Key components of the delirium syndrome and mortality: greater impact of acute change and disorganised thinking in a prospective cohort study

Background Delirium increases the risk of mortality during an acute hospital admission. Full syndromal delirium (FSD) is associated with greatest risk and subsyndromal delirium (SSD) is associated with intermediate risk, compared to patients with no delirium – suggesting a dose-response relationship. It is not clear how individual diagnostic symptoms of delirium influence the association with mortality. Our objectives were to measure the prevalence of FSD and SSD, and assess the effect that FSD, SSD and individual symptoms of delirium (from the Confusion Assessment Method-short version (s-CAM)) have on mortality rates. Methods Exploratory analysis of a prospective cohort (aged ≥70 years) with acute (unplanned) medical admission (4/6/2007–4/11/2007). The outcome was mortality (data censored 6/10/2011). The principal exposures were FSD and SSD compared to no delirium (as measured by the CAM), along with individual delirium symptoms on the CAM. Cox regression was used to estimate the impact FSD and SSD and individual CAM items had on mortality. Results The cohort (n = 610) mean age was 83 (SD 7); 59% were female. On admission, 11% had FSD and 33% had SSD. Of the key diagnostic symptoms for delirium, 17% acute onset, 19% inattention, 17% disorganised thinking and 17% altered level of consciousness. Unadjusted analysis found FSD had an increased hazard ratio (HR) of 2.31 (95% CI 1.71, 3.12), for SSD the HR was 1.26 (1.00, 1.59). Adjusted analysis remained significant for FSD (1.55 95% CI 1.10, 2.18) but nonsignificant for SSD (HR = 0.92 95% CI 0.70, 1.19). Two CAM items were significantly associated with mortality following adjustment: acute onset and disorganised thinking. Conclusion We observed a dose-response relationship between mortality and delirium, FSD had the greatest risk and SSD having intermediate risk. The CAM items “acute-onset” and “disorganised thinking” drove the associations observed. Clinically, this highlights the necessity of identifying individual symptoms of delirium.


Background
Delirium is an acute neuropsychiatric syndrome affecting around 25% of general hospital patients aged over 65 years [1][2][3][4]. It is characterised by acute onset and fluctuating course of disturbed attention, consciousness, orientation, memory, arousal and, behaviour, and alterations in perception and sleep cycle [5].
The aetiology of delirium is complex and multifactorial, including causes such as infection, sleep deprivation, pain, specific organ failures and metabolic disturbances [1,[6][7][8]. Each individual's threshold for delirium differs depending on predisposing risk factors such as age and frailty.
Many operational definitions exist for delirium, including formal classifications in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and algorithms such as the Confusion Assessment Method (CAM) [9]. Intermediate states, subsyndromal delirium (SSD), can be defined where individuals have symptoms of delirium but insufficient to meet the criteria for full syndromal delirium (FSD) [10].
FSD is associated with a number of poor outcomes, such as longer hospital stays, increased risk of posthospital institutionalisation post-discharge, and accelerated cognitive decline [3,8,[11][12][13][14]. FSD carries its own risk of death, independent of an individual's exposure to established risk factors [3,[15][16][17][18]. The literature on SSD and adverse outcomes is less conclusive, partly because of variable definitions of SSD in relation to symptom clusters and/or severity [10,19,20].
It is possible that a dose-response relationship between FSD and mortality operates, such that SSD carries intermediate risk [21]. However, this has often not been systematically evaluated in the same cohort, using standardised definitions and maximally adjusting for a wide range of acute and chronic health factors [19]. It is also not clear whether specific delirium symptoms drive the mortality relationship observed. In particular, no studies have estimated mortality rates associated with individual diagnostic items from rating scales such as the CAM.
Our objectives were to: (1) examine the prevalence of FSD and SSD in a representative cohort of older acute hospital inpatients over the age of 70 years; (2) estimate the impact of FSD and SSD (as measured by the short CAM (s-CAM) on admission) on mortality rates and (3) assess the impact individual key diagnostic items on the s-CAM have on this relationship.

Design
We undertook an exploratory retrospective analysis of data collected on a cohort of older people with acute medical illness admitted into hospital between 4/6/2007 to 4/ 11/2007. Characteristics of the cohort have been described previously [22]. In brief, participants were eligible for inclusion if they were: ≥70 years old with an unplanned medical admission who were admitted >48 h. All clinical assessments were conducted by psychiatrists within 72 h of admission. Participants who lacked English language skills necessary to complete basic cognitive assessments were excluded. We sought verbal consent from participants or, if they lacked capacity to consent, verbal assent from their carers. The study involved the collection of routine clinical data that has subsequently been fully anonymised. The findings of these assessments were documented on the medical notes so that clinical teams could act on them if they wished. The exclusion of patients unable to give written informed consent or those without a relative to give assent for their participation may have caused selection bias, excluding the patient population we wished to study. The study and its verbal consent procedure was approved by the Royal Free Hospital NHS Trust Ethics Committee (06/Q0501/31).

Outcome
Mortality was flagged by the UK Office for National Statistics (ONS) (mortality data censored 6/10/2011).

Main exposures Delirium
Participants were assessed using the Confusion Assessment Method, short version (s-CAM), which details the following delirium features: (1) acute onset, (2) inattention, (3) disorganised thinking, (4) altered level of consciousness [23]. The s-CAM has high sensitivity of >94% and specificity >90% for the detection of delirium and accurately distinguishes between delirium and dementia [24]. FSD was defined as persons demonstrating abnormalities in features 1 + 2 + (3 or 4). SSD was defined as having one or more s-CAM symptoms, but not fulfilling criteria for FSD. All participants without symptoms of FSD or SSD were defined as 'no delirium'.

Covariates
Demographic data (age, sex, place of residence, ethnic origin and marital status) was collected from hospital records. Other assessments included the Charlson Co-morbidity Index [25,26], Waterlow Scale [27] and a modified version of the Acute Physiology and Chronic Health Evaluation (APACHE II) [28][29][30] (omitting the arterial blood gas). Severity of functional impairment prior to hospital admission was gathered from next of kin or other carers using the Functional Assessment Staging Scale (FAST) [31].

Data analysis
Differences in categorical and continuous variables according to delirium status were assessed using chisquare, ANOVA and Kruskal Wallis tests as appropriate. Continuous variables with skewed data (CCI and APACHE II scores) were categorised into standard quartiles for the final analysis.
Survival estimates for FSD, SSD and no delirium were compared using Kaplan-Meier curves and log-rank tests. Cox regression was used to examine the relationship between FSD, SSD and no delirium with mortality risk, sequentially adjusting for relevant confounders in a multivariable model. Finally, the relationship between each CAM criterion and mortality was estimated in the whole cohort, irrespective of syndromal status.
Proportional hazard assumptions were met for all Cox regression analyses, confirmed by Schoenfeld Residuals ≥0.05. Finally, candidate prediction models were compared using Harrell's c statistics. Data were analysed using STATA version 12.
Mean age was 83 (sd 7) and over half were female (59%). A majority of the participants lived in their home (71%) and were of White British origin (70%) ( Table 1).
Prevalence of FSD and SSD increased with age, though there was no association with gender. FSD and SSD became more prevalent as age increased. Participants with FSD and SSD were more likely to live in nursing or sheltered accommodation. There was an overall higher prevalence of having a pre-existing dementia diagnosis, higher Waterlow scores, higher APACHE II scores and greater length of hospital stay.
After sequential adjustment for age, sex, CCI, Waterlow and APACHE II, acute onset (HR 1.41 95% CI 1.07, 1.86) and disorganised thinking (HR 1.42 95% CI 1.05, 1.92) were associated with mortality, whereas this was no longer the case for estimates for inattention (HR 1.24 95% CI 0.92, 1.67) and altered level of consciousness (HR 1.33 95% CI 0.98, 1.79). C-statistics for all models were very close (0.66 to 0.67), suggesting comparable predictive ability for this set of variables (Table 3).

Discussion
We demonstrated a dose-response relationship between SSD, FSD and mortality, even after adjustment for a wide range of acute and chronic health factors. Individual s-CAM items contribute differentially to this relationship; acute onset and disorganised thinking appear to drive the association. Taken together, these findings emphasise that neurocognitive symptoms that arise in the context of acute illness in older people identified individuals at higher risk for dying.
This study had several strengths. The large cohort size and prospective data in a diverse socio-economic and ethnic population benefited from standardised assessments by experts and automatic notification of deaths from the UK Office of National Statistics. Data was collected within a 72 h time-period after admission so it is not possible to establish whether cases of delirium were prevalent or incident and although the s-CAM has been shown to have good interrater reliability of 0.81-1.00 [32] we do not have data on this for our study. In keeping with other studies, limitations include the possibility of residual confounding. We identified FSD and SSD at a prevalence and associated with adverse outcomes consistent with the range established from systematic reviews [1,2].
Participants with SSD had outcomes intermediate to those with no delirium and FSDparticularly in relation to acute illness severity, poor prognosis and outcomes, suggesting a dose-response relationship between delirium severity and mortality risk, which is in keeping with previous work [19,21]. However, few other studies have been able to establish these associations while also accounting for a wide range of acute and chronic health factors.
There is little literature exploring the individual mortality risk associated with each key symptom of delirium. We found each individual item on the short s-CAM was significantly associated with mortality, though acute onset and disorganised thinking had  Percentage of eligible patients and 95% confidence intervals stratified into survival time less than or more than 6 months following hospital admission. Death was flagged by the UK Office of National Statistics and certified by a death certificate. Median length and 95% confidence intervals for survival time was calculated following hospital admission. Complete case = 357 <, less than; >, more than; NA not available greater risk of mortality when all items were mutually adjusted.
A number of underlying mechanisms may explain the observed dose-response relationship between delirium and mortality. The causes of delirium can persist, which itself could lead to protracted delirium, prolonged hospital stays [15], and increased risk of death [33]. In turn, longer hospital stays could expose patients to a greater risk of iatrogenic harm [34,35] for example: participants with hypoactive delirium have a greater risk of aspiration pneumonia, whereas participants with hyperactive delirium have greater risk of falls [36,37] which in turn could cause longer hospital stays, further health deterioration and greater risk of death. Disorganised thinking could be a particularly adverse symptom because it may represent more profound neurocognitive disturbance particularly detrimental in frail, older participants predisposed to chronic and severe physical illness [3,[38][39][40].

Conclusions
Emergency admission of an older patient presenting with FSD or SSD is a strong potential indicator of risk of death. Clinically it is important to be aware that each key symptom of FSD is strongly related to death, and participants presenting with just one symptom still carry an increased riskhighlighting the necessity of recognising each symptom separately. Better awareness of the mortality risk associated with delirium would strengthen arguments for early intervention, better treatment and quality of care, considering care plans and encouragement of discussion of prognosis with the patient and/or carer.