Authors
- Orimadegun, Adebola Emmanuel MBBS, MSc Clinical Trials, FWACP
- Akingbola, Titilola Stella MBBS, MSc, FWACP
Abstract
Review question/objective: The objective of this review is to assess the effectiveness of intravenous calcium given during exchange blood transfusion (EBT) in neonates.
More specifically, the objectives of the review are to determine whether:
1. the proportion of neonates with post-EBT hypocalcaemia differ between those given intravenous calcium during EBT and those not given;
2. the frequency of deaths among neonates given intravenous calcium during EBT differs from those not given; and
3. intravenous calcium is effective in reducing the incidence of post-EBT seizures.
Background: Neonatal hyperbilirubinaemia is an abnormally high level of bilirubin in the circulating blood, resulting in clinically visible icterus or jaundice. A serum bilirubin level above 5 mg per dL (86 [mu]mol per L) is a frequently encountered problem worldwide and is a common reason for neonates to present to the emergency department.1Unconjugated bilirubin is toxic to infants' brains when the concentration exceeds a certain level. An unconjugated serum bilirubin concentration at toxicity level is described as 'severe hyperbilirubinaemia'. The concentrations that define toxic level vary, depending on the gestational age of the neonates and fetal maturity.2,3 Severe hyperbilirubinaemia can cause encephalopathy if not promptly treated, with significant complications such as athetoid cerebral palsy, sensorineural hearing loss, paralysis of upward gaze, dental enamel dysplasia and death.4,5 Recent reports indicate that these conditions, though rare, are still occurring despite the availability of efficient methods for treatment of hyperbilirubinaemia and its prevention.1,4-14 These complications can be prevented if the level of bilirubin is reduced rapidly with exchange blood transfusion.
Exchange blood transfusion (EBT) is the most rapid and effective method for lowering serum bilirubin concentrations, but it is rarely needed when intensive phototherapy is effective.1,3,15 In the presence of hemolytic disease, severe anaemia, or a rapid rise in the total serum bilirubin level (greater than 1 mg per dL per hour in less than six hours), EBT is the recommended treatment. EBT also removes partially hemolyzed and antibody-coated erythrocytes and which is then replaced with uncoated donor red blood cells. If intensive phototherapy fails to lower the bilirubin level, then EBT is always considered as the next line of treatment in any newborn with non-hemolytic jaundice.1Complications of EBT can include hypocalcaemia, seizures and even death within 24 hours. The potential seriousness of these complications makes clinicians consider intensive phototherapy before EBT.15However, the option of intensive phototherapy may not be feasible and could be quite ineffective in resource limited settings where the required facilities and electrical power supply are inadequate. Under these circumstances neonates with severe hyperbilirubinaemia will most likely be treated with EBT.
Exchange transfusion of blood collected with acid-citrate-dextrose (ACD) containing bags may produce hypocalcaemia.16To decrease the morbidity from chelation of divalent cations by citrate, routine administration of calcium gluconate during EBT was advocated,17-19but tetany, convulsion and death may still occur when ACD blood is used.16However, there are controversies about the effectiveness of intravenous calcium in reducing these calcium-related morbidities. A preliminary search for systematic reviews in MEDLINE, the Cochrane Library, Campbell Library and the Joanna Briggs Database of Systematic Reviews and Implementation Reports failed to identify any existing publications on this topic. As a result, this review will examine current quantitative evidence regarding the effectiveness of routine administration of intravenous calcium during EBT in the treatment of severe hyperbilirubinaemia, with specific aim to describe incidences of hypocalcaemia, seizures and deaths after such a transfusion.
Article Content
Inclusion criteria
Types of participants
This review will consider studies that include preterm and term neonates (one to 28 days) who had hyperbilirubinaemia treated with exchange blood transfusion worldwide.
Types of intervention(s)/phenomena of interest
This review will consider studies that evaluate the routine use of intravenous calcium during exchange blood transfusion for treatment of hyperbilirubinaemia and those with no administration of intravenous calcium.
Types of outcomes
This review will consider studies that include the following outcome measures:
* Post-EBT hypocalcaemia
* Post-EBT seizure
* All-cause mortality within 24 hours after EBT.
Types of studies
This review will consider both experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies and analytical cross sectional studies.
Search strategy
The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in English language will be considered for inclusion in this review. Studies published from January 1973 to December 2013 will be considered for inclusion in this review because EBT has gradually been replaced by phototherapy and plasmapheresis in the last two decades, particularly in developed counties.
A number of electronic databases will be searched to locate relevant studies in this subject area. The databases to be searched include:
MEDLINE/PubMed
CINAHL
Cochrane Controlled Trials Register
WHO global health library
Directory of Open Access Journals (DOAJ)
EMBASE
Database of Abstracts of Reviews of Effectiveness (DARE)
African Journals Online
Google Scholar.
The search for unpublished studies will include the following sources:
Dissertation Abstracts
Conference proceedings
Research and clinical trials registers
Web sites of relevant associations
Direct communication with neonatal and midwifery organizations
Neonatal nurse or midwife researchers.
All databases will also be searched using the relevant keywords of the review topic and their synonyms and related words. Initial keywords to be used will include:
Calcium
Calcium Gluconate
Calcium Gluconate/administration & dosage
Calcium/administration & dosage*
Calcium/blood
Calcium/calcium gluconate
Citrates
Citrates/adverse effects
Exchange blood transfusion/EBT
Exchange Transfusion, Whole Blood*
Hypocalcaemia/hypocalcemia
Hypocalcemia/etiology*
Hypocalcemia/prevention & control
Infant, Newborn
Infusions, Intravenous
Jaundice, Neonatal/therapy
Neonatal seizure
Neonates/newborns.
These keywords will subsequently be combined as search terms with the appropriate operators ("AND"/"OR"). Advanced search options will be used where available. Hand-searches will be conducted of journals relevant to the review topic and accessible through Nigerian libraries or online to ensure that useful studies that have not been listed in the major indexing services are located. For highly relevant journals, hand-searches will be conducted for all available issues for 1973 - 2013.
Moreover, reference lists of all studies and review papers will be examined to identify additional research studies. Full text versions of the studies located will be used for the initial assessment against the inclusion and exclusion criteria. Only articles written in English language will be reviewed. Two reviewers will conduct assessment articles independently. Bibliographic details of the studies located will be organized using the Endnote X5 software program.
Assessment of methodological quality
Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix V). Any disagreements that arise between the two reviewers will be resolved through discussion, or with a third reviewer.
Data collection
Data will be extracted from the retrieved articles using the standardized data extraction tool from JBI-MAStARI (Appendix VI). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives.
Data synthesis
Quantitative data will, where possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subjected to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.
Conflicts of interest
The authors declare no conflict of interest.
Acknowledgements
We are grateful for the assistance rendered by the team at Malaria Alert Centre: a Collaborating Center of the Joanna Briggs Institute at Jimma University, Ethiopia.
References
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Appendix I: Appraisal instruments
MAStARI appraisal instrument
Appendix II: Data extraction instruments
MAStARI data extraction instrument
Keywords: calcium; exchange blood transfusion: infant