Home > Health & Research > Health Education Campaigns & Programs > Cochrane Neonatal Review > Albumin infusion for low serum albumin in preterm newborn infants

Albumin infusion for low serum albumin in preterm newborn infants

Skip sharing on social media links
Share this:

Authors

Luke A Jardine1, Sue Jenkins-Marsh2, Mark W Davies3

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


1Mater Mother's Hospital, Brisbane, Australia [top]
2Research Ethics and Governance Unit, Office of Health and Medical Research, Centre for Health Care Improvement, Queensland Health, Brisbane, Australia [top]
3Grantley Stable Neonatal Unit, Royal Brisbane and Women's Hospital, Department of Paediatrics & Child Health, The University of Queensland, Brisbane, Australia [top]

Citation example: Jardine LA, Jenkins-Marsh S, Davies MW. Albumin infusion for low serum albumin in preterm newborn infants. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD004208. DOI: 10.1002/14651858.CD004208.pub2.

Contact person

Luke A Jardine

Mater Mother's Hospital
Raymond Terrace
Brisbane
Queensland
4101
Australia

E-mail: Luke.Jardine@mater.org.au

Dates

Assessed as Up-to-date: 03 August 2009
Date of Search: 28 July 2009
Next Stage Expected: 03 August 2011
Protocol First Published: Issue 2, 2003
Review First Published: Issue 3, 2004
Last Citation Issue: Issue 3, 2004

What's new

Date / Event Description
03 August 2009
Updated

This review updates the existing review "Albumin infusion for low serum albumin in preterm newborn infants" published in The Cochrane Library, Issue 3, 2004 (Jardine 2004)

One new study was identified and considered for inclusion in this review, but was then excluded. The previous paper that was awaiting translation was excluded after review.

No change to conclusions.

History

Date / Event Description
11 September 2008
Amended

Converted to new review format.

03 January 2007
Updated

This review updates the existing review "Albumin infusion for low serum albumin in preterm newborn infants" published in The Cochrane Library, Issue 3, 2004 (Jardine 2004).

One new paper was identified. This paper is awaiting translation into English to see if it meets eligibility criteria.

Other minor additions to the background have been made to provide more information on the normal physiology of albumin.

03 June 2004
New citation: conclusions changed

Substantive amendment

Abstract

Background

Intravenous albumin infusion is used to treat hypoalbuminaemia in critically ill infants. Hypoalbuminaemia occurs in a number of clinical situations including prematurity, respiratory distress syndrome (RDS), chronic lung disease (CLD), necrotising enterocolitis (NEC), intracranial haemorrhage, hydrops fetalis and oedema. Fluid overload is a potential side effect of albumin administration. Albumin is a blood product and therefore carries the potential risk of infection and adverse reactions. Albumin is also a scarce and expensive resource.

Objectives

To assess the effect of albumin infusions on morbidity, mortality, and other significant side effects in preterm neonates with low serum albumin.

Search methods

Searches were made of MEDLINE from 1966 to July 2009, CINAHL from 1982 to July 2009 and the current Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2009). Previous reviews (including cross references) and abstracts were also searched.

Selection criteria

All randomised and quasi randomised controlled trials in which individual patients were allocated to albumin infusion versus control were included. Cross-over studies were excluded. Participants were preterm infants who had hypoalbuminaemia. Types of interventions included albumin infusion versus placebo (e.g. crystalloid) or no treatment.

Data collection and analysis

The reviewers worked independently to search for trials for inclusion and to assess methodological quality. Studies were assessed using the following key criteria: blinding of randomisation, blinding of intervention, completeness of follow-up and blinding of outcome measurement.

Results

Only two small studies were found for inclusion in this review and only one reported clinically relevant outcomes. This study found no significant differences for the primary outcome measure of death (relative risk 1.5, 95% confidence interval 0.3 - 7.43) or secondary outcome measures of intraventricular haemorrhage, patent ductus arteriosus, necrotising enterocolitis, bronchopulmonary dysplasia, duration of mechanical ventilation and duration of oxygen therapy.

Authors' conclusions

There is a lack of evidence from randomised trials to determine whether the routine use of albumin infusion in preterm neonates with low serum albumin reduces mortality or morbidity and no evidence to assess whether albumin infusion is associated with significant side effects. There is a need for good quality, double-blind randomised controlled trials to assess the safety and efficacy of albumin infusions in preterm neonates with low serum albumin.

Plain language summary

Albumin infusion for low serum albumin in preterm newborn infants

There is a lack of evidence from randomised trials to either support or refute the routine use of albumin infusion for premature babies with a low albumin level. Albumin is a protein that is normally present in the blood. In premature infants, the albumin level in the blood can be low. Albumin is often given to premature babies with a low albumin level. Only two small randomised controlled trials have studied the use of albumin in sick premature babies, and the trials are not big enough or good enough to decide whether giving albumin helps babies in the short or long-term. Therefore, the question of whether giving albumin does any good and is safe cannot be answered.

[top]

Background

This review updates the existing review of "Albumin infusion for low serum albumin in newborn preterm infants" which was published in The Cochrane Library, Issue 3, 2004 (Jardine 2004).

Description of the condition

Serum albumin levels are routinely measured and reported in intensive care nurseries and hypoalbuminaemia is a common finding in preterm (< 37 weeks) neonates (< 28 days). An older child or adult with a serum albumin level below 30 g/litre is classified as having hypoalbuminaemia (Greenough 1998). Normal albumin levels in preterm infants have been difficult to define. Serum albumin levels in preterm infants are significantly lower than those in term infants (Bergstrand 1972; Cartlidge 1986; Zlotkin 1987; Reading 1990). Cartlidge and Rutter (Cartlidge 1986) demonstrated that serum albumin levels in the early neonatal period increased significantly with gestational age from a mean of 19 g/litre (90% confidence interval ~ 12 to ~ 28 g/litre) below 30 weeks to a mean of 31 g/litre (90% confidence interval ~ 22 to ~ 39 g/litre) at term.

Albumin accounts for approximately 50% of the serum proteins and is the major protein produced by hepatocytes in the liver (Vanek 1998). Albumin is not stored in the liver and is immediately excreted into the hepatic lymph system or the sinusoids (Uhing 2004). Albumin circulates from the intravascular space across the capillary wall into the interstitium and returns to the intravascular space via the lymphatic system. This circulation half-life is approximately 16 hours (Margarson 1998). The degradation half-life of albumin is 17 to 20 days (Doweiko 1991).

The causes of hypoalbuminaemia can be grouped into four basic categories: decreased synthesis; increased catabolism; increased loss and altered distribution between intravascular and extravascular body compartments (Uhing 2004). Hypoalbuminaemia occurs in a number of clinical situations including prematurity, the acutely sick infant, respiratory distress syndrome (RDS), chronic lung disease (CLD), necrotising enterocolitis (NEC), intracranial haemorrhage, hydrops fetalis and oedema (Green 1993; Greenough 1999; Atkinson 1989; Bergstrand 1972; Cartlidge 1986; Zlotkin 1987; Reading 1990).

Description of the intervention

Intravenous albumin infusion to treat hypoalbuminaemia is used in intensive care nurseries. Green and Morgan (Green 1993) suggested giving 20% albumin whenever the serum albumin falls below 25 g/litre. Intravenous albumin has also been administered to high risk infants who are hypotensive and in respiratory distress (Lay 1980). It has been advocated in the past that ill infants with RDS should be given albumin infusions whenever their serum albumin falls below 20 g/litre (Greenough 1992); however, it is now recommended that care should be taken as albumin infusions may be harmful (Greenough 1999).

Using albumin to treat hypoalbuminaemia is different from using albumin for volume expansion, which has been assessed in other Cochrane reviews (Alderson 2004; Bunn 2003; Osborn 2004).

How the intervention might work

There are several clearly defined physiological functions of serum albumin. These include a binding and transport function, an effect on colloid osmotic pressure (with serum albumin accounting for approximately 60% to 80% of the colloid osmotic pressure), a role as a free radical scavenger and anticoagulant effects (primarily in inhibiting platelet aggregation and increasing prothrombin and partial prothrombin time) (Margarson 1998).

In acute and chronic lung disease of the newborn, alveolar capillary membrane permeability is increased and high albumin levels are present in the alveolar aspirate (Watts 1995). In conjunction with this, pulmonary oedema is often found. Protein leakage into the alveolar space has been shown to occur in adults with respiratory distress syndrome. Leakage of protein into the alveolar space interferes with lung function and inactivates surfactant (Moison 1998). It has been suggested that albumin infusions should increase the capillary colloid pressure, thereby resulting in a decrease in flow of fluid out of the capillaries. This should then lessen fluid accumulation in the lungs, bowel wall and other interstitial spaces that could cause decreased pulmonary oxygen uptake, decreased absorption across the bowel wall or increased bowel wall secretions (Vanek 1998). However, it could also be argued that the underlying capillary leak will not be altered by albumin infusion and that increasing the amount of intravascular albumin will increase the amount that leaks out of the circulation, into the tissues, increasing oedema.

Low albumin levels have been found in infants who develop necrotising enterocolitis (Atkinson 1989). Albumin contributes to the antioxidant capacity of plasma; therefore, low levels of plasma albumin may lessen the total plasma antioxidant capacity. This may be of importance for preterm infants who are at risk of disease processes where reactive oxygen species are believed to play an important role such as respiratory distress syndrome, chronic neonatal lung disease and intracranial haemorrhage (Moison 1998).

Hypoalbuminaemia in adult surgical and medical patients has been associated with an increased incidence of pneumonia, septicaemia, mortality and longer hospital stay (Vanek 1998). Goldwasser and Feldman (Goldwasser 1997) showed that serum albumin concentration is inversely related to the risk of death in adult patients. Conversely a systematic review of albumin administration in critically ill adults found no evidence that albumin administration reduced mortality and suggested that it may increase mortality in selected patients (Cochrane 1998). Studies in adults have looked at the influence of albumin on duration of intensive care stay and rate of recovery. Stockwell et al (Stockwell 1992) showed no difference between duration of stay, complications or outcomes in two groups of patients who had either albumin or gelatin for fluid replacement.

There are documented cases of the complete absence of albumin, analbuminaemia, as a result of a rare genetic condition (Watkins 1994). These patients suffered only mild abnormalities of lipid metabolism and mild oedema; half of the reported patients were entirely asymptomatic. Several studies have shown that oedema in preterm infants is common but poorly correlated with hypoalbuminaemia (Cartlidge 1986; Reading 1990; Kenny 1995) and the routine administration of albumin for oedema is not warranted.

Why it is important to do this review

Fluid overload is a potential side effect of albumin administration. Complications of fluid overload include PDA, NEC, and possibly CLD (Greenough 1999). Albumin is a blood product and therefore carries the potential risk of infection and adverse reactions. Although the risks are low, these risks should be considered. Albumin (which comes in a number of commercial preparations with concentrations ranging from 4% to 20%) is also a scarce and expensive resource with hospitals frequently experiencing shortages (Golub 1994).

This review is required to determine if the potential benefits of albumin transfusion for preterm infants with low serum albumin outweigh the potential side effects.

Objectives

The primary objective was to determine the effect of albumin infusions on morbidity and mortality in preterm neonates with low serum albumin. A secondary objective was to assess whether albumin infusion is associated with significant side effects.

Data permitting, subgroup analyses were planned to determine whether results differed by:

Population:

  1. gestational age (e.g. extremely premature [less than or equal to 28 weeks] versus premature [29 to 36 weeks]).
  2. birthweight (e.g. very low birth weight infants, < 1500 grams, versus infants greater than or equal to 1500 grams or extremely low birth weight infants [ < 1000 grams] versus infants greater than or equal to 1000 grams).
  3. infants with particular illnesses or signs (e.g. oedema, RDS, CLD)
  4. hypoalbuminaemia (e.g. less than 30 g/L or less than 25 g/L or less than 20 g/L)

Intervention:

  1. dose of albumin infused (e.g. < 1.5 g/kg/dose versus greater than or equal to 1.5 g/kg/dose)
  2. type of treatment used in the control group (placebo [e.g. crystalloid] or no treatment)
  3. whether albumin is a single infusion on one occasion or a policy of repeated infusions to maintain a serum albumin above a certain level

[top]

Methods

Criteria for considering studies for this review

Types of studies

All randomised and some non-randomised (e.g. quasi-randomised) controlled trials in which individual patients were allocated to albumin infusion versus control. Cross-over studies were excluded.

Types of participants

Preterm infants who had hypoalbuminaemia. Hypoalbuminaemia defined as < 30 g/L, < 25 g/L and < 20 g/L.

Types of interventions

Albumin infusion versus placebo (i.e. any other non-colloidal fluid that does not contain albumin) or no treatment. Albumin infusion included any regimen from a single infusion on one occasion to a policy of repeated infusions to maintain the serum albumin above a certain level.

Types of outcome measures

Primary outcomes

Mortality (neonatal [28 days], before discharge).
Neurodevelopmental outcome at one year, 18 months, two years, five years.

Secondary outcomes

Chronic lung disease (requiring oxygen at 28 days or 36 weeks postmenstrual age).
Intraventricular haemorrhage (any, grade 3 - 4).
Duration of mechanical ventilation (IPPV) - hours/days.
Duration of respiratory support (IPPV or CPAP) - hours/days.
Duration of oxygen therapy - hours/days.
Septicaemia.
Necrotising enterocolitis.
Duration of ICN stay - hours/days.
Duration of hospital stay - hours/days.
Patent ductus arteriosus requiring therapy (medical or surgical).
CostImmediate adverse effects (e.g. hypertension, increased ventilation requirements and increased oxygenation).

Search methods for identification of studies

The standard search strategy for the Cochrane Neonatal Review Group was used:

Electronic searches

Searches were made of MEDLINE from 1966 to July 2009, CINAHL from 1982 to July 2009 and the current Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2009), using the following strategy:

MeSH search terms 'serum albumin', OR 'albumins'; OR the text words 'albumin', OR 'albumen', OR 'hypoalbuminemia', OR 'hypoalbuminaemia', OR 'hypo-albuminemia', OR 'hypo-albuminaemia';
AND
MeSH search term 'infant, newborn'
AND
MeSH terms '*Albumins / ad [Administration & Dosage]', OR 'Albumins / tu [Therapeutic Use]', OR '*Albumins / pd [Pharmacology]', OR the text word phrase "albumin infusion"

Searches were not restricted to publications in the English language or published data.

Searching other resources

Previous reviews (including cross references), and abstracts were also searched.

Data collection and analysis

Standard methods of the Cochrane Collaboration (Higgins 2009) and its Neonatal Review Group were used.

Selection of studies

All randomized and quasi-randomized controlled trials fulfilling the selection criteria described in the previous section were included. The review authors worked independent to search and select the studies for inclusion. The review authors resolved any disagreement by discussion.

Data extraction and management

The review authors separately extracted, assessed and coded all data for each study. Any disagreement was resolved by discussion.

Assessment of risk of bias in included studies

Studies were assessed using the following key criteria: blinding of randomisation, blinding of intervention, completeness of follow up and blinding of outcome measurement. However, quality criteria did not determine whether a study was excluded or included from this review. Data were extracted independently by the reviewers. Differences were resolved by discussion and consensus of the reviewers. Investigators were contacted for additional information and data where necessary. This information was added to the Characteristics of Included Studies Table.

In addition, the following issues were evaluated and entered into the Risk of Bias Table:

  1. Sequence generation: Was the allocation sequence adequately generated?
  2. Allocation concealment: Was allocation adequately concealed?
  3. Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
  4. Incomplete outcome data: Were incomplete outcome data adequately addressed?
  5. Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?
  6. Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?

Measures of treatment effect

For individual trials, where possible, mean differences (and 95% confidence intervals) were reported for continuous variables. For categorical outcomes, the relative risk and risk difference (and 95% confidence intervals) were reported.

Assessment of heterogeneity

We planned to estimate the treatment effects of individual trials and examine heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I-squared statistic. If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc sub group analyses.

Data synthesis

For the meta-analysis, where possible, weighted mean differences (and 95% confidence intervals) were planned to be reported for continuous variables, and the relative risk and risk difference (and 95% confidence intervals) for categorical outcomes. A fixed effects model was planned. Number needed to treat was to be calculated where appropriate.

Subgroup analysis and investigation of heterogeneity

Data permitting, subgroup analyses were planned to determine whether results differed by:

Population:
  1. gestational age (e.g. extremely premature [less than or equal to 28 weeks] versus premature [29 to 36 weeks]);
  2. birthweight (e.g. very low birth weight infants, < 1500 grams, versus infants greater than or equal to 1500 grams or extremely low birth weight infants [ < 1000 grams] versus
  3. infants greater than or equal to 1000 grams);
  4. infants with particular illnesses or signs (e.g. oedema, RDS, CLD);
  5. hypoalbuminaemia (e.g. less than 30 g/L or less than 25 g/L or less than 20 g/L).
Intervention:
  1. dose of albumin infused (e.g. < 1.5 g/kg/dose versus greater than or equal to 1.5 g/kg/dose);
  2. type of treatment used in the control group (placebo [e.g. crystalloid] or no treatment);
  3. whether albumin is a single infusion on one occasion or a policy of repeated infusions to maintain a serum albumin above a certain level.

[top]

Results

Description of studies

The above search strategy found five possible studies for inclusion. Review of these studies identified only two eligible studies of albumin infusions in hypoalbuminaemic preterm infants.

Kanarek et al (Kanarek 1992) studied the concurrent administration of albumin versus placebo with total parenteral nutrition (TPN) in 24 premature infants (12 in each group). To be eligible the infants had to:

  • have respiratory distress requiring assisted ventilation;
  • have had significant hypotension (2 SD below the mean for gestational age, necessitating the use of a plasma expander and/or inotropic agents);
  • have a plasma albumin level below 30 g/L at 48 to 72 hours of life;
  • require TPN for nutritional support.

Therefore, the population studied in this study was a subset of the population of interest for this review. The albumin was added to the TPN in quantities that were calculated to raise the serum albumin above 30 g/L (maximum 1 g/kg/day).

Greenough et al (Greenough 1993) studied the effect of albumin infusion versus placebo on 40 premature infants (28 to 34 weeks gestational age, 20 in each group). Study subjects were newborn infants who were ventilator dependant at less than seven days of age and had a serum albumin level of less than/or equal to 30 g/L. Therefore, the population studied in this study was also a subset of the population of interest for this review. Infants were not eligible if they were receiving peritoneal dialysis, had chest drains in situ or were hypotensive (defined as systolic blood pressure less than 40 mmHg). Infants were randomised (the method of randomisation is unknown) to receive either albumin administered as 5 ml/kg of 20% salt-poor human albumin or placebo (5 ml/kg of the infants maintenance fluids). Attempts were made to contact the primary author and no reply was received (we requested clarification of blinding of randomisation, blinding of intervention, completeness of follow up and blinding of outcome measurement; and whether other data were available for any of our primary and secondary outcomes).

The study by Bland et al (Bland 1973) investigated albumin infusions in low birth weight newborn infants at risk for respiratory distress who were acidaemic with a low total serum protein level (whether they were hypoalbuminaemic or not is unknown).

The study by Porto et al (Porto 2005) investigated albumin infusion in preterm infants receiving TPN. Infants were not randomised to groups on the basis of their albumin level. Some infants in the control group did not meet our pre-specified definition of hypoalbuminaemia and, therefore, this study was not included in this review.

The study by Rubin et al (Rubin 1997) investigated albumin infusions in patients receiving TPN for greater than six days who had serum albumin concentrations of < 2.5 g/dL. It states in the methods that patients who were "under age" (not further defined) were excluded, therefore, this study was not considered for this review.

Risk of bias in included studies

Kanarek et al (Kanarek 1992):

  • blinding of randomisation (allocation concealment) - yes;
  • blinding of intervention - yes;
  • completeness of follow up - yes;
  • blinding of outcome measurement - unknown.

Greenough et al (Greenough 1993):

  • blinding of randomisation (allocation concealment) - unknown;
  • blinding of intervention - unknown;
  • completeness of follow up - no (data were analysed and reported for only 15 out of 20 subjects in each group);
  • blinding of outcome measurement - unknown.

Effects of interventions

The following is a report of the results of individual studies. Due to the significant heterogeneity in study quality and the lack of pre-specified outcomes in one of the studies, there has been no attempt to pool the results.

The results below are organised using our pre-specified primary and secondary outcomes.

Kanarek et al (Kanarek 1992)

This study found no significant effect of albumin infusion on any of our pre-specified primary and secondary outcomes.

Primary outcome measures:
  • Mortality - there were 3/12 deaths in the experimental group and 2/12 deaths in the control group: RR 1.5 (95% confidence interval 0.3 to 7.43). It is not stated whether mortality is 28 day mortality or at discharge;
  • Neurodevelopmental outcomes were not assessed or reported.
Secondary outcomes:
  • There were 5/12 intraventricular haemorrhages (not further defined) in the experimental group and 4/12 in the control group: RR 1.25 (95% confidence interval 0.44 to 3.55);
  • There was 0/12 infants with necrotising enterocolitis in the experimental group and 1/12 in the control group: RR 0.33 (95% confidence interval 0.01 to 7.45);
  • 5/12 patients in the experimental group and 6/12 in the control group had bronchopulmonary dysplasia (not further defined): RR 0.83 (95% confidence interval 0.35 to 2.0);
  • 5/12 patients in the experimental group and 7/12 in the control group had a patent ductus arteriosus (not further defined): RR 0.71 (95% confidence interval 0.31 to 1.63);
  • The mean duration of assisted ventilation in the experimental group was 36.9 days (SD 22.9), the mean duration in the control group was 30.8 days (SD 15.2). Mean difference 6.1 days (95% confidence interval -9.45 to 21.65);
  • The mean duration of oxygen therapy in the experimental group was 45.7 days (SD 19.1), the mean duration in the control group was 40.4 days (SD 12.5). Mean difference 5.3 days (95% confidence interval -7.62 to 18.22).

The mean arterial blood pressures (MABP) were reported for days three and six. There were no significant differences between the two groups in the first few days of life: the mean (SD) MABP was 35.8 (3.8) mmHg in the albumin group and 34.4 (2.4) mmHg in the control group. When TPN was commenced on day three the control group's MABP was unchanged for the rest of the study whereas the albumin group's MABP continued to rise up until day six when the mean (SD) MABP was 38.9 (4.8) mmHg. No data are given for MABP on day six in the control group; however it is stated that the difference in MABP between the two groups was statistically significant (p < 0.05). Immediate adverse events of albumin infusion including hypertension was one of our secondary outcome measures: none of these data represent hypertension and this reported difference is unlikely to have any clinical significance.

Other outcomes that were reported in this study that we did not pre-specify include:

  • Time taken to tolerate full feeds - albumin group mean (SD) 16.8 (7.6) days, and control group mean (SD) 18.8 (6.9) days;
  • Time taken to regain birth weight - albumin group mean (SD) 18.9 (5.9) days, and control group (SD) 24.9 (2.1) days.

Greenough et al (Greenough 1993)

Primary outcome measures:
  • Mortality and neurodevelopmental outcomes were not assessed or reported
Secondary outcomes:

None of our secondary outcomes were reported.
The discussion section of the study report states that there were no adverse effects with albumin in this study (none of the infants required increased oxygen or ventilator support).

Other outcomes (that we did not pre-specify) were reported in this study; these included:

  • Fluid input versus output in 12 hour periods preceding infusion, during infusion and post infusion. No significant differences were reported;
  • Albumin concentration pre and post infusion. The albumin concentration increased significantly in the albumin group but not in the placebo group;
  • Weight pre and post infusion. Weight decreased significantly in the albumin group and increased significantly in the placebo group;
  • Peak inspiratory pressures pre and post infusion. There was no significant difference reported;
  • Inspired oxygen concentration pre and post infusion. This did fall significantly in the albumin group, and in the placebo group it also fell but not significantly.

Discussion

The studies included in our review investigated a small, specific subset of the total number of preterm infants receiving albumin infusions. Only one of the studies reported clinically relevant outcomes (Kanarek 1992) - it found no significant differences for our primary outcome measure of death or secondary outcome measures of IVH, PDA, NEC, bronchopulmonary dysplasia, duration of mechanical ventilation and duration of oxygen therapy. There was a statistically significantly higher mean arterial BP in the albumin group at six days of age; however, this is unlikely to have any clinical relevance. The results of this single small study should be treated with caution - the confidence intervals for reported outcomes are wide and a real difference might be masked by a type 2 error. Conversely, any differences seen could easily be due to chance alone. Our second primary outcome (neurodevelopmental outcome) and some of our secondary outcomes were not assessed in the included studies (i.e. there were insufficient or no data to assess other clinically important outcomes). The study by Greenough et al (Greenough 1993) did not to report any of our primary and secondary outcome measures.

In some neonatal intensive care units albumin is used frequently. For example, at the Grantley Stable Neonatal Unit in Brisbane, Australia, 12% of all preterm infants admitted and 38% of babies < 30 weeks GA will get at least one infusion of 20% albumin to increase serum albumin levels or treat oedema [data from the NeoData database, Royal Women's Hospital, Brisbane for years 2000 to 2002 inclusive]. Such an extensive use of this treatment should be based on better evidence than is currently available.

Authors' conclusions

Implications for practice

There is a lack of evidence from randomised trials to determine whether the routine use of albumin infusion, in preterm neonates with low serum albumin, reduces mortality or morbidity, or is associated with significant side effects.

Implications for research

If albumin infusion for hypoalbuminaemic pre-term infants is thought to be worthwhile then there is a need for good quality, double-blind randomised controlled trials to assess the safety and efficacy of this practice.

Acknowledgements

Yolanda Montagne, Trials Search Coordinator, CNRG, for conducting the current search.

Contributions of authors

All three reviewers conducted the search for studies and assessed them for inclusion in this review.
LAJ wrote the review.
MWD and SJM co-wrote the review.

LAJ and MWD updated the current review.

Potential conflict of interest

  • None noted.

[top]

Characteristics of studies

Characteristics of Included Studies

Greenough 1993

Methods

RCT. The method of randomisation is unknown. Whether group allocation was blinded is unknown. Whether the intervention was blinded is unknown. Data is analysed and reported for 30 of the 40 enrolled participants. None of the outcomes reported are said to be blinded.

Participants

Infants between 24 and 34 weeks gestation were eligible for the study if they were ventilator-dependant at less than 7 days of age and had a serum albumin level of less than or equal to 30g/l. They were not eligible if they were receiving peritoneal dialysis, had chest drains in situ or were hypotensive. Hypotension was defined as a systolic blood pressure less than 40 mmHg.
40 infants were entered into the study. Data was incomplete for 5 in each group. The analysis was performed on the remaining 30 participants (15 in each group).

Interventions

40 patients were randomly allocated to receive either albumin (n=20; 5 ml/kg 20% salt-poor human albumin) or placebo (n=20; 5 ml/kg of infant's maintenance fluids). The volume of the trial infusion was subtracted from the total daily fluid requirement and given at the maintenance rate.

Outcomes

Primary outcome measures: mortality and neurodevelopmental outcomes were not assessed or reported.

Secondary outcomes: none of our secondary outcomes were reported. The discussion section of the study report states that there were no adverse effects with albumin in this study (none of the infants required increased oxygen or ventilator support).

Other outcomes (that we did not pre-specify) reported:
Fluid input versus output in 12 hour periods preceding infusion, during infusion and post infusion.
Albumin concentration pre and post infusion.
Weight pre and post infusion.
Peak inspiratory pressures pre and post infusion.
Inspired oxygen concentration pre and post infusion.

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

RCT. The method of randomisation is unknown.

Allocation concealment? Unclear

Whether group allocation was blinded is unknown.

Blinding? Unclear

Whether the intervention was blinded is unknown.

None of the outcomes reported are said to be blinded.

Incomplete outcome data addressed? No

Data is analysed and reported for 30 of the 40 enrolled participants.

Free of selective reporting? Unclear
Free of other bias? Yes

Kanarek 1992

Methods

RCT. The method of randomisation is unknown. Group allocation was blinded (sealed envelopes). The intervention was blinded. Follow up was complete. It is unknown if outcome measurement was blinded.

Participants

To be eligible the infants had to (1) have respiratory distress requiring assisted ventilation; (2) have had significant hypotension (2 SD below the mean for gestational age, necessitating the use of a plasma expander and/or inotropic agents); (3) have a plasma albumin level below 30 g/L at 48 to 72 hours of life and (4) require TPN for nutritional support.

24 premature (not defined) infants were enrolled (12 in each group).

Interventions

The albumin was added to the TPN in quantities that were calculated to raise the serum albumin above 30 g/L (maximum 1 g/kg/day). 24 patients were randomised to receive either added albumin to their TPN (n=20) or standard TPN solution (n=20).

Outcomes

Primary outcome measures:
Mortality.

Secondary outcomes:
intraventricular haemorrhages (not further defined).
Necrotising enterocolitis.
Bronchopulmonary dysplasia (not further defined).
Patent ductus arteriosus (not further defined).
The duration of assisted ventilation.
The duration of oxygen therapy.
The mean arterial blood pressures (MABP) were reported for days 3 and 6.

Other outcomes:
Time taken to tolerate full feeds.
Time taken to regain birth weight.

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

RCT. The method of randomisation is unknown.

Allocation concealment? Yes

Group allocation was blinded (sealed envelopes).

Blinding? Unclear

The intervention was blinded.

It is unknown if outcome measurement was blinded.

Incomplete outcome data addressed? Yes

Outcome data was complete.

Free of selective reporting? Unclear
Free of other bias? Yes

Characteristics of excluded studies

Bland 1973

Reason for exclusion

This RCT investigated albumin infusions in low birth weight newborn infants at risk for respiratory distress who were acidaemic with a low total serum protein level (whether they were hypoalbuminaemic or not is unknown).

Porto 2005

Reason for exclusion

This RCT investigated albumin infusion in preterm infants receiving TPN. Infants were not randomised to groups on the basis of their albumin level. Some infants in the control group did not meet our pre-specified definition of hypoalbuminaemia.

Rubin 1997

Reason for exclusion

This RCT investigated albumin infusions in patients receiving TPN for greater than 6 days who had serum albumin concentrations of < 2.5 g/dL. It states in the methods that patients who were "under age" (not further defined) were excluded therefore this study was not considered for this review.

[top]

References to studies

Included studies

Greenough 1993

Greenough A, Emery E, Hird MF, Gamsu HR. Randomised controlled trial of albumin infusion in ill preterm infants. European Journal of Pediatrics 1993;152:157-9.

Kanarek 1992

Kanarek KS, Williams PR, Blair C. Concurrent administration of albumin with total parenteral nutrition in sick newborn infants. Journal of Parenteral and Enteral Nutrition 1992;16:49-53.

Excluded studies

Bland 1973

Bland RD, Clarke TL, Harden LB, Meyer JL, Ries JP, Madden WA et al. Early albumin infusion to infants at risk for respiratory distress. Archives of Disease in Childhood 1973;48:800-5.

Porto 2005

Porto BS, Jorge SM, de Assis MG. Exogenous human albumin supplementation in total parenteral nutrition of critically ill newborns. Jornal de Pediatria 2005;81:41-6.

Rubin 1997

H Rubin, S Carlson, M DeMeo, D Granger, R Craig. Randomized, double blind study of intravenous human albumin in hypoalbuminemic patients receiving total parenteral nutrition. Critical Care Medicine 1997;25:249-52.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Alderson 2004

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 Database of Systematic Reviews 2004, Issue 4. Art. No.: CD004208. DOI: 10.1002/14651858.CD004208.pub2.

Atkinson 1989

Atkinson SD, Tuggle DW, Tunell WP. Hypoalbuminemia may predispose infants to necrotizing enterocolitis. Journal of Pediatric Surgery 1989;24:674-6.

Bergstrand 1972

Bergstrand C, Karlsson B. Alpha-foetoprotein, albumin and total protein in serum from preterm and term infants and small for gestational age infants. Acta Paediatrica Scandinavica 1972;61:128-32.

Bunn 2003

Bunn F, Alderson P, Hawkins V. Colloid solutions for fluid resuscitation. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001319. DOI: 10.1002/14651858.CD001319.pub2.

Cartlidge 1986

Cartlidge PH, Rutter N. Serum albumin concentrations and oedema in the newborn. Archives of Disease in Childhood 1986;61:657-60.

Cochrane 1998

Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. BMJ 1998;317:235-40.

Doweiko 1991

Doweiko JP, Nompleggi DJ. Role of albumin in human physiology and pathophysiology. Journal of Parenteral Enteral Nutrition 1991;15:207-11.

Goldwasser 1997

Goldwasser P, Feldman J. Association of serum albumin and mortality risk. Journal of Clinical Epidemiology 1997;50:693-703.

Golub 1994

Golub R, Sorrento JJ, Jr., Cantu R, Jr., Nierman DM, Moideen A, Stein HD. Efficacy of albumin supplementation in the surgical intensive care unit: a prospective, randomized study. Critical Care Medicine 1994;22:613-9.

Green 1993

Green A, Morgan I. The pre-term infant - clinical and biochemical problems. In: Green A, Morgan I, editor(s). Neonatology and Clinical Biochemistry. London: ACB Venture Publications, 1993:62-76.

Greenough 1992

Greenough A, Morley C, Roberton NRC. Acute respiratory disease in the newborn. In: Roberton NRC, editor(s). Textbook of Neonatology. Second edition. London: Churchill Livingston, 1992:385-504.

Greenough 1998

Greenough A. Use and misuse of albumin infusions in neonatal care. European Journal of Pediatrics 1998;157:699-702.

Greenough 1999

Greenough A, Roberton NRC. Acute respiratory disease in the newborn. In: Rennie JM, Roberton NRC, editor(s). Textbook of Neonatology. Third edition. Edinburgh: Churchill Livingston, 1999:481-607.

Higgins 2009

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2009. Available from www.cochrane-handbook.org.

Kenny 1995

Kenny SE, Pierro A, Isherwood D, Donnell SC, Van Saene HK, Lloyd DA. Hypoalbuminaemia in surgical neonates receiving parenteral nutrition. Journal of Pediatric Surgery 1995;30:454-7.

Lay 1980

Lay KS, Bancalari E, Malkus M, Baker R, Strauss J. Acute effects of albumin transfusion on blood volume and renal function in premature infants with respiratory distress syndrome. Journal of Pediatrics 1980;97:619-23.

Margarson 1998

Margarson MP, Soni N. Serum albumin: touchstone or totem? Anaesthesia 1998;53:789-803.

Moison 1998

Moison RM, Haasnoot AA, Van Zoeren-Grobben D, Berger HM. Plasma proteins in acute and chronic lung disease of the newborn. Free Radical Biology and Medicine 1998;25:321-8.

Osborn 2004

Osborn DA, Evans N. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD002055. DOI: 10.1002/14651858.CD002055.pub2.

Reading 1990

Reading RF, Ellis R, Fleetwood A. Plasma albumin and total protein in preterm babies from birth to eight weeks. Early Human Development 1990;22:81-7.

Stockwell 1992

Stockwell MA, Soni N, Riley B. Colloid solutions in the critically ill. A randomised comparison of albumin and polygeline. 1. Outcome and duration of stay in the intensive care unit. Anaesthesia 1992;47:3-6.

Uhing 2004

Uhing, MR. The albumin controversy. Clinics in Perinatology 2004;31:475-88.

Vanek 1998

Vanek V. The use of serum albumin as a prognostic or nutritional marker and the pros and cons of IV albumin therapy. Nutrition in Clinical Practice 1998;13:110-22.

Watkins 1994

Watkins S, Madison J, Galliano M, Minchiotti L, Putnam FW. Analbuminemia: three cases resulting from different point mutations in the albumin gene. Proceedings of the National Academy of Sciences of the United States of America 1994;91:9417-21.

Watts 1995

Watts CL, Bruce MC. Comparison of secretory component for immunoglobulin A with albumin as reference proteins in tracheal aspirate from preterm infants. Journal of Pediatrics 1995;127:113-22.

Zlotkin 1987

Zlotkin SH, Casselman CW. Percentile estimates of reference values for total protein and albumin in sera of premature infants (less than 37 weeks of gestation). Clinical Chemistry 1987;33:411-3.

Other published versions of this review

Jardine 2004

Jardine LA, Jenkins-Manning S, Davies MW. Albumin infusion for low serum albumin in preterm newborn infants. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD004208. DOI: 10.1002/14651858.CD004208.pub2.

[top]

Data and analyses

1 Albumin vs placebo in infants with plasma albumin < 30g/L and requiring assisted ventilation (not defined)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Mortality 1 24 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.2 IVH - any grade 1 24 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.3 Bronchopulmonary dysplasia (not defined) 1 24 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.4 Necrotising enterocolitis 1 24 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.5 Patent ductus arteriosus 1 24 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.6 Duration of assisted ventilation (days) 1 24 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.7 Duration of oxygen therapy (days) 1 24 Mean Difference (IV, Fixed, 95% CI) Subtotals only

[top]

Sources of support

Internal sources

  • Grantley Stable Neonatal Unit, Royal Women's Hospital, Brisbane, Australia
  • Royal Children's Hospital, Brisbane, Australia
  • Dept of Paediatrics and Child Health, University of Queensland, Brisbane, Australia
  • Centre for Clinical Studies, Mater Hospital, Brisbane, Australia

External sources

  • Department of Health and Ageing, Commonwealth Government, Canberra ACT - Supporting the Centre for Clinical Studies, Mater Hospital, Australia

This review is published as a Cochrane review in The Cochrane Library, Issue 2, 2010 (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.