INSPIRE Trial Finds Wide Variation in RBC Transfusions Across European NICUs

Transfusions for very preterm infants in Europe are frequently administered at hemoglobin (Hb) levels above the restrictive thresholds identified in recent trials, according to a study published in JAMA Network Open, underscoring continued variation in practice and gaps in implementation of evidence-based guidelines.

In 2020, two large randomized clinical trials – the Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants (ETTNO) trial and the Transfusion of Prematures (TOP) trial – found that liberal RBC thresholds were no better than restrictive thresholds in terms of mortality or neurodevelopmental impairment at 2 years of corrected age.

The INSPIRE Trial

In the International Neonatal Transfusion Point Prevalence (INSPIRE) trial, investigators sought to describe RBC transfusion rates, indications, volumes, increments and adverse effects in Europe and to evaluate clinical Hb transfusion triggers compared with recent RCTs.

Researchers prospectively assessed transfusion practices in 64 NICUs across 22 European countries over a six-week study period. The study included 1,143 infants born before 32 weeks’ gestation and admitted to the NICU during the study period. The infants had a median gestational age at birth of 28 weeks plus two days and median birth weight of 1,030 g. They were followed until death, discharge or end of study period.

In the INSPIRE trial, 34.6% of infants received one or more RBC transfusions, with a total of 903 transfusions given. The median number of transfusions per infant was two. The overall observed RBC transfusion prevalence rate was 3.4 RBC transfusion days per 100 admission days during first 28 days of life. After the first 28 days of life, the prevalence was two RBC transfusion days per 100 admission days. The proportion of infants who received at least one RBC transfusion was 24.1% by day 7 of life and 36.5% by day 28.

The most common primary indication for RBC transfusion was Hb threshold (82.8%), followed by active bleeding (5%), surgical procedures (3.4%) and other reasons (8.8%). Among the 748 transfusions given based on an Hb threshold, 738 had known volume and duration data (unknown in 1.3%). Most of these were given at a volume of 15 mL/kg (63.7%), followed by 20 mL/kg (22.8%). Transfusion volumes were 25 mL/kg in 2.2% of transfusions.

Out of 903 transfusions, there were two cases of possible transfusion-associated adverse events (0.2%). One was associated with culture-proven sepsis following the transfusion. The second was associated with an increase in oxygen demand after transfusion.

Many Transfusions Exceeded Restrictive Thresholds

When compared with the restrictive and liberal thresholds used in the ETTNO and TOP trials, many transfusions in INSPIRE were administered above the restrictive range. Relative to the ETTNO thresholds, 44.4% of infants had pretransfusion Hb levels below the restrictive threshold, 48.3% between restrictive and liberal thresholds and 7.3% above the liberal threshold.

However, compared with the TOP trial, a lower proportion of transfusions (36.4%) had pretransfusion Hb levels below the restrictive threshold; 56.1% had levels between the evaluated restrictive and liberal threshold, and 7.5% were given above the liberal threshold. There was a wide range in Hb thresholds across neonatal intensive care units, even within similar clinical scenarios.

While the INSPIRE trial found substantial differences in RBC transfusion thresholds, volumes, durations and infusion rates across 22 European countries, the authors noted that the differences were only partly explained by variations in patient characteristics.

“The primary indication for most of the blood transfusions (82.8%) was Hb threshold,” the authors wrote. “Interestingly, most transfusions based on Hb threshold were given for pretransfusion thresholds above the restrictive thresholds, suggesting that most European countries have not implemented the restrictive thresholds in daily practice.”

The authors concluded that additional research is needed to understand and improve the incomplete uptake of the RCT evidence.