Contributed by Zoë Tieges, PhD, Psychology Research Fellow, Geriatric Medicine, Usher Institute, The University of Edinburgh, Edinburgh, UK
Research question: do patients with delirium experience poorer outcomes when they have certain symptoms?
Delirium is a syndrome with a wide spectrum of clinical presentations. According to DSM-5 (and the recent DSM-5 Text Revision) criteria, the key diagnostic features of delirium are attention deficits and an acute onset of symptoms, typically developing over the course of a few hours to days. However, we know that delirium may present with additional disturbances in level of arousal (from reduced responsiveness and drowsiness to hypervigilance and severe agitation), orientation (awareness of time, place and person), visuospatial ability, thought process (disorganised thinking), and so on. Patients may also experience symptoms of psychosis, including hallucinations and delusions, which can be very distressing.1
It has been well established that a diagnosis of delirium in hospital is independently associated with poor outcomes, including a 2-fold risk of mortality, longer stay in hospital, new institutionalisation and an 8-fold increased risk of new dementia.2, 3 Delirium severity scores may also predict outcomes4 although the evidence to support this relationship remains mixed.5 Importantly, there remains uncertainty as to how the individual symptom domains of delirium, including attention deficits and altered arousal, are linked to adverse patient outcomes. In other words, it is largely unclear whether specific symptoms drive the observed association between delirium and patient outcomes.
Our systematic review and meta-analysis
In this context, we performed a systematic review, published in BMC Geriatrics in 2021, which synthesized the available evidence examining the associations between delirium symptom domains and patient outcomes.6 Our primary outcome was 30-day mortality, but we also considered mortality at other time points, as well as length of hospital stay and dementia. There were no restrictions on language or study design, and in addition to an inclusive search strategy, we contacted delirium researchers around the world in order to identify unpublished work. We included studies involving patients aged 18 and over in non-intensive care units, which used a validated delirium screening or rating system, and which reported on associations between symptom domains of delirium (attention deficits, altered arousal, psychotic features, etc.) and our primary outcome mortality.
We screened 7092 citations, reviewed the full texts of 97 records and included seven articles reporting six studies with a total of 6002 patients; 1112 (18.5%) of these patients had delirium.7-12 All six studies were cohort studies, published between 2013 and 2020 from the USA, UK, Italy and Brazil. Various comparison groups were used in the original studies: non-delirious patients, patients (both with and without delirium) who did not display the relevant symptom domain, or delirious patients without the relevant symptom.
Altered arousal was assessed in five studies using the short CAM (s-CAM; ‘level of consciousness’ item), the Glasgow Coma Scale,13 and/or the Observational Scale for Level of Arousal (OSLA).14 Exploratory random-effects meta-analysis showed that the presence of altered level of arousal, compared to normal arousal, was associated with a 2.8-fold higher risk of mortality (95% Confidence Interval (CI) 2.33-3.37), with follow-up time points ranging from 30 days to 12 months. The quality of evidence was low to moderate. One study found that altered arousal (measured with the OSLA) in itself was a stronger indicator of mortality than a diagnosis of delirium,11 suggesting that this feature may have prognostic value over and above diagnostic classification.
Attention deficits were measured in three studies using a computerised test of sustained and focused attention implemented on the Edinburgh Delirium Test Box (separate from the reference standard delirium assessment )counting backwards from 20 to 1 and the Months of the Year Backwards test,9 or patient observation (as part of the s-CAM).10 Results from the meta-analysis showed that attention deficits (pooled across patients with and without delirium) associated with delirium conferred a 2.57-fold higher risk of mortality (95% CI 1.74-3.80) ranging from in-hospital mortality to follow-up beyond 12 months (low quality of evidence). Importantly, only one of the three studies (with a sample of N=2521 acute geriatric and medical older patients) reported an association between attention deficits in older delirious patients and in-hospital mortality (OR 3.26, 95% CI 2.03–5.24) compared to a non-delirious group.9 However, the delirium prevalence in this study was only 2.9%, whereas deficits of attention were found in 35.4% of patients. This strongly suggests that delirium was poorly documented and that some patients with delirium may have been misclassified as non-delirious. This, in turn, could have resulted in a decrease in the size of the association seen with outcome.
The evidence for the association between other symptom domains of delirium and mortality, or other outcomes, was sparse. In single studies, where presence of disorientation, memory deficits and disorganised thinking was assessed, an association between these symptom domains and higher mortality was found. We found no studies which collected data on the association between psychotic features, visuospatial impairments or affective disturbances in delirium, or studies reporting on other outcomes than mortality.
Overall, the evidence regarding the association between symptom domains in delirium and mortality and other patient outcomes is small and inconclusive. One notable study limitation was that studies differed with regards to the comparison group used. We did not carry out subgroup analyses because insufficient data on subgroups were available, and it was therefore not possible to distinguish the impact of the individual delirium symptom domains versus the overall impact of a delirium diagnosis. Including non-delirious patients in the comparisons may be problematic because this comparison may be confounded by the presence of delirium itself, and the prognostic significance of features such as attention deficits and altered arousal may be very different in the context of delirium versus no delirium. Thus, whilst our findings suggest that individual symptom domains of delirium may have prognostic value, particularly level of arousal, this needs to be confirmed in future studies. Of interest, a systematic review in hospitalised patients found that those with altered arousal had an adjusted 6-fold increased mortality risk, despite none of the studies taking delirium into account.15
Where do we go from here?
We need a better understanding of the delirium symptom domains (if any) that drive the association between delirium and patient outcomes. In other words, are there particular symptom domains that put a delirious patient at increased risk of death or other negative outcomes? Such information would be extremely useful in guiding discussions on prognosis and management, developing better delirium assessment tools, and refining operationalisations of delirium.
To this end, we should report the symptom domain scores more explicitly and consistently, as well as the assessment tools used (including scoring systems). Many symptom domains are commonly assessed as part of delirium assessment tools such as the 3D-CAM16 and the DRS-R98,17 but scores on individual test items are rarely reported. Another issue is that determining the presence of individual features of delirium is largely based on the interviewer’s subjective impression following informant history, observation and interview.18, 19 Additionally, standardisation of methods for measuring and reporting delirium symptom domains will facilitate progress in this area of research. At present, many symptoms of delirium lack clear operational definitions. For example, there is no consensus on how to operationalise ‘visuospatial ability’ and ‘disorganised thinking’ in the context of delirium, and to some extent, this is also true for the core deficit of attention. These issues present a continuing challenge to the study of delirium.
The degree (or intensity/severity) of disturbances in arousal, attention and other symptom domains was not considered in the reviewed studies. Some grading of the extent of individual disturbances may add additional prognostic information beyond a binary score (i.e., absent/present) but requires further research. This approach requires tools which provide graded scores reflecting the degree of impairment. For example, the DelApp, a smartphone-based test of attention which was purposely designed for assessing the presence and degree of arousal disturbance and attention deficits in delirium provides a score of 0-10.20 Further, a more in-depth analysis of triggers and consequences of individual delirium features might shed light on underappreciated benefits of interventions for delirium.19 Future studies should also consider other serious consequences of delirium, such as emotional distress, anxiety and depression, and health-related quality of life. 21
Our review, while only a small step forward in better understanding the relationship between key symptom domains of delirium and outcomes, will hopefully provide a foundation for future work. The steadily increasing volume of potentially available high-quality data on delirium and patient outcomes, along with large-scale routine and clinical implementation data, can be leveraged for advancing the delirium research agenda. Further, exploiting data science tools to extract meaning from such large volumes of data has the potential to accelerate progress in this important research area.
- Wilson JE, Mart MF, Cunningham C, Shehabi Y, Girard TD, MacLullich AMJ, Slooter AJC, Ely EW: Delirium. Nat Rev Dis Primers 2020, 6(1):90.
- Davis DH, Muniz Terrera G, Keage H, Rahkonen T, Oinas M, Matthews FE, Cunningham C, Polvikoski T, Sulkava R, MacLullich AM et al: Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain 2012, 135:2809-2816.
- Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA: Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA 2010, 304(4):443-451.
- Jackson TA, Wilson D, Richardson S, Lord JM: Predicting outcome in older hospital patients with delirium: a systematic literature review. Int J Geriatr Psychiatry 2016, 31(4):392-399.
- Rosgen BK, Krewulak KD, Stelfox HT, Ely EW, Davidson JE, Fiest KM: The association of delirium severity with patient and health system outcomes in hospitalised patients: a systematic review. Age Ageing 2020, 49(4):549-557.
- Tieges Z, Quinn T, MacKenzie L, Davis D, Muniz-Terrera G, MacLullich AMJ, Shenkin SD: Association between components of the delirium syndrome and outcomes in hospitalised adults: a systematic review and meta-analysis. BMC Geriatr 2021, 21(1):162.
- Jackson TA, McCluskey L, Davis D, MacLullich AMJ, Gladman JR, Sheehan B, Lord JM: Clinical and biological features of delirium and their predictive effects on outcome; a prospective cohort study. In: British Geriatrics Society Communications to the Autumn Meeting: 1 April 2018 2017; London, UK. Age and Ageing: ii21–ii22.
- Han JH, Brummel NE, Chandrasekhar R, Wilson JE, Liu X, Vasilevskis EE, Girard TD, Carlo ME, Dittus RS, Schnelle JF et al: Exploring Delirium’s Heterogeneity: Association Between Arousal Subtypes at Initial Presentation and 6-Month Mortality in Older Emergency Department Patients. Am J Geriatr Psychiatry 2017, 25(3):233-242.
- Bellelli G, Nobili A, Annoni G, Morandi A, Djade CD, Meagher DJ, Maclullich AM, Davis D, Mazzone A, Tettamanti M et al: Under-detection of delirium and impact of neurocognitive deficits on in-hospital mortality among acute geriatric and medical wards. Eur J Intern Med 2015, 26(9):696-704.
- Diwell RA, Davis DH, Vickerstaff V, Sampson EL: Key components of the delirium syndrome and mortality: greater impact of acute change and disorganised thinking in a prospective cohort study. BMC Geriatr 2018, 18(1):24.
- Hall RJ, Davis D, Tieges Z, MacLullich AMJ: Do level of arousal or inattention predict mortality at one year? In: 8th annual meeting of the European Delirium Association Leuven, Belgium. 2013.
- Garcez FB, Jacob-Filho W, Avelino-Silva TJ: Association Between Level of Arousal and 30-Day Survival in Acutely Ill Older Adults. J Am Med Dir Assoc 2020, 21(4):493-499.
- Teasdale G, Jennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 1974, 2(7872):81-84.
- Hall R, Stiobhairt A, Allerhand M, MacLullich AMJ, Tieges Z: The Observational Scale of Level of Arousal: A brief tool for assessing and monitoring level of arousal in patients with delirium outside the ICU. International Journal of Geriatric Psychiatry 2020, 35(9):1021-1027.
- Todd A, Blackley S, Burton JK, Stott DJ, Ely EW, Tieges Z, MacLullich AMJ, Shenkin SD: Reduced level of arousal and increased mortality in adult acute medical admissions: a systematic review and meta-analysis. BMC Geriatr 2017, 17(1):283.
- Marcantonio ER, Ngo LH, O’Connor M, Jones RN, Crane PK, Metzger ED, Inouye SK: 3D-CAM: derivation and validation of a 3-minute diagnostic interview for CAM-defined delirium: a cross-sectional diagnostic test study. Ann Intern Med 2014, 161(8):554-561.
- Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N: Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci 2001, 13(2):229-242.
- Tieges Z, Evans JJ, Neufeld KJ, MacLullich AMJ: The neuropsychology of delirium: advancing the science of delirium assessment. International Journal of Geriatric Psychiatry 2018, 33(11):1501-1511.
- MacLullich AMJ, Hosie A, Tieges Z, Davis DHJ: Three key areas in progressing delirium practice and knowledge: recognition and relief of distress, new directions in delirium epidemiology and developing better research assessments. Age Ageing 2022, 51(11).
- Tieges Z, Stott DJ, Shaw R, Tang E, Rutter LM, Nouzova E, Duncan N, Clarke C, Weir CJ, Assi V et al: A smartphone-based test for the assessment of attention deficits in delirium: A case-control diagnostic test accuracy study in older hospitalised patients. PLoS ONE [Electronic Resource] 2020, 15(1):e0227471.
- Rose L, Burry L, Agar M, Blackwood B, Campbell NL, Clarke M, Devlin JW, Lee J, Marshall JC, Needham DM et al: A core outcome set for studies evaluating interventions to prevent and/or treat delirium for adults requiring an acute care hospital admission: an international key stakeholder informed consensus study. BMC Med 2021, 19(1):143.