Abstract
Background
Delirium is a frequent and serious complication in critically ill patients, particularly those receiving extracorporeal membrane oxygenation (ECMO), and is associated with increased morbidity and mortality. This study aimed to evaluate the association between different sedation drugs and the occurrence of delirium in patients receiving ECMO, as well as to explore other potential risk factors by analyzing baseline characteristics and laboratory findings.
Methods
A retrospective cohort study was conducted on patients receiving ECMO who were monitored for delirium. Baseline characteristics, laboratory findings, and the duration and types of sedative drugs used were analyzed to determine their association with delirium. Logistic regression analysis was performed to evaluate the effect of sedatives on delirium risk.
Results
Of the 51 patients on ECMO (mean age: 56 years; males: 39), 34 developed delirium, while 17 did not. Significant differences were observed in the use of tracheostomy and sedative drug combinations between groups. Logistic regression revealed that midazolam was associated with a significantly higher risk of delirium (odds ratio: 15.39, 95% confidence interval: 2.14–110.70), whereas sufentanil and dexmedetomidine did not show significant associations.
Conclusions
Midazolam use was strongly associated with increased delirium risk in patients on ECMO, whereas sufentanil and dexmedetomidine were not associated with delirium. These findings highlight the importance of sedative management in critically ill patients undergoing ECMO.
Keywords: Extracorporeal membrane oxygenation (ECMO), delirium, sedatives, risk factors, retrospective study
Highlight box.
Key findings
• This single-center retrospective study demonstrated that exposure to midazolam was independently associated with an increased risk of delirium in patients undergoing extracorporeal membrane oxygenation (ECMO), whereas sufentanil and dexmedetomidine were not. This association remained significant after multivariable adjustment, suggesting a potential drug-specific contribution beyond overall disease severity.
What is known and what is new?
• Delirium is a frequent and serious complication in critically ill patients, and benzodiazepines are well-recognized risk factors in general intensive care unit (ICU) populations. However, data focusing specifically on patients receiving ECMO are limited. This study is among the first to evaluate the relationship between commonly used sedative agents and delirium in an ECMO cohort, highlighting a particularly strong association between midazolam exposure and delirium in this high-risk population.
What is the implication, and what should change now?
• Given the vulnerability of ECMO patients to neurological complications, these findings underscore the importance of careful sedative selection and vigilant delirium monitoring during ECMO support. Although hypothesis-generating, the results suggest that minimizing benzodiazepine exposure when clinically feasible and considering alternative sedation strategies may help reduce delirium risk. Prospective multicenter studies are warranted to validate these observations and to develop optimized, individualized sedation protocols for patients receiving ECMO.
Introduction
Delirium is a common and serious complication in critically ill patients, particularly in those receiving extracorporeal membrane oxygenation (ECMO). Patients in the intensive care unit (ICU) are at a significantly elevated risk of developing delirium due to factors such as multisystem illnesses, comorbidities, the administration of psychoactive medications, and advanced age (1). The pathophysiology of delirium is multifactorial, involving a combination of metabolic, pharmacological, and environmental factors. Delirium in the ICU is linked to complications and negative outcomes, including prolonged hospital stays (2) and increased morbidity and mortality (3).
Sedation management plays a pivotal role in the development of delirium in patients receiving ECMO; however, the specific effects of various sedatives remain underexplored (4,5). Previous studies have shown that benzodiazepines, such as midazolam, are commonly associated with increased delirium risk in critically ill patients (6,7). We hypothesized that midazolam exposure would be independently associated with a higher risk of delirium in patients undergoing ECMO, potentially due to altered pharmacokinetics caused by circuit sequestration and deeper-than-intended sedation. However, limited research has focused on the role of sedation drugs in delirium in patients undergoing ECMO (8,9). This study aimed to evaluate the association between different sedation drugs and the occurrence of delirium in patients receiving ECMO, as well as to explore other potential risk factors by analyzing baseline characteristics and laboratory findings. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2086/rc).
Methods
A total of 111 patients treated with ECMO at our institution between January 2022 and December 2023 were initially considered for inclusion. However, due to the nature of ECMO therapy, many patients were unable to undergo delirium screening using the Confusion Assessment Method for the ICU (CAM-ICU) because of their critical condition or death during their hospital stay; these patients were excluded from the analysis, resulting in a final cohort of 51 survivors in the analysis.
ECMO at our institution is typically indicated for patients with severe, life-threatening respiratory or cardiac failure that is refractory to conventional medical management. The criteria for selecting an appropriate ECMO type are shown in Figure 1 (10). venoarterial (VA) ECMO was performed in patients who underwent cardiopulmonary resuscitation or required norepinephrine at ≥0.5 µg/kg/min, along with an ejection fraction of ≤20%; VA ECMO was selected for patients with severe cardiac failure. For veno-venous (VV) ECMO, indications were primarily consistent with established international criteria, including those utilized in the EOLIA trial for severe respiratory failure [e.g., severe hypoxemia with partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) <100 on FiO2 1.0, or refractory hypercapnic acidosis with pH <7.2 despite optimal ventilatory support]. In patients with both respiratory and cardiac failure, the decision to use either venoarteriovenous (V-AV) ECMO or VA ECMO was made depending on the severity of heart failure.
Figure 1.
Criteria for extracorporeal membrane oxygenation type selection in pulmonary failure (10). CPR, cardiopulmonary resuscitation; EF, ejection fraction; FiO2, fraction of inspired oxygen; P/F, PaO2/FiO2 ratio; PaO2, partial pressure of arterial oxygen; V-AV, venoarteriovenous; VA, venoarterial; VV, veno-venous.
Delirium was assessed using the CAM-ICU at least twice daily by trained ICU nurses when patients were sufficiently arousable [Richmond Agitation-Sedation Scale (RASS) ≥−3], in accordance with routine ICU practice. Delirium was defined as the presence of any positive CAM-ICU assessment during ECMO support. Sedation was managed according to clinical practice guidelines, with patients receiving one or more of the following sedative drugs: midazolam, sufentanil, and dexmedetomidine. Neuromuscular blocking agents were not routinely used during ECMO support in this cohort. To achieve sedation, the initial drug infusion rates were set as follows: midazolam at 40 mcg/kg/h, sufentanil at 0.6 mcg/kg/h, and dexmedetomidine at 0.2 mcg/kg/h. Sedative selection was guided by clinical judgment, including hemodynamic stability, anticipated duration of ECMO support, and economic considerations. In South Korea, midazolam is the only sedative reimbursed by the national health insurance system, contributing to its preferred use in prolonged and deeper sedation settings. Crossover between sedatives commonly occurred during prolonged ECMO support. Therefore, exposure-based classification was applied; patients were grouped according to whether each sedative was administered at any time during ECMO therapy.
This study compared the baseline characteristics, laboratory findings, and sedation protocols between patients with and without delirium.
Statistical analysis
Data were analyzed using descriptive statistics and chi-squared tests for categorical variables, and t-tests for continuous variables. Multivariable logistic regression analysis was performed to identify independent factors associated with delirium, with delirium occurrence as the binary outcome variable. Two-tailed tests were performed, and P values <0.05 were regarded as statistically significant. Statistical analyses were conducted using SPSS (version 22.0; IBM, Armonk, NY, USA).
Ethical considerations
This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was reviewed and approved by the Institutional Review Board of Hallym University Sacred Heart Hospital (IRB No. 2024-12-014), which waived the need for informed consent owing to the retrospective study design.
Results
A total of 51 patients were included in the final analysis, with 34 and 17 patients in the delirium and non-delirium groups, respectively. The baseline characteristics of both groups showed no significant differences in sex, age, body mass index, ECMO type, ECMO run time, or past medical history. However, patients with delirium were significantly more likely to require tracheostomy than those without (76.5% vs. 23.5%, respectively; P=0.001). The median sedation duration was similar between the two groups (3.5 days in the delirium group vs. 3.3 days in the non-delirium group, P=0.81), but sedation drug type differed significantly (P=0.01, Cramer’s V =0.438, Table 1).
Table 1. Comparison of baseline characteristics in patients with and without delirium.
| Variables | Delirium (n=34) | No delirium (n=17) | P value |
|---|---|---|---|
| Sex, male, n (%) | 27 (79.4) | 12 (70.6) | 0.48 |
| Age, years, mean (range) | 55 (18−79) | 59 (35−81) | 0.31 |
| BMI (kg/m2), mean | 24.8 | 24.1 | 0.54 |
| ECMO type, n | 0.35 | ||
| VA | 24 | 15 | |
| VV | 9 | 2 | |
| V-AV | 1 | 0 | |
| ECMO run (hours), mean | 425.9 | 308.4 | 0.20 |
| Tracheostomy, n (%) | 26 (76.5) | 4 (23.5) | 0.001 |
| Time to tracheostomy since ECMO (days), mean | 5.04 | 5.00 | 0.98 |
| Sedation duration (days), mean | 3.5 | 3.3 | 0.81 |
| Sedation drugs, n | 0.01 | ||
| None | 2 | 2 | |
| Midazolam + sufentanil | 14 | 6 | |
| Midazolam + sufentanil + dexmedetomidine | 16 | 3 | |
| Sufentanil + dexmedetomidine | 2 | 5 | |
| Sufentanil | 0 | 1 | |
| RASS, median [IQR] | 1 [1.0, 2.0] | −1 [−1.0, 0] | 0.001 |
| Past medical history, n (%) | |||
| Hypertension | 13 (38.2) | 6 (35.3) | >0.99 |
| Diabetes mellitus | 14 (41.2) | 8 (47.1) | 0.77 |
| Coronary artery disease | 3 (8.8) | 3 (17.6) | 0.39 |
| Cerebrovascular accident | 2 (5.9) | 1 (5.9) | >0.99 |
| Alcohol drinking, n | 12 | 7 | 0.76 |
BMI, body mass index; ECMO, extracorporeal membrane oxygenation; IQR, interquartile range; RASS, Richmond Agitation and Sedation Scale; V-AV, venoarteriovenous; VA, venoarterial; VV, venovenous.
Midazolam was the most commonly used sedative in both groups, likely owing to its cost-effectiveness, as it is the only drug covered by South Korea’s National Health Insurance. Many patients in both groups received midazolam and sufentanil, while the combination of midazolam + sufentanil + dexmedetomidine was more frequently used in the delirium group than in the non-delirium group. These findings highlight the preference for midazolam for sedation, driven by cost considerations related to the high expense of sufentanil and dexmedetomidine.
Laboratory findings such as pH, PaO2, partial pressure of arterial carbon dioxide (PaCO2), lactate, creatinine, albumin, Simplified Acute Physiology Score (SAPS) II, and Sequential Organ Failure Assessment (SOFA) scores, which are used to estimate mortality and assess illness severity in medical or surgical ICU patients, were not significantly different between the delirium and non-delirium groups, suggesting that these factors were not directly associated with delirium occurrence (Table 2). Multivariable logistic regression was performed to identify independent factors associated with delirium. Logistic regression analysis showed that midazolam was significantly associated with an increased risk of delirium [odds ratio: 15.39, 95% confidence interval (CI): 2.14–110.70, P=0.007], while sufentanil (odds ratio: 0.14, 95% CI: 0.01–2.69, P=0.20) and dexmedetomidine (odds ratio 2.48, 95% CI: 0.54–11.40, P=0.24; Table 3) were not significantly associated with delirium. These results underscore the role of midazolam as a major contributor to delirium in patients on ECMO, whereas the effects of sufentanil and dexmedetomidine are less clear. To evaluate whether the association between midazolam and delirium was influenced by differences in baseline severity rather than a drug-specific effect, an additional comparison was performed between patients with and without midazolam exposure (Table 4). Although the midazolam group showed higher body mass index (BMI), higher SOFA scores, and more frequent tracheostomy—indicating greater illness severity and prolonged sedation needs—the association between midazolam use and delirium remained significant after multivariable adjustment.
Table 2. Comparison of laboratory findings between patients with and without delirium.
| Pre-ECMO variables | Delirium (n=34) | No delirium (n=17) | P value |
|---|---|---|---|
| ABGA | |||
| pH | 7.28 | 7.32 | 0.36 |
| PaO2 (mmHg) | 101.9 | 114.2 | 0.72 |
| PaCO2 (mmHg) | 67.6 | 36.5 | 0.37 |
| Lactate (mmol/L) | 4.5 | 6.2 | 0.28 |
| Creatinine (mg/dL) | 1.70 | 1.78 | 0.90 |
| Albumin (g/dL) | 3.6 | 3.5 | 0.90 |
| SAPS II score | 59.4 | 58.5 | 0.92 |
| SOFA score | 10.4 | 10.3 | 0.94 |
Data are presented as mean. ABGA, arterial blood gas analysis; ECMO, extracorporeal membrane oxygenation; PaCO2, partial arterial carbon dioxide pressure; PaO2, partial pressure of arterial oxygen; SAPS, simplified acute physiology score; SOFA, sequential organ failure assessment.
Table 3. Logistic regression analysis on delirium effect of sedation drugs.
| Sedation drugs | Odds ratio | 95% CI | P value |
|---|---|---|---|
| Midazolam | 15.39 | 2.14–110.70 | 0.007 |
| Sufentanil | 0.14 | 0.01–2.69 | 0.20 |
| Dexmedetomidine | 2.48 | 0.54–11.40 | 0.24 |
CI, confidence interval.
Table 4. Baseline characteristics according to midazolam exposure.
| Variables | Midazolam exposed (n=39) | Midazolam non-exposed (n=12) | P value |
|---|---|---|---|
| Sex, male, n (%) | 32 (82.0) | 7 (58.3) | 0.09 |
| Age, years, mean (range) | 55 (18−79) | 62 (40−81) | 0.09 |
| BMI (kg/m2), mean | 25.2 | 22.5 | 0.03 |
| ECMO type, n | 0.75 | ||
| VA | 29 | 10 | |
| VV | 9 | 2 | |
| V-AV | 1 | 0 | |
| ECMO run (hours) | 393.6 | 364.5 | 0.78 |
| Tracheostomy, n (%) | 26 (66.6) | 4 (33.3) | 0.04 |
| Sedation duration (days) | 3.7 | 2.3 | 0.08 |
| SAPS II, mean | 61.5 | 49.2 | 0.20 |
| SOFA, mean | 10.9 | 7.8 | 0.045 |
| Delirium, n (%) | 30 (76.9) | 4 (33.3) | 0.005 |
BMI, body mass index; ECMO, extracorporeal membrane oxygenation; SAPS, simplified acute physiology score; SOFA, sequential organ failure assessment; V-AV, venoarteriovenous; VA, venoarterial; VV, venovenous.
Discussion
Delirium is a frequent and serious complication in critically ill patients, especially those undergoing ECMO. While the association between delirium and sedative drugs, as well as delirium in patients on ECMO, has been extensively studied in general ICU populations (11-13), research focusing on sedation practices and their relationship with delirium in patients on ECMO is lacking. ECMO is a highly specialized treatment for critically ill patients with severe cardiac or respiratory failure, and the unique pathophysiological changes associated with it may influence both the choice of sedative drugs and the risk of delirium (14).
There is a paucity of research specifically examining the association between sedation drugs and delirium risk in the ECMO population. The findings provide insights into the role of sedation management in the development of delirium in patients receiving ECMO. Among the sedatives used, midazolam was significantly associated with an increased risk of delirium. Previous studies have suggested that benzodiazepines such as midazolam can lead to over-sedation and contribute to delirium, particularly in critically ill patients (15,16). However, the relationship between sedative drug choice and delirium in patients undergoing ECMO remains poorly understood. The novelty of this study lies in its focus on patients undergoing ECMO, a cohort with distinct characteristics and a high risk of complications, including delirium. By analyzing the effects of sedation drugs such as midazolam, sufentanil, and dexmedetomidine on delirium risk in this unique population, we provide important new insights into sedation management strategies for patients undergoing ECMO. In this study, the odds ratio of 15.39 underscores the strength of the association of midazolam with delirium risk. In contrast, sufentanil and dexmedetomidine did not demonstrate significant associations with delirium, which is consistent with previous research suggesting that opioid and alpha-2 adrenergic agonists may have less impact on delirium development than benzodiazepines (17,18).
While baseline characteristics and laboratory findings (including the severity of illness scores such as SAPS II and SOFA) did not significantly differ between patients with and without delirium, sedation drug type emerged as a crucial factor. This reinforces the importance of careful sedation management, particularly when using medications with a higher potential to cause delirium (19). Given the critical nature of ECMO treatment and the challenges in managing sedation, our findings suggest that clinicians should carefully consider the choice of sedative drugs, particularly midazolam, which is associated with a higher risk of delirium. The findings highlight the need for further research on sedation protocols in patients receiving ECMO and the potential for individualized sedation strategies to improve patient outcomes (8).
Patients receiving ECMO have unique characteristics that increase their susceptibility to delirium compared with general ICU populations. Prolonged deep sedation, frequent tracheostomy, and altered cerebral perfusion due to extracorporeal circulation all contribute to this vulnerability. In addition, the ECMO circuit may influence drug pharmacokinetics and systemic inflammation, further amplifying sedative effects.
In our study, patients with delirium were significantly more likely to undergo tracheostomy compared to those without delirium. This finding may be partly explained by the fact that tracheostomy is usually performed in patients requiring prolonged mechanical ventilation and deeper or extended sedation, both of which are well-known risk factors for delirium. Furthermore, the need for tracheostomy may reflect greater illness severity and longer ICU stay, which could contribute to the increased likelihood of delirium. Although our study could not determine whether tracheostomy itself is an independent risk factor or simply a marker of clinical severity, this association highlights the importance of careful delirium monitoring and prevention strategies in patients undergoing tracheostomy during ECMO support.
An important consideration in interpreting our findings is the role of economic and reimbursement factors in sedation practices. In South Korea, midazolam is the only sedative agent reimbursed by the National Health Insurance, making it the most frequently used drug in ECMO patients despite its known association with delirium. In contrast, sufentanil and dexmedetomidine are significantly more expensive and are not routinely covered, which limits their use in daily practice. This cost-driven preference for midazolam may inadvertently increase the risk of delirium in ECMO patients, underscoring the need for policy-level discussions and institutional protocols that balance economic constraints with patient safety. Because sedative choice was often driven by clinical severity and anticipated duration of ventilation, residual confounding may persist despite multivariable adjustment. Therefore, the findings should be interpreted with caution. Nevertheless, midazolam remained significantly associated with delirium in our multivariable regression analysis, suggesting a potential drug-specific contribution beyond disease severity alone, although the possibility of residual confounding cannot be completely ruled out. Because VV-ECMO and VA-ECMO patients have distinct etiologies and baseline neurological risk profiles, pooling these populations may introduce heterogeneity. Owing to the limited sample size, meaningful subgroup analyses were not feasible; therefore, the findings should be interpreted as hypothesis-generating. This study was further limited by its retrospective design and relatively small sample size from a single center, which may reduce the generalizability and statistical power. In addition, detailed day-by-day sedation depth, CAM-ICU trajectories, and cumulative sedative dosages could not be systematically analyzed due to incomplete longitudinal documentation inherent to the retrospective design. Furthermore, anticholinergic burden could not be quantified using validated tools such as the Anticholinergic Cognitive Burden (ACB) score, as comprehensive medication data required for such assessment were not consistently available. Accordingly, further multicenter studies with larger sample sizes are warranted to confirm these results and to explore other potential factors contributing to delirium in patients on ECMO (13).
Conclusions
This study suggests a possible association between midazolam exposure and an increased risk of delirium in patients undergoing ECMO, whereas sufentanil and dexmedetomidine did not demonstrate a similar relationship. These findings should be interpreted with caution, as the limited sample size and single-center retrospective design reduce the strength of causal inference.
Given the significant clinical impact of delirium in this vulnerable population, this study provides hypothesis-generating evidence supporting the need for more careful sedative selection and delirium monitoring during ECMO support. Further large-scale prospective multicenter studies are needed to validate these observations and better define optimal sedation strategies for patients receiving ECMO. In addition, research aimed at developing tailored sedation protocols that incorporate individual patient characteristics and clinical conditions could provide more effective strategies for preventing delirium and improving patient prognosis in this high-risk population.
Supplementary
The article’s supplementary files as
Acknowledgments
We thank all participants who participated in this study.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was reviewed and approved by the Institutional Review Board of Hallym University Sacred Heart Hospital (IRB No. 2024-12-014), which waived the need for informed consent owing to the retrospective study design.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2086/rc
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2086/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2086/dss
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