Delirium is a common problem in intensive care unit (ICU) patients, characterized by an acute onset and fluctuating course of impaired cognitive functioning, so that a patient’s ability to receive, process, store, and recall information is strikingly impaired. [It represents the most frequent form of brain dysfunction in critically ill patients and is now recognized as a form of acute cerebral failure associated with severely poor outcomes]. It is associated with poor outcomes in ICU patients, including increased morbidity, prolonged length of stay, higher mortality rates, and Long-term Cognitive Decline (Ely et al., 2004; Thomason et al., 2005; Goldberg et al., 2020; Yan et al., 2023; Inouye et al., 1999). The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is a widely validated and reliable tool for the diagnosis of delirium in the ICU setting (Ely et al., 2001), which was employed in this study to identify our patient cohort. Critically, emerging evidence indicates that even after hospital discharge, survivors of ICU delirium face a significantly elevated risk of long-term cognitive impairment and accelerated progression to dementia, highlighting the profound and lasting impact of this condition (Fong and Inouye, 2022; Pandharipande et al., 2013). The incidence of delirium in ICU settings ranges from 19 to 82% (Ely et al., 2004; Ely et al., 2001; Inouye et al., 2014; Su et al., 2016; Rosa et al., 2019), highlighting the urgent need for reliable biomarkers to enhance diagnostic precision and therapeutic strategies. Despite advances in critical care, delirium remains under-recognized and inadequately managed, underscoring the need for reliable biomarkers that can aid in risk stratification and prognosis.

Red cell distribution width (RDW), a routine hematological parameter reflecting red blood cell size variation, has emerged as a potential prognostic marker in various clinical contexts, including cardiovascular diseases, cancers, and critical illnesses (Kim et al., 2022; Seo et al., 2020; Kim et al., 2023). Elevated RDW indicates a severe imbalance in red blood cell regulation, involving both defective erythropoiesis and unusual red blood cell longevity, possibly linked to several metabolic disorders, such as shortened lifespan of telomere length, oxidative stress, inflammation, poor nutritional status, dyslipidemia, hypertension, erythrocyte fragmentation, and alteration of erythropoietin function, both of which are implicated in the pathophysiology of delirium.

Given the shared pathways of inflammation and physiological stress between elevated RDW and delirium and the established prognostic value of RDW in critical illness, we hypothesized that RDW would be associated with mortality in critically ill patients with delirium. However, data specifically examining this association in a delirium-focused cohort are limited.

This study aims to investigate the relationship between RDW levels and 30-day mortality in ICU patients diagnosed with delirium using data sourced from the MIMIC-IV database. By shedding light on this association, we strive to enhance the understanding of RDW’s prognostic value, potentially informing clinical decision-making and improving outcomes for critically ill patients. Through rigorous analysis, this study seeks to contribute meaningful insights that could guide therapeutic strategies and optimize care for patients experiencing delirium in the intensive care setting.

This study aims to elucidate the association between RDW and mortality in critically ill patients with delirium and to evaluate the predictive value of RDW for prognosis. Our findings demonstrate that elevated RDW levels are a significant independent risk factor for 30-day mortality in these patients, even after adjusting for potential confounders. Our findings reveal a linear correlation between RDW elevation and mortality risk, providing novel insights into hematological biomarkers for neurological critical care outcomes.

RDW is a routine parameter in complete blood counts. Although RDW is affected to some degree by any type of anemia, researchers suggest that anemia is a risk factor for both dementia and cognitive impairment (Andro et al., 2013; Peters et al., 2008; Winchester et al., 2018; Qiang et al., 2023). C-reactive protein (CRP) and pro-inflammatory cytokines such as IL-6 have been consistently linked to the occurrence and duration of delirium in critically ill and postoperative patients (Leng et al., 2025; Mosharaf et al., 2025; Brummel et al., 2024). Sajjad et al. demonstrated that elevated levels of interleukin-8 (IL-8) in cerebrospinal fluid were significantly associated with delirium, highlighting the role of neuroinflammation (Spence et al., 2025; Denver et al., 2025). Similarly, researchers found that IL-1β levels were higher in delirium patients (Lopez-Rodriguez et al., 2021; Yu et al., 2023). The biological rationale is that systemic inflammation can disrupt the blood–brain barrier, activate microglia, and alter neurotransmission, leading to acute cognitive dysfunction (Brummel et al., 2024; Taylor et al., 2022; Stock et al., 2013; Hirsch et al., 2016). RDW fits directly into this paradigm, as pro-inflammatory cytokines (e.g., IL-6, TNF-α) are known to suppress erythropoiesis and alter red blood cell membrane integrity, directly leading to anisocytosis and elevated RDW (Zheng et al., 2019; Kim et al., 2018; Miao et al., 2019). DomingoAP (Pascual-Figal et al., 2009) persisted in that higher RDW levels were associated with worse long-term outcomes, regardless of hemoglobin levels and anemia status. RDW and inflammation-related indices based on complete blood counts (Lionte et al., 2021), such as hs-CRP, NLR, and MLR, were strongly associated with in-hospital mortality. IL-6 levels were significantly associated with an increase in RDW. Serum selenium may potentially mediate the effects on RDW through IL-6 (Lionte et al., 2021; Semba et al., 2010). A longitudinal study of 2,344 critically ill patients with COPD found that an increase in RDW was associated with an increased risk of 28-day all-cause mortality (Lan et al., 2024). A 9-year follow-up study involved 623 participants. Proteomics data showed that changes in IGFBP2 and C7 over 9 years mediated the association between changes in RDW and 6-year all-cause mortality. Cellular senescence may contribute to the association between RDW and mortality (Osawa et al., 2022). Several clinical studies have shown that an increase in RDW may be associated with other diseases, including acute pancreatitis, acute cerebral infarction, chronic kidney disease, gastrointestinal disorders, cancer, and cardiovascular disease (Osawa et al., 2022; Hammarsten et al., 2010; Kim et al., 2012; Chen et al., 2010; Ramírez-Moreno et al., 2013; Sánchez-Chaparro et al., 2010). At the same time, RDW in different diseases provides diagnostic and prognostic value (Parizadeh et al., 2019; Xanthopoulos et al., 2017; Sarkar et al., 2022; Felker et al., 2007).

Delirium is the most common manifestation of brain dysfunction in critically ill patients and is independently predictive of excess death, length of stay, cost of care, and acquired dementia (Stollings et al., 2021). The development of delirium is associated with a variety of factors, including infection, hypoxia, and metabolic disturbances (Inouye et al., 2014). Peripheral inflammation is a well-established trigger of delirium (Maclullich et al., 2008), and IL-1, IL-1β, IL-6, IL-8, tumor necrosis factor (TNF), and prostaglandin E2 (PGE2) stimuli trigger tissue macrophage and blood monocyte activation and secretion of inflammatory mediators (Sajjad et al., 2020; Cape et al., 2014; Hoogland et al., 2015). Although these molecules have a restricted ability to pass through the blood–brain barrier (BBB), they are also synthesized in the brain’s endothelial and epithelial cells and are directly secreted into the brain. They are primed if there is prior brain pathology, such as amyloid or earlier neurodegeneration; these microglia produce increased levels of these mediators, which affect both astrocytes and neurons (Podgoreanu et al., 2020). Cytokine-stimulated astrocytes produce increased levels of chemokines, contributing to the recruitment of monocytes and other immune cell populations to the brain. However, their activation also leads to the loss of metabolic support for neuronal energy metabolism. Thus, microglial-derived inflammatory mediators, such as IL-1β and TNF, directly affect neuronal function to produce both dysfunction and injury or cell death, which collectively may contribute to acute behavioral manifestations in delirium syndrome. Moreover, patients with delirium often experience restricted mobility, sleep deprivation (Stollings et al., 2021), and malnutrition (Volkert et al., 2024), all of which can further compromise immune function and overall physical condition, thereby increasing the risk of mortality. In our study, the 30-day mortality rate was significantly higher in the high RDW group of delirium patients compared to the low RDW group. This may be because elevated RDW levels reflect more severe states of inflammation, anemia, hypoxia, and cellular senescence, which interact with the pathogenesis of delirium to worsen the clinical course and outcomes of patients. Therefore, elevated RDW can be construed as a hematological manifestation of the same systemic inflammatory state that drives neuroinflammation and delirium.

Elevated RDW is a recognized marker of sustained systemic inflammation, characterized by elevated levels of pro-inflammatory cytokines (e.g., IL-6, TNF-α). In critically ill patients, these cytokines can compromise the integrity of the blood–brain barrier (BBB), facilitating their translocation into the central nervous system (Liu and Zhang, 2025). Once within the brain parenchyma, they activate microglia, the brain’s resident immune cells, triggering neuroinflammation. This state impairs synaptic function, reduces cerebral plasticity, and exacerbates neuronal injury, providing a plausible pathway linking high RDW to the severity and poor outcomes of delirium (Hickman et al., 2018). Furthermore, this pervasive systemic inflammatory state can directly worsen the severity of concurrent organ failures (e.g., septic shock and acute respiratory distress syndrome), contributing to multi-organ dysfunction and death. Linking RDW, Anemia, and Cerebral Oxygen Delivery: While RDW is distinct from hemoglobin levels, a high RDW often coincides with anemia of chronic disease. The conjunction of anemia, reduced oxygen-carrying capacity, and high RDW reflecting underlying inflammation and oxidative stress may create a double-hit scenario (Weiss and Goodnough, 2005). This could lead to suboptimal cerebral oxygen delivery in a brain already vulnerable to critical illness and neuroinflammation, potentially precipitating ischemic neuronal damage and impeding recovery, thereby increasing mortality risk. Future studies measuring cerebral oxygenation or biomarkers of neuronal injury, neurofilament light chain, alongside RDW, could help to validate this hypothesis.

RDW, as a marker of a pre-existing pro-inflammatory or chronic inflammatory state, can be used as a predictor of delirium progression. In general, a higher RDW is associated with increases in the erythrocyte sedimentation rate (ESR) and the inflammatory markers IL-6, C-reactive protein, and receptors for TNF I and II (Lippi et al., 2009; Lee and Kim, 2010). Pro-inflammatory cytokines found in patients with SIRS, including TNF-α, IL-6, and IL-1β, suppress erythrocyte maturation, allowing newer, larger reticulocytes to enter the peripheral circulation and increase RDW. Furthermore, pro-inflammatory cytokines can have direct inhibitory effects on the half-life of red blood cell circulation and deformability of the red blood cell membrane, which in turn can manifest as an increase in RDW. These observations provide support for the biological plausibility of RDW as a marker of inflammation in critical illness. The association between elevated RDW and poor outcomes is not unique to delirium but has been consistently reported in other neurological conditions, such as ischemic stroke (Feng et al., 2017) and Alzheimer’s disease (Huang et al., 2022). This consistency across diverse brain pathologies strengthens the argument that RDW is not a disease-specific marker but rather a proxy for a maladaptive systemic physiological state (e.g., chronic inflammation, oxidative stress, and nutritional deficiency) that negatively impacts brain resilience and recovery capacity. The acutely vulnerable brain during delirium may be particularly susceptible to the deleterious effects of this state. Subgroup analysis revealed that elevated red cell distribution width (RDW) was consistently and significantly associated with increased 30-day mortality across all patient subgroups (adjusted HR > 1), underscoring its robustness as a prognostic marker for delirium. Notably, the effect was significantly stronger in patients aged <65 years (HR 1.33, 95% CI 1.26–1.41) compared to those aged ≥65 years (HR 1.11, 95% CI 1.09–1.13; P for interaction <0.001), suggesting that RDW elevation may represent a more acute and severe pathological insult in younger, typically resilient individuals. The universal association across comorbidities implies a shared underlying pathophysiology, likely centered on systemic inflammation and oxidative stress, which concurrently drive RDW elevation, neuronal injury in delirium, and multi-organ failure. This finding suggests that RDW is an integrative hematological marker of global physiological derangement. Future research should prioritize investigating the mechanisms behind heightened vulnerability in younger patients and exploring the utility of RDW for risk stratification in this specific demographic. Furthermore, increased RDW mirrors a profound deregulation of erythrocyte homeostasis involving both impaired erythropoiesis and abnormal red blood cell survival, which may be attributed to a variety of underlying metabolic abnormalities, such as shortening of telomere length, oxidative stress, inflammation, poor nutritional status, dyslipidemia (Lippi et al., 2013), hypertension, erythrocyte fragmentation, and alteration of erythropoietin function.

Despite the robust associations observed, this study has limitations that warrant consideration. First, the retrospective design precludes a definitive causal inference between RDW and delirium-related mortality. Although we adjusted for extensive confounders, unmeasured variables or residual confounding factors may persist. Second, RDW was measured only once within 24 h of ICU admission, limiting insights into dynamic changes and their temporal relationship with delirium progression. Third, the lack of delirium subtype data and neurobiological markers hinders mechanistic exploration. Future prospective studies should integrate serial RDW measurements, delirium phenotyping, and multi-omics approaches to disentangle causality. Nonetheless, this study underscores the clinical utility of RDW in risk stratification, urging further investigation of its role within the delirium pathophysiology spectrum.

This cohort study suggests that an increase in RDW is associated with a higher risk of 30-day all-cause mortality in critically ill patients with delirium.