Outcome of delirium in critically ill patients
Systematic review and meta-analysis
Outcome of delirium in critically ill patients: systematic review and meta-analysis by Jorge IF Salluh and colleagues (BMJ 2015;350:h2538)
Objectives—To determine the relation between delirium in critically ill patients and their outcomes in the short term (in the intensive care unit and in hospital) and after discharge from hospital
Design—Systematic review and meta-analysis of published studies
Data sources—PubMed, Embase, CINAHL, Cochrane Library, and PsychINFO, with no language restrictions, up to 1 January 2015
Eligibility criteria for selection studies—Reports were eligible for inclusion if they were prospective observational cohorts or clinical trials of adults in intensive care units who were assessed with a validated delirium screening or rating system, and if the association was measured between delirium and at least one of four clinical endpoints (death during admission, length of stay, duration of mechanical ventilation, and any outcome after hospital discharge). Studies were excluded if they primarily enrolled patients with a neurological disorder or patients admitted to intensive care after cardiac surgery or organ/tissue transplantation, or centered on sedation management or alcohol or substance withdrawal. Data were extracted on characteristics of studies, populations sampled, identification of delirium, and outcomes. Random effects models and meta-regression analyses were used to pool data from individual studies
Results—Delirium was identified in 5280 of 16 595 (31.8%) critically ill patients reported in 42 studies. When compared with control patients without delirium, patients with delirium had significantly higher mortality during admission (risk ratio 2.19, 94% confidence interval 1.78 to 2.70; P<0.001) as well as longer durations of mechanical ventilation and lengths of stay in the intensive care unit and in hospital (standard mean differences 1.79 (95% confidence interval 0.31 to 3.27; P<0.001), 1.38 (0.99 to 1.77; P<0.001), and 0.97 (0.61 to 1.33; P<0.001), respectively). Available studies indicated an association between delirium and cognitive impairment after discharge
Conclusions—Nearly a third of patients admitted to an intensive care unit develop delirium, and these patients are at increased risk of dying during admission, longer stays in hospital, and cognitive impairment after discharge
Why do the study?
Delirium, or acute confusional state, is a serious psychiatric disorder that presents with inattention and generalised severe disorganisation of behaviour. It occurs often in patients who are in hospital and is associated with adverse short term outcomes, such as increased mortality. Delirium can also have long term consequences, including higher mortality, functional disability, admission to residential care, cognitive impairment, and dementia.
We know that the risk of delirium is high in certain patients, such as older people and those with pre-existing cognitive impairments, and in particular those who are admitted to an intensive care unit (ICU). Because delirium is often overlooked or misdiagnosed, many observational studies have found varying prevalences of delirium in patients admitted to the ICU. We do not know the precise frequency with which delirium occurs in critically ill patients and what the long term consequences are. With this knowledge, doctors might be able to better target therapies to those patients at a higher risk.
What did the authors do?
The authors summarised the existing literature by meta-analysis. They searched the literature and selected studies that had to fulfil two criteria. Firstly, they had to be prospective cohort studies or clinical trials that used a validated instrument to screen for or diagnose delirium. Secondly, the studies must have measured a clinically relevant short term outcome, such as death, length of stay, or time of ventilation, or a clinical outcome after discharge from hospital. Use of a validated instrument, such as the confusion assessment method, is important because the diagnosis of delirium is difficult and the absence of a validated instrument to screen for delirium is likely to be a major cause in the varying prevalences found by previous studies.
To further increase the methodological quality of the analysis, the researchers excluded studies without a control population and studies that had enrolled patients with a primary disorder of the central nervous system (stroke, traumatic brain injury, central nervous system infections, brain tumours, or recent intracranial surgery). They also excluded studies on patients undergoing cardiac surgery or organ or tissue transplantation and studies that focused on patients experiencing alcohol or substance withdrawal.
Three of the study’s authors independently abstracted data from the selected articles, and a fourth author verified accuracy and reliability of the abstracted data by sampling 10% of the references selected at each stage of the search. They used the Newcastle-Ottawa scale to assess methodological quality of included studies. This scale grades three aspects of a study: the selection of study groups, the comparability of groups, and the quality of outcome ascertainment. It has a score from 0 to 8, where scores over 5 are considered to be a sufficient quality.
The data they extracted were: patients’ characteristics and outcomes (mortality in the ICU and hospital), length of stay (in the ICU and hospital), and duration of mechanical ventilation in those with and without delirium. The principal outcome of interest was mortality in the ICU and hospital. With these data, the researchers could calculate the strength of the relation between delirium and mortality. They expressed this as risk ratios with 95% confidence intervals.
The authors also assessed the degree of heterogeneity among studies by reviewing the I statistic. This is a statistical test that gives you the degree to which heterogeneity is higher than the expected heterogeneity. Again, this is important here, as we have seen that previous studies have yielded conflicting results, and one can do a useful meta-analysis—that is, a combined estimate— only when the effects found in the individual studies are similar enough to do that.
What did they find?
The authors collected 197 articles for detailed analysis. Of these, only 42 articles (16 595 patients) met the criteria above, and were included in the systematic review. There were 40 prospective cohort studies and two randomised trials. Not all of the studies included all the outcomes the authors were interested in: most had only short term results and eight also had longer term outcomes. All cohort studies scored higher than 5 on the Newcastle-Ottawa scale, and the two trials were found to have a low risk of bias.
Delirium was identified in 5280 (31.8%) of 16 595 patients. The most widely used instrument to diagnose delirium was the confusion assessment method. The figure 1 shows the main result of the study—short term mortality of patients with delirium, which was present in 28 studies. The left hand side of the figure shows the mortality in patients with and without delirium. The plot translates this into a risk ratio: the more to the right the square of each study is, the higher the risk of death with delirium. You see that the size of these squares differs as well: the bigger the study, the bigger the square. At the bottom of the plot is a diamond, which gives a summary risk ratio of around two. This means that ICU patients with delirium have a twofold risk of dying in the hospital versus those without delirium.
In a similar manner, the authors calculated length of stay and found that patients with delirium had a mean length of stay in intensive care that was one day and nine hours longer than patients without delirium. Overall length of stay in the hospital was also longer. Ten studies reported duration of mechanical ventilation, and these findings point in the same direction: the mean duration of mechanical ventilation was 1.79 days longer in patients with delirium.
Finally, the authors looked at longer term outcomes. Here, they had fewer studies to work with, so were unable to undertake a formal meta-analysis. Two studies found increased mortality by six months in patients who had delirium when they were in intensive care (41.2% v 15.4%, and 34% v 15%), and one study showed that the number of days of delirium in intensive care was significantly associated with time to death within one year after admission to the ICU (hazard ratio 1.10, 95% confidence interval 1.02 to 1.18). But the authors also found a recent study in which such an association was not found. In all, they found four studies that documented an association of delirium with worse cognitive functioning at various long term intervals (3-12 months).
What are the study’s strengths and weaknesses?
A key strength of this study is its size. It is three times larger than an earlier meta-analysis looking at the same question. Another strength is that only studies that used a validated instrument to diagnose delirium were selected.
One major weakness of the study is the heterogeneity of the included studies. This is a problem for all meta-analyses because authors are limited by the available literature. Heterogeneity was high. If you take another look at the figure at the bottom left, I=72%. This level of heterogeneity is not unexpected, because there were major differences between studies in the patient populations, the methods used to detect and rate delirium, and the timeframes for mortality.
The authors also found the possibility for moderate publication bias. They found a small fraction of studies with much higher than expected mortality figures, which suggests that studies with lower figures might not have been published. Another important limitation is generalisability. The authors excluded studies of patients after cardiac surgery and organ transplantation. The authors viewed those patients as distinct categories that deserve a separate analysis.
What do the findings mean?
Delirium was detected in nearly a third of critically ill patients and was associated with a number of negative outcomes, including increased hospital mortality, longer length of stay, and longer duration of mechanical ventilation. Available data also suggested an association between delirium and cognitive impairment and mortality after discharge. The study, however, cannot clarify the nature of this association, specifically whether delirium is a condition that is causatively linked to adverse outcomes or whether it is a marker of the severity of a disease.
Despite this uncertainty, the results do support current guidelines that recommend active screening for and fast treatment of delirium in critically ill patients. Delirium is a potentially modifiable risk factor for adverse outcomes in critically ill patients in hospital.Wim Weber, European research editor
Correspondence to: firstname.lastname@example.org
Competing interests: WW is European research editor for The BMJ and helps select research for publication.
Provenance and peer review: Commissioned; not externally peer reviewed.
- Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263-306.
Cite this as: Student BMJ 2015;23:h3361