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.
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.
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 do so with 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 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) and low cerebral blood flow (Meek 1999) in the first day of life are also associated with late P/IVH. In addition, in the studies by Kluckow 2000 and Osborn 2003, low upper body blood flow in the first day of life (as measured by flow in the superior vena cava) was associated with a significant increase in mortality in infants born < 30 weeks' gestation.
Clinical features suggesting reduced perfusion include low blood pressure, reduced cutaneous perfusion and metabolic acidosis. However, systemic arterial pressure has been shown to be poorly correlated with systemic blood flow in preterm infants (Kluckow 1996; Kluckow 2000; Osborn 2001b). 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 blood pressure using inotropes such as dopamine and dobutamine (Greenough 1993; Hentschel 1995; Klarr 1994; Roze 1993) and corticosteroids (Bourchier 1997). Trials of dopamine versus 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 1999). Despite an increase in systemic blood pressure, dopamine was shown to reduce aortic blood flow in one study (Roze 1993). In another study in very preterm infants with low systemic blood flow (SBF), dobutamine which produced little change in blood pressure resulted in a significantly greater increase in SBF than dopamine, which produced a significantly greater increase in blood pressure (Osborn 2002). 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 blood pressure (Barr 1977; Bignall 1989). Observational studies have also found an increased incidence of 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).
The question addressed by this review was what is the evidence from randomised controlled trials for 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 blood pressure, 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 systemic blood flow on the first day of life (Miall-Allen 1987; Goldstein 1995; Kluckow 2000; 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.
In very preterm infants, to determine the effect of early volume expansion compared to early inotrope use in reducing morbidity and mortality. 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 blood pressure, 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.
Secondary outcome measures included any of the following;
1. Backup use of volume or inotropes (in first 72 hours)
2. Failure to correct low systemic blood flow (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 >= 120 micromol/l, oliguria <= 0.5mls/kg/hour)
6. Airleak (any and gross including pneumothorax or pneumomediastinum)
7. Chronic lung disease (at 28 post natal days or near term post menstrual age)
8. Proven necrotising enterocolitis
9. Retinopathy of prematurity (any grade and severe)
Subgroup analyses were planned for the following identified subcategories:
1. Including only trials where volume expansion was given a) in the first day of life, and b) in the first 12 hours of life
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:
The standard search strategy of the Neonatal Review Group was used. See Review Group details for more information. This included searches of the Oxford Database of Perinatal Trials, with an updated search in this review including searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2004), MEDLINE (1996-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.
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 4.2 was used for meta-analysis.
Sensitivity analysis was planned on the basis of methodological quality.
See 'Table of included studies'.
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 < 1501g (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 mls/kg plasma protein fraction prior to enrolment if thought to be shocked (49% of infants). Infants in the study by Lundstrom 2000 were enrolled if the mean blood pressure was in the normal range (29-40 mmHg) and they had not received volume or inotrope in the preceding 3 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 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 blood pressure, left ventricular output and cerebral blood flow are calculated from the reported 95% confidence intervals.
Interventions: Gill 1993 compared albumin 4.5% 20 mls/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 mls/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 blood pressure and ultrasound determined left ventricular outputs were also measured. No periventricular leucomalacia was observed. No other clinical data were available according to randomised groups.
Both Gill 1993 and Lundstrom 2000 are adequately randomised, unblinded studies of volume versus dopamine with no losses to follow up and analysed by intention to treat (see 'Table of included studies').
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 which 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 blood pressure 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 blood pressure (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
but 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 blood pressure 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.
In a single small study enrolling hypotensive very preterm infants on the first day of life, dopamine was better than albumin at increasing blood pressure. 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 blood pressure has been linked to cerebral injury (Low 1993, Miall-Allen 1987), low blood pressure is poorly correlated with cardiac output in very preterm infants in the first days of life (Kluckow 1996; Osborn 2001b). Low blood flow in the first day of life is strongly predictive of cerebral injury (Kluckow 2000; Meek 1999; Osborn 2003). It is uncertain whether selecting infants on the basis of a low mean blood pressure and using blood pressure 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.
None
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Gill | A | |||||
| Gill 1993 | 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 | 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) | 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 | 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 | 49% of infants received volume expansion prior to study. | A |
| Lundstrom 2000 | Adequate randomisation: yes, sealed envelopes Allocation concealment: yes Blinding of intervention: no Blinding of measurement: not stated Losses to follow up: none | 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 | Intervention: Group 1 (n = 13): albumin 20% 15 mls/kg Group 2 (n = 11): dopamine 5 mcg/kg/min | Stated primary outcome: mean arterial BP, left ventricular output, global cerebral blood flow Other outcomes: mortality, peri/intraventricular haemorrhage, periventricular leucomalacia | Clinical data for mortality obtained from author. | A |
| Study | Reason for exclusion |
| Kawczynski 1996 | Not randomized. |
| Rennie 1989 | Non randomised comparison of dopamine and plasma. |
* Gill AB, Weindling AM. Randomised controlled trial of plasma protein fraction versus dopamine in hypotensive very low birthweight infants. Arch Dis Child 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. Pediatr Res 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 Hum Dev 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.
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Rennie 1989 {published data only}
Rennie JM. Cerebral blood flow velocity variability after cardiovascular support in premature babies. Arch Dis Child 1989;64:897-901.
* indicates the primary reference for the study
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| The review is published as a Cochrane review in The
Cochrane Library, Issue 3, 2005 (see http://www.thecochranelibrary.com for
information). Cochrane reviews are regularly updated as new evidence emerges
and in response to comments and criticisms, and The Cochrane Library should
be consulted for the most recent version of the Review. |