Summary of findings

This systematic review and meta-analysis demonstrates that acute medical patients with reduced level of arousal on admission to hospital have a substantially higher risk of mortality compared with those with normal or heightened level of arousal. The meta-analysis, performed using 14 of the 21 studies, found reduced level of arousal was associated with a 5.7-fold increased risk of in-hospital mortality. We felt it was important to perform a meta-analysis on these studies to confirm the underlying effect size. Sensitivity analysis including only those studies using GCS- the most widely used clinical arousal test, which has been in use without change for several decades- confirmed the direction of the observed effect with a pooled OR of 9.16. This was performed to reduce the degree of heterogeneity but note significant clinical heterogeneity remains. Studies not included in the meta-analysis showed results in the same direction, but some upper confidence intervals were close to one, suggesting some overlap between the group. This occurred in three studies. These studies were generally small and used different cut-offs to determine low and high GCS. Meta-regression was not performed due to heterogeneity of studies.

These findings have important caveats in that the included studies were heterogeneous in the populations studied and methods used to measure level of arousal. Although overall we considered the available evidence to be of low quality the consistency between studies in demonstrating a positive association between reduced level of arousal and mortality and the narrow CI for the pooled data is notable.

Delirium is also associated with increased mortality [15,16,17,18] and the majority of patients with acute-onset reduced level of arousal meet criteria for delirium [4, 5, 8, 13]. Additionally, some delirium studies exclude patients with severely reduced level of arousal [19]; this restricted spectrum may have led to underestimation of the relationship between delirium diagnosis and mortality.

The 5.7-fold mortality rate can be compared with other illness severity indicators: for example raised lactate (>4 mmol/L) on admission to hospital has an OR for in hospital mortality of four (95% CI 1.7-14.1) [43,44,45] and hypotension <100mmHg has an OR of 2.0 (95% CI 1.3-2.8) [46] and <90mmHg OR 3.88 (95% CI 2.62-5.75) [47].

Strengths of the review

This was a large and comprehensive systematic review evaluating over 23,000 references using an inclusive search strategy. All references, abstracts and full texts were assessed by two independent reviewers. We translated articles as able, followed up conference abstracts and performed forward citation searches. We contacted authors for data and clarification. In light of predicted significant heterogeneity, a random effects model was used in the meta-analysis.

Limitations of the review

It is possible that relevant studies could have been missed. We did not include non-published studies or the grey literature. We were able to translate five non-English studies but there remained nine we could not translate. No full text was available for 28 abstracts; mainly conference abstracts. We searched for future publication of full text for these articles but none were identified. Not all studies presented the data required to calculate OR but available data was increased following correspondence with study authors. Another three study authors attempted to retrieve their raw data but were unable. The available evidence from the studies included in this review was considered of low quality overall, due to the risk of bias, clinical heterogeneity and the risk of publication bias. However, similar results were found if studies that were retrospective and/or used no validated arousal scale, were removed.

Interpretation and implications for clinical practice and further research

No previous systematic review has explored the relationship between reduced level of arousal and mortality. We were unable to explore the reasons underpinning this association. It is possible that patients with reduced level of arousal had more severe illness, however, multivariate analyses suggest reduced level of arousal is still associated with increased mortality after correcting for vital signs, and thus this is unlikely to be the sole explanation. It is plausible that reduced level of arousal contributes causally to poor outcomes, through increased risk of aspiration pneumonia, increased practical challenges of providing medical care, and impairing the ability to undergo rehabilitation.

The poor prognosis of delirium is increasingly recognised [14,15,16,17]. The majority of studies did not present sufficient information to allow us to comment on the presence of delirium, but it is established that acute-onset reduced level of arousal, in non-comatose patients, is a highly specific indicator of delirium [4, 5, 8, 13]. Only two [4, 34] of the included studies looked for delirium amongst their patients. Many studies of delirium specifically exclude patients with reduced level of arousal [19]. Given the 5.7-fold increased risk of in-hospital mortality in this group clinicians need to be vigilant regarding these patients, consider discussion around prognosis with patients and families, and actively seek evidence to diagnose delirium and manage it appropriately.

Future research should examine the outcomes of both reduced level of arousal and delirium, considering likely aetiologies and causes of death. This would require prospective cohort studies evaluating sufficient numbers of patients, including those with primary neurological disease and/or surgical conditions for predetermined sub-group analyses. Validated level of arousal scales should be used rather than descriptive terms. Comprehensive characterisation of patient demographics, co-morbidities including dementia, drugs (particularly use of psychoactive or sedative drugs) and alcohol use should be reported. Delirium studies should include patients who are too drowsy to undergo cognitive testing or interview. This could be achieved by using specific level of arousal assessment instruments, or by using delirium scales with embedded level of arousal measurement such as the 4 “A”s Test (4AT) [48].