With each publication from Maitland et al we are granted a brief glimpse of a greater medical truth. Only our view is obstructed, as we peer through the constricted aperture created by the questions regarding its external validity.
In 2011, Maitland et al published the FEAST trial in the NEJM (1). This landmark trial called into question the safety and utility of one of the most ubiquitous interventions in medicine today, the fluid bolus. The authors enrolled 3141 pediatric patients presenting with sepsis to six clinical centers in Africa. Patients were randomized to receive an IV fluid bolus (either saline or albumin), plus a continuous infusion or an infusion alone.
Results were surprising to say the least. The trial was stopped premature of its 3600 predetermined sample size due to an increased rate of 48-hour mortality, 10.6%, 10.5%, and 7.3% in the albumin-bolus, saline-bolus, and no bolus control groups, respectively. This was the first trial empirically examining the efficacy of a fluid bolus as a treatment for septic shock, in which the authors found that the use of IV fluid boluses were associated with an increase in both 48-hour and 28-day mortality. And yet, 8 years since the publication of this trial, rapid fluid administration is still paramount in the management of septic shock. Many argue that these results may not be externally valid outside the context in which they were tested. Are fluid boluses detrimental when used in a population of critically ill adults with access to ICU level care? While there is a growing body of literature suggesting Maitland et al’s results are applicable more broadly than originally considered, the concerns regarding the FEAST trial’s external validity have limited its influence on the greater management of sepsis and septic shock. Now with the publication of TRACT trial in the NEJM, Maitland et al again ask us to consider the validity of another long held medical practice (2).
Much like the administration of IV crystalloid, the current management of severe anemia is, in theory, fairly straightforward. Guided by the results of the TRICC trial (3), published in the NEJM by Herbert et al in 1999, in which the authors randomized critically ill patients in the ICU with no signs of active hemorrhage to one of two different transfusion thresholds, 7 g/dL vs 10 g/dL. The authors enrolled 838 patients, 413 assigned to the restrictive group and 420 to the liberal group. Patients randomized to the liberal transfusion strategy successfully had their hemoglobin maintained at a higher level than their restrictive strategy counterparts. The average daily hemoglobin concentrations were 8.5±0.7 g/dL in the restrictive-strategy group and 10.7±0.7 g/dL in the liberal-strategy group. To achieve this higher hemoglobin value clinicians were required to transfuse significantly larger quantities of PRBCs, 2.6±4.1 PRBCs per patient in the restrictive-strategy group vs 5.6±5.3 in the liberal-strategy group.
30-day mortality was 18.7 percent in the restrictive-strategy group vs 23.3 percent in the liberal-strategy group (P=0.11). In-hospital mortality was 22.2 percent vs. 28.1 percent in the restrictive -strategy and liberal strategy respectively (P=0.05). In addition, ICU mortality and 60-day mortality both trended towards favoring the restrictive-strategy group. Cardiac events such as MI and pulmonary edema were also a more frequent occurrence in the liberal transfusion strategy group (13.2% vs 21.1%).
The results of the TRICC trial have been validated in many populations both pediatric and adult (4, 5, 6). And while it is clear an empirically restrictive strategy is superior to an empirically liberal one, it is important to note that this trial demonstrated 7 g/dL was preferable to 10 g/dL. It did not determine if 7 g/dL was better than 6 g/dL, 5 g/dL, or if empiric transfusion strategies based on hemoglobin levels were superior to transfusion triggers based on signs indicating the anemia was leading to physiological distress. Until now such questions had been relegated to the musings of the rebellious mind. With the publication of the TRACT trial in the NEJM, we now have clinical data suggesting a single threshold may not be ideal (2).
In a factorial, open-label, randomized, controlled trial Maitland et al enrolled children 2 months to 12 years of age with uncomplicated severe anemia. The patients were randomized to an immediate transfusion or a control group, in which a transfusion was deferred unless the patient’s hemoglobin dropped below 4 g/dL or they developed clinical signs of severe anemia, defined as prostration or respiratory distress. Patients randomized to receive an immediate transfusion, received 20 ml/kg or 30 ml/kg of whole blood equivalent determined by a second randomization (the results presented as an additional paper in the NEJM (7)). If a second transfusion was indicated, it was done so at the same volume as the first. Patients randomized to the control group who met the threshold for transfusion were transfused 20 ml/kg of whole blood equivalents.
From September 17, 2014 to May 15, 2017 Maitland et al enrolled a total of 1565 children, 778 assigned to the immediate-transfusion group (390 and 388 in the 20 ml and 30 ml groups, respectively), and 787 to the control group. All 778 patients in the immediate transfusion group received at least one blood transfusion. In comparison, only 386 (49.0%) received a transfusion in the control group. Reasons for transfusion in the control groups were a drop in the hemoglobin level to below 4g per deciliter (76.4%), a new sign of clinical severity (14.8%), or the patient received a new diagnosis of sickle cell disease (1.8%). Overall, during the initial hospitalization, the mean total volume of whole-blood equivalent transfused per child was 314±228 ml vs 142±224 ml in the immediate-transfusion and control groups, respectively.
The more aggressive transfusion strategy resulted in fewer patients experiencing a severe anemia (hemoglobin< 4g/dL), 1.4% vs 39.3%, as well as more children experiencing an early hemoglobin recovery (> 9 g/dL), 51.3% vs 5.5%. But these improvements in laboratory values did not translate into improvements in patient outcomes. The authors reported no difference in their primary outcome, 28-day mortality, 0.9% in the immediate group vs 1.7% in the control group. Nor did they identify a difference in mortality at 3 or 6 months. They also found no difference in complications due to severe anemia or readmission to the hospital during the subsequent 6-months. In fact, at 28-days the difference in hemoglobin levels between the two groups was minimal, only 0.60 g/dL higher in the immediate-transfusion group.
Once again Maitland et al have challenged what we thought we knew about medicine. The authors have again generated data that can be applied instantly by many practicing around the world. But for some, we are uncertain how these results apply to patients outside the confines of the population studied. External validity concerns the ability of a trial’s results to be applied to a population outside the cohort studied. In this case can a highly restrictive transfusion strategy be employed in patients outside of the four hospitals in Uganda and Malawi that enrolled patients in this trial? More broadly, can we apply these transfusions strategies to pediatric patients in industrialized nations with the benefits of ICU level care? More broadly still, is the question of how these transfusion strategies apply to adult patients with critical anemia.
Is the population treated in this trial unique, preventing these results from being applied to a broader population of anemic children or even adults? Similar to the FEAST trial, a large portion of the patients (62.9%) had malaria and 21.7% were diagnosed with sickle cell disease. Should this limit the trial’s generalizability? Without further study these concerns will remain unanswered, but almost every study examining transfusion strategies in various subtypes of patients have found restrictive strategies more preferable to liberal ones.
Can we apply the results from this population more broadly, to a population treated in healthcare systems with access to ICU level care? The major concern held by the authors was whether allowing hemoglobin levels to fall so low without intensive monitoring was safe. This is the reason a strict hemoglobin monitoring strategy was incorporated into the trial’s methodology. Frequent blood draws are well within the capabilities of any modern ICU, some would argue to a fault. And so the real question is can we apply the results of this trial, not to an ICU setting where hemoglobin levels can be monitored frequently, but to an environment that does not have the capability to regularly monitor a patient’s hemoglobin levels?
Finally, can these results be applied in an adult population with critical anemia? Current pediatric transfusion guidelines appear fairly similar to their adult counterparts (8), recommending a transfusion trigger of 7 g/dL. The TRIPICU trial (4), in a sense validated the findings of the TRICC trial in a pediatric population, demonstrating that a transfusion trigger of 7 g/dL was superior to a trigger of 9.5 g/dL. But similar to the TRICC trial, the authors only asked a dichotomous question and did not examine whether a lower transfusion threshold was preferred to either of these levels.
There is a greater medical truth hidden in the pages of this document. Transfusion of red blood cells can likely occur at a much lower threshold than what we generally employ, and the level at which anemia becomes detrimental probably varies from patient to patient. But like FEAST, it is doubtful these results will be broadly applied. Instead we are stuck in an endless cycle of dismissal and denial. A trial like this could not have been done outside of this population, but we are unable to apply the results generally because of the population in which it was conducted. And while it remains unclear whether the results of the TRACT trial are generalizable to blood transfusion strategies outside the confines of this cohort, the results should cause us to question the absurd dichotomy in which we currently exist. Where a patient with a hemoglobin of 7.1 g/dL is fine and that same patient at 6.9 g/dL is in urgent need of red blood cells, with no consideration of the clinical context which surround these abstract data points.
- Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-95.
- Maitland K, Kiguli S, Olupot-olupot P, et al. Immediate Transfusion in African Children with Uncomplicated Severe Anemia. N Engl J Med. 2019;381(5):407-419.
- Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409-17.
- Lacroix J, Hébert PC, Hutchison JS, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356(16):1609-19.
- Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11-21.
- Mazer CD, Whitlock RP, Fergusson DA, et al. Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery. N Engl J Med. 2017;377(22):2133-2144.
- Maitland K, Olupot-olupot P, Kiguli S, et al. Transfusion Volume for Children with Severe Anemia in Africa. N Engl J Med. 2019;381(5):420-431.
- Doctor A, Cholette JM, Remy KE, et al. Recommendations on RBC transfusion in general critically ill children based on hemoglobin and/or physiologic thresholds from the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. Pediatr Crit Care Med 2018;19:Suppl 1:S98-S113.