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Dopamine versus dobutamine for hypotensive preterm infants

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Authors

Subhedar NV, Shaw NJ

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


Dates

Date edited: 27/05/2003
Date of last substantive update: 07/05/2003
Date of last minor update: 07/05/2003
Date next stage expected 28/08/2004
Protocol first published: Issue 4, 1998
Review first published: Issue 4, 1999

Contact reviewer

Nimish V Subhedar

Consultant Neonatal Paediatrician
Neonatal Intensive Care Unit
Liverpool Women's Hospital
Crown Street
Liverpool
UK
L 8 7SS
Telephone 1: +44 151 702 4272
Facsimile: +44 151 702 4272

E-mail: nvsubhedar_lwh@yahoo.com

Secondary contact person's name: Dr. N. J. Shaw

Contribution of reviewers

  • None noted.

Sources of Support

Internal sources of support

Liverpool Women's Hospital, Liverpool, UK

External sources of support

None

What's new

This review updates the existing review of "Dopamine versus dobutamine for hypotensive preterm infants" which was published in The Cochrane Library, Issue 4, 1999.

This update incorporates data from one additional study of 66 babies (Ruelas-Orozco 2000). Inclusion of this study increases the total number of babies included in this review to 209. Although there are no changes to the Reviewer's Conclusions in this update, inclusion of this new study has modified the pooled estimate of effect of dopamine versus dobutamine in terms of treatment failure. The NNT with dopamine versus dobutamine to avoid one treatment failure is 4-5 rather than 3-4 as in the previous version of this review.

Other changes in this review are relatively minor. They include details of one study by Roze 1993 suggesting dobutamine may be more effective in increasing left ventricular output; changes updating the text of the Background section; and updating the list of excluded studies and additional references.

Dates

Date review re-formatted: 08/09/1999
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 08/09/2003
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Synopsis

Dopamine improves low blood pressure (hypotension) in preterm babies more effectively than dobutamine in the short-term, but evidence on safety and long-term effectiveness is needed.

Hypotension may cause brain injury and other serious problems for preterm babies (born before 37 weeks). Treatment aims to maintain blood flow to the brain and other organs, by using fluids or drugs to increase blood pressure. Inotrope drugs, including dopamine and dobutamine, are commonly used to increase blood pressure. However, the safest and most effective drug for treating hypotension in preterm babies has been unclear. The review found that dopamine was more effective than dobutamine for short-term treatment, but the effects of these drugs on long-term outcomes is unknown. More trials are needed.

Abstract

Background

Inotropes are widely used in preterm infants to treat systemic hypotension. The most commonly used drugs are dopamine and dobutamine. These agents have different modes of action which may result in different haemodynamic effects.

Objectives

To compare the effectiveness and safety of dopamine and dobutamine in the treatment of systemic hypotension in preterm infants.

Search strategy

Searches of electronic and other databases were performed including MEDLINE (1966-2002), EMBASE (1988-2002), Science Citation Index (1981-2002), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2003). Previous reviews were searched for references to relevant trials and leading authors in the field were contacted for information about other published and unpublished studies.

Selection criteria

Randomised controlled trials where short and/or long term effects of treatment with dopamine and dobutamine for the treatment of systemic arterial hypotension were compared were selected for this review. Trials studying newborn infants born before 37 completed weeks gestation and less than 28 days of age were eligible for inclusion. Systemic arterial hypotension was not defined specifically, but accepted as defined in individual studies. Studies were not limited by birthweight, lower gestational age threshold or by route or duration of administration of inotropic agents. Study quality and eligibility were assessed independently by each reviewer.

Data collection & analysis

Data extraction was performed independently by each reviewer, with differences being resolved by discussion. The following outcomes were determined: mortality in the neonatal period, long term neurodevelopmental outcome, radiological evidence of severe neurological injury, short term haemodynamic changes and incidence of adverse effects. The effect of interventions was expressed either as Relative Risk (RR), Risk Difference (RD) or as Weighted Mean Difference (WMD) with their 95% Confidence Interval (CI).

Main results

Five trials met the pre-defined criteria for inclusion in this review. There was no evidence of a significant difference between dopamine and dobutamine in terms of neonatal mortality (RD 0.02 95% CI -0.12 to 0.16), incidence of periventricular leukomalacia (RD -0.08, 95% CI -0.19 to 0.04), or severe periventricular haemorrhage (RD -0.02, 95% CI -0.13 to 0.09). Dopamine was more successful than dobutamine in treating systemic hypotension, with fewer infants having treatment failure (RD -0.23, 95% CI -0.34 to -0.13; NNT = 4.4, 95% CI 2.9 to 7.7). Treatment with dobutamine was associated with a significantly greater increase in left ventricular output in the single study reporting that outcome. There was no evidence of a significant difference between the two agents with respect to the incidence of tachycardia (RD -0.06, 95% CI -0.25 to 0.14). None of the studies reported the incidence of adverse long term neurodevelopmental outcome.

Reviewers' conclusions

Dopamine is more effective than dobutamine in the short term treatment of systemic hypotension in preterm infants. There was no evidence of an effect on the incidence of adverse neuroradiological sequelae (severe periventricular haemorrhage and/or periventricular leucomalacia), or on the incidence of tachycardia. However, in the absence of data confirming long term benefit and safety of dopamine compared to dobutamine, no firm recommendations can be made regarding the choice of drug to treat hypotension.

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Background

Systemic arterial hypotension is associated with periventricular haemorrhage and poor long term neurodevelopmental outcome in preterm infants (Cunningham 1999, Bada 1990, Goldstein 1995, Low 1993). Preterm infants with low cerebral blood flow are at risk of periventricular haemorrhage (Meek 1999). It remains unclear whether a causal association exists between low cerebral blood flow and periventricular leucomalacia, although this association is widely quoted. There is no convincing evidence that systemic hypotension is associated with the development of periventricular leucomalacia (Perlman 1996, Trounce 1988).

The rationale for aggressively treating systemic hypotension in preterm infants has been to preserve adequate organ perfusion and, in particular, cerebral blood flow. It has been argued that sick preterm infants have impaired cerebral autoregulation resulting in a pressure-passive cerebral circulation. In this setting, hypotension may lead to low cerebral blood flow. In contrast, other studies have suggested that cerebral perfusion may be independent of systemic blood pressure (BP) indicating the presence of intact cerebral autoregulation (Tyszczuk 1998).

Measurement of cerebral blood flow is difficult to perform and not routinely used in clinical practice. The relative ease with which BP can be monitored continuously has led to its widespread use as a measure of adequacy of the systemic circulation. More recently, the introduction of Doppler echocardiography has enabled measurements of cardiac output to be made non-invasively. In contrast to the widely held belief that normal systemic BP indicates satisfactory cardiac output, studies in ventilated preterm infants have shown that the two variables are in fact poorly correlated (Kluckow 1996).

There is no consensus amongst neonatologists about what is the acceptable lower limit for systemic arterial blood pressure (BP). In infants below 31 weeks gestation, a sustained mean BP below 30 mmHg for one hour was associated with an adverse short term neurological outcome (Miall-Allen 1987). In a cohort of very low birthweight infants, duration of systemic hypotension (defined as a systolic BP below 35 mmHg in infants less than 750 grams, and below 40 mmHg in those between 750 and 1500 grams) was independently associated with poor neurodevelopmental outcome at two years of age (Goldstein 1995). Other workers have attempted to derive a reference range from BP recordings in healthy preterm infants during the first week of life (Cunningham 1999).

A number of therapeutic strategies including volume expansion, corticosteroids and inotropic agents have been used in an attempt to treat systemic hypotension in preterm neonates (So 1997, Gaissmaier 1999, Gill 1993a). Left ventricular dysfunction has been demonstrated in very low birthweight infants with systemic hypotension (Gill 1993b). Inotropes may be beneficial in these infants by enhancing myocardial contractility, thereby increasing cardiac output and/or systemic BP. Any effects on the peripheral systemic vasculature are also likely to influence the overall haemodynamic response to inotropic therapy.

Dopamine and dobutamine are the inotropes most commonly used in neonatal intensive care. Dopamine, a naturally occurring precursor of noradrenaline, may have specific dopaminergic actions in addition to well recognised alpha and beta adrenergic effects (Keeley 1988). It is generally accepted that the inotropic and peripheral vasoconstrictor effects of dopamine predominate in the newborn period, although there is considerable controversy surrounding the existence of any vasodilator effects in renal, coronary and cerebral circulations (Seri 1995, Barrington 1995). Dobutamine is a synthetic catecholamine with principally beta adrenergic actions (Keeley 1988). It has been suggested that it may offer the same beneficial inotropic effects as dopamine without the tendency for peripheral vasoconstriction.

The optimal dose of dopamine and dobutamine for the treatment of hypotensive preterm infants is uncertain. Pharmacokinetic studies have demonstrated wide variations in plasma concentrations between individuals for a given dose of dopamine or dobutamine. This is likely to be related to differences in plasma clearance rates which are independent of birthweight and gestational age. In addition, there is a poor correlation between plasma dopamine or dobutamine concentration and blood pressure response.(Bhatt-Mehta 1991, Martinez 1992, Zaritsky 1988, Padbury 1986).

Early studies of dopamine in infants and older children suggested high doses (> 10 micrograms/kg/min) may be necessary to treat hypotension (Lang 1980). Randomised controlled trials comparing dopamine with either colloid infusion or corticosteroid therapy in hypotensive preterm infants have demonstrated that successfully treated infants will respond at a median dose of 7.5 to 10 micrograms/kg/minute (Gill 1993a, Bourchier 1997). However, uncontrolled studies in preterm infants have demonstrated that lower dose therapy (2 to 8 micrograms/kg/minute) may also be effective in some individuals (Seri 1984, Seri 1993).

There are few studies of dobutamine in human neonates. A positive effect on left ventricular performance has been demonstrated at doses of 5 and 10 micrograms/kg/minute in term and preterm infants (Stopfkuchen 1987, Stopfkuchen 1990, Martinez 1992). Systemic blood flow increases in preterm infants at doses of 10 to 20 micrograms/kg/min (Osborn 2002).

Objectives

The aim of this review was to compare the effectiveness and safety of dopamine versus dobutamine in the treatment of systemic hypotension in preterm infants. The specific objectives were:

  1. To compare the effectiveness of treatment with dopamine versus dobutamine in reducing mortality and improving long term neurodevelopmental outcome in hypotensive preterm infants.
  2. To compare the effectiveness of both agents in reducing the incidence of adverse neuroradiological sequelae (severe periventricular haemorrhage and/or periventricular leucomalacia).
  3. To compare the effectiveness of both agents in increasing systemic arterial BP and/or cardiac output.
  4. To compare the frequency of adverse events related to treatment with dopamine versus dobutamine.

Criteria for considering studies for this review

Types of studies

All randomised and quasi-randomised controlled trials where short and/or long term effects of treatment with dopamine were compared to treatment with dobutamine in the neonatal period (< 28 days). Trials comparing either drug with placebo or no treatment were excluded.

Types of participants

Newborn infants born before 37 completed weeks gestation and less than 28 days of age with systemic arterial hypotension. No specific definition of systemic arterial hypotension was required for inclusion; this was as defined in individual studies. No birthweight or lower gestational age limits.

Types of interventions

Continuous infusion with dopamine or dobutamine. Trials were not limited in terms of dose, route or duration of drug administration.

Types of outcome measures

  1. Mortality within the neonatal period (< 28 days)
  2. Long term neurodevelopmental outcome (at two years)
  3. Radiological evidence of severe neurological injury (Grade 3/4 periventricular haemorrhage*, periventricular leukomalacia)
  4. Short term haemodynamic changes (systemic arterial BP, cardiac output)
  5. The occurrence of side effects, eg. tachycardia, arrhythmia

* Papile 1978

Search strategy for identification of studies

See: Collaborative Review Group search strategy

The standard search method of the Cochrane Neonatal Review Group as described in the Cochrane Library was used.

Searches of electronic and other databases were performed. These included MEDLINE (1966-2002), EMBASE (1988-2002), Science Citation Index (1981-2002), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003) and the Cochrane Neonatal Group's specialised register of controlled trials.

We used the following keywords/MeSH headings: neonate, newborn, infant, dopamine, dobutamine, hypotensive, hypotension, and inotrope.

Previous reviews were searched for references to relevant trials. Leading experts in the field were identified from these references and contacted for information about other published and unpublished studies. A total of nine experts were contacted, of whom six replied.

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Methods of the review

The standard method of the Cochrane Collaboration described in the Cochrane Collaboration Handbook was used to perform this systematic review.

The methodological quality of studies was assessed as recommended by the Neonatal Review Group, and this was performed independently by each reviewer. Data extraction from included studies was also performed independently by each reviewer, with differences being resolved by discussion. Studies published in abstract form only were excluded from this review, unless additional unpublished data were available from the author.

We attempted to contact all authors of eligible trials by letter and e-mail for information regarding individual patient data for changes in BP and long term outcomes when this was not reported in the original paper. This information was provided for only one study (Hentschel 1995).

Statistical analysis was performed using a fixed effects model. An intention-to-treat analysis was performed within groups as randomised, whether or not the alternate drug was given. The effect of interventions is expressed either as Relative Risk (RR), Risk Difference (RD) and Number Needed to Treat (NNT) or as Weighted Mean Difference (WMD) with their respective 95% Confidence Interval (CI).

Description of studies

See: Table of included studies
See: Table of excluded studies

Included Trials

Six trials were identified as meeting the criteria for inclusion into the review; five of these have been published in full (Greenough 1993, Roze 1993, Klarr 1994, Hentschel 1995, Ruelas-Orozco 2000). One trial (Chatterjee 1993) has been published only in abstract form, and further unpublished data are awaited prior to assessment for inclusion into this review. A further five randomised controlled trials were considered, but subsequently rejected because they reported comparisons between dopamine and either plasma protein fraction (Gill 1993a), hydrocortisone (Bourchier 1997) or no treatment (Cuevas 1991, DiSessa 1981); Osborn 2002 compared the effect of dopamine and dobutamine, but enrolled preterm infants with low systemic blood flow (as assessed by superior vena cava flow) rather than systemic hypotension.

Subjects

Included trials were broadly consistent with respect to infants studied: the study populations comprised ventilated preterm infants with a range of gestational age between 23 and 36 weeks, and birthweight between 552 and 2610 grams. All trials included infants who remained hypotensive despite a trial of volume expansion. Two studies only included infants who had intraarterial BP monitoring (Greenough 1993, Klarr 1994). Only one study (Greenough 1993) reported changes in systolic BP, whereas the other studies reported mean BP values.

Definition of systemic hypotension and treatment success

The following definitions of systemic hypotension were used: systolic BP < 40 mmHg (Greenough 1993); mean BP < 30 mmHg (Ruelas-Orozco 2000); mean BP < 30 mmHg for more than one hour (Roze 1993); mean BP < 31 mmHg for 30 minutes (Klarr 1994); mean BP below 10th percentile for the normal range quoted by Watkins 1989 (Hentschel 1995). Successful treatment of hypotension was achieved when an individual infant responded to treatment with an increase in BP above this threshold. An assessment of treatment success or failure was made at 2 hours (Ruelas-Orozco 2000) or 3 hours (Greenough 1993). Timing of assessment was not stated in two studies (Roze 1993, Klarr 1994). Treatment success was not a stated outcome measure in one study (Hentschel 1995).

Interventions

Inotropic therapy was commenced at a median age of less than 24 hours of age in most studies, although Hentschel 1995 studied infants up to 17 days of age. Both inotropic agents were administered as continuous infusions at doses between 5 and 20 micrograms/kg/min. Only two studies specified that the intravenous route was used for infusions (Klarr 1994, Hentschel 1995). Most studies included a stepwise increase in dose with one agent until either successful treatment of hypotension, or failure despite maximum dosage. However, the total duration of treatment with each inotrope was unclear in all studies.

Crossover of infants who had persistent hypotension despite maximal treatment with one drug was included as part of the study design in two trials (Roze 1993, Ruelas-Orozco 2000). In these trials, treatment was changed from one drug to the other at the maximal dose. Klarr 1994 permitted combination treatment with dopamine and dobutamine in infants failing to respond to a single agent.

Co-interventions

The proportion of infants exposed to antenatal corticosteroids was not reported in any study. The use of postnatal corticosteroids was specifically prohibited in two studies (Hentschel 1995, Klarr 1994). Only one study reported the use of surfactant replacement therapy (Klarr 1994).

Outcomes

Most trials reported only short term (< 4 hours) haemodynamic outcomes. The time interval between starting the drug and assessment of response varied between studies. Greenough 1993 assessed response at two time points, one hour and three hours post-treatment. Hentschel 1995 studied changes in BP at between 30 and 45 minutes post-treatment. Ruelas-Orozco 2000 reported BP response at 2 hours post-treatment. The other two studies also reported short term changes, but did not report the actual interval between onset of treatment and assessment of outcome.

Changes in BP with treatment were reported in all studies. One study (Greenough 1993) only reported percentage rise in systolic BP for change in BP at one hour, but absolute and percentage change in BP at three hours. Ruelas-Orozco 2000 and Roze 1993 only reported pre- and post-treatment group mean BP. Four studies (Greenough 1993, Klarr 1994, Roze 1993, Ruelas-Orozco 2000) compared the effects of dopamine and dobutamine in terms of the proportion of infants who failed to respond by normalising BP.

Change in left ventricular output (LVO) was assessed in only one study (Roze 1993) which reported percentage change in LVO along with pre- and post-treatment group mean LVO.

Important medium term outcomes were available for three out of five included studies. The incidence of periventricular leukomalacia and mortality < 28 days was available for three studies (Hentschel 1995, Klarr 1994 and Roze 1993). The incidence of severe grades 3/4 periventricular haemorrhage was available for two studies (Hentschel 1995 and Klarr 1994).

Long term outcome (neurodevelopmental outcome at two years of age) was not reported in any study.

The incidence of adverse effects of treatment was reported in only two studies. One study investigated the incidence of tachycardia defined as a heart rate > 180 beats per minute (Klarr 1994). Ruelas-Orozco 2000 also reported group mean changes in heart rate. The incidence of cardiac arrhythmia was not reported in any study.

Methodological quality of included studies

See: Table of included studies

The overall methodological quality of the five studies was variable.

Blinding of randomisation was stated as performed in all but one study (Roze 1993). The process of randomisation successfully produced broadly similar groups in all studies. Two studies blinded carers to the intervention, although in Roze 1993 only doctors were blinded (Klarr 1994, Roze 1993). Follow up of randomised infants was complete in all studies, although outcome assessment was blinded in only two studies (Klarr 1994, Hentschel 1995).

One study failed to report outcomes on a strict intention-to-treat basis (Klarr 1994). In this study, nine infants were excluded post-randomisation, but original outcome data in this group were unavailable, thus preventing an intention-to-treat analysis. The same study reported changes in BP only in successfully treated infants.

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Results

Five trials were included in this review (Greenough 1993, Hentschel 1995, Klarr 1994, Roze 1993, Ruelas-Orozco 2000).

See: Table of comparisons

The effectiveness of treatment with dopamine versus dobutamine in reducing mortality and improving long term neurodevelopmental outcome in hypotensive preterm infants:

  1. Mortality (< 28 days)
    1. None of the three trials which assessed effect of dopamine compared to dobutamine on neonatal mortality found evidence of a significant effect, nor did the meta-analysis (RR 1.17, 95% CI 0.47 to 2.92; RD 0.02, 95% CI -0.12 to 0.16).
  2. Long term neurodevelopmental outcome
    1. None of the studies evaluated long term neurodevelopmental outcome

The effectiveness of treatment with dopamine versus dobutamine in reducing the incidence of adverse neuroradiological sequelae (periventricular leucomalacia and/or severe periventricular haemorrhage):

  1. Periventricular leukomalacia
    1. Information about the incidence of periventricular leukomalacia was available from three studies. There was no evidence of a significant effect in the incidence of periventricular leukomalacia in any individual study, nor in the meta-analysis (RR 0.43, 95% CI 0.12 to 1.52; RD -0.08, 95% CI -0.19 to 0.04).
  2. Grade 3 or 4 periventricular haemorrhage
    1. There was no evidence of a significant effect with respect to the incidence of severe periventricular haemorrhage in either of the two studies reporting this outcome. Meta-analysis also did not reveal a significant effect (RR 0.73, 95% CI 0.15 to 3.50; RD -0.02, 95% CI -0.13 to 0.09).

The effectiveness of treatment with dopamine versus dobutamine in increasing systemic arterial BP and/or cardiac output:

  1. Treatment failure
    1. Treatment with dopamine was more successful than with dobutamine in all four studies reporting this outcome, with fewer infants having persistent hypotension despite inotropic therapy. This significant effect was confirmed in the meta-analysis (RR 0.41, 95% CI 0.25 to 0.65; RD -0.23, 95% CI -0.34 to -0.13; NNT = 4.3, 95% CI 2.9 to 7.7).
  2. Short term change in BP
    1. Greenough 1993 assessed the percentage change in systolic BP after starting treatment. The median percentage rise in systolic BP at one hour with dopamine was 17% (range -3 to +95%) compared with 11% (range -25 to +50%) for dobutamine. At three hours after starting treatment, the median rise in systolic BP was 23% (range -3 to 100%) with dopamine, versus 11% (range -6 to 45%) for dobutamine (p < 0.05).
    2. Ruelas-Orozco 2000 reported group mean BP at baseline and at 2 hours post-treatment. Mean (SD) mean BP rose from 26.8 (3.7) to 42.2 (10.3) mmHg with 5 mcg/kg/min of dopamine, compared to 25.6 (3.7) to 38.2 (7.3) mmHg with 5 mcg/kg/min of dobutamine.
    3. The precise timing of BP assessment was not specified in two studies. Roze 1993 reported the group mean BP before treatment and at the highest drug infusion dose. Mean (SE) mean BP rose from 25.6 (1.2) to 37.7 (1.5) mmHg with dopamine, compared to 24.4 (1.0) to 32.0 (1.4) mmHg with dobutamine (both p < 0.026). Klarr 1994 reported the change in mean BP at the time of successful treatment of hypotension: mean (SD) change in mean BP in this study was 11.3 (6.8) mmHg and 6.8 (4.4) mmHg for infants treated with dopamine and dobutamine, respectively. The rise in BP was significantly greater in responding infants who had received dopamine.
    4. A pooled estimate of the short term effect on BP of dopamine versus dobutamine has not been calculated because of the variation in measuring and reporting BP in the included studies.
  3. Change in left ventricular output (LVO)
    1. Roze 1993 only reported group mean LVO before treatment and at the highest drug infusion dose. Mean (SE) LVO fell from 245 (23) to 206 (21) ml/kg/min with dopamine, compared to a rise from 269 (36) to 313 (37) ml/kg/min with dobutamine. Mean (SE) change in LVO before treatment and at the highest dose was -14 (8) % with dopamine versus +21(7) % with dobutamine (p=0.005). From the published data calculation of absolute changes in LVO with dopamine and dobutamine was not possible, and this outcome was therefore not included in the analyses.

Frequency of adverse events related to treatment with dopamine versus dobutamine:

Klarr 1994 did not demonstrate a statistically significant difference in the incidence of tachycardia with dopamine versus dobutamine therapy: (RR 0.74, 95% CI 0.26 to 2.08; RD -0.06, 95% CI -0.25 to 0.14). Roze 1993 also did not demonstrate a significant difference in change in heart rate between the two treatments: mean (SE) increase in heart rate of +8 (4)% and +15 (5)% for dopamine and dobutamine treated infants, respectively. Similarly, Ruelas-Orozco 2000 did not demonstrate a significant difference in heart rate between the two treatments. No studies evaluated the incidence of cardiac arrhythmia.

There was no evidence of statistical heterogeneity between trials for any of the pooled outcome measures reported above.

Discussion

Summary of results

The results of this review suggest that dopamine is more effective than dobutamine in the short term treatment of systemic hypotension in preterm infants. The size of effect demonstrated means that between four and five infants would need to be treated with dopamine in preference to dobutamine to avoid one treatment failure. One study suggested that dobutamine may be more effective in increasing LVO compared to dopamine. There was no evidence of a statistically significant effect in any medium to long term outcome. There was no evidence of a statistically significant difference in the incidence of tachycardia between the two agents. The effect of dopamine compared to dobutamine with respect to long term neurodevelopmental outcome remains unknown.

Systemic arterial hypotension

Systemic hypotension is associated with cerebral injury (in particular, periventricular haemorrhage) in very low birthweight infants (Miall-Allen 1987, Cunningham 1999; Bada 1990). A causal link has been proposed whereby hypotension results in low cerebral perfusion pressure and low cerebral blood flow (Lou 1979). This concept of failure of autoregulation of cerebral blood flow in sick hypotensive preterm neonates has been challenged (Tyszczuk 1998). There is no convincing evidence that treatment of systemic hypotension using any agent is effective in increasing cerebral perfusion or decreasing cerebral injury .

There is no consensus regarding either the definition of hypotension or the threshold level of BP below which neurological injury is inevitable. One of two common approaches to define systemic arterial hypotension has been adopted by the studies included in this review: either to use an absolute threshold of BP (either mean BP < 30 mmHg, or systolic BP < 40 mmHg), or to use a value below the reference range derived from a population of stable 'healthy' preterm infants. It remains uncertain whether hypotension defined in this way is harmful and whether treatment to 'normalise' BP is beneficial. Nevertheless, aggressive treatment of hypotension is widely practiced. If a clinician chooses to treat systemic hypotension in a preterm infant, the evidence from this review suggests that dopamine is the more effective agent, at least in the short term.

It should be noted that treatment with dopamine whilst increasing systemic BP may result in a decrease in left ventricular output in some babies.

Dosage regimes

The dose of dopamine and dobutamine used in the studies included in this review is consistent with the information available from dose-response studies, and from previous randomised controlled studies (Seri 1984, Seri 1993, Gill 1993a, Bourchier 1997, Martinez 1992, Osborn 2002). There are few data regarding dose-response with dobutamine in hypotensive preterm infants and it is possible that higher doses of dobutamine than were used in these studies may be required to elicit the desired response in BP.

Limitations

The results of this review should be interpreted with some caution.

In total, only 209 infants were enrolled into the five trials. Therefore, even a relatively large, potentially clinically significant short term effect cannot reliably be excluded. Long term outcomes were not assessed in any study. None of the studies reported the incidence of exposure to antenatal corticosteroids; only one study reported the use of surfactant replacement therapy (Klarr 1994). This may limit the applicability of the results of this review.

Each study used different definitions of systemic hypotension and some included non-invasive methods of blood pressure monitoring to assess the effect of interventions. All studies concentrated predominantly on short term effects, mainly changes in BP and/or successful treatment of hypotension. Only one study reported changes in left ventricular output (Roze 1993). However, the incidence and characteristics of ductal flow were not reported in this study. Significant left to right ductal shunting will increase left ventricular output and yet reduce systemic perfusion (Evans 1996).

Total duration of therapy with one agent was unclear. Some trials also allowed treatment with the alternate drug and therefore interpretation of the effects of each treatment on medium and long term outcomes is difficult.

There was potential for bias in some of the included studies where the intervention and/or outcome assessment was either not blinded or blinding was not specified (Greenough 1993, Hentschel 1995, Roze 1993, Ruelas-Orozco 2000). Klarr 1994 did not perform an intention-to-treat analysis.

This review predominantly relied on published data. Unpublished outcome data were provided by one author (Hentschel 1995). Access to original patient data would have allowed us to calculate, for example, a pooled estimate of the effect of dopamine versus dobutamine in terms of change in BP.

Reviewers' conclusions

Implications for practice

Dopamine is more effective than dobutamine in the short term treatment of systemic hypotension in preterm infants. If short term treatment of systemic hypotension is considered to be the goal of cardiovascular support, dopamine should be used in preference to dobutamine.

However, in the absence of data confirming (1) that treatment of systemic hypotension is beneficial, and (2) the long term benefit and safety of dopamine compared to dobutamine, no firm recommendations can be made regarding the choice of drug to treat hypotension.

Implications for research

There is an urgent need to define the pathophysiological processes involved in the development of neurological injury in the preterm neonate.

The key questions are:

  1. Is there a causal relationship between systemic hypotension, low cerebral blood flow and neurological injury? What is the underlying pathophysiology?
  2. What is the importance of other factors (such as ductal shunting, high mean airway pressure and arterial carbon dioxide tension) which may affect this relationship?
  3. Is there an identifiable lower threshold of cerebral blood flow, cerebral perfusion pressure, systemic BP or cardiac output which can be used to identify reliably those infants who will subsequently suffer a significant neurological insult?
  4. If systemic hypotension is identified as an independent factor contributing to neurological injury, is it related to poor myocardial contractility and low cardiac output or to low systemic vascular resistance?
  5. Which agents (and at what doses) are effective in raising BP and/or cerebral blood flow?
  6. Further research will need to address these questions prior to undertaking large randomised controlled trials to investigate whether correction of systemic hypotension has any long term benefit in terms of survival and neurodevelopmental outcome.

Acknowledgements

We acknowledge the unpublished data provided by Dr. Hentschel for this review.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Greenough 1993 Randomised
Single centre trial
Blinding of randomisation: yes (sealed envelopes)
Blinding of intervention: no
Blinding of outcome assessment: unclear
Complete follow-up: yes
Preterm ventilated infants
Gestational age 23 - 34 weeks
Birthweight 552 - 1980 g
Age 1 - 6 days
Treatment with antenatal steroids: unclear
Treatment with surfactant: unclear
Baseline respiratory severity: FiO2 0.23 - 1.0
Pre-treatment with volume expansion: yes
Major exclusions: none stated
Dopamine (N = 20) versus Dobutamine (N = 20)
Route not specified
Starting dose 5 mcg/kg/min
Maximum dose 15 mcg/kg/min
Volume expansion: no
Corticosteroids: unclear
Successful treatment of hypotension
Rise in systolic BP with treatment (1 hour and 3 hours)
Invasive BP monitoring
Definition of hypotension: Systolic BP < 40 mmHg
Definition of success: BP > 40 mmHg at 3 hours
A
Hentschel 1995 Randomised
Single centre trial
Blinding of randomisation: yes
Blinding of treatment: no
Blinding of outcome assessment: yes
Complete follow-up: yes
Preterm ventilated infants
Gestational age 25 - 36 weeks
Birthweight 830 - 2610 g
Age 2 hrs - 17 days
Treatment with antenatal steroids: unclear
Treatment with surfactant: unclear
Baseline respiratory severity: unclear
Pre-treatment with volume expansion: yes
Major exclusions: NEC
Dopamine (N = 10) versus Dobutamine (N = 10)
Central venous infusion
Starting dose 10 mcg/kg/min
Maximum dose 10 mcg/kg/min
Volume expansion: no
Corticosteroids: no
Rise in mean BP with treatment (30 - 45 mins)
Neonatal mortality
Periventricular haemorrhage
Periventricular leukomalacia
Invasive and non-invasive BP monitoring
Definition of hypotension: Mean BP < 10th percentile
A
Klarr 1994 Randomised
Single centre trial
Blinding of randomisation: yes (sealed envelopes)
Blinding of intervention: yes
Blinding of outcome assessment: yes
Complete follow-up: yes
Preterm ventilated infants
Gestational age 24 - 34 weeks
Birthweight 590 - 2275 g
Age (mean) Dopamine 9.2; Dobutamine 8.7 hrs
Treatment with antenatal steroids: unclear
Treatment with surfactant: yes (artificial)
Baseline respiratory severity (mean): OI 7.3 Dopamine; OI 7.0 Dobutamine
Pre-treatment with volume expansion: yes
Major exclusions: Life threatening anomalies, CHD, Air leak
Dopamine (N = 31) versus Dobutamine (N = 32)
Infusion through umbilical or peripheral vein
Starting dose 5 mcg/kg/min
Maximum dose 20 mcg/kg/min
Combination therapy with other drug if treatment failure
Volume expansion: unclear
Corticosteroids: no
Successful treatment of hypotension
Rise in mean BP with treatment in successfully treated infants
Neonatal mortality
Periventricular haemorrhage
Periventricular leukomalacia
Invasive BP monitoring
Definition of hypotension: Mean BP < 31 mmHg
Definition of success: Mean BP > 30 mmHg for 30 minutes
A
Roze 1993 Randomised
Single centre trial
Blinding of randomisation: unclear
Blinding of intervention: (yes)
Blinding of outcome assessment: unclear
Complete follow-up: yes
Preterm ventilated infants
Gestational age 26 -31 weeks
Birthweight 670 - 1800 g
Age: unclear
Treatment with antenatal steroids: unclear
Treatment with surfactant: unclear
Baseline respiratory severity (mean): a/A 0.23 Dopamine; a/A 0.26 Dobutamine
Pre-treatment with volume expansion: yes
Major exclusions: not specified
Dopamine (N = 10) versus Dobutamine (N = 10)
Route not specified
Starting dose 5 mcg/kg/min
Maximum dose 20 mcg/kg/min
Crossover to other drug if treatment failure
Volume expansion: unclear
Corticosteroids: unclear
Successful treatment of hypotension
Change in mean BP
Change in left ventricular output
Neonatal mortality
Periventricular leukomalacia
Invasive and non-invasive BP monitoring
Definition of hypotension: Mean BP < 30 mmHg
Definition of success: Mean BP > 30 mmHg for unspecified period
Criteria for crossover: failure to achieve mean BP > 30 mmHg at dose of 20 mcg/kg/min
B
Ruelas-Orozco 2000 Randomised
Single centre trial
Blinding of randomisation: yes (table of numbers)
Blinding of intervention: no
Blinding of outcome assessment: no
Complete follow-up: yes
Preterm ventilated infants
Mean birth weight approx. 1345 grams
Mean age approx, . 21.5 hours
Treatment with antenatal steroids: unclear
Treatment with surfactant: unclear
Baseline respiratory severity: mean OI 18.9 (dopamine) and 21.5 (dobutamine)
Pre-treatment with volume expansion: yes
Major exclusions: history of maternal haemorrhage, hydrops
Dopamine (N = 33) versus Dobutamine (N = 33)
Route not specified
Starting dose 5 mcg/kg/min
Maximum dose 10 mcg/kg/min
Volume expansion: no
Corticosteroids: unclear
Successful treatment of hypotension Invasive and non-invasive BP monitoring
Definition of hypotension: Mean BP < 30 mmHg
Definition of success: Mean BP > 30 mmHg at 2 hours
Criteria for crossover: failure to achieve mean BP > 30 mmHg at dose of 10 mcg/kg/min within 2 hours
A

Characteristics of excluded studies

Study Reason for exclusion
Bourchier 1997 Randomised trial comparing the effects of dopamine versus hydrocortisone in very low birth weight infants with systemic hypotension.
Cuevas 1991 Randomised trial of two low-dose dopamine regimes versus no dopamine in preterm infants with RDS. Sub-group analysis was performed in infants with systemic hypotension.
DiSessa 1981 Placebo-controlled, randomised trial of dopamine in term or near-term asphyxiated infants.
Gill 1993a Randomised trial comparing the effects of dopamine versus plasma protein fraction in hypotensive very low birthweight infants.
Lopez 1997 Non-randomised study comparing haemodynamic parameters in preterm infants receiving dopamine plus dobutamine versus dopamine alone.
Lundstrom 2000 Randomised trial comparing the effects of dopamine, volume expansion with 20% Albumin and no treatment in normotensive preterm infants.
Miall-Allen 1989 Non-randomised study reporting the effect of addition of dobutamine in hypotensive preterm infants who did not respond to dopamine .
Osborn 2002 Randomised double-blind controlled cross-over trial comparing the effects of dopamine versus dobutamine in preterm infants with low superior vena cava flow.

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References to studies

Included studies

Greenough 1993

{published data only}

Greenough A, Emery EF. Randomized trial comparing dopamine and dobutamine in preterm infants. Eur J Pediatr 1993;152:925-927.

Hentschel 1995

{published and unpublished data}

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. Biol Neonate 1995;68:318-324.

Klarr 1994

{published data only}

Klarr JM, Faix RG, Pryce CJE, Bhatt-Mehta V. Randomized, blind trial of dopamine versus dobutamine for treatment of hypotension in preterm infants with respiratory distress syndrome. J Pediatr 1994;125:117-122.

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. Arch Dis Child 1993;69:59-63.

Ruelas-Orozco 2000

{published data only}

Ruelas-Orozco G, Varga-Origel A. Assessment of therapy for arterial hypotension in critically ill preterm infants. Am J Perinatol 2000;17(2):95-99.

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. Arch Dis Child 1997;76:F174-178.

Cuevas 1991

{published data only}

Cuevas L, Yeh TF, John EG, Cuevas D, Plides RS. The effect of low-dose dopamine infusion on cardiopulmonary and renal status in premature newborns with respiratory distress syndrome. Am J Dis Child 1991;145:799-803.

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. J Pediatr 1981;99:772-776.

Gill 1993a

{published data only}

Gill AB, Weindling AM. Randomised controlled trial of plasma protein fraction versus dopamine in hypotensive very lowbirthweight infants. Arch Dis Child 1993;69:284-287.

Lopez 1997

{published data only}

Lopez SL, Leighton JO, Walther FJ. Supranormal cardiac output in the dopamine- and dobutamine-dependent preterm infant. Pediatr Cardiol 1997;18:292-296.

Lundstrom 2000

{published data only}

Lundstrom K, Pryds O, Greisen G. The haemodynamic effects of dopamine and volume expansion in sick preterm infants. Early Hum Dev 2000;57:157-163.

Miall-Allen 1989

{published data only}

Miall-Allen VM, Whitelaw AG. Response to dopamine and dobutamine in the preterm infant less than 30 weeks gestation. Crit Care Med 1989;17:1166-1169.

Osborn 2002

{published data only}

Osborn D, Evans N, Kluckow M. Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow. J Pediatr 2002;140:183-191.

References to studies awaiting assessment

Chatterjee 1993

{published data only}

Chatterjee A, Bussey ME, Leuschen MP. The pharmacodynamics of inotropic drugs in premature neonates [abstract]. Pediatr Res 1993;33:206A.

* indicates the primary reference for the study

Other references

Additional references

Bada 1990

Bada HS, Korones SB, Perry EH, Arheart KL, Ray JD, Pourcyrous M, Magill HL, Runyan W 3rd, Somes GW, Clark FC, et al. Mean arterial blood pressure changes in premature infants and those at risk for intraventricular hemorrhage. J Pediatr 1990;117:607-614.

Barrington 1995

Barrington KJ. Circulatory effects of dopamine in neonates. J Pediatr 1995;127:843-844.

Bhatt-Mehta 1991

Bhatt-Mehta V, Nahata MC, McClead RE, Menke JA. Dopamine pharmacokinetics in critically ill newborn infants. Eur J Clin Pharmacol 1991;40:593-597.

Cunningham 1999

Cunningham S, Symon AG, Elton RA, Zhu C, McIntosh N. Intra-arterial blood pressure reference ranges, death and morbidity in very low birthweight infants during the first seven days of life. Early Hum Dev 1999;56:151-65.

Evans 1996

Evans N, Kluckow M. Early determinants of right and left ventricular output in ventilated preterm infants. Arch Dis Child 1996; 74;F88-94.

Gaissmaier 1999

Gaissmaier RE, Pohlandt FJ. Single-dose dexamethasone treatment of hypotension in preterm infants. J Pediatr 1999;134:701-705.

Gill 1993b

Gill AB, Weindling AM. Echocardiographic assessment of cardiac function in shocked very low birthweight infants. Arch Dis Child 1993;68:17-21.

Goldstein 1995

Goldstein RF, Thompson RJ, Oehler JM et al. Influence of acidosis, hypoxaemia, and hypotension on neurodevelopmetal outcome in very low birth weight infants. Pediatrics 1995;95:238-243.

Keeley 1988

Keeley SR, Bohn DJ. The use of inotropic and afterload-reducing agents in neonates. Clin Perinatol 1988;15:467-489.

Kluckow 1996

Kluckow M, Evans N. Relationship between blood pressure and cardiac output in preterm infants requiring mechanical ventilation. J Pediatr 1996;129:506-512.

Lang 1980

Lang P, Williams RG, Norwood WI, Castaneda AR. The hemodynamic effects of dopamine in infants after corrective cardiac surgery. J Pediatr 1980;96:630-634.

Lou 1979

Lou HC, Skov H, Pedersen H. Low cerebral blood flow: a risk factor in the neonate. J Pediatr 1979;95:606-609.

Low 1993

Low JA, Froese AB, Galbraith RS, Smith JT, Sauerbrei EE, Derrick EJ. The association between preterm newborn hypotension and hypoxemia and outcome during the first year. Acta Paediatr 1993;82:433-437.

Martinez 1992

Martinez AM, Padbury JF, Thio S. Dobutamine pharmacokinetics and cardiovascular responses in critically ill neonates. Pediatrics 1992;89:47-51.

Meek 1999

Meek JH, Tyszczuk L, Elwell CE, Wyatt JS. Low cerebral blood flow is a risk factor for severe intraventricular haemorrhage. Arch Dis Child Fetal Neonatal Ed 1999;81:15-18.

Miall-Allen 1987

Miall-Allen VM, De Vries LS, Whitelaw AGL. Mean arterial blood pressure and neonatal cerebral lesions. Arch Dis Child 1987;62:1068-1069.

Padbury 1986

Padbury JF, Agata Y, Baylen BG et al. Dopamine pharmacokinetics in critically ill newborn infants. J Pediatr 1986;110:293-298.

Papile 1978

Papile L-A, Burnstein J, Burstein R, Koeffler H. Incidence and evolution of subependymal and intraventricular haemorrhage: a study of infants with birthweight < 1500g. J Pediatr 1978;92:529-534.

Perlman 1996

Perlman JM, Risser R, Broyles RS. Bilateral cystic periventricular leukomalacia in the premature infant: associated risk factors. Pediatrics 1996;97:822-827.

Seri 1984

Seri I, Tulassay T, Machay T, Csomor S. Cardiovascular response to dopamine in hypotensive preterm neonates with severe hyaline membrane disease. Eur J Pediatr 1984;142:3-9.

Seri 1993

Seri I, Rudas G, Bors Z, Kanyicksa B, Tulassay T. Effects of low-dose dopamine infusion on cardiovascular and renal functions, cerebral blood flow, and plasma catecholamine levels in sick preterm neonates. Pediatr Res 1993;34:742-749.

Seri 1995

Seri I. Cardiovascular, renal, and endocrine actions of dopamine in neonates and children. J Pediatr 1995;126:333-344.

So 1997

So KW, Fok TF, Ng PC, Wong WW, Cheung KL. Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants. Arch Dis Child 1997;76:F43-F46.

Stopfkuchen 1987

Stopfkuchen H, Schranz D, Huth R, Jungst B-K. Effects of dobutamine on left ventricular performance in newborns as determined by systolic time intervals. Eur J Pediatr 1987;146:135-139.

Stopfkuchen 1990

Stopfkuchen H, Queisser-Luft A, Vogel K. Cardiovasular responses to dobutamine determined by systolic time intervals in preterm infants. Crit Care Med 1990;18:722-724.

Trounce 1988

Trounce JQ, Shaw DE, Levene MI, Rutter N. Clinical risk factors and periventricular leucomalacia. Arch Dis Child 1988;63:17-22.

Tyszczuk 1998

Tyszczuk L, Meek J, Elwell C, Wyatt JS. Cerebral blood flow is independent of mean arterial blood pressure in preterm infants undergoing intensive care. Pediatrics 1998;102:337-341.

Watkins 1989

Watkins AM, West CR, Cooke RW. Blood pressure and cerebral haemorrhage and ischaemia in very low birthweight infants. Early Hum Dev 1989;19:103-110.

Zaritsky 1988

Zaritsky A, Lotze A, Stull R, Goldstein DS. Steady-state dopamine clearance in critically ill infants and children. Crit Care Med 1988;16:217-220.

Other published versions of this review

Subhedar 1999

Subhedar NV, Shah NJ. Dopamine versus dobutamine for hypotensive preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 1999. Oxford: Update Software.

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Data and analyses

01 Dopamine versus dobutamine

Comparison or outcome Studies Participants Statistical method Effect size
01.01 Mortality < 28 days 2 103 RR (fixed), 95% CI 1.17 [0.47, 2.92]
01.02 Periventricular leukomalacia 2 103 RR (fixed), 95% CI 0.43 [0.12, 1.52]
01.03 Periventricular haemorrhage grade 3/4 2 83 RR (fixed), 95% CI 0.73 [0.15, 3.50]
01.04 Treatment failure 4 189 RR (fixed), 95% CI 0.41 [0.25, 0.65]
01.05 Tachycardia 1 63 RR (fixed), 95% CI 0.74 [0.26, 2.08]

Additional tables

  • None noted.

Amended sections

Cover sheet
Synopsis
Abstract
Background
Search strategy for identification of studies
Methods of the review
Description of studies
Methodological quality of included studies
Results
Discussion
References to studies
Other references
Characteristics of Included Studies
Characteristics of excluded studies
Comparisons, data or analyses

Contact details for co-reviewers

Dr N J Shaw

Consultant Neonatologist
Neonatal Intensive Care Unit
Liverpool Women's Hospital
Crown Street
Liverpool
UK
L8 7SS
Telephone 1: +44 151 708 9988
Facsimile: +44 151 702 4313

E-mail: Ben.Shaw@lwh-tr.nwest.nhs.uk


This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2003 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and cirticisms, and The Cochrane Library should be consulted for the most recent version of the Review.