Our data demonstrate that RDW at the time of PICU admission is associated with different validated parameters for respiratory failure in our cohort of PICU patients. The need for mechanical ventilation, and the nadir P/F ratios in ventilated patients are both associated with RDW values on admission, and largely remain so in regression models after correcting for both disease severity and anaemia.
Why is this relevant? An increase in RDW can be linked to hypoxemia [
2]. Transient decreases in oxygen partial pressures (PaO
2) will lead to a ‘pulsed’ erythropoietin (EPO) release through hypoxia-inducible transcription factors. These will in its turn trigger the release of immature reticulocytes into the circulation leading to anisocytosis and a higher RDW in the affected patient [
2]. Supporting this hypoxemia – anisocytosis pathway and the value of RDW in lung pathology, elevated RDW values have been found in diverse respiratory disease processes reflecting differences in disease severity. Grant has linked higher RDW values with worse pulmonary function tests in a cohort of patients without clinically evident respiratory diseases [
12]. Similarly, Sincer has demonstrated a higher RDW in patients with COPD compared to a control group, even when corrected for known reasons for a high RDW such as folate, iron or vitamin B12 deficiencies [
19]. The association between RDW and mortality has been shown in COPD patients [
20]. Furthermore, in a cohort of patients with pulmonary embolism, an elevated RDW on admission was associated with worse hemodynamic parameters and early mortality [
21]. Also, higher RDW values could be linked to worse long-term outcome after pulmonary embolism, with a higher percentage of late mortality and post-pulmonary embolism pulmonary hypertension in patients with a high RDW [
22]. Until recently, the value of RDW in children admitted to the PICU had not been reported. A recent study by Said et al. in critically ill children showed that admission RDW is associated with pediatric ICU mortality and morbidity, independent of illness severity [
23]. The relationship between RDW and organ failure was not studied specifically, although there was a weak association between the RDW value and the number of ventilation free days [
23]. The observed worse respiratory outcome for patients with a higher RDW may have several underlying reasons. The independent association of RDW with outcome may imply that anisocytosis itself may be a possible causable factor in organ dysfunction. The role of the microcirculation has been suggested in this pathophysiological process [
24,
25]. In a recent study, Fontana et al. discuss the relationship between RDW values and microcirculatory changes using sublingual Sidestream Dark Field videomicroscopy in a cohort of patients with sepsis [
26]. The RDW was elevated in 61% (
n = 74) patients in this study, and the authors found no correlation between RDW and the microcirculatory parameters. This shows that RDW reflects a general degree of illness in a patient, and emphasizes the added value of RDW in evaluating a patient’s general condition. The median RDW in their cohort was 13.8%, more than their upper-normal limit of RDW of 13.4%, indicating the worsened physical condition in this group. However, as not all septic patients had elevated RDW values, it becomes clear that the RDW is not a specific marker of this disease. Furthermore, the lack of relation between the RDW and microcirculatory parameters is interesting, as we might assume that an increase in RDW would result in more abberant and large erythrocytes that could obstruct the capillaries. This anisocytosis and its role in the complex field of microcirculation in different organs in the critically ill patient warrants further research. Other factors may be involved as well. Firstly, the presence of anaemia is the most likely cause of a change in RDW, which is the reason we corrected our statistical model for this parameter [
24]. Secondly, oxidative stress, present in lung injury and ventilated patients through the generation of reactive oxygen species shortens the RBC lifespan [
3]. Oxidative stress will thus promote the release of young cellular forms into the circulation. Thirdly, another factor potentially causing a change in RDW is vitamin D3 deficiency [
27]. Vitamin D3 plays an important role in erythropoiesis and cell proliferation, so a small change in vitamin D3 concentration will affect bone marrow erythropoiesis. But more generally, it has also been proposed that RDW may reflect the patient’s degree of physiologic reserve or chronic inflammation [
8]. This hypothesis is further supported by the fact that a RBC’s half-life is approximately 28 days, meaning that RDW on admission to the PICU was influenced by a chronic state or an event that happened some time before this measurement was made.
Many confounding factors should be taken into account when considering the prognosis of patient’s disease, e.g. the underlying disease and inflammatory markers like CRP, LDH, or lactate levels. RDW is possibly influenced or associated with these factors. Regardless of these possible influencing factors, RDW is attractive as a pragmatic clinical biomarker for respiratory dysfunction by its low cost and universal availability compared to other proposed biomarkers. Interestingly, the CRP level and WBC count level on admission were not associated with the need for mechanical ventilation, in contrast to RDW and RDW quintiles.
Despite the robust data, our study has several limitations. Since this was a secondary analysis of an existing database, we were not able to assess all possible confounding variables, such as measures of iron deficiency, markers of nutritional status, or other biomarkers of inflammation. Our cohort was too small to assess whether the PRISM and PIM scores may be improved in their possibility to predict adverse outcome in PICU patients when incorporating RDW values in their score calculation, but this has been a topic of recent research [
8]. We did use RDW values on admission, but it is possible that the values were already increased during the days preceding the admission. This study does not provide an answer as to whether an increase of RDW is a consequence of, or a reason for respiratory dysfunction. It is already shown that inflammation increases RDW values, and inflammatory pathways will cause worse pulmonary function. Criteria for sepsis were not routinely recorded on admission for our patients. This limits us in interpreting the results, as we are unable to take the context of sepsis into account when assessing RDW as an independent biomarker for respiratory dysfunction. Neverteless, as previously mentioned, sepsis is not always associated with increased RDW values [
26]. The confounding factor of age is to be taken into account as well. Younger patients admitted to the ICU are already at higher risk for organ dysfunction, have physiologically higher RDW values, and are thus over-represented in the higher RDW quintiles. We thus decided to include age as a confounder in the multivariate analysis. We did not record reasons for tracheal intubation, and thus cannot differentiate between patients that received mechanical ventilation because of low oxygenation, insufficient work of breathing (i.e. insufficient ventilation) or a combination of these. We used P/F ratios as a parameter for oxygenation dysfunction. This parameter, although still widely used in clinical practice and clinical trials, ignores the effect of the mean airway pressure (Paw) on oxygenation. As an alternative parameter, the oxygenation index (FiO
2 × Paw/PaO
2) takes the Paw into account and is by many considered to be a better indicator of lung injury. Unfortunately, the Paw was not available for a substantial amount of patients in our database, and for this reason we were unable to include the oxygenation index as a parameter for oxygenation dysfunction
.
In summary, the RDW value on admission of our PICU patients was independently associated with respiratory failure, reflected by the greater need for mechanical ventilation, fewer ventilator-free days and lower nadir P/F ratios in the patients with highest RDW values on admission. As a widely available and pragmatic biomarker, the RDW value is able to predict who is at risk for respiratory failure in our cohort, allowing for an early tailored approach toward respiratory monitoring. RDW may be a valuable prognostic parameter for lung or other organ dysfunction in the PICU. Further research is needed to confirm this link for the different organ systems in pediatric populations. Future studies in the field of microcirculation may have their value in assessing the cause-effect relation of organ dysfunction and anisocytosis in critically ill children.