In the present study, we present several important epidemiological findings on delirium in patients with ADHF in a prospective fashion. The major findings included the following: 1) The incidence of delirium in this study population was 27.3%, and the median time from admission to delirium was 2 days; 2) hyperactive delirium was the most common subtype; 3) delirium was associated with increased mortality; and 4) the independent risk factors for delirium in the patients with ADHF were older age, male sex, high clinical frailty scale score, and dementia. Considering the lack of evidence concerning delirium in patients with ADHF, we believe that our prospective observational data bridge the evidence gap in this field and contribute to the advancements in the management of delirium in patients with ADHF.
Incidence of delirium in patients with ADHF
The incidence of delirium in this study was slightly higher than that in previous retrospective studies of patients with ADHF; the incidence was reported to be 17–23% during hospitalization [4, 6]. This can be attributed to the advanced age of our study population compared with that in previous studies because older age is one of the common risk factors of delirium. Herein, we employed the DSM–5 in a prospective fashion. Delirium occurred at the early phase after the onset of ADHF in this study. This is consistent with several previous reports demonstrating that delirium occurred most frequently on the day of the surgery and the next day, and tended to occur until 5 days of surgery [14,15,16]. However, it is also important to know the possibility of relatively later-phase occurrence of delirium because 4 (11.1%) of 36 patients started to develop delirium after ≥10 days (Fig. 1).
In addition, it is notable that hyperactive delirium was the most common subtype (86.1%) in the present study, whereas hypoactive delirium was the most common subtype after cardiac surgery in some previous studies [5, 17]. Because the mechanism and pathophysiology of delirium are poorly understood with several disparate etiologies indicated in previous reports, including hypoxemia, decreased blood supply to the brain, or electrolyte disturbances associated with heart failure, it is difficult to discuss the reason why hyperactive delirium was the most common subtype in this study [7, 18,19,20,21]. However, we speculated that impaired circadian rhythm due to insufficient melatonin secretion and expansion of neuroinflammation in patients with ADHF might be associated with the increased incidence of hyperactive delirium . At any rate, we should note that the evaluation of the subtype is recommended for risk stratification because the mortality of patients with hypoactive delirium is higher than that of patients with hyperactive delirium [1, 8, 10]. Although the clinical benefits of medications such as antipsychotics for treating delirium are still controversial due to a lack of qualified evidence, we hope that further understanding about the different incidences of hyperactive and hypoactive delirium due to underlying clinical conditions provides readers with some insights into this field [10, 22, 23].
Prognosis and risk factors for delirium in patients with ADHF
As the 30-day mortality of ADHF was reported to be 7.0–17.2%, the 90-day mortality in our study population of 8.4% is consistent with that reported in previous studies [24, 25]. We showed that the prognosis of the patients with ADHF who developed delirium was worse than that of those without delirium. Delirium was independently associated with the 90-day all-cause mortality, with an adjusted HR of 6.8 (95% CI, 1.1–42.6, p = 0.042) in the present study. To the best of our knowledge, there were only two retrospective reports available concerning this topic; Uthamalingam et al. and Honda et al. reported that the adjusted HRs for the presence of delirium in relation to the all-cause mortality were 2.10 (95% CI, 1.53–2.88, p < 0.0001) at 90 days and 2.38 (95% CI, 1.30–4.35, p = 0.005) at a median of 335 days in patients with ADHF, respectively [4, 6]. Our results are consistent with these reports in view of the high risk of delirium in association with mortality; however, the HR was estimated to be higher than that in these two reports. This difference may be attributed to an underestimation of the incidence of delirium associated with the retrospective study design, which then resulted in a lower estimation of the HR.
There are several possible mechanisms underlying the poor prognosis in patients with ADHF complicated with delirium. First, delirium itself implies the presence of poor and severe conditions, such as multiple organ failure due to ADHF . In the present study, the BNP level on admission was higher in the patients with delirium. Although it was adjusted in the multivariable Cox regression analysis, there could be some unmeasured confounders regarding the severity of AHDF. Second, it is possible that treatments for heart failure can be sometimes disturbed by agitated behaviors due to delirium, such as self-extubation, catheter removal, or excessive afterload associated with excessive physical activities, as we showed that hyperactive delirium was the most common subtype in the present study . Last, difficulty in controlling heart failure, such as noncompliance in taking medications and disruption of daily weight monitoring after discharge, might also be associated with the poor outcome . Regarding the risk factors of delirium, advanced age, male sex, high clinical frailty scale score, and dementia were associated with the occurrence of delirium in this study. These risk factors have been proven with sufficient evidence, except for controversies on sex [2, 29, 30]. At any rate, it is notable that advanced age remained as a risk factor even in this advanced-aged study population.
With the lack of prospective evidence concerning delirium in patients with ADHF, our data contribute to better understanding of delirium in patients with ADHF, and it is noteworthy that hyperactive delirium was the most common subtype observed in the present study. Considering that hyperactive delirium was the most common subtype and deleterious patients were more tachycardiac with a tendency to be prescribed less β-blockers, we speculated that increased autonomic drive, especially of sympathetic systems, on heart function may have deleterious effects and can be a possible therapeutic target in the future . Physicians should consider delirium when treating ADHF, and evaluation of early occurrence of and accurate diagnosis of delirium in relation to the prognosis in patients with ADHF should be strongly considered in future trials.
There are several limitations in the present study, which should be considered when interpreting our results. First, the effect of delirium subtype on mortality could not be assessed in the current study due to the limited number of patients who developed non-hyperactive delirium subtypes. The results of this single-center study should be validated in a multicenter study. Second, we regrettably did not plan to assess the long-term prognosis when we prepared the research protocol, although one of the final goals of medicine is to improve long-term outcomes, such as survival and quality of life. The reason was based on a scheduled transfer of institution of the primary investigator (M.P). Third, the relationship between delirium and sedative–hypnotic drug use could not be assessed because the decision for administration of such drugs for the patients depended on the individual judgment of each attending physician. More specific proposal for the management of delirium in patients with ADHF could be needed. Fourth, the use of oral or intravenous sedative medications, especially benzodiazepines, is not a normal practice because it results in the development or worsening of delirium later in the course [32, 33]. Lastly, DSM-5 is a much less practical tool, whereas the Confusion Assessment Method is used widely as an efficient and fast tool both for screening and for diagnosis of delirium [3,4,5,6,7,8,9,10]. However, our prospective data remain important, considering the lack of evidence to discuss future perspectives in managing delirium occurring in patients with ADHF.