Review question: does the administration of calcium during exchange blood transfusion (EBT) reduce the risk of low blood calcium and risk of death from low blood calcium levels among neonates receiving exchange blood transfusion?
Background: EBT is a type of massive blood transfusion (where blood is taken from a healthy person and infused into the bloodstream of an ill person) which predisposes to low blood calcium as a result of the bonding (chelating) effect of anticlotting chemicals used to preserve donor's blood. Low blood calcium can cause abnormal functions of muscles (including the heart) and nerves. In this review, we investigated the benefits of administered calcium on blood calcium levels and the safety of calcium administration to newborn infants receiving EBT.
We searched medical databases for clinical trials that administered calcium or no calcium to newborns aged from birth to 28 days receiving EBT and monitored a range of symptoms including death and heart problems.
Study characteristics: we identified only one poorly designed study for inclusion.
Results: we found that giving calcium to newborn infants raised blood calcium levels immediately after EBT while blood calcium was reduced among newborn infants who did not receive calcium during EBT. However, despite the observed trends in the values of blood calcium in both groups of the study, the average values of blood calcium in both groups remained within normal limits. In addition, the information available for this review was limited as the effects of giving or not giving calcium during EBT was not studied beyond the time of EBT.
Conclusion: based on the findings in this review, there is no good-quality evidence to support or reject continual use of calcium during EBT. We are unable to make conclusions, as the evidence that we found is limited and of very low quality and could change if more results from larger and better-designed studies become available.
Very low-quality data from one quasi-randomised controlled trial suggested that the mean serum total and ionised calcium increased in the study group but decreased in the control group immediately after EBT. However, the mean values of total and ionised calcium in both arms of studies remained within international reference ranges. Unfortunately, data were not available to assess the trend of total and ionised serum calcium to the end of the first week after EBT. Therefore, due to the very low quality of evidence available, it is difficult to support or reject the continual use of prophylactic intravenous calcium in newborn infants receiving EBT. Researchers are encouraged to conduct more robustly designed trials with larger numbers of participants, and particularly, addressing the pattern of differences based on gestational age of participants, type of anticoagulant used, and the volume of blood used.
Exchange blood transfusion (EBT) is a form of whole blood transfusion in which the total blood volume is replaced within a few hours. In perinatal and neonatal medicine, EBT is most often used in the management of severe anaemia or severe hyperbilirubinaemia in the first week of life. Hypocalcaemia, one of the common morbidities associated with EBT, is thought to arise from the chelating effects of the citrate commonly used as an anticoagulant in the donor's blood. This disorder manifests with muscular and nervous irritability and cardiac arrhythmias.
To determine whether the use of prophylactic calcium reduces the risk of hypocalcaemia-related morbidities and death among newborn infants receiving EBT.
We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 5), MEDLINE via PubMed (1966 to 29 June 2016), Embase (1980 to 29 June 2016), and CINAHL (1982 to 29 June 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.
All randomised and quasi-randomised trials of prophylactic intravenous calcium in EBT for newborns.
Two review authors independently assessed and extracted data on methods, participants, interventions, and outcomes (mean total and ionised serum calcium before and after EBT and the presence of adverse events such as hypoglycaemia, apnoea, cardiac arrest, and death immediately after EBT). We reported results as means difference (MD) with 95% confidence intervals (CI) for continuous outcomes and risk ratio (RR) and risk differences (RD) and 95% CIs for dichotomous outcomes. We assessed quality using the Cochrane 'Risk of bias' assessment tool and the GRADE system.
We found only one quasi-randomised trial with 30 participants that met our inclusion criteria. In the small trial, total and ionised serum calcium levels were measured immediately before and immediately after EBT. All the participants were included in the final analysis and all the important outcomes were reported.
Primary outcomes
There was one death in each group (RR 1.00, 95% CI 0.07 to 14.55; RD 0.00, 95% CI -0.18 to 0.18; participants = 30; studies = 1). The study did not report the presence of cardiac arrhythmias within one week of EBT and the number of infants with serum calcium levels (total less than 8 mg/dL (2 mmol/L) or ionised less than 4.4 mg/dL (1.1 mmol/L)).
Pair-wise comparison of EBT with intravenous 10% calcium gluconate versus EBT without intravenous calcium (change from baseline) showed mean total serum calcium was raised in the intervention group compared to the control group (MD -0.46, 95% CI -0.81 to -0.11; participants = 30; studies = 1). Very low-quality evidence also indicated an increase in the levels of mean ionised serum calcium in the intervention group compared to the control group (MD -0.22, 95% CI -0.33 to -0.11; participants = 30; studies = 1).
Secondary outcomes
Adverse reactions to intravenous calcium therapy included cardiac arrest in one neonate in the intervention arm (RR 3.00, 95% CI 0.13 to 68.26; RD 0.07, 95% CI -0.10 to 0.23; participants = 30; studies = 1). There was apnoea and hypoglycaemia (RR 1.00, 95% CI 0.07 to 14.55; RD 0.00, 95% CI -0.18 to 0.18; participants = 30; studies = 1) in the two neonates who died. Data were not available for other major secondary outcomes such as the number of infants with reduced serum magnesium, reduced parathormone, increased calcitonin, presence of seizures, carpopedal spasm, jitteriness and prolonged QTc interval on electrocardiography within one week of EBT.