Home > Health & Research > Health Education Campaigns & Programs > Cochrane Neonatal Review > Base administration or fluid bolus for preventing morbidity and mortality in preterm infants with metabolic acidosis

Base administration or fluid bolus for preventing morbidity and mortality in preterm infants with metabolic acidosis

Skip sharing on social media links
Share this:

Authors

Cassie J Lawn1, Fiona J Weir2, William McGuire3

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


1Neonatal Medicine, Royal Sussex County Hospital, Brighton, UK [top]
2Nightingales Child Development Centre, Haywards Heath, UK [top]
3Centre for Reviews and Dissemination, Hull York Medical School, York, UK [top]

Citation example: Lawn CJ, Weir FJ, McGuire W. Base administration or fluid bolus for preventing morbidity and mortality in preterm infants with metabolic acidosis. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD003215. DOI: 10.1002/14651858.CD003215.pub2.

Contact person

Cassie J Lawn

Neonatal Medicine
Royal Sussex County Hospital
Eastern Road
Brighton
East Sussex
BN2 5BE
UK

E-mail: cassie.lawn@bsuh.nhs.uk

Dates

Assessed as Up-to-date: 25 August 2010
Date of Search: 25 August 2010
Next Stage Expected: 25 August 2012
Protocol First Published: Issue 3, 2001
Review First Published: Issue 2, 2005
Last Citation Issue: Issue 2, 2005

What's new

Date / Event Description
25 August 2010
Updated

This updates the existing review "Base administration or fluid bolus for preventing morbidity and mortality in preterm infants with metabolic acidosis" published in the Cochrane Database of Systematic Reviews (Lawn 2005).

Updated search found no new published trials. Additional data from one unpublished pilot trial is included in this update.

No changes to conclusions.

History

Date / Event Description
16 October 2008
Amended

Converted to new review format.

10 February 2005
New citation: conclusions changed

Substantive amendment

Abstract

Background

Metabolic acidosis in the early newborn period is associated with adverse outcomes in preterm infants. The most commonly used strategies to correct metabolic acidosis are intravascular infusion of base, for example sodium bicarbonate, and intravascular infusion of a fluid bolus, usually a crystalloid or colloid solution.

Objectives

To determine the effect of either infusion of base or of a fluid bolus on mortality and adverse neurodevelopmental outcomes in preterm infants with metabolic acidosis.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), MEDLINE (1966 to January 2005), EMBASE (1980 to January 2005), CINAHL (1982 to January 2005).
The search was updated in 2010.

Selection criteria

Randomised or quasi-randomised controlled trials that evaluated the following treatments for preterm infants with metabolic acidosis:

  1. Infusion of base versus no treatment;
  2. Infusion of fluid bolus versus no treatment;
  3. Infusion of base versus fluid bolus.

Data collection and analysis

We extracted the data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors, and synthesis of data using relative risk and risk difference.

Results

We found two small randomised controlled trails that fulfilled the eligibility criteria (Corbet 1977; Dixon 1999) and one unpublished pilot trial (Lawn 2005). Corbet 1977 compared treating infants with sodium bicarbonate infusion (N = 30) versus no treatment (N = 32) and did not find evidence of an effect on mortality [relative risk (RR) 1.39 (95% confidence interval 0.72 to 2.67)] or in the incidence of intra/periventricular haemorrhage [RR 1.24 (95% confidence interval 0.47 to 3.28)]. Addition of the unpublished data of Lawn 2005 does not change the overall estimate of effect on mortality [typical RR 1.45 (95%CI 0.82 to 2.56)]. Dixon 1999 compared treatment with sodium bicarbonate (N = 16) versus fluid bolus (N = 20). The primary outcome assessed was arterial blood pH/base excess two hours after the intervention. Other clinical outcomes were not reported. Neither trial assessed longer term neurodevelopmental outcomes.

Authors' conclusions

There is insufficient evidence from randomised controlled trials to determine whether infusion of base or fluid bolus reduces morbidity and mortality in preterm infants with metabolic acidosis. Further large randomised trials are needed.

Plain language summary

Base administration or fluid bolus for preventing morbidity and mortality in preterm infants with metabolic acidosis

Sick preterm infants are easily affected by reduced oxygen levels, cold and poor blood circulation. Their blood becomes acid with a build up of lactic acid (metabolic acidosis) that their kidneys cannot correct. Metabolic acidosis in preterm infants may cause bleeding in the brain (intra or periventricular haemorrhage) and problems with longer-term neurodevelopment (including hearing, vision and cognitive ability). Solutions of the alkaline sodium bicarbonate or tris-(hydroxymethyl) amino methane (THAM) can be given to correct the acidity. These solutions are more concentrated than blood (hyperosmolar), which can change blood flow and cause bleeding in the brain, especially when given rapidly or in large quantities. The rationale for their use is to prevent the adverse outcomes that are associated with acidosis in preterm infants.
The review authors searched the medical literature and found two small randomised controlled trials (98 infants) measuring/investigating the benefit of either infusion of base or of a fluid injection (bolus) in the treatment of preterm infants with metabolic acidosis. Infants were given an infusion of sodium bicarbonate on the first day of postnatal life, compared with no treatment or a fluid bolus with albumin. There was no clear evidence that the base infusion corrected metabolic acidosis more effectively. One of the studies (62 newborns) reported no difference in early deaths at one week or in the incidence of bleeding in the brain. Neither study assessed longer-term neurological disabilities.

[top]

Background

Description of the condition

Sick preterm infants are susceptible to hypoxia, cold stress, and/or hypoperfusion resulting in accumulation of non-carbonic acids in the blood. The co-existence of immature renal function with inadequate hydrogen ion excretion and a low bicarbonate reabsorption threshold makes these infants particularly susceptible to the development of metabolic acidosis. Neonatal intensive care aims to optimise organ perfusion and oxygenation by treating underlying conditions such as infection or hypovolaemia, and by maintaining key parameters, including acid-base balance, in a physiological range.

Metabolic acidosis in preterm infants has been associated with the development of periventricular haemorrhage (Moriette 1977; Levene 1982; Cooke 1997), periventricular leukomalacia (Low 1990), and poor longer term neurodevelopmental outcomes in very low birth weight infants (Goldstein 1995; Aylward 1993). An inverse relationship between the degree of acidosis at birth and cognitive abilities assessed between four and seven years of age has been demonstrated in term and preterm infants (Stevens 1999). The development of intraventricular haemorrhage has been associated with fluctuations in cerebral arterial blood flow velocity (Perlman 1983). Cerebral vascular resistance is decreased in term infants with metabolic acidosis in the first week of life (Morrison 1995) and low arterial pH has been associated with increased cerebral artery blood flow velocity in very low birth weight infants (Weir 1999).

The definition of metabolic acidosis in preterm infants has not been clearly established. A normal arterial blood pH in the term infant has been defined as pH 7.27 to 7.43 at up to 24 hours post birth and 7.32 to 7.42 at seven days of age (Koch 1968). In normal pregnancies fetal pH does not change with gestational age (Soothill 1986). Normal arterial base excess in the first 28 days of life has been defined as - 5 to + 5 mmol/litre in the preterm infant (Rennie 1999). The Joint Working Group of the British Association of Perinatal Medicine recommended maintaining an arterial pH above 7.25 as below this pH various physiological and cellular functions are compromised (BAPM 1992).

Description of the intervention

A postal survey of British neonatologists found that most used fluid boluses (4.5% human albumin, fresh frozen plasma, blood, normal saline) or base (sodium bicarbonate and Tris-(Hydroxymethyl) Amino Methane (THAM)) infusions to correct metabolic acidosis in preterm infants (Simpson 1994). However, the use of any type of additional fluid in the preterm infant must be considered carefully. Systematic review of the use of albumin in resuscitation of critically ill patients of all age groups demonstrated statistically significantly increased mortality rates for those receiving albumin compared to controls (Alderson 2001). A systematic review of restricted versus liberal water intake in preterm infants showed restricted water intake reduced the risk of patent ductus arteriosus, necrotizing enterocolitis and death and a trend toward reduced risk of bronchopulmonary dysplasia (Bell 2001).

Both sodium bicarbonate (4.2% or 2.1%) and THAM are hyperosmolar. Sodium bicarbonate may cause hypernatraemia and has been associated with intraventricular haemorrhage when given rapidly and in large quantities (Papile 1978; Simmons 1974). There are also concerns that intravenous infusion of base can cause a transient paradoxical worsening of intracellular acidosis, loss of cerebral vascular autoregulation, decreased cerebral blood flow and acute changes in cerebrospinal fluid pH (Lou 1978; Lou 1979). Observational data have suggested that treatment with sodium bicarbonate on the first day of life is associated with a higher incidence of intraventricular haemorrhage in very preterm infants (Synnes 2001).

Objectives

To determine the effect of either base or fluid bolus administration on morbidity and mortality in preterm infants with metabolic acidosis.

In separate comparisons we will assess:

  1. infusion of base (either THAM or sodium bicarbonate) versus no treatment;
  2. infusion of fluid bolus versus no treatment;
  3. infusion of base versus fluid bolus.

Pre-specified subgroup analyses:

  1. trials where all participating infants were treated in the first seven days of postnatal life compared with infants treated at a later stage;
  2. trials where all participating infants were born at less than 32 weeks' gestational age compared with more mature preterm infants;
  3. trials where all participating infants were born at less than 28 weeks' gestational age compared with more mature preterm infants;
  4. trials where all participating infants had severe acidaemia (pH less than 7.15) compared with less severe acidaemia;
  5. trials where all participating infants had clinical indicators of poor perfusion (low blood pressure, poor cutaneous perfusion, receiving inotropic support or volume support for hypotension) compared with trial where infants did not have these indicators.

[top]

Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi-randomised controlled trials.

Types of participants

Newborn infants less than 37 weeks' gestational age who are less than 28 days of age with metabolic acidosis defined as arterial or capillary pH less than 7.25 and base excess worse than -6 mmol/litre.

Types of interventions

Infusion of base (either THAM or sodium bicarbonate) given either as a bolus (no longer than 20 minutes) or by slower infusion. Fluid bolus ("volume expansion") may include normal saline, 4.5% human albumin solution, fresh frozen plasma, or blood and should be at least 10 millilitres per kilogram additional volume given over less than six hours.

Types of outcome measures

Primary outcomes
  1. Neonatal mortality and mortality to discharge.
  2. Peri or intraventricular haemorrhage (any or severe grades).
  3. Periventricular leukomalacia.
  4. Neurodevelopmental outcomes at greater than, or equal to, 12 months of age (corrected for preterm birth) measured using validated assessment tools such as Bayley Scales of Infant Development, and classifications of disability, including (a) auditory and (b) visual disability. The composite outcome of "severe neurodevelopmental disability" is defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment.
Secondary outcomes
  1. Failure to improve arterial pH to more than 7.25 or base excess to better than -6 mmol/litre within four hours of treatment.

Search methods for identification of studies

Electronic searches

We used the standard search strategy of the Cochrane Neonatal Review Group, including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), MEDLINE (1966 to January 2005), EMBASE (1980 to January 2005), and CINAHL (1982 to January 2005). The search strategy used the following text words and MeSH terms: "(metabolic acidosis and infant - premature) and (colloid(s) or plasma or sodium chloride or albumin or sodium bicarbonate or THAM)". We did not apply any language restriction.

In August, 2010, we updated the search as follows: MEDLINE (search via PubMed), CINAHL, EMBASE and CENTRAL (The Cochrane Library) were searched from 2005 to 2010. Search terms: metabolic acidosis AND (colloid OR colloids OR plasma OR sodium chloride OR albumin OR sodium bicarbonate OR THAM). Limits: human, infant and clinical trial. No language restrictions were applied.

Searching other resources

We examined references in previous reviews and in studies identified as potentially relevant. We undertook a Science Citation Index "forward search" for all of the studies that we identified as potentially eligible for inclusion.

Data collection and analysis

Selection of studies

CJL and WM screened the title and abstract of all studies identified by the above search strategy and obtained the full articles for all potentially relevant trials. CJL and WM re-assessed independently the full text of any eligible reports and excluded those studies that did not meet all of the inclusion criteria.

Data extraction and management

WM and CJL extracted relevant information and data from each included study. Each reviewer extracted the data separately, compared data, and resolved differences by discussion until consensus was achieved. We contacted the trial investigators for further information as required. CJL provided unpublished data from the pilot trial Lawn 2005.

Assessment of risk of bias in included studies

CJL and WM used the criteria and standard methods of the Cochrane Neonatal Review Group to assess independently the methodological quality of the included trials in terms of allocation concealment, blinding of parents or caregivers and assessors to intervention, and completeness of assessment in all randomised individuals. Where necessary, we requested additional information from trial authors to clarify methodology and results.

Measures of treatment effect

We presented outcomes for categorical data as relative risk and risk difference with respective 95% confidence intervals. For continuous data, we planned to use the weighted mean difference with 95% confidence interval.

Assessment of heterogeneity

We planned to estimate the treatment effects of individual trials and examine heterogeneity between trial results by inspecting the forest plots and quantifying the impact of heterogeneity in any meta-analysis using a measure of the degree of inconsistency in the studies' results (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. We planned to use a fixed effects model for meta-analyses.

[top]

Results

Description of studies

We identified four published randomised trials for potential inclusion (Sinclair 1968; Bland 1976; Corbet 1977; Dixon 1999).

We included two published trials (Corbet 1977; Dixon 1999). In addition, unpublished data from the pilot trial of Lawn and coworkers (Lawn 2005) are included in this review. Details are presented in the table 'Characteristics of Included Studies'.

INCLUDED STUDIES:

1. Corbet 1977 randomly allocated newborn preterm infants within the first few hours after birth to receive either "liberal" sodium bicarbonate infusions (N = 30) or "conservative" bicarbonate infusions (N = 32) given with their standard maintenance intravascular infusions of 10% glucose. Those infants in the "liberal" group were allocated to receive sodium bicarbonate at doses of 5 to 15 mmol /decilitre of 10% glucose, titrated on the degree of acidosis. The bicarbonate infusion was continued until the infant's arterial blood pH reached 7.30. These infants received an average of 3.6 mmol/kilogram of sodium bicarbonate in first 24 hours of postnatal life. The infants in the "conservative" group did not have any sodium bicarbonate added to their maintenance glucose infusions.

This trial did not strictly fulfil our a priori inclusion criteria since biochemically confirmed acidosis was not per se an eligibility criterion for participation in the trial. The investigators recruited infants thought to be at "high-risk" of acidosis (birth weight less than 1500 grams, or birth weight less than 2000 grams and infant needing mechanical ventilation, or Apgar score less than four at one minute, or infant with a clinical diagnosis of hyaline membrane disease). However, we made a consensus decision to include the trial because there was post hoc evidence that most participating infants fulfilled our review criterion for acidosis: All of the participating infants were acidotic (pH less than 7.30) at enrolment and most had arterial blood pH values less than 7.25. The mean arterial blood pH of participating infants was 7.16 at trial entry. Participating infants were followed up until the end of the first week of postnatal life. The primary outcomes assessed were time to correction of acidosis, mortality in the first week of postnatal life, and incidence of intraventricular haemorrhage.

2. Dixon 1999 randomly allocated 36 normotensive newborn infants with metabolic acidosis (defined as a simultaneous arterial blood pH less than 7.25 and base excess worse than -6 mmol/litre) to receive an intravenous infusion over 30 minutes of either 10 millilitres per kilogram of 4.5% albumin infusion (N = 20) or 4.2% sodium bicarbonate (N = 16): dose in millimoles calculated as one-sixth of product of weight (kilograms) and base excess (mmol/litre). Most of the participating infants were preterm. Thirty-three of the 36 infants were born before 36 weeks' gestation. The primary outcome assessed was arterial blood pH and base excess two hours after the intervention. Other clinical outcomes were not reported.

3. Lawn 2005 conducted a pilot trial of a continuous weak intra-arterial infusion of sodium bicarbonate. The pilot study enrolled 20 infants born at the Royal Sussex County Hospital and St Thomas' Hospital, London weighing less than 1000 g with a gestational age less than 32 weeks. The study aimed to reduce the number of bolus treatments with bicarbonate or fluid to treat metabolic acidosis by giving a continuous weak infusion of sodium bicarbonate intra-arterially. The primary outcome measure was the number of bolus bicarbonate or fluid treatments required by both groups.

Infants were randomised by serial sealed envelopes into treatment and control groups. Treatment groups received continuous heparinised sodium bicarbonate infusion into the umbilical artery catheter (UAC) or peripheral arterial line for 96 hrs starting within 12 hrs of birth; infants in the control group received standard heparinised half normal saline solution into the arterial line.

Treatment of metabolic acidosis was according to neonatal intensive care unit protocol and was the same in both groups. Records were kept of the number, type and amount of fluid boluses given and the indication for their use as well as of the number and amount of bicarbonate boluses given for the duration of the study (96 hours after intra-arterial infusion is commenced).

All infants had arterial blood pressure monitoring and hourly blood pressure heart rate and oxygen requirement noted for 96 hours. Minimum six hourly arterial blood gases were to be measured for the first 48 hours and then at least 12 hourly for the next 48 hours as was standard practice. Blood volume losses were recorded in both groups. Both groups had twelve hourly urea and electrolyte estimations for the first 48 hours and 24 hourly for the next 48 hours, which was standard unit practice for babies under 1000g in the first 96 hours of life. Cranial ultrasound scans were be performed on control and treatment groups on days one, two and seven of life. Doppler ultrasound measurement of middle cerebral artery blood flow velocity will be made during the first 24 hours of life and on the second day of life in both study groups when the baby was clinically stable.

The median gestational age was 26 + 6weeks for control infants (range 24 + 3 to 29 + 0 weeks ) and 25 + 4 weeks for treated infants (range 24 + 1 to 28 + 5 weeks).

This was a pilot study for a planned study of 160 infants; the larger trial was not conducted.

EXCLUDED STUDIES

Two trials were excluded (Bland 1976; Sinclair 1968). Details are presented in the table 'Characteristics of excluded studies'.

  1. Sinclair 1968 randomly allocated 20 low birth weight infants with evidence of hypoxia and/or acidaemia to receive either a "slow" or a "rapid" infusion of sodium bicarbonate. This trial was not eligible for inclusion in this review as there was not a comparison group who did not receive any base or who received fluid bolus.
  2. Bland 1976 randomly allocated 51 hypoproteinaemic preterm infants "at risk of developing acidaemia" to receive either an infusion of sodium bicarbonate over 5 to 10 minutes or an infusion of glucose or albumin within the first two hours after birth. This study was excluded because most of the participating infants were not acidotic at trial entry.

Risk of bias in included studies

Corbet 1977 allocated infants to a comparison group using a random numbers table but it is not clear from the published report whether this ensured allocation concealment. Dixon 1999 randomised participants using sealed envelopes and achieved satisfactory allocation concealment. In both trials it is unlikely that healthcare givers and assessors were blind to the intervention. Follow up was complete in both trials.

Effects of interventions

Infusion of base versus no treatment (Comparison 1):

Mortality (Outcome 1.1): Corbet 1977 did not find evidence of an effect on mortality: Relative risk 1.39 (95% confidence interval 0.72 to 2.67), risk difference 0.12 (95% confidence interval -0.12 to 0.36). Addition of the unpublished data of Lawn 2005 did not change the overall estimate of effect on mortality [typical RR 1.45 (95%CI 0.82 to 2.56)].

Intraventricular haemorrhage (Outcome 1.2): Corbet 1977 did not find a statistically significant difference in the incidence of intra/periventricular haemorrhage (only post-mortem diagnoses were available): Relative risk 1.24 (95% confidence interval 0.47 to 3.28), risk difference 0.05 (95% confidence interval -0.16 to 0.25).

This trial did not assess longer term neurodevelopmental outcomes.

Failure to improve pH to more than 7.25 and base excess to less than -6 mmol/litre within 4 hours of treatment: Corbet 1977 did not find any statistically significant difference in the rate at which pH was corrected, or in the mean arterial blood pH levels two hours after commencing the intervention. These data were presented graphically and could not be extracted for calculation of mean differences.

Infusion of fluid bolus versus no treatment: (No trials identified).

Infusion of base versus fluid bolus (Comparison 2):

Dixon 1999: There were not any data on mortality, incidence of periventricular haemorrhage, or longer term neurodevelopment.

Failure to improve pH to more than 7.25 and base excess to less than -6 mmol/litre within 4 hours of treatment (Comparison 2.1): Dixon 1999 reported that two of 16 infants given base versus nine of 20 infants given a fluid bolus had persistent acidosis (arterial blood pH less than 7.25 and base excess worse than -6 mmol/litre) at two hours post-intervention. This difference was of borderline statistical significance: Relative risk 0.28 (95% confidence interval 0.07 to 1.11), risk difference -0.33 (95% confidence interval -0.60 to -0.05).

Sub-group analyses

  1. All infants treated in the first seven days of life: In both included trials, all of the participating infants were enrolled on the first day of postnatal life.
  2. Infants less than 32 weeks' gestational age: Subgroup data were not available from either trial.
  3. Infants less than 28 weeks' gestational age: Subgroup data were not available from either trial.
  4. Infants with severe acidaemia (pH less than 7.15): Subgroup data were not available from either trial.
  5. Infants who had clinical indicators of poor perfusion (low blood pressure, poor cutaneous perfusion, receiving inotropic support or volume support for hypotension): Subgroup data were not available from Corbet 1977. In Dixon 1999, infants with hypotension were not eligible to participate.

Discussion

Although both interventions have been long-established in clinical practice (Simpson 1994), the available data do not provide evidence of benefit for either infusion of base or of a fluid bolus in the treatment of preterm infants with metabolic acidosis. Both trials included in this review assessed short term outcomes only (mainly correction of acidosis) and neither study assessed longer term neurological morbidity.

The rationale for the use of an infusion of base is that correction of metabolic acidosis will prevent the adverse outcomes that are associated with acidosis in preterm infants. In fact, the trial that compared treatment with sodium bicarbonate infusion versus no treatment did not find a statistically significant difference in the rate of resolution of metabolic acidosis (Corbet 1977). However, this may be due to the very slow rate of infusion of sodium bicarbonate in the intervention group. Infants received 3.6 millimoles per kilogram over the first 24 hours of postnatal life. The trial did not find a statistically significant effect on early neonatal mortality, but included only 62 infants and was underpowered to detect an small but clinically important effect. Given the lack of robust evidence of benefit (and theoretical potential for harm), it has been argued that treating preterm infants with metabolic acidosis with infusions of base should be regarded as experimental and should not be undertaken out with the context of a randomised controlled trial (Ammari 2002).

Similar concerns about the lack of evidence of benefit and potential for harm have been raised about the use of infusion of a fluid bolus in treating preterm infants with metabolic acidosis or other evidence of systemic underperfusion (Hope 1998). There is some biological plausibility that a fluid bolus may improve organ perfusion in infants with hypovolaemia. However, in the absence of a clear precipitating event such as haemorrhage, hypovolaemia is probably a rare cause of metabolic acidosis in preterm infants. Because systemic underperfusion and hypovolaemia are very difficult to assess clinically, many infants may receive treatment with a fluid bolus inappropriately. A Cochrane review found insufficient evidence that routine early volume expansion with blood products or crystalloid solutions prevents morbidity and mortality in very preterm infants (Osborn 2004). In this review, we did not find any randomised controlled trials that compared the effect of treatment with fluid bolus versus no treatment in preterm infants with metabolic acidosis. Dixon 1999 compared base infusion with fluid bolus and found some evidence (of borderline clinical significance) that base infusion corrected metabolic acidosis more effectively than fluid bolus. This trial specifically excluded infants with evidence of hypotension from participating.

Authors' conclusions

Implications for practice

There are insufficient data from randomised controlled trials to guide clinical practice.

Implications for research

Further randomised controlled trials are needed to determine if treating preterm infants with metabolic acidosis with either base or fluid bolus infusion prevents morbidity and mortality. Randomised trials may also examine the effects of these interventions in treating preterm infants with different degrees of metabolic acidosis (lower pH thresholds for intervention), analogous to recent studies that have attempted to determine the optimal target range for maintaining blood oxygen levels in preterm infants (Askie 2001; Tin 2001; Askie 2003).

Acknowledgements

We thank Professor Terence Stephenson for providing clarification on some aspects of his trial (Dixon 1999).

The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

CJL and FJW developed and wrote the review protocol. CJL and WM undertook the literature search, appraisal, and data extraction and completed the final review.

The August 2010 update was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Roger Soll and Diane Haughton). Additional information received from CJL. This update was reviewed and approved by CJL.

Declarations of interest

Cassie Lawn and Fiona Weir are co-investigators of the pilot unpublished randomised trial Lawn 2005. Unpublished data from this study are included in the review.

Potential conflict of interest

  • None noted.

[top]

Characteristics of studies

Characteristics of Included Studies

Corbet 1977

Methods

Blinding of randomisation: can't tell
Blinding of intervention: can't tell
Complete follow-up: yes
Blinding of outcome measurement: can't tell

Participants

Newborn preterm infants within the first few hours after birth: birth weight less than 1500 grams, or birth weight less than 2000 grams and infant needing mechanical ventilation, or Apgar score less than four at one minute, or infant with a clinical diagnosis of hyaline membrane disease.

Interventions
  1. "Liberal" sodium bicarbonate infusions (N=30) versus
  2. "conservative" sodium bicarbonate infusions (N=32) given with the standard maintenance intravascular infusions of 10% glucose.
Outcomes

Time to correction of acidosis, mortality in the first week of postnatal life, and incidence of intraventricular haemorrhage.

Notes

Those infants in the "liberal" group were allocated to receive sodium bicarbonate at doses of 5 to 15 mmol /decilitre of 10% glucose, titrated on the degree of acidosis. The bicarbonate infusion was continued until the infant's arterial blood pH reached 7.30. The infants in the conservative group did not have any sodium bicarbonate added to their maintenance glucose infusions.

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

Sequence generation: can't tell

Allocation concealment? Unclear

Blinding of randomisation: can't tell

Blinding? Unclear

Blinding of intervention: can't tell
Blinding of outcome measurement: can't tell

Incomplete outcome data addressed? Yes

Complete follow-up: yes

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

Dixon 1999

Methods

Blinding of randomisation: yes
Blinding of intervention: no
Complete follow-up: yes
Blinding of outcome measurement: can't tell

Participants

Neonates (mostly preterm) with metabolic acidosis (arterial blood pH < 7.25 and base excess of more than -6 mmol/litre). Exclusion criterion: infants with mean blood pressure less than third percentile for birth weight (Versmold 1981).

Interventions

Infusion over 30 minutes of :

  1. 10 ml/kg 4.5% albumin (N=20) versus
  2. 4.2% sodium bicarbonate (N=16): dose in mmol calculated as one-sixth of product of weight (kg) and base excess (mmol/L).
Outcomes

Arterial blood pH and base excess measured two hours post-intervention.

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

Sequence generation: can't tell

Allocation concealment? Yes

Blinding of randomisation: yes

Blinding? Unclear

Blinding of intervention: no
Blinding of outcome measurement: can't tell

Incomplete outcome data addressed? Yes

Complete follow-up: yes

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

Lawn 2005

Methods

Pilot randomised controlled trial

Participants

Enrolled 20 infants born at the Royal Sussex County Hospital and St Thomas' Hospital, London weighing less than 1000g with a gestational age less than 32 weeks.

The median gestational age was 26+6weeks for control infants (range 24+3 to 29+0 weeks ) and 25+4 weeks for treated infants (range 24+1 to 28+5 weeks).

Interventions

Treatment groups received continuous heparinised sodium bicarbonate infusion into the umbilical artery catheter (UAC) or peripheral arterial line for 96 hrs starting within 12 hrs of birth; infants in the control group received standard heparinised half normal saline solution into the arterial line.

Treatment of metabolic acidosis was according to neonatal intensive care unit protocol and was the same in both groups.

Outcomes

The study aimed to reduce the number of bolus treatments with bicarbonate or fluid to treat metabolic acidosis by giving a continuous weak infusion of sodium bicarbonate intra-arterially. The primary outcome measure was the number of bolus bicarbonate or fluid treatments required by both groups.

Records were kept of the number, type and amount of fluid boluses given and the indication for their use as well as of the number and amount of bicarbonate boluses given for the duration of the study (96 hours after intra-arterial infusion is commenced).

All infants had arterial blood pressure monitoring and hourly blood pressure heart rate and oxygen requirement noted for 96 hours. Minimum 6 hourly arterial blood gases were be measured for the first 48 hours and then at least 12 hourly for the next 48 hours as was standard practice. Blood volume losses were recorded in both groups. Both groups had twelve hourly urea and electrolyte estimations for the first 48 hours and 24 hourly for the next 48 hours, which was standard unit practice for babies under 1000g in the first 96 hours of life. Cranial ultrasound scans were be performed on control and treatment groups on days 1, 2 and 7 of life. Doppler ultrasound measurement of middle cerebral artery blood flow velocity will be made during the first 24 hours of life and on the second day of life in both study groups when the baby was clinically stable.

Notes

This was a pilot study for a planned study of 160 infants; the larger trial was not conducted.

IsrcTN22535466

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Serial sealed envelopes for randomisation. Computerised generation of sequence.

Allocation concealment? Yes

Infants were randomly assigned to treatment or control groups by serial sealed envelopes.

Blinding? No
Incomplete outcome data addressed? Yes
Free of selective reporting? Yes
Free of other bias? Unclear

Data complete for the 20 infant pilot study. The full study not undertaken due to difficulty recruiting < 1000g infants.

Characteristics of excluded studies

Bland 1976

Reason for exclusion

Bland 1976 compared giving rapid infusions of sodium bicarbonate versus albumin or dextrose-water infusions in preterm infants at risk of acidaemia within the first two hours of postnatal life. However, most of the participating infants were not acidotic at trial entry.

Sinclair 1968

Reason for exclusion

Sinclair 1968 randomised 20 infants with a birth weight of 1000-2500 g to receive one of four different treatment combinations which included a trial of rapid versus slow infusion of sodium bicarbonate, but without a comparison group who did not receive any base (or who received fluid bolus).

[top]

References to studies

Included studies

Corbet 1977

Corbet AJ, Adams JM, Kenny JD, Kennedy J, Rudolph AJ. Controlled trial of bicarbonate therapy in high-risk premature newborn infants. Journal of Pediatrics 1977;91(5):771-6.

Dixon 1999

Dixon H, Hawkins K, Stephenson T. Comparison of albumin versus bicarbonate treatment for neonatal metabolic acidosis. European Journal of Pediatrics 1999;158(5):414-5.

Lawn 2005

Unpublished data only

Lawn C, Weir F. Effect of continuous intra-arterial weak bicarbonate infusion on the use of fluid and bicarbonate boluses to correct metabolic acidosis in babies weighing less than 1000 g and who are less than 32 weeks gestation at birth. Personal communication: see Controlled-Trials.com External Web Site Policy.

Excluded studies

Bland 1976

Bland RD, Clarke TL, Harden LB. Rapid infusion of sodium bicarbonate and albumin into high-risk premature infants soon after birth: a controlled, prospective trial. American Journal of Obstetrics and Gynecology 1976;124(3):263-7.

Sinclair 1968

Sinclair JC, Engel K, Silverman WA. Early correction of hypoxemia and acidemia in infants of low birth weight: a controlled trial of oxygen breathing, rapid alkali infusion, and assisted ventilation. Pediatrics 1968;42(4):565-89.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Alderson 2001

Alderson P, Bunn F, Lefebvre C, Li Wan Po A, Li L, Roberts I, Schierhout G. The Albumin Reviewers. Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No.: CD001208. DOI: 10.1002/14651858.CD001208.

Ammari 2002

Ammari AN, Schulze KF. Uses and abuses of sodium bicarbonate in the neonatal intensive care unit. Current Opinion in Pediatrics 2002;14(2):151-6.

Askie 2001

Askie LM, Henderson-Smart DJ. Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD001077. DOI: 10.1002/14651858.CD001077.

Askie 2003

Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. Oxygen-saturation targets and outcomes in extremely preterm infants. New England Journal of Medicine 2003;349(10):959-67.

Aylward 1993

Aylward GP. Perinatal asphyxia: effects of biologic and environmental risks. Clinics in Perinatology 1993;20(2):433-49.

BAPM 1992

Development of audit measures and guidelines for good practice in the management of neonatal respiratory distress syndrome. Report of a Joint Working Group of the British Association of Perinatal Medicine and the Research Unit of the Royal College of Physicians. Archives of Disease in Childhood 1992;67(10):1221-7. [Other: PMID 7530835]

Bell 2001

Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No.: CD000503. DOI: 10.1002/14651858.CD000503.pub2.

Cooke 1981

Cooke RW. Factors associated with periventricular haemorrhage in very low birthweight infants. Archives of Disease in Childhood 1981;56(6):425-31. [Other: PMID7259272]

Goldstein 1995

Goldstein RF, Thompson RJ Jr, Oehler JM, Brazy JE. Influence of acidosis, hypoxemia and hypotension on neurodevelopmental outcome in very low birthweight infants. Pediatrics 1995;95(2):238-43. [Other: PMID 7530835]

Hope 1998

Hope P. Pump up the volume? The routine early use of colloid in very preterm infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 1998;78(3):F163-5.

Koch 1968

Koch G, Wendel H. Adjustment of arterial blood gases and acid base balance in the normal newborn infant during the first week of life. Biology of the Neonate 1968;12(3):136-61. [Other: PMID 564604]

Levene 1982

Levene MI, Fawer CL, Lamont RF. Risk factors in the development of intraventricular haemorrhage in the preterm neonate. Archives of Disease in Childhood 1982;57(6):410-7.

Lou 1978

Lou HC, Lassen NA, Friis-Hansen B. Decreased cerebral blood flow after administration of sodium bicarbonate in the distressed newborn infant. Acta Neurologica Scandinavica 1978;57(3):239-47. [Other: PMID 665145]

Lou 1979

Lou HC, Lassen NA, Friis-Hansen B. Impaired autoregulation of cerebral blood flow in the distressed newborn infant. Journal of Pediatrics 1979;94(1):118-21. [Other: PMID 758388]

Low 1990

Low JA, Froese AF, Galbraith RS, Sauerbrei EE, McKinven JP, Karchmar EJ. The association of fetal and newborn metabolic acidosis with severe periventricular leukomalacia in the pre-term newborn. American Journal of Obstetrics and Gynecology 1990;162(4):977-81. [Other: PMID 2183620]

Moriette 1977

Moriette G, Relier JP, Larroche JC. Intraventricular haemorrhages in hyaline membrane disease. Archives Francaises de Pediatrie 1977;34(6):492-504. [Other: PMID907432]

Morrison 1995

Morrison FK, Patel NB, Howie PW, Mires GJ, Herd RM. Neonatal cerebral arterial flow velocity waveforms in term infants with and without metabolic acidosis at delivery. Early Human Development 1995;42(3):155-68. [Other: PMID 7493584]

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.

Papile 1978

Papile LA, Burstein J, Burstein R, Koffler H, Koops B. Relationship of intravenous sodium bicarbonate infusions and cerebral intraventricular hemorrhage. Journal of Pediatrics 1978;93(5):834-6.

Perlman 1983

Perlman JM, McMenamin JB, Volpe JJ. Fluctuating cerebral blood-flow velocity in respiratory distress syndrome. Relation to the development of intraventricular hemorrhage. New England Journal of Medicine 1983;309(4):204-9. [Other: PMID 6866033]

Rennie 1999

Rennie JM, Roberton NRC. In: Textbook of Neonatology. 3rd edition. Churchill Livingstone, 1999:Appendix 6, 1408.

Simmons 1974

Simmons MA, Adcock EW 3rd, Bard H, Battaglia FC. Hypernatremia and intracranial hemorrhage in neonates. New England Journal of Medicine 1974;291(1):6-10. [Other: PMID]

Simpson 1994

Simpson JM, Hawkins K, Gull N, Stephenson TJ. Treatment of metabolic acidosis in the newborn. An observational and questionnaire study. British Journal of Intensive Care 1994;4:80-6. [Other: ISSN 09617930]

Soothill 1986

Soothill PW, Nicolaides KH, Rodeck CH, Gamsu H. Blood gases and acid-base status of the human second-trimester fetus. Obstetrics and Gynecology 1986;68(2):173-6.

Stevens 1999

Stevens CP, Raz S, Sander CJ. Peripartum hypoxic risk and cognitive outcome: a study of term and preterm birth children at early school age. Neuropsychology 1999;13(4):598-608. [Other: PMID10527069]

Synnes 2001

Synnes AR, Chien LY, Peliowski A, Baboolal R, Lee SK; Canadian NICU Network. Variations in intraventricular hemorrhage incidence rates among Canadian neonatal intensive care units. Journal of Pediatrics 2001;138(4):525-31.

Tin 2001

Tin W, Milligan DW, Pennefather P, Hey E. Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation. Archives of Disease of Childhood. Fetal and Neonatal Edition 2001;84(2):F106-10.

Versmold 1981

Versmold HT, Kitterman JA, Phibbs RH, Gregory GA, Tooley WH. Aortic blood pressure during the first 12 hours of life in infants with birth weight 610 to 4, 220 grams. Pediatrics 1981;67(5):607-13.

Weir 1999

Weir FJ, Ohlsson A, Myhr TL, Fong K, Ryan ML. A patent ductus arteriosus is associated with reduced middle cerebral artery blood flow velocity. European Journal of Pediatrics 1999;158(6):484-7. [Other: PMID 10378397]

Other published versions of this review

Lawn 2005

Lawn CJ, Weir FJ, McGuire W. Base administration or fluid bolus for preventing morbidity and mortality in preterm infants with metabolic acidosis. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD003215. DOI: 10.1002/14651858.CD003215.pub2 .

[top]

Data and analyses

1 Base (sodium bicarbonate or THAM) versus no treatment

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Mortality 2 82 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.82, 2.56]
1.2 Intra (and/or peri) ventricular haemorrhage (post-mortem diagnoses only) 1 62 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.47, 3.28]

2 Base (sodium bicarbonate or THAM) versus fluid bolus

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Failure to improve pH to more than 7.25 or base excess above -6 mmol/litre at 2 hours post treatment. 1 36 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.07, 1.11]

[top]

Sources of support

Internal sources

  • Ninewells Hospital and Medical School, Dundee, UK

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 11, 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.