Delirium after cardiac arrest: incidence, risk factors, and association with neurologic outcome—insights from the Freiburg Delirium Registry

All outcome variables were evaluated by manual case-by-case review of medical and patient records. Since only data from the index hospital stay were evaluated, no patients were lost to a follow-up. Registry was checked for data integrity and plausibility according to the RECORD recommendations for data clearing [13].

Patients after cardiac arrest [in-hospital (IHCA) as well as out-of-hospital (OHCA)] and CPR for ≥ 5 min, or CPR < 5 min and GCS ≤ 7, underwent a target temperature management (TTM). Typically, TTM was maintained for 24 h at 33 °C, followed by slow rewarming at a rate of 0.2 °C/h, and ensuring fever avoidance for 48 h. Early detection and treatment of the cause for cardiac arrest was advocated. Most patients underwent coronary angiography, computed tomography (CT), or both after cardiac arrest. The management of vasopressors and fluid therapy was based on individual patient needs and clinical assessment of the intensivist in charge. Target mean arterial pressure (MAP) was > 80 mmHg for the first 24 h, and > 65 mmHg afterward till 08/2019. Since 08/2019, target MAP was > 65 mmHg [14]. A lung-protective ventilation was advocated targeting paCO₂ 35–45 mmHg and paO₂ ≥ 70 mmHg. For analgosedation, sufentanil and isoflurane or propofol were typically used targeting RASS-4 during the first 24 h after arrest. After reaching normothermia subsequent to TTM, an immediate wake-up trial was advocated.

Delirium was defined by Nursing Delirium screening scale (NuDesc) ≥ 2 in at least one assessment and in selected patients confirmed by the documented assessment in the electronic files. The NuDesc score is routinely assessed by specially trained nurses in all ICU patients at least once per 8-h shift, corresponding to three assessments daily. To minimize a short-term observation bias, nurses perform a “representative screening” that reflects the patient’s overall condition during their shift. If a representative screening cannot be documented due to the patient’s fluctuating condition, multiple screenings may be performed. The NuDesc is approved, easy to use, and has high sensitivity and specificity for the detection of delirium [15‐17]. In selected cases with conflicting results from NuDesc and the documented delirium assessment, a retrospective adjudication was performed. The motoric subtype of delirium was defined according to literature using the Richmond agitation and sedation scale (RASS), which is assessed at least three times daily on our ICU [18]. Specifically, hyperactive delirium was presumed when delirium was diagnosed and RASS was ≥ 1 in at least two consecutive evaluations [19]. Hypoactive delirium was presumed when RASS was ≤ 0 in at least two consecutive evaluations. Mixed delirium was presumed in case of alternant positive and negative RASS evaluations.

Delirium-free days within a 10-day period [referred to as delirium-free days (10)] were defined as days with a NuDesc score ≤ 1 within the first 10 days after the initial documented delirium evaluation, which typically occurred shortly after extubation. For patients discharged from the ICU without delirium before day 10, all subsequent days following discharge were considered delirium-free. Conversely, for patients who were reintubated or deceased before day 10, all days following reintubation or death were considered non-delirium-free. Neurologic outcome was determined by cerebral performance category (CPC) score at ICU discharge. Favorable neurological outcome was defined as CPC ≤ 2 [20].

In patients with suspected or diagnosed delirium, our local protocol recommends a combination of pharmacological and non-pharmacological interventions. Non-pharmacological measures include reducing or discontinuing sedatives, ensuring adequate pain management, promoting daytime activation, reorientation by staff, involving relatives, and optimizing the patient’s environment (e.g., adequate daylight, quiet rooms with fewer patients). Other steps include quiet alarm management, minimal monitoring, removal of unnecessary cannulas, and encouraging oral feeding to restore the day-night cycle. Pharmacological treatments are only considered if these measures prove insufficient. Risperidone is the first-line treatment, with haloperidol as the second line, both administered at low doses and discontinued as soon as delirium resolves or improves.

All relevant data are given in standardized tables, either as n (%) for categorical data or as median and interquartile range (25th–75th) for continuous data.

For data analysis, SPSS (version 26, IBM Statistics) and Prism (version 10, GraphPad) were employed. For statistical analysis, Mann–Whitney U test was used for analysis of continuous variables. For categorical variables, Fisher’s exact test was used when number of expected values was smaller than five, otherwise Pearson’s Chi-squared test was performed. Delirium-free days were compared using the Mann–Whitney U test. Risk factors for delirium and delirium-free days were tested by multivariable regression analysis. Predictors for delirium were predefined according to literature heaving a plausible effect on delirium incidence. Similarly, predictors of outcome were predefined and tested in a multivariable regression analysis. Odds ratio (OR) with 95% confidence interval (CI) are reported as computed by the regression analysis or Fisher’s exact test. A p value of < 0.05 was considered statistically significant. Youden’s J was calculated as sensitivity + specificity − 1. The value of J was determined from the receiver operating characteristic (ROC) curve, where it represents the maximum sum of sensitivity and specificity.

In the FDR, 430 patients after cardiac arrest were registered. Of these, 213/430 (49.5%) patients were excluded according to predefined exclusion criteria. Specifically, 28/430 (6.5%) due to a transferal before delirium evaluation, 184/430 (42.8%) due to death before delirium evaluation, and 1/430 (0.2%) due to profound hypothermic arrest. This led to 217/430 (50.5%) patients included in the analysis (Fig. 1). Mean age was 63 (55–72) years and 51/217 (23.5%) were female.

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Delirium was diagnosed in 199/217 (91.7%) of all patients. Mixed delirium was the most common form of delirium, detected in 138/199 (69.3%) patients, followed by hypoactive 39/199 (19.6%) and hyperactive delirium 22/199 (11.1%). The median delirium-free days (10) were 6 (1–8) in patients with delirium. In 88.4% of all patients with delirium, delirium began during the first 2 days after extubation (Fig. 2).

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Patients with delirium were older compared to patients without [63 (56–73) versus 51 (39–64) years; p = 0.001] and had more often arterial hypertension, while other comorbidities including neurologic and psychiatric diseases were similar. For baseline characteristics, see Table 1. Duration of ICU stay was significantly longer in patients with delirium compared to patients without and cause for cardiac arrest was more often of cardiac origin. No significant differences were identified concerning bystander CPR, shockable initial rhythm, no-flow duration, and low-flow duration. Duration of invasive ventilation was significantly longer in patients with delirium compared to patients without, as was the duration from cardiac arrest to first spontaneous breathing. No differences were identified between the use of isoflurane and propofol as sedatives (Table 2). No difference was identified concerning dosage of sedatives at various time points and delirium (supplemental Fig. 1).

Only age was significantly associated with incidence of delirium with an OR 1.05 (1.02–1.09) in our dataset. Age and the duration of invasive ventilation were significantly associated with the number of delirium-free days (Fig. 3).

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A favorable neurological outcome was documented in 162/217 (74.7%) patients. Outcome in patients without delirium was significantly more often favorable compared to patients with delirium (94.4% versus 72.9%; p = 0.048) and hyperactive delirium was significantly more often present in patients with favorable outcome (Fig. 4a).

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Patients with favorable neurological outcome had significantly more delirium-free days (10) [7 (6.0–8.75) versus 0 (0–0.5), p < 0.001] (Fig. 4b). In the receiver operating characteristic (ROC), delirium-free days (10) predicted the neurological outcome with an area under ROC of 0.933 (p < 0.001) and the best discriminator at > 3.5 delirium-free days (Youdens J 0.817, likelihood-ratio 9.81) (Fig. 4c).

While the presence of delirium was not associated with favorable outcome, the number of delirium-free days (10) was a good predictor of favorable neurologic outcome (Fig. 5).

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When discussing the results presented in our study, some limitations have to be considered. We present single-center retrospective data. Therefore, our results should be considered hypotheses-generating only and have to be confirmed in larger trials. In addition, we do not have follow-up data of the patients discharged. As we defined the neurologic outcome at the time of ICU discharge, the CPC may still have changed during rehabilitation, especially in patients with an unfavorable outcome. Since all patients included in this study received TTM, the data presented may not be generalizable to patients who underwent CPR without TTM. In addition, there are data indicating that the specificity of other screening tests such as the CAM-ICU may be higher than the NuDesc used in our registry [17]. However, no validation of delirium screening scores for patients after cardiac arrest exists. The NuDesc assesses five different symptoms including “psychomotoric retardation.” In particular, this assessment point cannot differentiate between patients with delirium or hypoxic brain damage. Consequently, a possible missclassification of patients with hypoxic brain injury cannot be excluded. However, this highlights the complexity of diagnosing delirium in post-cardiac arrest patients, where overlapping symptoms of brain injury and delirium complicate clinical interpretation. Furthermore, this potential overlap makes it difficult to determine causality. Whether delirium per se worsens the neurological outcome or is the expression of hypoxic brain damage, which we rather assume, remains unclear and requires further research.

Since we did not use structured clinical interviews, some variables are likely to be underreported.