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M.S.Y. Ng et al.
tify any association between mean PRBC age and nosoco- mial infection risk (OR: 1.57, 95% CI: 0.39-6.27, Table 3).
No association between PRBC age and HLOS
A
Ten datasets were analyzed in the HLOS analyses cov- ering 14,063 patients. The incidence rates were found to decrease by 3.1% and 0.4% for each additional day of mean PRBC age and maximum PRBC age, respectively. However, neither rate was statistically significant after controlling for age, sex and PRBC volume. There was sig- nificant heterogeneity in the mean PRBC age analyses with an I2 value of 98.6%. Patient subgroup analyses iden- tified ICU and other patients as major sources of hetero- geneity compared to cardiac surgery patients (Online Supplementary Figure S11). However, all patient subgroups groups generated similar effect estimates. The effect esti- mate for studies originating from the USA was significant- ly different to studies from Europe and other countries, however, there was only one study in the USA group (Online Supplementary Figure S11).Time-lapse analyses found that the incidence rate ratio remained stable over time (Online Supplementary Figure S12). On extremes analysis, the incidence rates for days in hospital increased by 8.3% in patients with a mean PRBC of at least 30 days compared to less than ten days. Similar to the general analyses, this rate was not statistically significant after adjusting for age, sex and PRBC volume transfused.
Discussion
The use of IPD enabled consistent treatment and out- come measures throughout analyses, leading to reduced variability and improved precision compared to paper level meta-analyses.5 The association between stored PRBCs and mortality aligned with the results of observa-
10,11,19 tional, but not RCT paper level meta-analyses. These
RCT meta-analyses included small pilot trials and com- bined diverse populations. Furthermore, PRBCs also vary significantly within a blood bank due to donor, prepara- tion and storage factors.20 The increased variability and confounding factors may have obscured associations between PRBC age and mortality.19 While large RCTs have not associated PRBC age with mortality, these RCTs did not test PRBCs at the end of shelf life.7-9,21
The extremes analyses addressed this issue by compar- ing patients transfused with a mean PRBC of at least 30 days to those transfused with a mean PRBC of less than ten days from observational studies. In this way, the pooled IPD analysis bridged the dissonance between clin- ical approaches (which tested stored PRBC aged 17 ± 13 days) and in vitro protocols (which sampled PRBCs over the course of shelf life).22 The association between PRBC >30 days old and mortality differed from secondary analy- ses of the Informing Fresh versus Old Red Cell Management (INFORM) study.23 In the secondary analy- ses, the use of maximum PRBC age to define stored PRBCs may have overestimated the aggregate PRBC age transfused.24 Patients transfused with predominantly fresh PRBC units, but with the addition of one PRBC unit >35 days old could inflate the number of “survivors” in the stored PRBC group.
The finding that PRBC age was not associated with nosocomial infection corroborated the results from large RCTs.7,21 However, the datasets available for IPD analysis
B
Figure 2. Forest plots and funnel plots for mortality analysis as a function of mean PRBC age. Mortality odds ratios were calculated for each study using logistic regression with mean PRBC age transfused as the independent variable. Age, sex and PRBC volume were covariates. (A) Odds ratios were then combined using random effects models. (B) Funnel plots were generated for each analyses to assess for publication bias. OR: odds ratio; CI: confidence interval.
had lower rates of associating PRBC age with nosocomial infections compared to unavailable datasets – potentially leading to an underestimation of the relationship between PRBC age and nosocomial infection risk.19
There was no association between PRBC age and HLOS. This may have occurred due to substantial HLOS variability as it is a composite indicator of disease severity, treatment efficacy and safety, that is heavily modulated by social factors. This pooled patient analysis was the first assessment of HLOS across multiple clinical PRBC age studies. Published studies describing PRBC storage effects have reported HLOS as stratified count data,25 median and interquartile range,26-28 median and range,29 mean and standard error,30 and Pearson’s correlation result31 – mak- ing paper level meta-analyses difficult. The IPD analysis abrogated this issue by using patient level HLOS data, allowing one consistent measure across all studies.
The potential limitations of this study include long recruitment time, applicable to high-volume PRBC trans- fusion, potential confounding factors and selection bias. PRBC processing and transfusion guidelines may have
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haematologica | 2018; 103(9)