No Effect of Transfusion Threshold on Sepsis Survival

Published - Written by Rupa Kanapathipillai

Yet who would have thought the old man to have had so much blood in him? (Macbeth Act V, Scene 1)

Our fascination with blood dates back to the dawn of time.   Poets, writers and philosophers have waxed lyrical about it.  Blood as a life source, elixir and contagion  – it is an entity that has been described as everything from sacred to poison.  Before the 20th century, removing blood (blood-letting) was thought to be therapeutic.  With the advent of blood typing, transfusion became possible and widely applied.  But when you transfuse a critically ill patient, how much blood is enough?

For centuries, the role of blood transfusions in the management of unwell patients has been debated.  The recommendations for blood transfusion in critical care remain complex. Both the TRICC and FOCUS trials, previously published in the NEJM, support the use of a more restrictive transfusion threshold in a broad population of ICU patients and in high-risk patients after hip surgery respectively. In this week’s NEJM, Holst et al, provide further insight into hemoglobin thresholds for transfusion in patients with septic shock.

The trial was a multicenter, parallel group study conducted between December 2011 and December 2013, across 32 intensive care units in Denmark, Sweden, Norway and Finland. 1224 patients were screened who were 18 years of age and older, met criteria for septic shock, and had hemoglobin concentrations of 9g per deciliter or below. 1000 patients were randomized to two blood transfusion thresholds – 503 patients to 9g per deciliter and 497 to 7g per deciliter. Randomization was stratified by site and the presence or absence of active hematological malignancy.

Patients received single units of cross-matched, pre-storage leuko-reduced red blood cells when blood concentrations of hemoglobin decreased below the 9g or 7 g per deciliter transfusion threshold.  Hemoglobin concentrations were reassessed within 3 hours of termination of transfusion, or before initiation of another transfusion.  Patients received the intervention for the entire ICU stay to a maximum duration of 90 days following randomization.  Decision to repeat the transfusion at the allocated transfusion threshold was left to the discretion of the attending doctor, during and after ICU discharge.

The primary endpoint was mortality 90 days after randomization; secondary outcomes included the of use of life-support (use of vasopressor/inotropic therapy, mechanical ventilation, or renal replacement therapy) at days 5, 14, 28 post randomization, number of patients with serious adverse reactions, ischemic events, percent of days alive without vasopressor support, mechanical ventilation or renal replacement therapy, and percentage of days alive and out of hospital in the 90 days after randomization.

During the study period, 1545 blood transfusions were given in the lower Hgb- threshold group and 3088 transfusions were given in the higher Hgb-threshold group (p<0.0001).  The median cumulative number of blood transfusions after randomization was 1 (IQR 0-3) unit in the lower Hgb-threshold group and 4 (2-7) units (p<0.0001) in the higher Hgb-threshold group.

No significant difference in 90-day mortality was found between the two transfusion thresholds; 216 patients (43.0%) in the lower Hgb-threshold group and 223 patients (45.0%) in the higher Hgb-threshold group died (RR 0.94 95% CI 0.78 – 1.09, p=0.44).  Similar results were found when adjusted for baseline risk factors.  No heterogeneity in the effect of transfusion on 90-day mortality was seen in patients with chronic cardiovascular disease, patients aged 70 years or above, or those with simplified acute physiology score II above 53 at baseline.  The numbers of ischemic events in the ICU were similar between groups; 7% in the lower Hgb-threshold group and 8% in the higher Hgb-threshold group.  The use of life-support at days 5, 14 and 28 was similar between the two intervention groups, as were the percentages of days alive without vasopressor/inotropic therapy, mechanical ventilation, renal replacement therapy and the percentage of days alive and out of hospital.

“It is noteworthy that outcomes were not adversely affected by using a 7 gm/dL transfusion trigger and about half the blood was required than was needed with the 9 gm/dL threshold,” Deputy Editor Dan Longo commented.

Importantly patients with acute myocardial infarction were excluded from this study and the FOCUS trial – the safety of lower transfusion thresholds in these patients remains unclear.

How will the results of this study change your clinical practice?  What transfusion thresholds are currently utilized in your ICU?  What is the quality of the evidence supporting these recommendations?