Focus Points

• The delirium syndrome has been recognized by clinicians over many centuries, but reliable diagnostic criteria and screening tools have only been available since the publication of the third edition of the Diagnostic and Statistical Manual of Mental Disorders in 1980.

• Screening uncovers remarkably high rates of delirium in a variety of acute inpatient settings, yet these cases go unrecognized by professional caregivers much of the time.

• The high costs and poor prognosis of these patients make delirium a major safety and quality challenge for hospitals.

• Despite identifiable risk factors, delirium is difficult to prevent and even more challenging to treat.

• Underlying mechanisms of delirium are poorly understood; consequently, targeted therapies remain a distant prospect.

Abstract

Delirium, a syndrome involving an acute disturbance of consciousness and attention with associated cognitive and behavioral change in the setting of illness or drug toxicity, has been recognized throughout the history of medicine. Only recently, however, have criteria and screening tools been developed to make diagnosis reliable and facilitate systematic investigation. Over the past 2 decades, prospective studies using standardized tools have shown delirium to be frequent wherever sick patients are found, yet, despite this, the syndrome remains under-recognized. Patients with delirium experience prolonged hospitalization, reduced survival, and increased risk for long-term decline in function and cognition. Because patients with delirium have complex and multiple medical problems, the mechanisms of delirium remain poorly explored, specific therapies are lacking, and there are few controlled trials from which to make evidence-based treatment recommendations. Nevertheless, recent progress has been made in the prevention of delirium using multicomponent interventions to address risk factors for the disorder.

Introduction

Astute clinicians have long noted sudden changes in cognition and behavior during acute, life-threatening illness. The term delirium, meaning, literally, “off track,” was first used in the 2nd century AD, but Greek physicians 2,500 years ago recognized the same disorder as “phrenitis,” from which the term frenzy derives.1 This terminology reflected their belief that the underlying pathophysiology involved inflammation of the diaphragm, the putative seat of consciousness.1 While this understanding of disease mechanism was flawed, the clinical descriptions of delirium, particularly febrile illness, are recognizable even today. For the ancients, delirium was considered a poor prognostic indicator. The ancients also recognized a quiet form of the disturbance, which they termed lethargy.1

The modern understanding of disease classification dates back to the 19th century, and it is not surprising that delirium features prominently in the writing of that era’s great clinicians. French physicians, such as Dupuytren, Bonhoeffer, and Chaslin, were the first to define a syndrome of confusion with core features of chaotic thinking, clouding of consciousness, and cognitive failure.2 Other manifestations, such as psychomotor changes, delusions, and hallucinations, were deemed secondary phenomena, providing a basis for distinguishing confusion from other forms of insanity and for linking conceptually both hypoactive and hyperactive delirium.2

Natural history and clinical-pathological correlation of delirium also date from the 19th century. Furthermore, it was determined then that delirium could be distinguished from dementia by its sudden onset and potential reversibility.3

Osler4 included many references to delirium prognosis in his landmark textbook, The Principles and Practice of Medicine, remarking “the disease is almost uniformly fatal.” Osler personally autopsied his patients, and noted a paucity of brain changes relative to the prominent features of brain failure.4

A fuller understanding of delirium, however, was only possible after a consensus was reached on diagnostic criteria for the disorder and clinical populations were studied systematically using the tools of epidemiology. This article will survey those investigations, with emphasis on the past 2 decades. Much has been learned about the prevalence, risk factors, and prognosis of delirium during that time. Some progress has been made towards prevention and treatment of the disorder, although there are few controlled clinical trials in the literature. Ironically, the gap between clinical knowledge and understanding of pathophysiology, so prominent from ancient times through the 19th century, remains present at the beginning of the 21st century.

Modern Diagnosis and Recognition

Prior to 1980, studies of delirium were largely series of cases gleaned from referrals to psychiatrists or neurologists, who made the diagnosis based on global clinical impression rather than defined criteria. Classic descriptions, based on patients with the most serious behavior change, presented a very skewed picture of the disorder.5 Lacking standards for describing the disorder, clinicians developed a bewildering profusion of terms, over 30 in number, to indicate the condition.6 Mortality rates for delirium reportedly ranged from 25% to 65%, reflecting the fact that only the most severe cases were investigated.7

The publication of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III),8 in 1980 firmly established the term “delirium” for acute confusional states seen in medically ill patients, and introduced standardized diagnostic criteria. Further refinements came with the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R),9 and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),10 following the research into disease phenomenology that was facilitated by a common consensus on terminology. The DSM-III, DSM-III-R, and DSM-IV all emphasized chronological criteria (delirium develops over hours to days and tends to fluctuate over the course of the day) and the presence of one or more underlying organic causes (including general medical conditions and drug toxicity).8-10 Other criteria underwent gradual evolution as more data became available. The DSM-III used the imprecise term “clouding of consciousness,”8 but the DSM-III-R and DSM-IV made the reduced ability to focus, sustain, or shift attention the hallmark feature of delirium.9,10 Associated symptoms, such as delusions, hallucinations, psychomotor changes, and sleep-wake cycle alterations, were included in the DSM-III and DSM-III-R, but were removed from the DSM-IV when validation studies showed these were difficult to track and were not part of the primary disturbance.8-11 Cognitive features, such as memory impairment, disorientation, and disorganized thinking, were prominent in the DSM-III and DSM-III-R, but could not accurately separate delirious patients from those with dementia at the bedside.8,9 Accordingly, the DSM-IV was modified to emphasize that cognitive and perceptual changes are “not better accounted for by a preexisting, established, or evolving dementia”—a simple statement that implies a robust assessing of baseline cognitive function through interviews of caregivers and family members.10

Diagnostic criteria are necessary but not sufficient for ensuring validity and reliability in the diagnosis of delirium. It is equally important to operationalize criteria and to develop reliable methods for detecting and rating the severity of the disturbance. These tools can assist clinicians lacking specialized expertise in mental illness, since delirium is most likely to occur in general medical and surgical settings. Over 20 instruments for assessing the features of delirium have appeared in the literature.12 Among those with the greatest documented diagnostic validity are the Delirium Symptom Interview (DSI),13 a structured interview based on the DSM-III; the Delirium Rating Scale (DRS),14 a DSM-III–based symptom rating scale completed after a psychiatric interview; the NEECHAM Confusion Scale,15 intended for nurses; the Memorial Delirium Assessment Scale (MDAS),16 developed for cancer patients; and the Confusion Assessment Method (CAM).17 Of these, the CAM is, by far, the most utilized by investigators, having been cited in over 70 publications since its introduction (determined from a MEDLINE search). This reflects ease of use more than accuracy—the CAM’s screening questions can be completed in under 10 minutes, but sensitivity and specificity in clinical settings depends on the setting and can fall far short of 90% (still far better than the unaided observer).18 The CAM has been translated into multiple languages and has recently been adapted for use in the intensive care unit of hospitals by adding cognitive tests accessible to intubated patients.19

These diagnostic criteria and screening tools represent current consensus based on the available evidence, but there are still some problematic areas. Perhaps the greatest challenge is differentiating delirium from dementia. Delirium is frequently superimposed on dementia and, in such instances, often is overlooked, despite its strong impact on outcome.20 Additionally, certain forms of dementia, such as Lewy Body dementia, can show acute fluctuations similar to delirium.21

A second controversy involves the motoric subtypes of delirium—a distinction that goes back to the ancient Greeks, who differentiated frenzy from lethargy. Currently, the DSM-IV groups hypoactive delirium (the far more frequent variety) with hyperactive states (such as in delirium tremens).10 Although data are meager, evidence suggests that motoric subtypes may differ in etiology22 and outcome.23

Finally, there is evidence that patients who do not meet all DSM-IV criteria (so-called “subsyndromal delirium”) may have clinical outcomes similar to, though not quite as severe as, patients with the full picture of delirium.24 Rather than being all-or-none, delirium represents a continuum in which the threshold for diagnosis is somewhat arbitrary.25

The Clinical Epidemiology of Delirium

The development of diagnostic criteria and screening tools has made possible the systematic, prospective study of delirium across various patient populations deemed to be at risk. Reports from various investigative groups began to appear in profusion in the late 1980s, and have continued to the present. The first studies focused on older medical inpatients, used loosely operationalized DSM-III or DSM-III-R criteria and, for the most part, relied upon a single physician to assign the diagnosis of delirium.26 Given that delirium shows fluctuating features and a continuum of severity, it might be expected that the findings from such work would not be easily reproduced. However, the degree of convergence was remarkable—approximately 15% of all patients had evidence of delirium at the time of admission for their medical problem (so-called prevalent cases), and an additional 10% or more went on to develop delirium later during their hospitalization (incident cases). Later studies, using stricter operational definitions; standardized assessment tools, such as the DSI or CAM; and expert panels rather than a single clinician, reported quite similar prevalence and incidence rates.27,28

As common as delirium was throughout all these studies, recognition and documentation by clinicians who were caring for the patient occurred in only 10% to 30% of cases.29 One barrier to recognition appears to be lack of understanding of the features of delirium—many clinicians still assume hyperactivity and flagrant thought disorder must be present, and do not recognize that quiet, withdrawn states also represent a serious condition. In teaching settings, the recognition of delirium can be improved by educating physicians about the diagnostic criteria and instructing them in the use of the CAM.30

The next wave of studies, beginning in the 1990s, applied DSM criteria and screening tools, such as the CAM, to identify delirium in populations other than medical inpatients. Among the settings found to have high rates of delirium prevalence were postoperative patients,31 intensive care units,32 emergency departments,33 subacute care units,34 and hospice units for patients with advanced cancer.35 In some settings where frailty is common, such as among elderly hip fracture patients, ≥50% of patients were found to have delirium.36 Simply stated, one finds delirium wherever there are sick patients.

The systematic search for delirium among defined populations has helped identify factors that increase the risk for developing the disorder. Some of these risk factors, such as dementia, prior alcoholism, and sensory impairment, represent predisposing factors that increase baseline vulnerability.28 Dementia, in fact, is the most commonly cited risk factor, and has the strongest and most consistent relationship with delirium. Other factors, such as severe medical illness, infection, and psychoactive medication (particularly narcotics, benzodiazepines, and anticholinergic drugs), are acute precipitating factors most likely to cause delirium in the already predisposed host.37 Despite the widespread belief that general anesthesia causes delirium, observational studies38 as well as randomized trials have shown no increased risk of cognitive decline compared with regional anesthesia.39

Follow-up of patients enrolled in these prospective studies has been revealing. Delirium has proven to be a predictor of higher mortality and length of stay,40 although in cases of prevalent delirium this may be the result of underlying factors, such as dementia and illness severity, rather than delirium per se.41 Mortality has been lower—approximately 10% rather than the 25% to 50% reported in earlier retrospective studies, reflecting the inclusion of less severe cases identified by improved screening tools. In contrast, long-term follow-up has challenged the age-old belief that delirium is a transient, reversible disorder. Over 50% of hospitalized patients with delirium sent to post-acute care facilities continue to manifest the disorder 1 month later, particularly those with baseline chronic cognitive impairment.42 Persistent symptoms of delirium, functional decline, and loss of independence can be seen 6–24 months after the episode of delirium.43-45

Mechanisms of Delirium

Nineteenth century pathologists found few structural changes in the brains of dying patients with delirium. The fact that the lesion responsible for delirium is a functional rather than a structural one makes it subtler and far more difficult to study. Understanding the mechanisms of delirium, therefore, had to wait until the development of more direct measures of brain function.

Romano and Engel46 gained important insights in the 1940s using electroencephalography (EEG) in delirious patients. They demonstrated a correlation between the clinical severity of delirium and the findings of diffuse slowing of cortical (alpha) brain activity.46 Pathological delta- and theta-wave activity became present in the more advanced stages. Anticholinergic toxicity could produce these findings, and correcting disturbances of oxygen delivery (eg, transfusing anemic patients or providing supplemental oxygen to those with pneumonia and hypoxia) could reverse both clinical and EEG manifestations.47

Considerable indirect evidence has emerged to support the hypothesis that delirium involves alterations in cholinergic and dopaminergic transmission in cortical and subcortical brain structures responsible for attention, such as the prefrontal cortices, anterior and right thalamus, and right basilar mesial temporoparietal cortex.48 The data is largely observational and based on small case series of patients with unique lesions, or routine studies (eg, single photon emission computerized tomography and brainstem-evoked potentials) in special populations, such as liver failure patients awaiting transplantation.49 The strongest evidence supports cholinergic failure as a common pathway in delirium. Among the many drugs known to cause delirium, for example, anticholinergic activity is highly prevalent.50 In patients with delirium who lack exposure to such agents, there is also evidence of the possible presence of endogenous anticholinergic substances.51

A growing body of data indicates that delirium may result from the direct and indirect effects of cytokines on the brain.52 This would certainly account for delirium in situations such as sepsis, but also in other conditions, as cytokines are released from brain cells after injury. Many of these insights came indirectly as the result of recent therapeutic advances—for example, the infusion of exogenous cytokines (eg, interferon-a, interleukin-2, tumor necrosis factor) can produce delirium and other central nervous system changes in a dose-dependent fashion.53

A host of other factors and substances, too numerous to mention in this brief review, have been implicated in the pathogenesis of delirium based on finding too much or too little of the factor in the blood or cerebrospinal fluid of patients with delirium. Because of comorbid medical illness in patients with delirium, the lack of animal models for the disorder, and the difficulty conducting controlled studies in such complex and vulnerable patients, it is difficult to determine if these factors are truly causative, or are merely artifacts and epiphenomena. Knowledge about delirium’s pathophysiology continues to lag behind the understanding of its clinical presentation and impact.

Interventions for Delirium

Despite over 2 millennia of research into the phenomenology of delirium, evidence-based interventions remain elusive. Randomized, controlled trials are difficult to mount in a population that is so sick, so heterogeneous, and from whom it is so difficult to obtain informed consent. In fact, a recent survey by Jackson and Lipman54 found only one randomized, controlled trial of pharmacotherapy in delirium, which was conducted in patients with acquired immunodeficiency syndrome.55

Historically, the emphasis has been on sedating the patient with delirium, based on the belief that delirium was a disorder of sleep and that rest would be restorative. From the ancient Greeks through the era of Osler, the emphasis was on the use of opiates.1 This tendency to favor sedatives (nowadays, lorazepam and similar agents) remains quite prevalent among practitioners,56 although sedatives can precipitate delirium37 and are less effective than neuroleptics such as haloperidol.55 The current understanding, embodied within the DSM-IV, that delirium is primarily a disorder of attention, should help discourage the use of sedative drugs to manage the disorder. Despite the growing popularity of atypical antipsychotic agents, no controlled studies have demonstrated their superiority in delirious patients.

Delirium often co-occurs with dementia, and both disorders are characterized by failures of cholinergic transmission. The literature includes case reports of delirium reversal with cholinesterase inhibitors such as donepezil,57 but, given the fluctuating and unpredictable nature of delirium, it is difficult to derive treatment recommendations from such limited evidence. Cholinesterase inhibitors are also reported to precipitate delirium, so caution is advised.58

It has long been assumed that the outcome of delirium could be improved by earlier identification of the disorder and comprehensive intervention to treat underlying causes and prevent subsequent complications, such as immobility, aspiration, and skin breakdown.7 Unfortunately, there are few controlled studies, and these show that early identification and comprehensive geriatric consultation for patients with established delirium has little impact on length of stay, functional outcomes, or survival.59

There has been somewhat more progress on developing multidisciplinary, multicomponent interventions to prevent delirium. Conceptually, these interventions were based on the understanding of multiple risk factors that emerged following the publication of prospective clinical studies conducted after the introduction of the DSM-III, as well as emerging evidence in the early 1990s about the effectiveness of comprehensive geriatric assessment and management in preventing functional and cognitive decline.60

One of the earliest of these studies,61 which used historical controls, involved geriatric consultation in patients undergoing surgery for femoral neck fractures. Delirium incidence was reportedly reduced from 61% to 48%.61 Stabilization of medical problems (eg, hypoxemia) and avoidance of anticholinergic drugs were two important components of the intervention.

More recently, in a randomized, controlled trial,62 a similar intervention in the hip fracture population was shown to reduce delirium incidence from 50% to 32% and to reduce delirium severity in those who experienced the complication despite the intervention.62 In a setting of general medical patients, a multicomponent intervention63 to address targeted risk factors (including visual and hearing impairment, sleep deprivation, dehydration, immobility, and cognitive impairment) through standardized interventions initiated by nurse specialists, therapists, and trained volunteers reduced the incidence of delirium from 15% to 10%.63 Although this regimen was intensive, the high costs and length of stay associated with delirium may make it cost effective when applied to patients with intermediate risk for delirium.64 Of some concern, however, was the fact that outcomes 6 months later were no different between groups.65 Delirium is a marker of frailty66 that demands comprehensive intervention and follow-up well past the acute hospitalization.

Although the patient safety movement is of comparatively recent origin, studies of iatrogenic illness done many decades ago found delirium to be the one of the most common complications of hospitalization.67 It is surprising that the patient safety movement and accrediting bodies such as the Joint Commission on Accreditation of Healthcare Organizations have not yet embraced delirium, despite the fact that system failure is such a prominent feature of the disorder.68 Exploratory studies of new care models for at-risk or frankly delirious patients are only now emerging,69 and further work is likely due to the tremendous resources consumed by patients with delirium.

Conclusion

The study of delirium is as old as the history of medicine itself, yet the most significant progress has only been possible as delirium’s nosology, phenomenology, and epidemiology were more precisely delineated in the past 2 decades. Physicians have learned much over that period, but remain frustrated in the ability to translate that knowledge into effective, evidence-based treatments. This reflects, in part, the very complexity of delirium and the multiple underlying conditions found in patients suffering from it.

Predicting the future is risky, but three trends appear likely based on the trajectory outlined in this article. First, it is reasonable to expect, based on demographic and economic concerns, that there will be increasing interest in finding cost-effective ways to prevent delirium in acute hospital settings. Few conditions will match delirium as a threat to patient safety and health system performance. Secondly, time pressures and staff shortages are likely to increase, which will heighten the importance of brief, systematic screening of cognitive status. Delirium screening hopefully will follow the path established for the identification of pain and become the “sixth vital sign” for all acutely ill patients. Finally, advances in noninvasive, functional neurodiagnosis and neuroimaging, which have elucidated mechanisms of other psychiatric conditions, will be applied increasingly to delirium, and may pave the way for targeted therapies to reverse the manifestations and improve functional outcomes in patients with established delirium. PP

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Dr. Francis is associate director of Health Services Research and Development (HSR&D), Quality Enhancement Research Initiative (QUERI), at the Department of Veterans Affairs in Washington, DC.

Disclosure: The author reports no financial, academic, or other support of this work.

Please direct all correspondence to: Joseph Francis Jr, MD, MPH, Associate Director, HSR&D (124Q), QUERI, Department of Veterans Affairs, 810 Vermont Ave, NW, Washington, DC 20420; Tel: 202-254-0207; Fax: 202-254-0461; E-mail: joe.francis@hq.med.va.gov.