Serum biomarkers of delirium in the elderly: a narrative review

Postoperative and intensive care unit (ICU) delirium remains a challenge for patients, families, and caregivers. Identified more than half a century ago in cardiac surgery patients, delirium today is characterized by criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-V, which can be summarized as a fluctuating disturbance of consciousness evolving over a short period of time, a change in cognition, and evidence from the current history, physical examination, or laboratory findings that the disturbance is caused by the direct physiological consequences of a general medical condition.

The suffering of delirious patients is severe as they may be restless, hallucinate, and be filled with fear. Unfortunately, problems continue even after the resolution of delirium. This syndrome may be associated with prolonged ICU and hospital stay [1, 2], more hospital readmissions [3], reduced quality of life, loss of independence, and increased mortality [1, 4‐7]. Furthermore, the duration of delirium is associated with worse long-term cognitive function [8, 9]. The increased socioeconomic burden should also not be underestimated [10]. However, a recently updated delirium guidance paper on prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult ICU patients summarizes that delirium in critically ill adults has not been consistently shown to be associated with ICU length of stay, discharge disposition to a place other than home, depression, functionality/dependence, or mortality [11].

Ranging from 10 to 80% [12‐14] or even up to 90% depending on the type of surgery [15], the overall incidence of delirium is high during hospital stay, especially in elderly patients. Delirium usually develops within 72 h after surgery and/or ICU admission. However, its impact is likely to be underestimated due to the predominance of hypoactive delirium.

Although the pathophysiology of delirium remains poorly understood, we know that the pathogenesis of the cognitive impairments associated with delirium is multifactorial. Certain entities such as drug overdose [16] but also drug withdrawal [17] bear delirium risk. As with so many disparate etiologies, it is highly unlikely that a single mechanism is solely responsible [18]. Therefore, research focuses on the assessment of modifiable pre-, intra-, and postoperative risk factors (e.g., dehydration, fluid balance, immobilization, analgesia, and sleep deprivation) associated with delirium, [18] as well as prediction, prevention, early detection, and treatment of this common psychiatric syndrome. One promising approach is the detection of elevated or lowered biomarkers as predictors or indicators of delirium [19, 20]. Furthermore, serum biomarkers may aid in risk stratification, diagnosis, and monitoring of delirium [19] and, finally, may help to find an effective treatment. This review aims to summarize the current state of knowledge on serum biomarkers of delirium.

We performed an updated review on biomarkers of delirium based on previous publications [19]. As age is one of the most consistently reported risk factors for developing delirium, we restricted our search to publications including patients aged 60 years and older [18, 21]. Study selection and quality assessment were performed by two independent authors (AH and KT). The results were compared, and disagreements were reviewed (MS).

Our updated findings are consistent with a review published 7 years ago, in 2011, by Khan and colleagues [19] who had reported a lack of evidence for the clinical use of biomarkers to aid in earlier detection, prevention, or treatment of delirium. As long as there are no adequate means of intervention, altered levels of biomarkers are unlikely to initiate any change in clinical practice. So far, no biomarker has been identified that would enable development of treatment strategies to lower the incidence, severity, or duration of delirium. A useful biomarker needs to be easily identifiable and reliable to enable targeted therapy while being cost-effective. These criteria were not applicable for any biomarker found in this literature review. Of note, we only reported data from patients aged 60 and older, as opposed to the review by Khan and colleagues [19].

Our main conclusion that none of the biomarkers described help to lower the incidence of delirium is based on several considerations. Pathophysiological explanations such as those addressed by the neurotransmitter hypothesis have already been described nearly 40 years ago [55]. Despite the knowledge of the role of neurotransmitters in the pathophysiology of delirium, with central cholinergic deficiency remaining the leading hypothesis [56], we have not yet been able to find a way to decrease the incidence of delirium. Dopamine excess and inflammation are important assumptions competing with or contributing to the hypothesis of cholinergic deficiency [57], but the focus should lie on modifiable factors causing delirium [18]. This includes stress reduction due to minimization of light and noise disturbances at night and adequate pain management among other things, but also preventive drug therapy in high-risk cohorts [58, 59]. Most importantly, the pathophysiology of delirium remains poorly understood [60] despite being first described by Hippocrates more than 2500 years ago [61]. So on the one hand, our findings are consistent with established theories such as the role of neurotransmitters, inflammation, and stress response in delirium (i.e., reported association of acetylcholine, IL-6, CRP, procalcitonin, and cortisol). On the other hand, there are new approaches that, however, lack sufficient evidence or validation for implementation into everyday clinical practice (i.e., BDNF, leptin, MMP-9, neopterin, phenylalanine–tyrosine ratio, prolactin, NLR, thioredoxin, 8-iso-prostaglandin F2α, AZGP1, and SERPINA3). As such, the latter are not readily available. Delirium biomarkers that are included in standard blood examinations (i.e., albumin and creatinine) may be useful to attribute higher delirium risk but are not targets specific to delirium prevention since they are routinely addressed with respect to other clinical questions. It is nevertheless interesting that an elevated creatinine level was reported to be an independent risk factor for delirium in a cardiac surgery cohort; clinicians should keep this in mind [39].

An almost exclusive association of the numerous investigated inflammatory biomarkers with delirium offers room for and discussion on a novel approach: The implementation of a widely used inflammatory marker (i.e., CRP or procalcitonin) as a diagnostic tool might help facilitate diagnosis of hypoactive delirium. The same can be said for biomarkers of metabolism. Moreover, these biomarkers could be implemented into a tool to assess delirium risk. Finally, the accepted role of amyloid β1-40 for delirium risk has also been confirmed. But clinical relevance here can be reduced to knowledge of its existence, since patients suffering from dementia are known to bear higher risk of delirium [62].

We acknowledge the following limitations of the presented review. First, we did not include any reports on biomarkers with a sample size lower than 10. Important biomarkers to be further explored in larger cohorts may thus have escaped our attention. Second, we focused on patients aged 60 and older, which led to the exclusion of numerous publications reporting other potentially important biomarkers for the elderly population including key articles on delirium biomarkers [63‐68]. Interestingly, putative delirium biomarkers such as NSE and S-100β were reported/found to be irrelevant [59]. Third, there is an imbalance between medical and surgical patients investigated. In addition, high-risk surgical groups (i.e., hip and cardiac surgery) are overrepresented, whereas another important high-risk group (i.e., ICU patients) is underrepresented in the reported literature. Last, all observational studies have outlined biomarker levels comparing delirious to non-delirious patients. Overall, delirium is diagnosed clinically by established delirium assessment methods and biomarker groups and could be helpful to diagnose patients where a delirium is not so obvious (i.e., hypoactive delirium). In addition, it is not easy to influence levels of the biomarkers reported here other than by following guidelines (e.g., hygiene directives, pain control, prevention and management of infections, avoidance of unnecessary surgery, and adequate nutrition).

The concluding observations offer no ground-breaking recommendation for the implementation of a specific biomarker of delirium. Inflammatory biomarkers and biomarkers of metabolism could assist in diagnosing delirium and in assessing delirium risk. Expert opinions state that especially the hypoactive form is frequently undiagnosed even when using established tools to diagnose delirium. The implementation of these biomarkers in delirium assessment tools could represent a new approach. However, authors found inflammatory biomarkers not consistently reported as delirium risk factors. Their level of evidence should first be investigated in a meta-analysis.