Routine administration of intravenous calcium during exchange blood transfusion for treatment of severe neonatal hyperbilirubinaemia: a systematic review of quantitative evidence protocol Adebola Emmanuel Orimadegun, MBBS, MSc Clinical Trials, FWACP 1,3 Titilola Stella Akingbola, MBBS, MSc, FWACP 2,3 1. Institute of Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria 2. Department of Haematology, College of Medicine, University of Ibadan, Ibadan, Nigeria 3. Joanna Briggs Institute Evidence Synthesis Group: Nigeria Corresponding author: Adebola Emmanuel Orimadegun beorimadegun@yahoo.com 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 μmol per L) is a frequently encountered problem worldwide and is a common reason for neonates to present to the emergency department. 1 Unconjugated 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 doi: 10.11124/jbisrir-2015-1963 Page 134
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. 1 Complications 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. 15 However, 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. 16 To decrease the morbidity from chelation of divalent cations by citrate, routine administration of calcium gluconate during EBT was advocated, 17-19 but tetany, convulsion and death may still occur when ACD blood is used. 16 However, 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. Keywords calcium; exchange blood transfusion: infant 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. doi: 10.11124/jbisrir-2015-1963 Page 135
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 doi: 10.11124/jbisrir-2015-1963 Page 136
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. doi: 10.11124/jbisrir-2015-1963 Page 137
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. doi: 10.11124/jbisrir-2015-1963 Page 138
References 1. American Academy of Pediatrics. Practice parameter: management of hyperbilirubinemia in the healthy term newborn. American Academy of Pediatrics. Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Pediatrics 1994;94(4 Pt 1):558-65. 2. Chou SC, Palmer RH, Ezhuthachan S, Newman C, Pradell-Boyd B, Maisels MJ, Testa MA. Management of hyperbilirubinemia in newborns: measuring performance by using a benchmarking model. Pediatrics 2003;112(6 Pt 1):1264-73. 3. American Academy of Pediatrics Subcommittee on H. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114(1):297-316. 4. Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics 1995;96(4 Pt 1):730-3. 5. Ebbesen F. Recurrence of kernicterus in term and near-term infants in Denmark. Acta Paediatr 2000;89(10):1213-7. 6. Ip S, Chung M, Kulig J, O'Brien R, Sege R, Glicken S, Maisels MJ, Lau J, American Academy of Pediatrics Subcommittee on H. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 2004;114(1):e130-53. 7. Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;140(4):396-403. 8. Watchko JF. Recurrence of kernicterus in term and near-term infants in Denmark. Acta Paediatr 2001;90(9):1080. 9. Gupta K, Chintu C. Familial nonhemolytic unconjugated hyperbilirubinemia (Crigler Najjar syndrome) with kernicterus - report of a case in Zambian child. East Afr Med J 1982;59(3):225-9. 10. Ogunlesi TA, Ogunfowora OB. Predictors of acute bilirubin encephalopathy among Nigerian term babies with moderate-to-severe hyperbilirubinaemia. J Trop Pediatr 2011;57(2):80-6. 11. Horn AR, Kirsten GF, Kroon SM, Henning PA, Moller G, Pieper C, Adhikari M, Cooper P, Hoek B, Delport S, Nazo M, Mawela B. Phototherapy and exchange transfusion for neonatal hyperbilirubinaemia: neonatal academic hospitals' consensus guidelines for South African hospitals and primary care facilities. S Afr Med J 2006;96(9):819-24. 12. Wolf MJ, Wolf B, Beunen G, Casaer P. Neurodevelopmental outcome at 1 year in Zimbabwean neonates with extreme hyperbilirubinaemia. Eur J Pediatr 1999;158(2):111-4. 13. Owa JA, Durosinmi MA, Alabi AO. Determinants of severity of neonatal hyperbilirubinaemia in ABO incompatibility in Nigeria. Trop Doct 1991;21(1):19-22. 14. Keet MP, Dyer RP, Botha MC, De Villiers JN. Hyperbilirubinaemia in newborn infants with birthweight exceeding 2,500 G. S Afr Med J 1966;40(13):286-92. 15. Jackson JC. Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics 1997;99(5):E7. 16. Farquhar JW, Smith H. Clinical and biochemical changes during exchange transfusion. Arch Dis Child 1958;33(168):142-59. doi: 10.11124/jbisrir-2015-1963 Page 139
17. Sherman DM, Tsygura IT. [Effect of intravenous administration of calcium chloride on the effectiveness of infusion therapy of acute massive blood loss]. Biull Eksp Biol Med 1978;86(12):697-700. 18. Diamond LK, Allen FH, Jr., Thomas WO, Jr. Erythroblastosis fetalis. VII. Treatment with exchange transfusion. N Engl J Med 1951;244(2):39-49. 19. Miller G, McCord AB, Joos HA, Clausen SW. Studies of serum electrolyte changes during exchange transfusion in infants with erythroblastosis fetalis. AMA Am J Dis Child 1952;84(5):637-9. doi: 10.11124/jbisrir-2015-1963 Page 140
Appendix I: Appraisal instruments MAStARI appraisal instrumenti a test message Insert page bre doi: 10.11124/jbisrir-2015-1963 Page 141
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Appendix II: Data extraction instruments MAStARI data extraction instrument Insert page break doi: 10.11124/jbisrir-2015-1963 Page 144
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