A Half‐Century of Delirium Research: Time to Close the Gap

Fifty-one years ago, Engel and Romano launched the modern era of delirium study with electroencephalographic (EEG) data from patients with acute confusion caused by a variety of disturbances.1 Their now-classic finding of alpha slowing and delta and theta wave intrusion correlated with clinical severity and occurred regardless of the patient's underlying medical condition. They found that treating the medical precipitant of delirium could reverse both the clinical and EEG manifestations of the disturbance.2 Recent work has reproduced these findings using more exact methods,3, 4 but has not altered Engel and Romano's fundamental view that delirium represents a global failure of brain metabolism. Also, in the last half-century, particularly the last decade, investigators have clarified the phenomenology of delirium and reached a tentative consensus about diagnostic criteria. Although hallucinations, delusions, and agitation may be the most flagrant features of delirium, most older patients have quieter presentations.5 Essential to delirium, however, are the presence of deficits in attention and cognition, an acute and fluctuating course, and an underlying medical etiology. Using case definitions that emphasize those criteria, investigators have found delirium to be surprisingly common among older hospitalized patients (perhaps 1 of 3 older patients).6 Although Engel and Romano highlighted the reversibility of delirium, recent studies have shown a poor long-term prognosis and a potential for prolonged or persistent symptoms.7, 8 These advances in the clinical epidemiology of delirium have not brought us closer to its underlying mechanism. Why does such a gap remain? First, there is the nature of delirium—fluctuating and transient, often clearing in the time it takes just to obtain informed consent from the patient's proxy. This rapid timeframe makes careful physiological investigation difficult. Second, our methods for studying the brain in living subjects are still cumbersome for severely ill and uncooperative patients. Third, patients with delirium are complex; multiple acute and chronic problems, polypharmacy, and underlying brain diseases confound attempts to measure solely the delirious state. Finally, we have only a fragmentary knowledge of the normal mechanisms of CNS arousal, so tentative hypotheses are difficult to formulate. Multiple neurotransmitters are involved in arousal and attention, but substantial evidence assigns a major role to acetylcholine. Anticholinergic intoxication in clinical settings has long been known to produce confusional states. Additionally, Itil demonstrated that experimental anticholinergic intoxication in mentally ill subjects (an approach unlikely to be sanctioned today) could reproduce the behavioral and EEG manifestations of delirium.9 Several conditions causing delirium, such as hypoxia, hypoglycemia, and thiamine deficiency, have a final common pathway of decreased acetylcholine synthesis.10 Finally, Alzheimer's disease, itself characterized by a failure of cholinergic transmission, increases the risk of delirium caused by anticholinergic medication.11 This well-accepted mechanism of delirium has not been accessible to the methods of clinical epidemiology. Several recent prospective studies have shown little correlation between delirium and anticholinergic drug use.5, 12, 13 Why should a relationship with such strong clinical and biological support remain undetectable? First, there is the problem of measurement. The use of a known anticholinergic drug gives a poor estimate of true exposure in a particular individual, given the wide variation among individuals in absorption, distribution, and target organ sensitivity.14 It is impractical to measure blood levels of all known anticholinergic agents, and even if it were not, this would miss the in vivo antimuscarinic effects of drugs not ordinarily considered to have anticholinergic activity.15 An additional problem is confounding by underlying disease. Patients at high risk of delirium because of underlying dementia may be more or less likely to use anticholinergic drugs if they present with behavioral symptoms, such as agitation or depression, that are treated with anticholinergic agents, or if their physicians wisely avoid a class of compounds to which they are especially sensitive. Finally, delirium itself is a heterogeneous disorder, and it is unlikely that anticholinergic mechanisms operate in all subtypes. In this month's Journal, Mach and colleagues present a study that begins to address these concerns.16 To the greatest extent possible, they excluded patients with known dementia or agitated behaviors. They measured total serum anticholinergic binding activity with a radioreceptor assay that was not limited to any specific drug. Despite their small sample size, itself a reflection of the difficulty of obtaining subjects for such studies, they detected a significant relationship between anticholinergic activity and delirium. Furthermore, successful resolution of delirium correlated with a decline in anticholinergic activity. Subjects whose delirium resolved typically had several medications discontinued, most of which have measurable antimuscarinic binding activity but few of which would be considered traditional anticholinergic drugs. This study also highlights the heterogeneity of delirium. Several patients had irreversible delirium; this group had the lowest level of serum anticholinergic activity at time of diagnosis. One could hypothesize that patients with irreversible delirium have more “endogenous” factors, e.g., occult dementia, underlying the disturbance and, therefore, would become confused with lesser degrees of exposure to acute precipitants such as anticholinergic drugs. Acknowledging the existence of this heterogeneity is essential to improve our understanding of the mechanisms of delirium.17 Questions remain about the specificity of the radioreceptor assay, yet it clearly represents an important tool for advancing our understanding of delirium. In the absence of direct experimentation, clinical studies must identify subsets of delirium that can be subjected to more detailed investigation of underlying mechanisms. Such studies will be arduous. Perhaps the most important message is a warning against complacency—despite a half-century of work, we still have far to go to close the gap between the phenomenology of delirium and its underlying pathophysiology.