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Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants

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Authors

David A Osborn1, Nicholas J Evans2

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


1RPA Newborn Care, Royal Prince Alfred Hospital, Camperdown, Australia [top]
2Neonatal Medicine, Royal Prince Alfred Hospital, Camperdown, Australia [top]

Citation example: Osborn DA, Evans NJ. Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD002056. DOI: 10.1002/14651858.CD002056.

Contact person

David A Osborn

RPA Newborn Care
Royal Prince Alfred Hospital
Missenden Road
Camperdown
New South Wales
2050
Australia

E-mail: david.osborn@email.cs.nsw.gov.au

Dates

Assessed as Up-to-date: 31 July 2008
Date of Search: 31 July 2008
Next Stage Expected: 31 August 2010
Protocol First Published: Issue 2, 2000
Review First Published: Issue 2, 2001
Last Citation Issue: Issue 2, 2001

What's new

Date / Event Description
31 July 2008
Updated

This review updates the existing review of "Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants" published in the Cochrane Database of Systematic Reviews, Issue 2, 2004 (Osborn 2004).

Updated literature search found no new studies.

Background updated.

No changes in conclusions.

20 April 2008
Amended

Converted to new review format.

History

Date / Event Description
09 February 2004
Updated

This review updates the existing review of "Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants" published in The Cochrane Library, Issue 3, 2001 (Osborn 2001).

Searches of data bases were updated to January 2004. One additional study found was ineligible for inclusion.

No change made to included studies, results or conclusions.

15 February 2001
New citation: conclusions changed

Substantive amendment

Abstract

Background

Reduced perfusion of organs such as the brain, heart, kidneys and the gastrointestinal tract may lead to acute dysfunction and be associated with permanent injury. Various strategies have been used to provide cardiovascular support to preterm infants including inotropes, corticosteroids and volume expansion.

Objectives

To determine the effect of early volume expansion compared to inotrope in reducing morbidity and mortality in very preterm infants. Subgroup analysis was planned according to method of diagnosis of poor perfusion, postnatal age of treatment and type of volume expansion and inotrope used.

Search methods

Updated searches were performed of the Cochrane Central Register of Controlled Trials (Issue 3, 2008), MEDLINE (1996 - July 2008), EMBASE (1980 - July 2008), previous reviews including cross references, abstracts and conferences.

Selection criteria

All randomised trials that compared volume expansion to an inotrope in preterm infants born less than/or equal to 32 weeks gestation or less than/or equal to 1500 g in the first days after birth were included.

Data collection and analysis

Data were extracted independently by each author and analysed using the standard methods of the Cochrane Collaboration and its Neonatal Review Group using relative risk (RR), risk difference (RD) and weighted mean difference (WMD).

Results

Two small studies comparing volume expansion (using albumin) with dopamine were included. Both studies were adequately randomised, unblinded studies of albumin vs. dopamine with no losses to follow-up and analysed by intention to treat. Data for clinical outcomes were available from one study in hypotensive preterm infants in the first day after birth. In this study, albumin had a higher failure rate for correcting hypotension dopamine (RR 5.23; 95% CI 1.33 to 20.55). As 49% of these infants had already been given volume, the question of which treatment should be given first was not answered. A second study compared albumin with dopamine in preterm infants with a normal mean blood pressure (BP) at a mean age of 32 hours. Dopamine produced a significant increase in mean BP when compared to infants who received albumin or no treatment, although the difference between the dopamine and albumin groups did not reach significance. Albumin and dopamine produced similar increases in left ventricular output but no significant change in cerebral blood flow. No difference was found in mortality (RR 1.45; 95% CI 0.53 to 3.95) or morbidity including any P/IVH, chronic lung disease or retinopathy. There was a higher rate of grade 2 - 4 P/IVH of borderline statistical significance in infants who received albumin in one study (RR 1.47; 95% CI 0.96 to 2.25: RD 0.27, 95% CI 0.00 to 0.54). No data were available for neurodevelopmental outcomes.

Authors' conclusions

Dopamine was more successful than albumin at correcting low BP in hypotensive preterm infants, many of whom had already received volume. Neither intervention has been shown to be superior at improving blood flow or in improving mortality and morbidity in preterm infants. The trials do not allow any firm conclusions to be made as to whether or when volume or dopamine should be used in preterm infants.

Plain language summary

Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants

Not enough evidence to show the effect of early volume expansion in very preterm babies. Low blood pressure and blood flow are common in preterm babies and can cause brain injury, organ damage and developmental problems. Increasing the amount of fluid in the blood stream (volume expansion) using albumin or salt solutions may increase the blood pressure and flow of blood. Inotrope drugs such as dopamine are used to increase the heart rate and blood pressure. The review of trials compared early volume expansion with inotropes. The review found dopamine is more effective than albumin at correcting low blood pressure in preterm babies but neither improves outcomes for babies. More research is needed.

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Background

Reduced perfusion of organs such as the brain, heart, kidneys and the gastrointestinal tract may lead to acute dysfunction and be associated with permanent injury. Twenty percent of surviving babies born very premature have some degree of neurodevelopmental disability (Lorenz 1998). Peri/intraventricular haemorrhage (P/IVH) is a major risk factor for neurodevelopmental disability (Vohr 2000). Low systemic blood pressure (BP) and blood flow have both been linked to cerebral injury (Miall-Allen 1987; Goldstein 1995; Low 1993). Low upper body blood flow (Kluckow 2000; Osborn 2003; Miletin 2008) and low cerebral blood flow (Meek 1999) in the first day after birth are also associated with late P/IVH. In addition, low upper body blood flow on the first day of life (as measured by flow in the superior vena cava) is associated with a significant increase in mortality (Osborn 2003; Kluckow 2000), necrotising enterocolitis (Osborn 2007) and subsequent neurodevelopmental impairment (Hunt 2004; Osborn 2007) in infants born < 30 weeks' gestation.

Clinical features suggesting reduced perfusion include low BP, reduced cutaneous perfusion and metabolic acidosis. However, systemic arterial pressure has been shown to be poorly correlated with systemic blood flow (SBF) in preterm infants (Kluckow 1996; Kluckow 2000; Osborn 2004). In addition, clinical measures of hypovolaemia including systemic hypotension have been found to be poorly correlated to blood volume (Barr 1977; Bauer 1993).

Various therapeutic strategies have been used to provide cardiovascular support to preterm infants including inotropes, corticosteroids and volume expansion. Most strategies have targeted low BP using inotropes such as dopamine vs. dobutamine (Greenough 1993; Hentschel 1995; Klarr 1994; Roze 1993), dopamine vs. adrenaline (Pellicer 2005; Valverde 2006), corticosteroids (Gaissmaier 1999), and corticosteroids vs. dopamine (Bourchier 1997). Trials of dopamine vs. dobutamine in very preterm infants with systemic hypotension have not found a difference between these inotropes at preventing mortality and P/IVH. Dopamine was more effective than dobutamine at treating systemic hypotension in very preterm infants (Subhedar 2003). Despite an increase in systemic BP, dopamine was shown to reduce aortic blood flow in one study (Roze 1993). In another study in very preterm infants with low SBF, dobutamine produced little change in BP but a significantly greater increase in SBF than dopamine, despite dopamine resulting in a significantly greater increase in BP (Osborn 2002). However, there was no significant difference in long-term outcomes (Osborn 2007; Osborn 2007a). Strategies to correct systemic hypotension and hypovolaemia have also included volume expansion. Observational studies have found increases in cardiac output after albumin infusion in sick preterm infants (Pladys 1997) and a small increase in systemic BP in hypotensive preterm infants (Barr 1977; Bignall 1989). Short-term increases in SBF have also been reported after saline infusion in preterm infants with low SBF (Osborn 2002). Observational studies have also reported an increase in P/IVH (Goldberg 1980) and chronic lung disease (Van Marter 1990) in preterm infants receiving volume expansion. A systematic review of randomised controlled trials of albumin infusions in critically ill patients including those with hypovolaemia, burns and hypoalbuminaemia found a significantly increased mortality for those patients receiving albumin compared to control (Alderson 2004).

This review evaluates the evidence from randomised controlled trials regarding the use of early volume expansion compared to inotrope to prevent mortality and morbidity in very preterm infants. In view of the difficulties of identifying infants with poor perfusion and hypovolaemia, subgroup analyses were planned according to method of diagnosis of poor perfusion [unselected preterm infants, preterm infants with clinical indicators of poor perfusion (low BP, reduced cutaneous perfusion and metabolic acidosis) and infants with ultrasound Doppler detected low blood flow]. As there is evidence to suggest that late P/IVH is associated with systemic hypotension and low SBF on the first day of life (Miall-Allen 1987; Goldstein 1995; Kluckow 2000; Miletin 2008; Osborn 2003), subgroup analyses were planned with the hypothesis that trials that treated infants early (before 12 to 24 hours) were more likely to prevent P/IVH. As different volume expanders and inotropes have different effects, subgroup analyses were planned according to type of volume expansion (normal saline, fresh frozen plasma, albumin, plasma substitute or blood) and inotrope used.

Objectives

To determine the effect of early volume expansion compared to early inotrope use in reducing morbidity and mortality in very preterm infants. Subgroup analyses were planned according to method of diagnosis of poor perfusion [unselected preterm infants, preterm infants with clinical indicators of poor perfusion (eg. low BP, reduced cutaneous perfusion and metabolic acidosis) and infants with ultrasound Doppler detected low blood flow], postnatal age at treatment and type of volume expansion and inotrope used.

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Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials that compare volume expansion with an inotrope.

Types of participants

Very preterm infants born less than/or equal to 32 weeks' gestation or less than/or equal to 1500g and enrolled and treated in the first 72 hours after birth. The mean or median age was taken as the criterion for inclusion. Eligible trials enrolled either unselected preterm infants (not selected on the basis of cardiovascular compromise), preterm infants with low BP or preterm infants with low blood flow. Trials enrolling only infants with suspected hypovolaemia due to acute blood loss (eg infants born with history of documented peripartum blood loss, tachycardia and pallor) were excluded.

Types of interventions

Volume expansion (including normal saline, fresh frozen plasma, plasma substitute or albumin) compared to inotrope infusion (including dopamine, dobutamine, epinephrine or isoprenaline).

Types of outcome measures

Primary outcome measures included any of the following:
  1. Neonatal mortality and mortality to discharge
  2. Peri/intraventricular haemorrhage (any or severe grades)
  3. Periventricular leucomalacia
  4. Neurodevelopmental disability (neurological abnormality including cerebral palsy, developmental delay or sensory impairment)
Secondary outcome measures included any of the following;
  1. Backup use of volume or inotropes (in first 72 hours)
  2. Failure to correct low SBF (eg Doppler ultrasound after volume expansion)
  3. Failure to correct systemic hypotension (enrolment criteria used in trial)
  4. Patent ductus arteriosus (PDA)
  5. Renal impairment (creatinine greater than/or equal to 120 micromol/l, oliguria less than/or equal to 0.5ml/kg/hour)
  6. Airleak (any and gross including pneumothorax or pneumomediastinum)
  7. Chronic lung disease (at 28 postnatal days or near term postmenstrual age)
  8. Proven necrotising enterocolitis
  9. Retinopathy of prematurity (any stage and severe stage 3 or greater)
Subgroup analyses were planned for the following identified subcategories:
  1. Including only trials where volume expansion was given a) in the first day after birth, and b) in the first 12 hours after birth,
  2. According to type of volume expansion used (normal saline, fresh frozen plasma, albumin or blood), and type of inotrope (dopamine, dobutamine. isoprenaline, adrenaline),
  3. According to whether trials enrolled:
    • Unselected preterm infants,
    • Preterm infants with clinical indicators of poor perfusion (low BP, poor cutaneous perfusion or metabolic acidosis),
    • Preterm infants with ultrasound Doppler diagnosed low blood flow,

All primary and secondary outcomes were to be included in subgroup analysis where available.

Search methods for identification of studies

An updated search was performed of Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 3, 2008), MEDLINE (1996 - July 2008), EMBASE (1980 - July 2008), previous reviews including cross references (all articles referenced), abstracts and conferences (Perinatal Society of Australia and New Zealand, and Pediatric Academic Societies and American Academy of Pediatrics meetings 2004 - 2008). The previously documented search strategy was expanded to include MeSH terms "[polygeline or albumins]" and text terms "[starch or albumin or albumen or gelofusine or plasma]"

This review updates a previous version (Osborn 2001). The previous update reported no new eligible reviews found up to January 2004. All updates used the standard search strategy of the Neonatal Review Group. The original review (Osborn 2001) included searches of the Oxford Database of Perinatal Trials. The January 2004 update included searches of CENTRAL (The Cochrane Library, Issue 1, 2004), MEDLINE (January 2004), previous reviews including cross references, abstracts and conferences (Perinatal Society of Australia and New Zealand, and Pediatric Academic Societies and American Academy of Pediatrics Meetings 1998 - 2003). The search of MEDLINE 1966 - January 2004 included MeSH searches using the following terms ("[colloids or plasma substitutes or sodium chloride or serum albumin or hypotension] and [dopamine or dobutamine or epinephrine or isoproterenol] and [infant-premature or newborn]") and text words were searched using the following terms ("[colloid or crystalloid or saline or volume or hypotension] and [dopamine or dobutamine or epinephrine or isoproterenol or inotrope or adrenaline or dopexamine or isoprenaline] and [infant-premature]"). No language restriction was used.

Data collection and analysis

Criteria and methods used to assess the methodological quality of the included trials: Standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The methodological quality of each trial was reviewed independently by the second author. 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.

Methods used to collect data from the included trials: Each author extracted data separately, then compared and resolved differences. Additional data will be requested from authors of each trial for the next update.

Methods used to synthesise the data: Standard method of Neonatal Review Group with use of relative risk, risk difference and weighted mean difference where appropriate. The fixed effects model using RevMan 5.0 was used for meta-analysis.

Sensitivity analysis was planned on the basis of methodological quality.

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Results

Description of studies

See table 'Characteristics of Included Studies'. No new studies comparing use of volume expansion vs. an inotrope in very preterm infants were found.

Two studies met criteria for inclusion in this review (Gill 1993; Lundstrom 2000). One non-randomised study comparing an inotrope to volume was excluded (Kawczynski 1996). No additional eligible studies were found. One additional study found was excluded (Rennie 1989) as it was a non-randomised comparison of infants receiving dopamine and plasma.

Participants: Both eligible studies enrolled very preterm infants either < 1501 g (Gill 1993) or < 33 weeks (Lundstrom 2000). Infants in the study by Gill 1993 were hypotensive (mean BP < 10th percentile) infants < 24 hours age with an indwelling arterial line. They were given 20 ml/kg plasma protein fraction prior to enrolment if thought to be in shock (49% of infants). Infants in the study by Lundstrom 2000 were enrolled if the mean BP was in the normal range (29 - 40 mmHg) and they had not received volume or inotrope in the preceding three hours. The authors state that this group were considered to be above the presumed normal upper limit for hypotension but from previous work may still be at risk of low left ventricular output and cerebral blood flow. The mean age of enrolment was 31.8 hours (range 5 - 224). The sample sizes were small with 39 infants in the study by Gill 1993 and 24 infants in the Lundstrom 2000 study. Lundstrom 2000 had a control group of 12 infants who received no treatment. The data for this group are not presented in this review but the statistical significance using ANOVA as reported in the paper is documented. The standard deviations for mean BP, left ventricular output and cerebral blood flow are calculated from the reported 95% confidence intervals.

Interventions: Gill 1993 compared albumin 4.5% 20 ml/kg over 20 minutes (repeated if the mean BP remained < 10th percentile) to dopamine 5 mcg/kg/min (increased every 30 minutes by 2.5 mcg/kg/min to maximum 10 mcg/kg/min if mean BP remained < 10th percentile). Lundstrom 2000 compared albumin 20% 15 ml/kg to dopamine 5 mcg/kg/min.

Outcomes: Gill 1993's primary outcome was correction of hypotension (mean BP > 10th percentile). Clinical data were available for P/IVH, duration of ventilation, chronic lung disease (abnormal x-ray and oxygen at 28 days) and retinopathy. Lundstrom 2000's primary outcome was change in cerebral blood flow measured using xenon clearance. Invasive arterial mean BP and ultrasound determined left ventricular outputs were also measured. No periventricular leucomalacia was observed. No other clinical data were available according to randomised groups.

Risk of bias in included studies

Both Gill 1993 and Lundstrom 2000 are adequately randomised, unblinded studies of volume vs. dopamine with no losses to follow-up and analysed by intention to treat (see table 'Characteristics of Included Studies').

Effects of interventions

ALBUMIN VS. DOPAMINE IN PRETERM INFANTS (Comparison 1):

Mortality: Two trials reported mortality (Gill 1993; Lundstrom 2000). Neither found evidence of effect. The meta-analysis showed no significant difference in mortality between infants receiving albumin and dopamine (RR 1.45; 95% CI 0.53 to 3.95: RD 0.08, 95% CI -0.12 to 0.27).

Peri/intraventricular haemorrhage: One study reported P/IVH (Gill 1993). All infants were reported to have a P/IVH, any grade. There was an increase in rate of grade 2 - 4 P/IVH with albumin that was of borderline statistical significance (RR 1.47; 95% CI 0.96 to 2.25: RD 0.27, 95% CI 0.00 to 0.54). Periventricular leucomalacia was reported by Lundstrom 2000 with no infants having this outcome.

Failed treatment: One study (Gill 1993) enrolled hypotensive very preterm infants and reported rates of treatment failure (hypotension). Infants receiving albumin had a higher failure rate (persistent hypotension) compared to infants receiving dopamine (RR 5.23; 95% CI 1.33 to 20.55; RD 0.44, 95% CI 0.19 to 0.70).

Chronic lung disease and retinopathy of prematurity were reported by one study (Gill 1993). No difference in the incidence of chronic lung disease (RR 0.7, 95% CI 0.4 to 1.3: RD -0.18, 95% CI -0.49 to 0.13) or retinopathy of prematurity (RR 0.83, 95% CI 0.37 to 1.84: RD -0.07, 95% CI -0.38 to 0.23) was found.

Neurodevelopmental outcome was not reported by either study.

Blood pressure and cardiovascular response: Lundstrom 2000 reported albumin produced a trend to a lower percent increase in mean BP compared to dopamine (Mean Difference -13.9%, 95% CI -43.6 to 15.8%). When compared to volume and no treatment, dopamine produced a significantly greater percent increase in mean BP (reported ANOVA in paper). Infants receiving albumin and dopamine had similar increases in left ventricular output (MD 3.4%, 95% CI -47.2 to 54.0%). These changes were significant compared to the untreated control group (reported ANOVA in paper). Changes in cerebral blood flow were not significantly different from each other (MD 5.9%, 95% CI -25.0 to 36.8%) or from the untreated control group.

SUBGROUP ANALYSIS:

Subgroup analysis by timing of intervention (< 24 hours): Gill 1993 enrolled infants < 24 hours of age and demonstrated no difference in mortality. There was an increased rate of grade 2 - 4 P/IVH of borderline significance in infants receiving albumin. This observation is consistent with the original hypothesis that early treatment is more likely to prevent P/IVH. The rate of failed treatment was higher in the albumin group (see above).

Subgroup analysis by types of infants enrolled: Lundstrom 2000 enrolled 'unselected' infants (without clinical evidence of cardiovascular compromise). No difference in rates of mortality or periventricular leucomalacia were found. Dopamine was better than albumin and control (but not albumin alone) at increasing mean BP and had similar effects to albumin on blood flow. Gill 1993 enrolled hypotensive preterm infants. No difference in mortality was found. Rates of grade 2 - 4 P/IVH were of borderline significance (see above). The rate of failed treatment was higher in the albumin group (see above).

Subgroup analysis by type of intervention: Both studies compared albumin and dopamine. No other analysis was possible.

HETEROGENEITY

There was no heterogeneity between the two studies for mortality, the only outcome where both studies contributed to the meta-analysis.

Discussion

In a single small study enrolling hypotensive very preterm infants on the first day after birth, dopamine was better than albumin at increasing BP. As 49% of these infants had already been given volume, the question of which treatment should be given first was not answered. In normotensive preterm infants with a mean age of 32 hours, albumin and dopamine produced similar increases in left ventricular output and did not affect cerebral blood flow. No difference was found in mortality or any morbidity including P/IVH, chronic lung disease and retinopathy. Infants who received dopamine had a lower rate of grade 2 - 4 P/IVH of borderline statistical significance compared to those receiving albumin in one study. No data were available for neurodevelopmental outcomes.

Limitations to the studies in this review include their small size limiting the power to detect clinically important outcomes, the enrolment of infants who may not have cardiovascular compromise, the unblinded treatment of infants and measurement of outcomes, and the failure to measure important outcomes including neurodevelopment. Whereas low BP has been linked to cerebral injury (Low 1993, Miall-Allen 1987), low BP is poorly correlated with cardiac output in very preterm infants in the first days after birth (Kluckow 1996; Osborn 2004). Low blood flow in the first day of life is strongly predictive of cerebral injury (Hunt 2004; Kluckow 2000; Meek 1999; Osborn 2003; Osborn 2007). It is uncertain whether selecting infants on the basis of a low mean BP and using BP as the primary outcome accurately identifies those infants in need of cardiovascular intervention and appropriately evaluates response to treatment. The study which examined the effect of volume and dopamine on blood flow enrolled normotensive preterm infants.

Authors' conclusions

Implications for practice

Dopamine was more successful than albumin at correcting low BP in hypotensive preterm infants. Neither intervention has been shown to be superior at improving blood flow, or in improving mortality and morbidity in preterm infants. The trials do not allow any firm conclusions to be made as to whether or when volume or dopamine should be used in preterm infants.

Implications for research

Studies are needed that identify infants with cardiovascular compromise and have the power to detect clinically important outcomes including mortality, peri/intraventricular haemorrhage and neurodevelopmental disability. In measuring short-term effects, measures of cerebral and organ blood flow or cardiac output should be included.

Acknowledgements

  • None noted.

Contributions of authors

DO wrote the review update. Both authors performed the literature search.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Gill 1993

Methods

Adequate randomisation: yes, random number generator, blocks of 10, using sealed envelopes
Allocation concealment: yes
Blinding of intervention: no
Blinding of measurement: no
Losses to follow up: none

Participants

Preterm infants < 1501 g and < 24 hours age, indwelling arterial line, hypotensive (mean BP < 10th percentile), given 20 mls/kg plasma protein fraction prior to insertion of line if clinician felt infant to be 'shocked'
Mean gestation: Group 1: 26.5 weeks (range 604-1452); Group 2: 27 (23-31)
Mean birthweight: Group 1: 980g (range 640-1300); Group 2: 990g (660-1450)

Interventions

Group 1 (n = 20): albumin 4.5% 20 mls/kg over 30 mins, repeated if mean BP not increased to > 10th percentile
Group 2 (n = 19): dopamine 5 mcg/kg/min, increased by 2.5 mcg/kg/min every 30 mins up to maximum 10 mcg/kg/min or mean BP > 10th percentile

Outcomes

Stated primary outcome: correction of hypotension (mean BP < 10th percentile)
Other outcomes: peri/intraventricular haemorrhage, duration of ventilation, chronic lung disease (oxygen at 28 days with abnormal chest x-ray), retinopathy of prematurity, mortality

Notes

49% of infants received volume expansion prior to study.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Lundstrom 2000

Methods

Adequate randomisation: yes, sealed envelopes
Allocation concealment: yes
Blinding of intervention: no
Blinding of measurement: not stated
Losses to follow up: none

Participants

Preterm infants < 33 weeks (median 28, range 25-32), arterial line, mean arterial BP 29 to 40 mmHg, normal blood glucose, no volume or inotrope support within preceding 3 hours
Mean postnatal age = 31.8 hrs (range 5-224)
Mean gestation: Group 1: 27.9 weeks; Group 2: 28.6
Mean birthweight: Group 1: 1134g; Group 2: 1238g

Interventions

Intervention:
Group 1 (n = 13): albumin 20% 15 mls/kg
Group 2 (n = 11): dopamine 5 mcg/kg/min

Outcomes

Stated primary outcome: mean arterial BP, left ventricular output, global cerebral blood flow
Other outcomes: mortality, peri/intraventricular haemorrhage, periventricular leucomalacia

Notes

Clinical data for mortality obtained from author.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Characteristics of excluded studies

Kawczynski 1996

Reason for exclusion

Not randomized.

Rennie 1989

Reason for exclusion

Non randomised comparison of dopamine and plasma.

Summary of findings tables

  • None noted.

Additional tables

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References to studies

Included studies

Gill 1993

* 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;69:384-7.

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).

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.

Excluded studies

Kawczynski 1996

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.

Rennie 1989

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

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Alderson 2004

The Albumin Reviewers (Alderson P, Bunn F, Lefebvre C, Li Wan Po A, Li L, Roberts I, Schierhout G). Human albumin solution for resuscitation and volume expansion in critically ill patients (Cochrane Review). Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD001208. DOI: 10.1002/14651858.CD001208.pub2 .

Barr 1977

Barr PA, Bailey PE, Sumners J, Cassady G. Relation between arterial blood pressure and blood volume and effect of infused albumin in sick preterm infants. Pediatrics 1977;60:282-9.

Bauer 1993

Bauer K, Linderkamp O, Versmold HT. Systolic blood pressure and blood volume in preterm infants. Archives of Disease in Childhood 1993;69:521-2.

Bignall 1989

Bignall S, Bailey PC, Bass CA, Cramb R, Rivers RP, Wadsworth J. The cardiovascular and oncotic effects of albumin infusion in premature infants. Early Human Development 1989;20:191-201.

Bourchier 1997

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 1997;76:F174-8.

Gaissmaier 1999

Gaissmaier RE, Pohlandt F. Single dose dexamethasone treatment of hypotension in preterm infants. Journal of Pediatrics 1999;134:701-5.

Goldberg 1980

Goldberg RN, Chung D, Goldman SL, Bancalari E. The association of rapid volume expansion and intraventricular hemorrhage in the preterm infant. Journal of Pediatrics 1980;96:1060-3.

Goldstein 1995

Goldstein RF, Thompson RJ Jr, Oehler JM, Brazy JE. Influence of acidosis, hypoxemia, and hypotension on neurodevelopmental outcome in very low birth weight infants. Pediatrics 1995;95:238-43.

Greenough 1993

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

Hentschel 1995

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.

Hunt 2004

Hunt RW, Evans N, Rieger I, Kluckow M. Low superior vena cava flow and neurodevelopment at 3 years in very preterm infants. Journal of Pediatrics 2004;145:588-92.

Klarr 1994

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.

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. Archives of Disease in Childhood 2000;82:F188-94.

Lorenz 1998

Lorenz JM, Wooliever DE, Jetton JR, Paneth N. A quantitative review of mortality and developmental disability in extremely premature newborns. Archives of Pediatrics and Adolescent Medicine 1998;152:426-35.

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 Paediatrica 1993;82:433-7.

Meek 1999

Meek JH, Tyszckuk L, Elwell CE, Wyatt S. Low cerebral blood flow is a risk factor for severe intraventricular haemorrhage. Archives of Disease in Childhood 1999;81:F15-18.

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.

Miletin 2008

Miletin J, Dempsey EM. Low superior vena cava flow on day one and adverse outcome in the very Low birth weight infant. Archives of Disease in Childhood. Fetal and Neonatal Edition 2008;93(5):F368-71.

Osborn 2002

Osborn D, 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 2003

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

Osborn 2004

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 & Neonatal Edition 2004;89:F168-73.

Osborn 2007

Osborn DA, Evans N, Kluckow M, Bowen JR, Rieger I. Low superior vena cava flow and effect of inotropes on neurodevelopment to 3 years in preterm infants. Pediatrics 2007;120:372-80.

Osborn 2007a

Osborn DA, Paradisis M, Evans N. The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow. Cochrane Database of Systematic Reviews 2007, Issue 1.

Pellicer 2005

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

Pladys 1997

Pladys P, Wodey E, Betremieux P, Beuchee A, Ecoffey C. Effects of volume expansion on cardiac output in the preterm infant. Acta Paediatrica 1997;86:1241-5.

Roze 1993

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.

Subhedar 2003

Subhedar NV, Shaw NJ. Dopamine versus dobutamine for hypotensive preterm neonates. Cochrane Database of Systematic Reviews 2003, Issue 3. Art. No.: CD003662. DOI: 10.1002/14651858.CD003662 .

Subhedar 2007

Subhedar NV, Duffy K, Ibrahim H. Corticosteroids for treating hypotension in preterm infants. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD003662. DOI: 10.1002/14651858.CD003662.pub3 .

Valverde 2006

Valverde E, Pellicer A, Madero R, Elorza D, Quero J, Cabanas F. Dopamine versus epinephrine for cardiovascular support in low birth weight infants: Analysis of systemic effects and neonatal clinical outcomes. Pediatrics 2006;117:e1213-22.

Van Marter 1990

Van Marter LJ, Leviton A, Allred EN, Pagano M, Kuban KC. Hydration during the first days of life and the risk of bronchopulmonary dysplasia in low birth weight infants. Journal of Pediatrics 1990;116:945-9.

Vohr 2000

Vohr BR, Wright LL, Dusick AM, Mele L, Verter J, Steichen JJ et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994. Pediatrics 2000;105:1216-26.

Other published versions of this review

Osborn 2001

Osborn DA, Evans N. Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants (Cochrane Review). Cochrane Database of Systematic Reviews 2001, Issue 3. Art. No.: CD002056. DOI: 10.1002/14651858.CD002056 .

Classification pending references

  • None noted.

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Data and analyses

1 Albumin versus dopamine in preterm infants

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Death 2 63 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.53, 3.95]
1.2 Peri/intraventricular haemorrhage, any grade 1 39 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.3 Peri/intraventricular haemorrhage, grade 2-4 1 39 Risk Ratio (M-H, Fixed, 95% CI) 1.47 [0.96, 2.25]
1.4 Periventricular leucomalacia 1 24 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.5 Failed treatment (persistent hypotension) 1 39 Risk Ratio (M-H, Fixed, 95% CI) 5.22 [1.33, 20.55]
1.6 CLD (oxygen at 28 days) 1 39 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.39, 1.29]
1.7 Retinopathy of prematurity 1 39 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.37, 1.84]
1.8 Change in cerebral blood flow (%) 1 24 Mean Difference (IV, Fixed, 95% CI) 5.90 [-24.98, 36.78]
1.9 Change in left ventricular output (%) 1 24 Mean Difference (IV, Fixed, 95% CI) 3.40 [-47.24, 54.04]
1.10 Change in mean BP (%) 1 24 Mean Difference (IV, Fixed, 95% CI) -13.90 [-43.56, 15.76]

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Sources of support

Internal sources

  • RPA Newborn Care, Royal Prince Alfred Hospital, Sydney, Australia

External sources

  • Centre for Perinatal Health Services Research, University of Sydney, Australia

This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2009 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.