Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition characterized by severe hypoxemia and respiratory failure, often requiring mechanical ventilation (MV) in the intensive care unit (ICU)¹. Despite advances in critical care, ARDS remains associated with high mortality and significant morbidity, including neurological complications such as delirium². Delirium, an acute confusional state, is a common occurrence in mechanically ventilated patients, with reported prevalence rates ranging from 60% to 80%³. It is associated with prolonged hospital stays, increased healthcare costs, and higher mortality rates⁴.

Delirium in ARDS patients is particularly concerning due to the interplay of hypoxia, systemic inflammation, and the use of sedatives and analgesics, which are known to exacerbate cognitive dysfunction⁵. Moreover, emerging evidence suggests that delirium is not merely an acute complication but also a predictor of long-term cognitive impairment, including deficits in memory, attention, and executive function⁶. These cognitive deficits can persist for

months or even years after hospital discharge, significantly impacting patients' quality of life and functional independence⁷.

The pathophysiology of delirium in ARDS is multifactorial, involving both patient-related and ICU-related factors. Patient-related factors include advanced age, pre-existing cognitive impairment, and comorbidities such as hypertension and diabetes⁸. ICU-related factors include the duration of mechanical ventilation, exposure to sedatives (e.g., benzodiazepines), and the severity of illness as measured by scoring systems like the APACHE II⁹. Additionally, ARDS-specific factors such as hypoxemia, hypercapnia, and systemic inflammation may further contribute to the development of delirium¹⁰.

Despite its clinical significance, delirium in ARDS patients remains underdiagnosed and undertreated. This is partly due to the challenges in assessing delirium in mechanically ventilated patients, who are often unable to communicate verbally¹¹. The Confusion Assessment Method for the ICU (CAM-ICU) has emerged as a reliable tool for delirium screening in this population, but its implementation remains inconsistent across ICUs¹².

This study aims to address these gaps by identifying risk factors for delirium in mechanically ventilated ARDS patients and evaluating its impact on long-term cognitive outcomes. By elucidating the epidemiology and consequences of delirium in this population, we hope to inform strategies for early detection, prevention, and management.

This prospective cohort study was conducted in a 30-bed medical-surgical intensive care unit (ICU) at a tertiary care hospital over a three-year period (June 2023 to December 2024). The study was approved by the Institutional Review Board (IRB) and Ethics Committee, and written informed consent was obtained from all participants or their legal representatives. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for cohort studies¹.

Study Population

The study population included adult patients (aged ≥18 years) diagnosed with Acute Respiratory Distress Syndrome (ARDS) according to the Berlin Definition². All patients required mechanical ventilation for at least 48 hours and were expected to remain in the ICU for a minimum of 72 hours. Patients were enrolled within 24 hours of initiation of mechanical ventilation.

Inclusion Criteria

1. Diagnosis of ARDS based on the Berlin Definition:
   • Acute onset within 1 week of a known clinical insult or new/worsening respiratory symptoms.
   • Bilateral opacities on chest imaging not fully explained by effusions, lobar/lung collapse, or nodules.
   • Respiratory failure not fully explained by cardiac failure or fluid overload.
   • Hypoxemia defined as a PaO₂/FiO₂ ratio ≤300 mmHg with positive end-expiratory pressure (PEEP) ≥5 cm H₂O³.
2. Requirement for invasive mechanical ventilation for ≥48 hours.
3. Willingness to participate in follow-up cognitive assessments at 6 and 12 months post-discharge.

Exclusion Criteria

1. Pre-existing neurological conditions (e.g., dementia, Parkinson’s disease, or history of stroke with residual cognitive deficits).
2. History of psychiatric disorders (e.g., schizophrenia, bipolar disorder).
3. Inability to complete cognitive assessments due to language barriers, severe physical disability, or lack of a reliable informant.
4. Patients with a life expectancy of less than 24 hours or those receiving palliative care.

Data Collection

Data were collected prospectively by trained research staff using a standardized case report form. The following variables were recorded:

• Demographic Data:Age, sex, body mass index (BMI), and smoking status.
• Clinical Data:Comorbidities (e.g., hypertension, diabetes, chronic obstructive pulmonary disease), severity of illness (APACHE II score), and cause of ARDS (e.g., pneumonia, sepsis, trauma).
• Ventilation Parameters:Duration of mechanical ventilation, PEEP levels, FiO₂, and PaO₂/FiO₂ ratio.
• Sedation and Analgesia:Type, dose, and duration of sedatives (e.g., benzodiazepines, propofol) and analgesics (e.g., opioids).
• Delirium Assessment:Delirium was assessed daily using the Confusion Assessment Method for the ICU (CAM-ICU)⁴. The CAM-ICU evaluates four features: (1) acute onset or fluctuating course, (2) inattention, (3) disorganized thinking, and (4) altered level of consciousness. A positive CAM-ICU score indicates delirium.
• Outcome Measures:
  • Primary Outcome:Incidence of delirium during ICU stay.
  • Secondary Outcomes:Duration of delirium, ICU and hospital length of stay, mortality, and long-term cognitive function.

Cognitive Function Assessment

Cognitive function was evaluated at 6 and 12 months post-discharge using the Montreal Cognitive Assessment (MoCA) tool⁵. The MoCA assesses multiple cognitive domains, including memory, attention, language, visuospatial abilities, and executive function. A score of <26 out of 30 indicates cognitive impairment. Assessments were conducted in person or via telephone by trained psychologists blinded to the patient’s ICU course.

Statistical Analysis

Data were analyzed using SPSS version 25 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range, IQR), depending on the distribution. Categorical variables were expressed as frequencies and percentages. Univariate analysis was performed to identify potential risk factors for delirium, and variables with p < 0.10 were included in a multivariate logistic regression model to identify independent predictors. A p-value <0.05 was considered statistically significant.

Table 1: Demographic and Clinical Characteristics of the Study Population

Table 2: Prevalence of Delirium in Mechanically Ventilated ARDS Patients

Table 2 shows that 68% (170 out of 250) of mechanically ventilated ARDS patients developed delirium during their ICU stay. The mean duration of delirium was 5.2 days (±2.8), with a median of 4 days (IQR: 2-7).

Table 3: Risk Factors for Delirium Identified by Univariate Analysis

Older patients had a 2.5-fold higher risk of developing delirium (OR: 2.5, 95% CI: 1.6-3.8, p < 0.001). Patients with higher illness severity scores had a 3.2-fold increased risk of delirium (OR: 3.2, 95% CI: 2.1-4.9, p < 0.001). Prolonged mechanical ventilation was associated with a 2.8-fold higher risk of delirium (OR: 2.8, 95% CI: 1.9-4.1, p < 0.001), likely due to prolonged exposure to sedatives and immobilization. Benzodiazepine use increased the risk of delirium by 2.1 times (OR: 2.1, 95% CI: 1.4-3.2, p = 0.001), consistent with their known neurocognitive side effects. Severe hypoxemia was associated with a 1.8-fold higher risk of delirium (OR: 1.8, 95% CI: 1.2-2.7, p = 0.01), emphasizing the role of oxygen deprivation in delirium pathogenesis.

Table 4: Independent Risk Factors for Delirium Identified by Multivariate Analysis

After adjusting for confounding variables, older age remained a significant independent predictor of delirium (aOR: 2.3, 95% CI: 1.5-3.6, p < 0.001). APACHE II Score > 25: Illness severity continued to be a strong predictor (aOR: 3.0, 95% CI: 2.0-4.5, p < 0.001). Duration of Mechanical Ventilation > 7 Days: Prolonged ventilation remained an independent risk factor (aOR: 2.6, 95% CI: 1.7-3.9, p < 0.001). Benzodiazepine use was independently associated with delirium (aOR: 1.9, 95% CI: 1.3-2.8, p = 0.002).

Table 5: Cognitive Outcomes at 6 and 12 Months Post-Discharge

The mean MoCA score improved slightly from 22.4 (±4.5) at 6 months to 23.8 (±4.2) at 12 months, but both scores remained below the threshold for normal cognitive function (MoCA <26). At 6 months, 75% of patients had cognitive impairment, which decreased to 66.7% at 12 months. This indicates that while some recovery occurs, a significant proportion of patients experience long-term cognitive deficits. Memory was the most commonly affected domain (65% at 6 months, 55.6% at 12 months), followed by attention and executive function.

Table 6: Association Between Delirium and Long-Term Cognitive Impairment

Patients who experienced delirium had a significantly higher prevalence of cognitive impairment at 6 months (76.5%) compared to those without delirium (25%, p < 0.001). The disparity persisted at 12 months, with 64.7% of delirium patients showing cognitive impairment compared to 12.5% of non-delirium patients (p < 0.001). Delirium patients had significantly lower MoCA scores at both 6 months (20.5 ± 4.1 vs. 25.3 ± 3.8) and 12 months (21.8 ± 4.0 vs. 26.1 ± 3.5) compared to non-delirium patients (p < 0.001).

In our study, 68% of mechanically ventilated ARDS patients developed delirium, which is consistent with previous reports. For instance, Ely et al. (2001) found that 60-80% of mechanically ventilated patients experience delirium during their ICU stay, emphasizing its commonality in critically ill populations.¹³ The high prevalence in ARDS patients may be attributed to the interplay of hypoxia, systemic inflammation, and the frequent use of sedatives and analgesics, all of which are known to exacerbate cognitive dysfunction. ¹⁴

Our identification of older age, higher APACHE II scores, prolonged mechanical ventilation, and benzodiazepine use as independent risk factors for delirium corroborates findings from prior studies. Pandharipande et al. (2006) demonstrated that benzodiazepines significantly increase the risk of delirium in ICU patients, likely due to their GABAergic effects and disruption of normal sleep-wake cycles. ¹⁵ Similarly, Shehabi et al. (2010) reported that prolonged mechanical ventilation is a strong predictor of delirium, possibly due to immobilization, sensory deprivation, and prolonged exposure to sedatives. ¹⁶ These findings underscore the importance of minimizing sedation and

optimizing ventilation strategies to reduce delirium incidence.

The pathophysiology of delirium in ARDS is multifactorial, involving both patient-related and ICU-related factors. Hypoxemia and hypercapnia, common in ARDS, can lead to cerebral hypoxia and impaired neurotransmitter function, contributing to delirium. ¹⁷ Additionally, systemic inflammation, a hallmark of ARDS, may disrupt the blood-brain barrier and promote neuroinflammation, further exacerbating cognitive dysfunction. ¹⁸ These mechanisms are supported by Hughes et al. (2012), who highlighted the role of inflammation and oxidative stress in the development of ICU delirium. ¹⁹

One of the most concerning findings of our study is the strong association between delirium and long-term cognitive impairment. At 6 months post-discharge, 75% of delirium patients exhibited cognitive impairment, compared to only 25% of non-delirium patients. This disparity persisted at 12 months, with 64.7% of delirium patients still experiencing cognitive deficits. These results are consistent with Girard et al. (2010), who found that delirium in ICU patients is independently associated with long-term cognitive impairment, particularly in memory and executive function domains. ²⁰

The mechanisms underlying this association remain poorly understood but may involve neuronal injury, synaptic dysfunction, and chronic neuroinflammation. Salluh et al. (2015) suggested that delirium may serve as a marker of underlying brain vulnerability, predisposing patients to long-term cognitive decline. ²¹ Our findings highlight the need for routine cognitive assessments in ARDS survivors and the development of targeted interventions to mitigate long-term cognitive deficits.

Our results are in line with several landmark studies on delirium in critically ill patients. For example, Pandharipande et al. (2013) reported that delirium is associated with a 3.2-fold increased risk of long-term cognitive impairment, similar to our findings. ²² Additionally, Ely et al. (2004) demonstrated that delirium duration is independently associated with worse cognitive outcomes, further supporting our observation that prolonged delirium contributes to long-term cognitive deficits. ²³

However, our study adds to the existing literature by focusing specifically on ARDS patients, a population at high risk for both delirium and long-term cognitive impairment due to the unique pathophysiology of ARDS. Unlike previous studies that examined mixed ICU populations, our findings highlight the need for ARDS-specific delirium prevention and management strategies.

The high prevalence of delirium and its association with long-term cognitive impairment have significant clinical implications. First, routine screening for delirium using validated tools like the CAM-ICU should be standard practice in ICUs. Early identification of delirium allows for timely intervention, potentially reducing its duration and severity.

Second, modifiable risk factors, such as minimizing benzodiazepine use and optimizing mechanical ventilation strategies, should be targeted to prevent delirium. Kress et al. (2000) demonstrated that daily sedation interruptions reduce the incidence of delirium and improve outcomes in mechanically ventilated patients. ²⁴ Similarly, Balas et al. (2012) found that early mobilization and minimizing sedation can significantly reduce delirium rates. ²⁵

Finally, the long-term cognitive deficits observed in our study underscore the need for follow-up care for ARDS survivors. Cognitive rehabilitation programs, as suggested by Hopkins et al. (2012), may help improve cognitive function and quality of life in these patients. ²⁵

Delirium is a common and serious complication in mechanically ventilated ARDS patients, with significant implications for long-term cognitive health. Early identification of risk factors and targeted interventions, such as minimizing sedation and implementing delirium prevention protocols, may improve outcomes. Further research is needed to elucidate the underlying mechanisms and develop effective strategies for prevention and management.

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