Pathoetiological Model of Delirium: a Comprehensive Understanding of the Neurobiology of Delirium and an Evidence-Based Approach to Prevention and Treatment

doi:10.1016/j.ccc.2008.06.004

Critical Care Clinics

Volume 24, Issue 4, October 2008, Pages 789-856

https://doi.org/10.1016/j.ccc.2008.06.004 Get rights and content

Delirium is the most common complication found in the general hospital setting. Yet, we know relatively little about its actual pathophysiology. This article contains a summary of what we know to date and how different proposed intrinsic and external factors may work together or by themselves to elicit the cascade of neurochemical events that leads to the development delirium. Given how devastating delirium can be, it is imperative that we better understand the causes and underlying pathophysiology. Elaborating a pathoetiology-based cohesive model to better grasp the basic mechanisms that mediate this syndrome will serve clinicians well in aspiring to find ways to correct these cascades, instituting rational treatment modalities, and developing effective preventive techniques.

Section snippets

Aging: acetylcholine, vascular supply, and delirium

Human studies have revealed that the cholinergic system is widely involved in arousal, attention, memory, and rapid-eye-movement (REM) sleep. A deficiency of cholinergic function relative to that of other neurotransmitters can be expected to alter the efficiency of these mental mechanisms [17]. In fact, one leading hypothesis is that delirium results from an impairment of central cholinergic transmission [18], [19], [20]. Low levels of acetylcholine (ACh) in plasma and cerebrospinal fluid (CSF)

Common pathways

At the end, it may very well be that all the known etiologic “factors” for the development of delirium may all act by similar mechanisms, namely causing changes to neuronal membrane function, which in turn leads to a number of neurotransmitter aberrations. Affected neurons begin to experience abnormalities of membrane function and polarization. This may lead to a domino-like effect known as “spreading depression” by which, as one neuron looses membrane integrity and stability, neighboring

Theoretic implications for prevention and treatment options

This is meant to be a theoretic treatise on the prevention and management of delirium. For a more clinical approach, please see Maldonado JR, Delirium in the Acute Care Setting: Characteristics, Diagnosis and Treatment, 2008 [384].

Future directions

Given the complexities already described and the multiple pathways and mechanisms that likely “go wrong together” or “cause a domino-like” effect, it would make sense to consider a treatment strategy that addresses all these factors simultaneously. Unfortunately, there are very limited data to support any of these approaches, let alone in combination. But only well-designed treatment trials will be able to determine whether the theory bears out in clinical success. The basic approach of

Summary

Delirium is an acute or subacute organic mental syndrome characterized by disturbance of consciousness, cognition, orientation, attention, psychomotor activity, sleep-wake cycle, and behavior. Delirium is likely to be the most common and the most serious complication in the medically ill, particularly the elderly and the critically ill. Not only does it cause distress to patients, families, and medical caregivers, but its presence is associated with increased morbidity and mortality, prolonged

Acknowledgment

The author thanks Emma Bakes, MS for her assistance in locating, reviewing and helping select many of the papers referenced throughout the manuscript. The author also acknowledges the thoughtful suggestions of Gregory Kapinos, MD particularly in the area of hypoxia & hypoperfusion, as well as his critique of the original manuscript.

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Incidence of confusional syndrome (delirium) in a Latin American university hospital
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Determinar la incidencia del delirio, la frecuencia de los subtipos motores y los factores asociados en pacientes hospitalizados en diferentes servicios de un hospital universitario en Bogotá, Colombia.
Se dio seguimiento a una cohorte de pacientes mayores de 18 años hospitalizados en los servicios de Medicina Interna, Geriatría, Cuidado Intensivo, Cirugía General y Ortopedia de un hospital universitario entre enero y junio de 2018. Para identificar la presencia de delirio, se utilizó la escala CAM (Confusion Assessment Method) y la CAM-ICU si el paciente presentaba disminución de las capacidades de comunicación. El subtipo de delirio se caracterizó utilizando la escala RASS (Richmond Agitation and Sedation Scale). Los pacientes fueron valorados el día de ingreso y luego cada 2 días hasta su alta hospitalaria. Se derivó a los pacientes en quienes se identificó delirio para tratamiento especializado interdisciplinario intrainstitucional.
Se evaluó a 531 pacientes que ingresaron durante ese periodo a los servicios mencionados. La incidencia global del delirio fue del 12% (IC95%, 0,3-14,8). En orden descendiente, el 31,8% de los pacientes hospitalizados en el servicio de Geriatría, el 15,6% en Cuidado Intensivo, el 8,7% en Medicina Interna, el 5,1% en Ortopedia y el 3,9% en Cirugía. El subtipo motor más frecuente fue el mixto (60,9%), seguido por el normoactivo (34,4%) y el hipoactivo (4,7%). Los factores asociados con la incidencia del delirio fueron la edad (RR ajustada = 1,07; IC95%, 1,05-1,09), la presencia de 4 o más comorbilidades (RR ajustada = 2,04; IC95%, 1,31-3,20) y la hospitalización en Cuidado Intensivo (RR ajustada = 2,02; IC95%, 1,22-3,35).
La incidencia del delirio es heterogénea en los diferentes servicios del hospital universitario. La mayor incidencia se presentó en pacientes ingresados en el servicio de Geriatría; el subtipo más frecuente fue el mixto y los principales factores asociados fueron la edad, la presencia de 4 o más comorbilidades y la hospitalización en Cuidado Intensivo.
Little is known about the incidence of delirium and its subtypes in patients admitted to different departments of university hospitals in Latin America.
To determine the incidence of delirium and the frequency of its subtypes, as well as its associated factors, in patients admitted to different departments of a university hospital in Bogotá, Colombia.
A cohort of patients over 18 years of age admitted to the internal medicine (IM), geriatrics (GU), general surgery (GSU), orthopaedics (OU) and intensive care unit (ICU) services of a university hospital was followed up between January and June 2018. To detect the presence of delirium, we used the CAM (Confusion Assessment Method) and the CAM-ICU if the patient had decreased communication skills. The delirium subtype was characterised using the RASS (Richmond Agitation and Sedation Scale). Patients were assessed on their admission date and then every two days until discharged from the hospital. Those in whom delirium was identified were referred for specialised intra-institutional interdisciplinary management.
A total of 531 patients admitted during the period were assessed. The overall incidence of delirium was 12% (95% CI, 0.3-14.8). They represented 31.8% of patients in the GU, 15.6% in the ICU, 8.7% in IM, 5.1% in the OU, and 3.9% in the GSU. The most frequent clinical display was the mixed subtype, at 60.9%, followed by the normoactive subtype (34.4%) and the hypoactive subtype (4.7%). The factors most associated with delirium were age (adjusted RR = 1.07; 95% CI, 1.05-1.09), the presence of four or more comorbidities (adjusted RR = 2.04; 95% CI, 1.31-3.20), and being a patient in the ICU (adjusted RR = 2.02; 95% CI, 1.22-3.35).
The incidence of delirium is heterogeneous in the different departments of the university hospital. The highest incidence occurred in patients that were admitted to the GU. The mixed subtype was the most frequent one, and the main associated factors were age, the presence of four or more comorbidities, and being an ICU patient.
Efficacy and moderators of prevention and treatment of delirium with melatonin receptor agonists: A systematic review and meta-analysis of randomized controlled trials
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Delirium is a complex and heterogeneous condition that significantly affects patient outcome. This study aimed to conduct a systematic review and meta-analysis to investigate the effects of melatonin and melatonin receptor agonists (MRAs) on delirium prevention and treatment.
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View all citing articles on Scopus

: Parts of the article were presented at the annual meetings of the Academy of Psychosomatic Medicine, Fort Myers, FL, November 9, 2004; the Canadian Academy of Psychosomatic Medicine (CAPM), Toronto, Canada. November 10, 2006; and. U.S. Psychiatric Congress & Mental Health Congress, Orlando, Florida, October 12, 2007.

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Pathoetiological Model of Delirium: a Comprehensive Understanding of the Neurobiology of Delirium and an Evidence-Based Approach to Prevention and Treatment

Section snippets

Aging: acetylcholine, vascular supply, and delirium

Common pathways

Theoretic implications for prevention and treatment options

Future directions

Summary

Acknowledgment

J Chronic Dis

Psychiatr Clin North Am

Clin Geriatr Med

J Cardiothorac Vasc Anesth

Am J Geriatr Psychiatry

A need to focus our research. Psychosomatics

Neurosci Lett

J Biol Chem

Exp Neurol

Biochem Pharmacol

Lancet

Psychosomatics

Brain Res

Brain Res

Rev Mal Respir

Brain Res

Psychosomatics

Psychosomatics

J Pain Symptom Manage

Am J Geriatr Psychiatry

Am J Med

Pain

J Pain Symptom Manage

Pain

Prog Neuropsychopharmacol Biol Psychiatry

Brain Res Bull

Basic mechanisms in the pathogenesis of delirium

Delirium in hospitalized older persons: outcomes and predictors

J Am Geriatr Soc

Clarifying confusion: the confusion assessment method. A new method for detection of delirium

Ann Intern Med

The impact of delirium in the intensive care unit on hospital length of stay

Intensive Care Med

Delirium in hospitalized older patients: recognition and risk factors

J Geriatr Psychiatry Neurol

Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit

Jama

Delirium. The occurrence and persistence of symptoms among elderly hospitalized patients

Arch Intern Med

Costs associated with delirium in mechanically ventilated patients

Crit Care Med

Acute delirium and functional decline in the hospitalized elderly patient

J Gerontol

The prognostic significance of delirium in older hospital patients

J Am Geriatr Soc

A prospective study of delirium in hospitalized elderly

Jama

Performance improvement: increasing recognition and treatment of postoperative delirium

Prog Cardiovasc Nurs

Impaired synthesis of acetylcholine in brain accompanying mild hypoxia and hypoglycemia

J Neurochem

Neural mechanisms of delirium: current hypotheses and evolving concepts

J Gerontol A Biol Sci Med Sci

Delirium in the elderly

J Geriatr Psychiatry Neurol

Endogenous anticholinergic substances may exist during acute illness in elderly medical patients

J Gerontol A Biol Sci Med Sci

Association of elevated plasma anticholinergic activity with delirium in surgical patients

Am J Psychiatry

Anticholinergic Model For Delirium

Semin Clin Neuropsychiatry

Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine

Semin Clin Neuropsychiatry

Anticholinergic delirium caused by topical homatropine ophthalmologic solution: confirmation by anticholinergic radioreceptor assay in two cases. J Neuropsychiatry Clin Neurosci

Acetylcholine and delirium

Dement Geriatr Cogn Disord

Confusion/delirium following cataract surgery: an incidence study of 1-year duration

Int Psychogeriatr

Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients

Anesthesiology

Subtle attentional deficits in the absence of dementia are associated with an increased risk of post-operative delirium

Dement Geriatr Cogn Disord