrenergic receptors with little effect on vascular resistance and increases in organ blood flows. At high doses (above 10 μg/kg/min), alpha-adrenergic effects occur resulting in increases in both pulmonary and systemic vascular resistance and BP. Dobutamine produces predominately beta-adrenergic effects with resulting inotropy and a reduction in pulmonary and systemic vascular resistance. Isoprenaline is almost purely a beta-agonist and has a pronounced chronotropic effect and produces pulmonary and systemic vasodilatation. There have been concerns regarding its potential to increase myocardial oxygen consumption. Adrenaline has both alpha and beta adrenergic effects, with beta adrenergic effects predominating at lower doses, producing increases in cardiac output, but alpha effects becoming important at high doses resulting in substantial increases in systemic vascular resistance and reduction in cardiac outputs. Pulmonary vascular resistance is increased to a lesser extent. Noradrenaline has both alpha and beta effects with alpha effects predominant and resulting in an increase in vascular resistance. Milrinone, a selective phosphodiesterase inhibitor, is inotropic and a vasodilator (an 'inodilator'). It is used in infants undergoing cardiac surgery to treat of prevent low cardiac output syndrome associated with poor myocardial contractility, a situation similar to the low SBF that occurs in extremely preterm infants in the first day after birth.

The primary outcomes of this review that might be expected to be improved by the treatment of low SBF with inotropes are those that have been strongly associated with low SBF in the preterm infant, including mortality, late PIVH and subsequent neurodevelopmental disability including motor impairments and cerebral palsy. There is some data to support necrotising enterocolitis being associated with low SBF (Osborn 2002a). Secondary outcomes for which there is evidence of association include renal impairments and hyperkalaemia. There are no data to date associating periventricular white matter injury with low SBF.

Objectives

The objective was to determine the effect of specific inotropes versus no treatment or another inotrope on morbidity and mortality in preterm infants with low SBF. Secondary objectives included:
1. Determining the evidence for use of a specific inotrope compared to a different inotrope
2. Determining whether there is a difference in effect from inotropes that lower vascular resistance (e.g. dobutamine, isoprenaline, milrinone) or those that increase vascular resistance (e.g. noradrenaline, higher dose dopamine and adrenaline)
3. Determine the evidence for use of inotropes according to clinical indication including immature infants in the first day after birth, infants with asphyxia or infants with sepsis

Criteria for considering studies for this review

Types of studies

Randomised and quasi-randomised controlled trials. Trials that use crossover design were eligible for inclusion of data for short term outcomes with the original treatment allocation used for data extraction.

Types of participants

Preterm infants (< 37 weeks gestational age) with low SBF or organ blood flow in the neonatal period. Low SBF may be determined on the basis of echocardiographically measured ventricular outputs or surrogates for SBF such as SVC flow. Low organ blood flow may be determined on the basis of techniques including ultrasound Doppler, near infrared spectroscopy or xenon clearance techniques where there is evidence in the literature that the measurement is associated with substantial clinical outcomes and/or actual organ blood flow. The review does not include studies that include surrogates of flow such as blood pressure, ultrasound Doppler measured velocities, pulsatility or resistive indices.

Types of interventions

Inotropes including adrenaline, dobutamine, dopamine, isoprenaline, noradrenaline and milrinone used to treat infants with low SBF or organ blood flow. Eligible comparisons included no treatment or placebo, or another inotrope.

Types of outcome measures

Primary outcomes:

Mortality including neonatal or to near term corrected age
Peri / intraventricular haemorrhage (PIVH) including all and late occurring PIVH (late = not present on an initial head ultrasound in the first hours after birth)
Proven necrotising enterocolitis (pneumatosis on x-ray, or at surgery or postmortem)
Developmental disabilities including motor impairments and cerebral palsy. Emphasis will be placed on assessments that are blinded to intervention, neurological status assessed by physician, assessments that are made later (e.g. three years for assessment of cerebral palsy status) and assessments that use a validated screening tool that has been shown to predict long term neurodevelopment

Secondary outcomes:

Failure to correct low SBF or organ blood flow. Low SBFs included ventricular outputs or SVC flows below the range normally seen in preterm infants (e.g. RVO or LVO < 150 mls/kg/min; SVC flow < 40 mls/kg/min). Data will be recorded where studies report outcomes that are approximate to these criteria
Persistent patent ductus arteriosus (PDA) after study enrolment
Chronic lung disease at near term equivalent age (defined as need for oxygen or ventilatory support)
Impaired renal function (e.g. creatinine ≥ 120 mmol/l or oliguria ≤ 0.5 mls/kg/hr)
Hyperkalaemia (potassium ≥ 6.5 mmol/l)
Pulmonary haemorrhage
Periventricular leucomalacia and / or periventricular white matter abnormalities on ultrasound or MRI
Retinopathy of prematurity, any or severe (≥ stage 3)
Increase in ventricular output when cardiac shunts excluded (either absolute or as a percentage of baseline)
Increase in organ blood flow (either absolute or as a percentage of baseline)
Increase in BP (either absolute or as a percentage of baseline)
Side effects of inotropes such as excessive tachycardia requiring dose reduction (e.g. heart rates > 180 bpm), hypotension requiring treatment (e.g. mean or systolic BP below 10^th centile for gestational age) and arrhythmias

Search strategy for identification of studies

See: Cochrane Neonatal Group search strategy.

The standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - April 2006), EMBASE (1980 - April 2006) and CINAHL (1982 - April 2006). References in studies identified as potentially relevant and references in previous reviews were searched. Additionally, the published abstracts of conference proceedings including the Perinatal Society of Australia and New Zealand 1998 - 2005 and the Pediatric Academic Societies and Societies for Pediatric Research Annual Meetings 2000-2005 were searched. Expert informants were contacted. The search strategy was adapted for individual databases and included a search on all fields for [infant, newborn OR infant, newborn, diseases OR neonat*] AND [inotrope OR cardiotonic agents OR dopamine OR dobutamine OR epinephrine OR adrenaline OR noradrenaline OR isoprenaline OR isoproterenol OR milrinone OR amrinone OR phosphodiesterase inhibitors] AND [randomized controlled trial OR clinical trial OR random* OR trial* OR comparative study OR controlled study] was conducted. No language restrictions were used.

Methods of the review

Standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. All reviewers independently assessed trials for eligibility for inclusion and methodological quality. Particular emphasis was placed on allocation concealment, blinding, completeness of follow up and blinding of outcome assessment. Allocation concealment was ranked: Grade A: adequate; Grade B: uncertain; Grade C: clearly inadequate. Additional information will be requested from authors of each trial to clarify methodology where required. Differences between reviewer authors were resolved by consensus.

Data was extracted from the included study independently by each reviewer author. Standard methods of the Neonatal Review Group were used to synthesise data with use of relative risk (RR), risk difference (RD) and weighted mean difference (WMD) where appropriate. Heterogeneity was looked for both within the forest plots and statistically using the chi-square test for heterogeneity. The fixed effects model was used using RevMan 4.2 for meta-analysis. If heterogeneity was found, then possible causes were explored. Sensitivity analysis was prespecified on the basis of methodological quality. Studies of adequate methodology were defined as those with adequate randomisation and allocation concealment and with < 10% losses to follow up analysed on an intention to treat basis.

Studies enrolling infants to treatment with different inotropes were not be combined in an overall analysis except where they fulfil criteria for analysis of expected effect on vascular resistance. The following comparisons were prespecified:
1. Individual inotrope versus no inotrope (no treatment or placebo) including separate comparisons of:

adrenaline versus no inotrope
dobutamine versus no inotrope
dopamine versus no inotrope
isoprenaline versus no inotrope
milrinone versus no inotrope
noradrenaline versus no inotrope

2. Individual inotrope (as above) versus a different inotrope.

3. The effect of inotrope according to the expected effect on systemic vascular resistance (see background), including separate comparisons of:

inotropes likely to lower vascular resistance at any dose (e.g. dobutamine, isoprenaline, milrinone)
inotropes at doses likely to raise vascular resistance (e.g. noradrenaline at any dose, dopamine ≥ 10 μg/kg/min, adrenaline ≥ 0.375 μg/kg/min)
inotropes likely to lower vascular resistance (e.g. dobutamine, isoprenaline, milrinone at any dose) versus inotropes at doses likely to raise vascular resistance (e.g. noradrenaline at any dose, dopamine ≥10 μg/kg/min, adrenaline ≥ 0.375 μg/kg/min)

Within each comparison, we planned subgroup analyses according to individual inotrope and dose range.

4. The effect of inotrope according to type of infant enrolled in trials including separate comparisons of the following types of infants:

immature infants in the first day after birth
infants with sepsis
infants with perinatal asphyxia (trials that enrol infants on the basis of a low Apgar score or cord arterial blood gas acidosis)

Description of studies

Sixteen reports of studies were excluded (see 'Table of Excluded Studies'). No studies were found that compared inotropes to no treatment in preterm infants with low SBF. One study (Osborn 2002a) met inclusion criteria that compared different inotropes.

Osborn 2002a enrolled infants < 30 weeks gestation and < 12 hours after birth with low SVC flow (< 41 mls/kg/min). Forty-two infants with low SVC flow were given volume (normal saline 10 mls/kg) over 20 minutes and then randomly allocated to dobutamine or dopamine. Infusions were commenced at 10 μg/kg/min. If at any time in the first 24 hours the infant failed to maintain SVC flow > 40 mls/kg/min, the dose was increased to 20 μg/kg/min. Infants crossed over to the other inotrope if SVC flow was still not maintained > 40 mls/kg/min. The primary outcome was maintenance of SVC flow > 40 mls/kg/min. SVC flow and RVO were measured echocardiographically 30 minutes after each change of dose of inotrope and 10 and 24 hours after birth. Head ultrasounds were performed at seven and 28 days. Neonatal morbidity and mortality were reported to discharge. Developmental assessment was performed at one and three years corrected age and included paediatrician examination and the Griffiths Mental Development Scales. A Griffiths development quotient at three years < 75 represents a delay > 2 sd below population norms.

Methodological quality of included studies

Osborn 2002a reported adequate randomisation, allocation concealment and blinding of intervention with identical syringes prepared in pharmacy allocated according to a computer generated random number sequence. Echocardiographic measures, neonatal outcomes and one and three years corrected age developmental assessments were also blinded by use of identical syringes with treatment allocation concealed until analysis performed. Four additional infants who were allocated treatment on the basis of hypotension were excluded from analysis as they did not meet prespecified enrolment criteria (SVC flow < 41 mls/kg/min). One surviving infant was not examined for retinopathy of prematurity. Five of 18 surviving infants were not assessed at three years of age. Follow up was complete for all other outcomes.

Results

Inotrope versus no treatment: no study found.

Comparison 01: Dobutamine versus dopamine in preterm infants with low SVC flow: One study eligible study (Osborn 2002a) was included.

Primary outcomes:
Osborn 2002a reported no significant difference in mortality to discharge (RR 1.41, 95% CI 0.79, 2.52), mortality before follow up (RR 1.27, 95% CI 0.74, 2.18), all PIVH (RR 1.01, 95% 0.52, 1.97), late PIVH (RR 0.57, 95% CI 0.22, 1.45), grade 3 or 4 PIVH (RR 0.39, 95% CI 0.12, 1.31) or necrotising enterocolitis (RR 2.73, 95% CI 0.31, 24.14). At 3 years, there was no significant difference in cerebral palsy (RR 0.16, 95% CI 0.01, 2.64) or deafness (RR 0.16, 95% CI 0.01, 2.64), no blind infant in either group and no difference in Developmental quotient > sd below norm (RR 0.16, 95% CI 0.01, 2.64). There was no significant difference in disability (RR 0.10, 95% CI 0.01, 1.56) defined as a development quotient > sd below norm, cerebral palsy, blind or deaf, or death and disability (RR 0.79, 95% CI 0.57, 1.11). Surviving infants treated with dobutamine had a significantly higher Griffiths quotient (MD 35.00, 95% CI 17.68, 52.32). There was no significant difference in death or disability at the latest time reported (RR 0.95, 95% CI 0.66, 1.38).

Secondary outcomes:
Osborn 2002a reported no significant difference in periventricular leucomalacia (RR 6.00, 95% CI 0.34, 104.89), renal impairment (RR 0.55, 95% CI 0.15, 2.00), pulmonary haemorrhage (RR 0.61, 95% CI 0.11, 3.26) or retinopathy of prematurity in survivors examined (RR 0.80, 95% CI 0.30, 2.13). There was a reduction of borderline significance in CLD defined as oxygen at 28 days (RR 0.55, 95% CI 0.30, 1.00),but not at 36 weeks (RR 0.83, 95% CI 0.27, 2.49). There was no significant difference in treatment failure (RR 0.58, 95% CI 0.28, 1.20). Dopamine produced a significantly greater increase in mean BP at 10 μg/kg/min (MD -4.50 mmHg, 95% CI -8.06, -0.94), 20 μg/kg/min (MD -4.60, 95% CI -8.74, -0.46) and at the highest dose reached (MD -7.20, 95% CI -11.41, -2.99). There was no significant difference in SVC flow at 10 μg/kg/min (MD 4.70 mls/kg/min, 95% CI -4.02, 13.42) or 20 μg/kg/min (MD 9.70, 95% CI -3.93, 23.33), but dobutamine produced a significantly greater increase in SVC flow at the highest dose reached (MD 13.10, 95% CI 2.87, 23.33). There was no significant difference in RVO at 10 μg/kg/in (MD 4.00, 95% CI -19.27, 27.27) or 20 μg/kg/min (MD 1.20, 95% CI -25.35, 27.75) or the highest dose reached (MD 10.70, 95% CI -19.16, 40.56).

Subgroup analyses:
The only eligible trial meets inclusion criteria for studies of adequate methodology. The trial compared dobutamine versus dopamine, compared inotropes likely to lower vascular resistance (dobutamine at any dose) versus inotropes at doses likely to raise vascular resistance (dopamine ≥ 10 μg/kg/min) and enrolled immature infants in the first day after birth.

Discussion

The single small study included in this review enrolled preterm infants on the basis of a surrogate for low systemic blood flow (SVC flow) that is not confounded by shunts across the adapting heart, had adequate randomisation and allocation concealment, and blinded treatment and measurement. The study was designed and powered to explore haemodynamic rather than clinical outcomes. However, there are several observations that can be made from this study. Infants treated with dopamine had a significantly greater increase in mean BP at both 10 and 20 μg/kg/min,but little change in SVC flow or RVO. Infants treated with dobutamine had little change in mean BP, but had a significantly greater increase in SVC flow at the highest dose reached with trends to increased SVC flow at both 10 and 20 μg/kg/min. However, treatment failure (defined as failure to increase and maintain normal SVC flows) was substantial on either inotrope, with 40% of the all babies enrolled not improving or maintaining SVC flow within the normal range. No consistent differences were reported in neonatal morbidity (including renal impairment, PIVH, periventricular leucomalacia or necrotising enterocolitis) that we hypothesised may be affected by interventions aimed at improving blood flow. There was no significant difference in mortality or combined death and disability at the latest time measured, although infants treated with dobutamine had significantly higher Griffiths quotients at three years. It is possible that the additional infants who survived in the dopamine group did so with impaired development. It is unclear from this study and previous reviews of inotropes for treatment of hypotension (Subhedar 2003) what the optimal strategy is for improving the cardiovascular status of the immature infant. Dopamine has been reported to lead to greater increases in BP in hypotensive infants (Subhedar 2003) and infants with low SBF (Osborn 2002a), but dobutamine increased SBF better than dopamine in infants with low SBF (Osborn 2002a). Neither inotrope has been shown to consistently improve any clinical outcome when given for hypotension or low SBF, and many infants with initial low SBF fail to maintain flows on either inotrope.

Several methodological issues affect the interpretation of the only study eligible for this review. Most infants enrolled were immature, ventilated preterm infants. However, infants with asphyxia and sepsis were not excluded. The applicability to infants with different reasons for cardiovascular compromise is unclear. All infants were given volume expansion prior to inotrope randomisation. Infants who failed to maintain SVC flow on the highest dose of inotrope crossed over to the other inotrope, so that a substantial proportion of infants were exposed to both inotropes. Cerebral and other organ blood flows were not measured. The dose of inotropes used included relatively high dose dopamine (20 μg/kg/min). This is a dose that some authors may caution using due to the substantial alpha effects that produce substantial increases in vascular resistance. However, it is within the dose range commonly reported in trials (Subhedar 2003). In addition, dopamine is usually titrated to achieve a BP above the minimally accepted pressure on gestation or birth weight criteria, a strategy that was not used in this study.

The inclusion of a single small study enrolling infants in the first day precludes strong conclusions to be made about the use of inotropes in preterm infants. No trial was found that compared inotrope use to another strategy of cardiovascular support in preterm infants with low systemic or organ blood flows. The only comparison able to be made was for dobutamine versus dopamine. However, the single small study was of adequate methodology and reported outcomes prespecified in protocol. The review has been performed by the research team who conducted the only eligible study.

The findings of this review suggest that further research is needed to determine the most effective strategies for providing cardiovascular support for extremely premature infants. Independent research groups considering replicating the trial included in this review should consider using another agent (e.g. low dose adrenaline) in infants who fail to respond to inotrope rather than a blinded crossover to the other agent. The trial should be adequately powered to detect important clinical differences. A trial comparing a strategy of targeting infants with hypotension with dopamine versus targeting infants with low SBF with dobutamine is needed. An alternative strategy that needs evaluation includes one aimed at preventing low SBF. Given that low SBF is associated with high systemic vascular resistance and poor myocardial contractility, researchers conducting trials aimed at preventing low SBF should consider using inotropes that have the potential to lower systemic vascular resistance and improve myocardial contractility, such as dobutamine or milrinone. Future trials should measure the effects of interventions on systemic and organ blood flows using validated measures. Doppler velocity indices of flow are not validated measures of actual organ blood flows. Ventricular outputs have been validated as measures of SBF after the first day, but are confounded by shunts across the adapting heart in the first day. Superior vena cava flow has been validated clinically as a surrogate measure of SBF in the first day. NIRS and xenon measurements are also potential techniques for determining the effect of cardiovascular interventions on organ blood flows in preterm infants.

Reviewers' conclusions

Implications for practice

There were no eligible studies that compared use of an inotrope to no treatment in preterm infants with low SBF. In preterm infants with low SBF, there is some evidence that dobutamine is better than dopamine at increasing and maintaining SBF. The only eligible trial did not demonstrate any consistent differences in clinical outcomes. However, this study was not sufficiently powered to prove or disprove effects on clinical outcomes. It is unclear what is the most effective strategy for improving the cardiovascular status of immature infants in the first day.

Implications for research

Further trials are needed to determine effective strategies for preventing and improving low systemic and organ blood flows in the first day after birth in extremely immature infants. A trial comparing a strategy of treating hypotension with dopamine versus treating low SBF with dobutamine in preterm infants in the first day is warranted.

Acknowledgements

Potential conflict of interest

The reviewer authors conducted the only included trial of inotropes in infants with low SBF. No funding was received from pharmaceutical companies.

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Osborn 2002a	Two centre. Randomised: yes, used computer generated random number sequence to allocate syringes. Stratified by centre. Blinded treatment: yes, used identical labelled and appearing syringes. Blinded measurement: yes, used identical syringes. Losses to follow up: yes, 4 infants (4/46 = 9%) with hypotension allocated treatment but excluded from analysis as not eligible (did not have low flow). One surviving infant was not examined for ROP. Five of 18 surviving infants were not assessed at 3 years of age. Follow up was complete for all other outcomes.	Inclusion criteria: <30 weeks gestation, <12 hours age, SVC flow <41 mls/kg/min. Exclusion criteria: structural heart disease, considered by treating physician to be unlikely to survive, previous inotropes. Mean (+/-sd) gestation (weeks): Dobutamine: 26.0 (2.1); Dopamine: 25.7 (1.5). Mean +/-sd birth weight (g): Dobutamine: 982 (324); Dopamine: 859 (190).	Normal saline 10 mls/kg over 20 minutes, then randomised to: Dobutamine 10 mcg/kg/min titrated up 20mcg/kg/min to maintain SVC flow >41 mls/kg/min (n = 22); or Dopamine 10mcg/kg/min titrated up 20 mcg/kg/min to maintain SVC flow >41 mls/kg/min (n = 20). If failed first inotrope, changed to other syringe.	Primary outcome: change in SVC flow mls/kg/min. Secondary outcomes: late P/IVH, all PIVH, grade 3 or 4 P/IVH, periventricular leucomalacia, mortality to discharge, necrotising enterocolitis, chronic lung disease (oxygen at 36 weeks postmenstrual age), cerebral palsy at 3 years, Griffith's Mental Development Scales at 1 year corrected age and 3 years age, deaf (hearing aids), blind (visual acuity <6/60), disability (deaf, blind, Griffith's quotient <=70, cerebral palsy).		A

Characteristics of excluded studies

Study	Reason for exclusion
Bourchier 1997	Enrolled hypotensive preterm infants. Cardiac outputs not reported.
Cason 1999	Enrolled hypotensive infants <= 34 weeks with RDS.
DiSessa 1981	Enrolled asphyxiated term or near term infants with mean BP >50 mmHg.
Gill 1993	Enrolled hypotensive preterm infants. Cardiac outputs not reported.
Greenough 1993	Enrolled hypotensive preterm infants. Cardiac outputs not reported.
Hentschel 1995	Enrolled hypotensive preterm infants. Cardiac outputs not reported. Reported mesenteric artery blood flow velocities.
Kawczynski 1996	Observational study. Enrolled hypotensive preterm infants with oliguria and acidosis. Cardiac outputs not reported.
Klarr 1994	Enrolled preterm infants with hypotension. Cardiac outputs not reported.
Lundstrom 2000	Enrolled normotensive (mean BP 29-40 mmHg) preterm infants. Reported cardiac outputs.
Padbury 1990	Observational study exploring pharmacokinetics of dopamine in sick neonates.
Pellicer 2005	Enrolled hypotensive preterm infants in first day. Reported changes and not absolute cerebral blood flow using NIRS.
Phillipos 1996	Enrolled hypotensive preterm infants.
Phillipos 2000	Enrolled hypotensive preterm infants.
Rennie 1989	Observational study in hypotensive preterm infants.
Repetto 1999	Observational study in hypotensive preterm infants.
Roze 1993	Enrolled hypotensive preterm infants. Reported left ventricular outputs. Mean cardiac outputs in normal range.

References to studies

References to included studies

Osborn 2002a {published and unpublished data}

Osborn DA, Evans N, Kluckow M. Dopamine but not dobutamine increases left ventricular (LV) stress, but neither improves LV contractility in very preterm infants. In: Proceedings Perinatal Society of Australia and New Zealand 6th Annual Congress. 2002:A145.

Osborn DA, Evans N, Kluckow M. Dopamine but not dobutamine increases left ventricular (LV) stress, but neither improves LV contractility in very preterm infants. Pediatric Research 2002;51:386A.

* Osborn DA, Evans N, Kluckow M. Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow. Journal of Pediatrics 2002;140:183-91.

Osborn DA, Kluckow M, Evans N. Randomized trial of dobutamine and dopamine in preterm infants with low systemic blood flow. In: Proceedings Perinatal Society of Australia and New Zealand 4th Annual Congress. 2000:85.

Osborn DA, Kluckow M, Evans N. Randomized trial of dobutamine and dopamine in preterm infants with low systemic blood flow. Pediatric Research 2000;47:422A.

Osborn DA, Kluckow M, Evans N. Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow - 3 year follow up. In: Proceedings Perinatal Society of Australia and New Zealand 9th Annual Congress. 2005:All.

Osborn DA,. Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow - 3 year follow up. Pediatric Research 2005;57:A.

References to excluded studies

Bourchier 1997 {published data only}

Bourchier D, Weston PJ. Randomised trial of dopamine compared with hydrocortisone for the treatment of hypotensive very low birthweight infants. Archives of Disease in Childhood Fetal Neonatal Ed 1997;76:F174-8.

Cason 1999 {published data only}

Cason DL, Amaker D, Carter D, Sutherland D, Bhatia J. Randomized double-blind trial of dopamine versus epinephrine for treatment of hypotension in premature infants with respiratory distress syndrome. Journal of Investigative Medicine 1999;47:119A.

DiSessa 1981 {published data only}

* DiSessa TG, Leitner M, Ti CC, Gluck L, Coen R, Friedman WF. The cardiovascular effects of dopamine in the severely asphyxiated neonate. Journal of Pediatrics 1981;99:772-6.

Leitner MJ, DiSessa TG, Coen RW, Ti C. Cardiovascular effects of low dose dopamine in the severely asphyxiated infant. Pediatric Research 1980;14:447A.

Gill 1993 {published data only}

* Gill AB, Weindling AM. Randomised controlled trial of plasma protein fraction versus dopamine in hypotensive very low birthweight infants. Archives of Disease in Childhood 1993;69:284-7.

Gill B, Weindling M. Randomised controlled trial to compare plasma protein fraction (PPF) and dopamine in the hypotensive very low birthweight (VLBW) infant. Pediatric Research 1994;35:273 (Abstract A84).

Greenough 1993 {published data only}

Greenough A, Emery EF. Randomized trial comparing dopamine and dobutamine in preterm infants. European Journal of Pediatrics 1993;152:925-7.

Hentschel 1995 {published data only}

Hentschel R, Hensel D, Brune T, Rabe H, Jorch G. Impact on blood pressure and intestinal perfusion of dobutamine or dopamine in hypotensive preterm infants. Biology of the Neonate 1995;68:318-24.

Kawczynski 1996 {published data only}

Kawczynski P, Piotrowski A. Circulatory and diuretic effects of dopexamine infusion in low-birth-weight infants with respiratory failure. Intensive Care Medicine 1996;22:65-70.

Klarr 1994 {published data only}

Klarr JM, Faix RG, Pryce CJ, Bhatt-Mehta V. Randomized, blind trial of dopamine versus dobutamine for treatment of hypotension in preterm infants with respiratory distress syndrome. Journal of Pediatrics 1994;125:117-22.

Lundstrom 2000 {published and unpublished data}

* Lundstrom K, Pryds O, Greisen G. The haemodynamic effects of dopamine and volume expansion in sick preterm infants. Early Human Development 2000;57:157-63.

Lundstrom KE. A randomized, controlled study of the influence of dopamine and volume expansion on CBF, LVO and MABP in hypotensive, preterm infants. Proceedings of 14th European Congress of Perinatal Medicine, Helsinki, Finland 1994:500.

Padbury 1990 {published data only}

Padbury JF, Agata Y, Baylen BG, Ludlow JK, Polk D, Habib DM, Martinez AM. Pharmacokinetics of dopamine in critically ill newborn infants. Journal of Pediatrics 1990;117:472-6.

Pellicer 2005 {published and unpublished data}

Pellicer A, Valverde E, Elorza MD, Madero R, Gaya F, Quero J, Cababnas F. Randomized blinded controlled trial on the effects on brain hemodynamics of dopamine v epinephrine for inotropic support in preterm infants. Pediatric Research 2003;53:Abstract 2364.

* Pellicer A, Valverde E, Elorza MD, Madero R, Gaya F, Quero J, et al. Cardiovascular support for low birth weight infants and cerebral hemodynamics: a randomized, blinded, clinical trial. Pediatrics 2005;115:1501-12.

Phillipos 1996 {published data only}

Phillipos EZ, Barrington KJ, Robertson MA. Dopamine versus epinephrine for inotropic support in the neonate: A randomized double blinded controlled trial. Pediatric Research 1996;39:238A.

Phillipos 2000 {published data only}

Phillipos EZ, Robertson MA. A randomized double blinded controlled trial of dopamine versus epinephrine for inotropic support in premature infants <1750 grams. Pediatric Research 2000;47:425A.

Rennie 1989 {published data only}

Rennie JM. Cerebral blood flow velocity variability after cardiovascular support in premature babies. Archives of Disease in Childhood 1989;64:897-901.

Repetto 1999 {published data only}

Repetto JE, Eyal FG, McHargue L, Alpan G. High dose dopamine for the treatment of neonatal hypotension. Pediatric Research 1999;45:221A.

Roze 1993 {published data only}

Roze JC, Tohier C, Maingueneau C, Lefevre M, Mouzard A. Response to dobutamine and dopamine in the hypotensive very preterm infant. Archives of Disease in Childhood 1993;69:59-63.

* indicates the primary reference for the study

Other references

Additional references

Evans 1996

Evans N, Kluckow M. Early determinants of right and left ventricular output in ventilated preterm infants. Archives of Disease in Childhood Fetal and Neonatal Edition 1996;74:F88-94.

Hunt 2001

Hunt RW, Evans NJ, Rieger I, Kluckow MR. Low superior vena cava flow in the first 24 hours of life and 3 year neurodevelopmetal outcome. Pediatric Research 2001;49:336A.

Kluckow 1996

Kluckow M, Evans N. Relationship between blood pressure and cardiac output in preterm infants requiring mechanical ventilation. Journal of Pediatrics 1996;129:506-12.

Kluckow 2000

Kluckow M, Evans N. Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Archives of Disease in Childhood Fetal and Neonatal Edition 2000;82:F188-94.

Kluckow 2000b

Kluckow M, Evans N. Superior vena cava flow in newborn infants: a novel marker of systemic blood flow. Archives of Disease in Childhood Fetal and Neonatal Edition 2000;82:F182-7.

Kluckow 2001

Kluckow M, Evans N. Low systemic blood flow and hyperkalemia in preterm infants. Journal of Pediatrics 2001;139:227-32.

Lopez 1997

Lopez SL, Leighton JO, Walther FJ. Supranormal cardiac output in the dopamine- and dobutamine-dependent preterm infant. Pediatric Cardiology 1997;18:292-6.

Meek 1999

Meek JH, Tyszczuk L, Elwell CE, Wyatt JS. Low cerebral blood flow is a risk factor for severe intraventricular haemorrhage. Archives of Disease in Childhood Fetal and Neonatal Edition 1999;81:F15-8.

Miall-Allen 1987

Miall-Allen VM, de Vries LS, Whitelaw AG. Mean arterial blood pressure and neonatal cerebral lesions. Archives of Disease in Childhood 1987;62:1068-9.

Osborn 2001

Osborn DA, Evans N. Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 2.

Osborn 2002b

Osborn D, Evans N, Kluckow M. Left ventricular (LV) contractility and wall stress in very preterm infants in the first day of life. Pediatric Research 2002;51:386A.

Osborn 2003

Osborn DA, Evans N, Kluckow M. Hemodynamic and antecedent risk factors of early and late peri/intraventricular hemorrhage in premature infants. Pediatrics 2003;112:33-9.

Osborn 2004a

Osborn DA, Evans N, Kluckow M. Clinical detection of low upper body blood flow in very premature infants using blood pressure, capillary refill time, and central-peripheral temperature difference. Archives of Disease in Childhood Fetal and Neonatal Edition 2004;89:F168-73.

Osborn 2004b

Osborn D, Evans N, Kluckow M. Diagnosis and treatment of low systemic blood flow in preterm infants. NeoReviews 2004;5:109-21.

Osborn 2004c

Osborn DA, Evans N. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 2.

Padbury 1987

Padbury JF, Agata Y, Baylen BG, Ludlow JK, Polk DH, Goldblatt E, Pescetti J. Dopamine pharmacokinetics in critically ill newborn infants. Journal of Pediatrics 1987;110:293-8.

Seri 1998

Seri I, Abbasi S, Wood DC, Gerdes JS. Regional hemodynamic effects of dopamine in the sick preterm neonate. Journal of Pediatrics 1998;133:728-34.

Seri 2001

Seri I. Circulatory support of the sick preterm infant. Seminars in Neonatology 2001;6:85-95.

Subhedar 2003

Subhedar NV, Shaw NJ. Dopamine versus dobutamine for hypotensive preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 3.

Comparisons and data

01 Dobutamine versus dopamine in preterm infants with low SVC flow

01.01 Mortality before discharge

01.02 Mortality before follow up

01.03 Any peri / intraventricular haemorrhage

01.04 Late peri / intraventricular haemorrhage

01.05 Peri / intraventricular haemorrhage grade 3 or 4

01.06 Necrotising enterocolitis

01.07 Cerebral palsy at 3 years in survivors assessed

01.08 Deafness at 3 years in survivors assessed

01.09 Blind at 3 years survivors assessed

01.10 Griffith's general Quotient >2sd below norm at 3 years in survivors assessed

01.11 Disability at 3 years in survivors assessed

01.12 Death or disability at 3 years

01.13 Death or disability at latest follow up

01.14 Griffith's Mental Scales of Development General Quotient at 3 years in survivors assessed

01.15 Periventricular leucomalacia in survivors

01.16 Renal impairment (creatinine >=120 mmol/l)

01.17 Pulmonary haemorrhage

01.18 Chronic lung disease (oxygen at 28 days) in survivors

01.19 Chronic lung disease (oxygen or respiratory support at 36 weeks PMA) in survivors

01.20 Retinopathy of prematurity in survivors examined

01.21 Failed treatment (did not maintain SVC flow >=41mls/kg/min in 1st 24 hours)

01.22 Change mean BP at 10mcg/kg/min

01.23 Change mean BP at 20mcg/kg/min

01.24 Change mean BP at highest dose reached

01.25 Change SVC flow at 10mcg/kg/min

01.26 Change SVC flow at 20mcg/kg/min

01.27 Change SVC flow at highest reached

01.28 Change RVO at 10mcg/kg/min

01.29 Change RVO at 20mcg/kg/min

01.30 Change RVO at highest dose reached

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Dobutamine versus dopamine in preterm infants with low SVC flow
01 Mortality before discharge	1	42	RR (fixed), 95% CI	1.41 [0.79, 2.52]
02 Mortality before follow up	1	42	RR (fixed), 95% CI	1.27 [0.74, 2.18]
03 Any peri / intraventricular haemorrhage	1	42	RR (fixed), 95% CI	1.01 [0.52, 1.97]
04 Late peri / intraventricular haemorrhage	1	42	RR (fixed), 95% CI	0.57 [0.22, 1.45]
05 Peri / intraventricular haemorrhage grade 3 or 4	1	42	RR (fixed), 95% CI	0.39 [0.12, 1.31]
06 Necrotising enterocolitis	1	42	RR (fixed), 95% CI	2.73 [0.31, 24.14]
07 Cerebral palsy at 3 years in survivors assessed	1	13	RR (fixed), 95% CI	0.16 [0.01, 2.64]
08 Deafness at 3 years in survivors assessed	1	13	RR (fixed), 95% CI	0.16 [0.01, 2.64]
09 Blind at 3 years survivors assessed	1	13	RR (fixed), 95% CI	Not estimable
10 Griffith's general Quotient >2sd below norm at 3 years in survivors assessed	1	13	RR (fixed), 95% CI	0.16 [0.01, 2.64]
11 Disability at 3 years in survivors assessed	1	13	RR (fixed), 95% CI	0.10 [0.01, 1.56]
12 Death or disability at 3 years	1	37	RR (fixed), 95% CI	0.79 [0.57, 1.11]
13 Death or disability at latest follow up	1	41	RR (fixed), 95% CI	0.95 [0.66, 1.38]
14 Griffith's Mental Scales of Development General Quotient at 3 years in survivors assessed	1	13	WMD (fixed), 95% CI	35.00 [17.68, 52.32]
15 Periventricular leucomalacia in survivors	1	24	RR (fixed), 95% CI	6.00 [0.34, 104.89]
16 Renal impairment (creatinine >=120 mmol/l)	1	42	RR (fixed), 95% CI	0.55 [0.15, 2.00]
17 Pulmonary haemorrhage	1	42	RR (fixed), 95% CI	0.61 [0.11, 3.26]
18 Chronic lung disease (oxygen at 28 days) in survivors	1	23	RR (fixed), 95% CI	0.55 [0.30, 1.00]
19 Chronic lung disease (oxygen or respiratory support at 36 weeks PMA) in survivors	1	19	RR (fixed), 95% CI	0.83 [0.27, 2.49]
20 Retinopathy of prematurity in survivors examined	1	20	RR (fixed), 95% CI	0.80 [0.30, 2.13]
21 Failed treatment (did not maintain SVC flow >=41mls/kg/min in 1st 24 hours)	1	42	RR (fixed), 95% CI	0.58 [0.28, 1.20]
22 Change mean BP at 10mcg/kg/min	1	42	WMD (fixed), 95% CI	-4.50 [-8.06, -0.94]
23 Change mean BP at 20mcg/kg/min	1	23	WMD (fixed), 95% CI	-4.60 [-8.74, -0.46]
24 Change mean BP at highest dose reached	1	42	WMD (fixed), 95% CI	-7.20 [-11.41, -2.99]
25 Change SVC flow at 10mcg/kg/min	1	42	WMD (fixed), 95% CI	4.70 [-4.02, 13.42]
26 Change SVC flow at 20mcg/kg/min	1	23	WMD (fixed), 95% CI	9.70 [-3.93, 23.33]
27 Change SVC flow at highest reached	1	42	WMD (fixed), 95% CI	13.10 [2.87, 23.33]
28 Change RVO at 10mcg/kg/min	1	42	WMD (fixed), 95% CI	4.00 [-19.27, 27.27]
29 Change RVO at 20mcg/kg/min	1	23	WMD (fixed), 95% CI	1.20 [-25.35, 27.75]
30 Change RVO at highest dose reached	1	42	WMD (fixed), 95% CI	10.70 [-19.16, 40.56]

Contact details for co-reviewers

Dr Nicholas J Evans
Director Neonatal Intensive Care
Neonatal Medicine
Royal Prince Alfred Hospital
Missenden Rd
Camperdown
NSW AUSTRALIA
2050
Telephone 1: 61 2 95156253
Telephone 2: 61 2 95158248
Facsimile: 61 2 95504375
E-mail: nevans@med.su.oz.au

Dr Mary Paradisis
Fellow
RPA Newborn Care
Royal Prince Alfred Hospital
Missenden Rd
Camperdown, Sydney
AUSTRALIA
2050
Telephone 1: 61 2 9515 8760
Telephone 2: 61 2 9515 8371
Facsimile: 61 2 9550 4375
E-mail: mary.paradisis@email.cs.nsw.gov.au

The review is published as a Cochrane review in The Cochrane Library, Issue 1, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the Review.