Abstract

Purpose: Transfusing red blood cells (RBCs) in non-bleeding critically ill patients once the haemoglobin meets a certain threshold is the standard of care, despite the lack of robust data suggesting improved outcomes with this practice. Our aim was to critically examine if there are discernible physiological benefits to RBC transfusion in patients with respiratory failure, individuals who are susceptible to transfusion-related adverse events.

Materials and methods: This is a single-centre, cross-sectional study including mechanically ventilated adults who were not bleeding and underwent an isolated RBC transfusion for a haemoglobin level of < 7 g/dl identified on a routine blood draw. We recorded vital signs and variables related to organ function (gas exchange, laboratory data and severity of illness) in the six hours pre- and post-transfusion that might plausibly benefit from the transfusion.

Results: Seventy-four patients met the inclusion criteria. There were no improvements in vital signs, laboratory data, vasopressor requirements and overall illness severity after RBC transfusion. Gas exchange as measured by the PaO2/FiO2 ratio, however, worsened (pre-transfusion 233±106, post-transfusion 199±92; p=0.01), an association which held after multivariate adjustment in the two time periods.

Conclusions: We found no change in common physiological parameters after RBC transfusion in patients intubated for hypoxaemic respiratory failure. In fact, the PaO2 /FiO2 ratio worsened slightly. This might be related to an adverse effect of the transfusion, perhaps mediated by a volume effect or direct lung injury. These data provide preliminary rationale of the nonutility of RBC transfusion based purely on an arbitrary haemoglobin threshold in this patient population.

Introduction

Transfusion of red blood cells (RBCs) is common practice in non-bleeding critically ill patients, despite the surprising sparsity of supportive evidence. In the intensive care unit (ICU), 44% of patients receive an RBC transfusion, 76% of which are not for acute blood loss.[1] There is undoubtedly a sound physiological rationale for RBC transfusion: it increases arterial oxygen content and, in turn, its delivery to organs.[2] The translation of this principle toward improved clinical outcomes, however, has not been definitively shown in individuals who are not bleeding.[3,4] In fact, much of the literature in this area suggests equivalent or improved outcomes by restricting RBC use. In 1999, a landmark trial demonstrated a strong trend toward decreased in-hospital mortality in ICU patients by restricting RBC transfusions,[5] thereby establishing the paradigm for transfusing at a haemoglobin level of 7 g/dl among euvolaemic ICU patients. This was later supported by similar findings in sepsis and other disease states.[6,7]

The clinical benefit of lower haemoglobin targets may be related to the many known downsides to RBC transfusion, including volume loading,[8] the development of lung injury,[9] and a general mild immunosuppressive effect.[10] Independent of specific adverse effects, transfused RBCs are less effective than native ones at oxygen delivery due to physiological changes accrued during procurement and storage (termed ‘RBC storage lesion’).[11] Examples are substantially reduced levels of 2,3-diphosphoglycerate as well as RBC membrane damage, which impair tissue oxygen unloading and disrupt microvascular flow, respectively.[11,12] Additionally, restrictive transfusion is likely well tolerated due to the many adaptive responses to anaemia: favourable alterations in blood flow patterns[13] along with increased stroke volume,[14] and oxygen extraction maintain tissue oxygenation.
Other than a universal haemoglobin cut-off, clinicians generally do not consider the baseline haemoglobin level, the severity of the clinical course, or the individual specific risk of transfusion in deciding to transfuse. This is because biomarkers (other than the haemoglobin level) to guide transfusion decisions have not been well established.[6] Therefore, our aim was to critically examine if there are discernible macro-physiological benefits to RBC transfusion in ICU patients with hypoxaemic respiratory failure, a group who may be particularly prone to adverse transfusion-related events.[9] We evaluated respiratory and circulatory function in a way commonly used by clinicians (vital signs, ventilator parameters, basic laboratory data, vasoactive drug doses), rather than more obscure biomarkers of oxygen delivery or tissue perfusion in order to provide practical information for clinicians.

Material and methods

Patients
This is a cross-sectional study from the medical intensive care unit (ICU) at Medstar Georgetown University Hospital, USA, from July 2018 to January 2020. All admitted patients are included into a prospectively maintained registry in which past medical history, admitting diagnosis and variables pertinent to their ICU course are recorded. We included patients who required invasive mechanical ventilation for acute hypoxaemic respiratory failure and received an RBC transfusion on the basis of a complete blood count test, drawn in routine fashion in the morning, showing the haemoglobin value to be ≤7.0 g/ dl. This represents the standard of care. We only considered each individual’s first RBC transfusion after intubation.

Excluded were patients who experienced overt bleeding during their ICU stay (of any severity), suffered from a myocardial infarction, underwent surgery during the hospitalisation, had a primary bone marrow disorder or inherited anaemia syndrome (such as sickle-cell disease), received multiple simultaneous blood products or for whom arterial blood gas data were not available during the study period. Laboratory data and documentation were extensively reviewed to ensure these transfusions were not performed as a result of bleeding.

Data
We recorded patient level variables plausibly affected by the receipt of an RBC transfusion in the six hours before and after patients were transfused. These included vital signs (heart rate, mean arterial pressure, respiratory rate, oxygen saturation, fluid balance and presence or absence of fever); indices of organ function (lactate, creatinine, vasopressor doses); ventilator and arterial blood gas data (FiO2 , PEEP, pH, pCO2 , PaO2 / FiO2 ratio) along with severity of illness as estimated by the Sequential Organ Failure Assessment (SOFA score).[15] Our institution generally sequentially uses norepinephrine, vasopressin (in a non-titratable fashion) followed by phenylephrine (rather than epinephrine) as a third vasopressor.

Vital signs, fluid balance and vasopressor doses are measured hourly, so we recorded mean values in each six-hour period (before and after). Similarly, we recorded mean values of laboratory or arterial blood gas data if multiple measurements were made during the study period. We settled on a six-hour timeframe to balance two competing principles: a period long enough to capture any potential impact of the RBC transfusion on common physiological parameters, but short enough that observed changes could reasonably be attributed to the RBC transfusion as much as possible, isolated from progression of the underlying disease or other interventions. For the SOFA score, however, we used the worst values of each component in the 12 hours before and after transfusion since certain components of the score are measured infrequently enough such that calculating it over a six-hour time period was impractical.

Analysis
Summary statistics describe the frequency and mean or median of each categorical and continuous variable, respectively. Patients act as their own control: the intervention is the RBC transfusion, the ‘control’ period is the six hours beforehand and ‘study’ period the six hours afterwards. Therefore, we conducted a matched pair analysis. McNemar’s test was used for paired categorical data; a paired t-test and the Wilcoxon signed-rank test were used for parametric and nonparametric continuous data, respectively. We formally tested for normality with the Shapiro-Wilk method.

To account for the dynamic nature of critically ill ICU patients, we adjusted statistically significant relationships for changes in severity of illness (SOFA score) along with other relevant covariates between time periods. To do so, we used the difference between the two measurements as the dependent variable in a linear regression model (with the difference in covariates in both time periods as independent variables). Given this is a hypothesis generating clinical inquiry rather than a pilot experimental trial, we elected not to control for familywise error rate associated with multiple comparisons. The analysis was performed with JMP15 Pro (SAS Institute, Cary, NC, USA). The study was approved by the Institutional Review Board of Medstar Georgetown University Hospital.

Results

Cohort characteristics
Seventy-four patients met the inclusion criteria (table 1). The causes of hypoxaemic respiratory failure in these individuals (as determined by the admitting intensivist) were: pneumonia (58, 78.3%), pulmonary oedema (6, 8.1%) and other/equivocal (10, 13.5%), including pulmonary embolism and acute pulmonary infiltrates of undetermined cause. Fifty-seven (77%) were weaned from mechanical ventilation, 10 (13.5%) underwent tracheostomy prior to discharge to long-term acute care, and seven (9.5%) were transitioned to comfort measures.

Table 1. Baseline characteristics