Articles
Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies

https://doi.org/10.1016/S1473-3099(13)70081-1Get rights and content

Summary

Background

Estimating attributable mortality of ventilator-associated pneumonia has been hampered by confounding factors, small sample sizes, and the difficulty of doing relevant subgroup analyses. We estimated the attributable mortality using the individual original patient data of published randomised trials of ventilator-associated pneumonia prevention.

Methods

We identified relevant studies through systematic review. We analysed individual patient data in a one-stage meta-analytical approach (in which we defined attributable mortality as the ratio between the relative risk reductions [RRR] of mortality and ventilator-associated pneumonia) and in competing risk analyses. Predefined subgroups included surgical, trauma, and medical patients, and patients with different categories of severity of illness scores.

Findings

Individual patient data were available for 6284 patients from 24 trials. The overall attributable mortality was 13%, with higher mortality rates in surgical patients and patients with mid-range severity scores at admission (ie, acute physiology and chronic health evaluation score [APACHE] 20–29 and simplified acute physiology score [SAPS 2] 35–58). Attributable mortality was close to zero in trauma, medical patients, and patients with low or high severity of illness scores. Competing risk analyses could be done for 5162 patients from 19 studies, and the overall daily hazard for intensive care unit (ICU) mortality after ventilator-associated pneumonia was 1·13 (95% CI 0·98–1·31). The overall daily risk of discharge after ventilator-associated pneumonia was 0·74 (0·68–0·80), leading to an overall cumulative risk for dying in the ICU of 2·20 (1·91–2·54). Highest cumulative risks for dying from ventilator-associated pneumonia were noted for surgical patients (2·97, 95% CI 2·24–3·94) and patients with mid-range severity scores at admission (ie, cumulative risks of 2·49 [1·81–3·44] for patients with APACHE scores of 20–29 and 2·72 [1·95–3·78] for those with SAPS 2 scores of 35–58).

Interpretation

The overall attributable mortality of ventilator-associated pneumonia is 13%, with higher rates for surgical patients and patients with a mid-range severity score at admission. Attributable mortality is mainly caused by prolonged exposure to the risk of dying due to increased length of ICU stay.

Funding

None.

Introduction

In a 1-day (May 8, 2007) point prevalence survey1 of 13 796 adult patients in 1265 intensive care units (ICUs) in 75 countries, 51% of all patients were infected, of whom 64% (4503 patients) had an infection of the respiratory tract. Many of these episodes could have been classified as ventilator-associated pneumonia, which is one of the most common nosocomial infections with major consequences for patient outcome. Yet, to what extent ventilator-associated pneumonia increases the likelihood of death in ICUs is unknown.

Different methods have been used to calculate the attributable mortality of ventilator-associated pneumonia, yielding estimates ranging from 0 to 60%. Most studies were observational, using cohorts of affected and non-affected patients to calculate relative risks (RRs) or odds ratios (ORs) in univariate and multivariate analyses. Such studies do not include adjustment for confounding, and a meta-analysis of all published observational cohort studies did not allow a reliable estimate of attributable mortality of ventilator-associated pneumonia because of extensive heterogeneity.2 Quantifying the effects of this disorder on patient outcome is also hampered because of the time-dependent nature of the disease, which might include time-dependent bias, and the fact that ICU mortality and discharge act as competing endpoints. To overcome these issues, innovative techniques such as multistate and competing risks models have been applied to estimate attributable mortality of ventilator-associated pneumonia.3, 4 Although these methods carefully address time effects, adjustment for confounding is still not possible because of the observational nature of the data. Randomisation is the only procedure to exclude the effects of confounding, and, therefore, studies in which patients have been randomly assigned to receive a preventive measure would allow a non-confounded estimate of attributable mortality by analysing the preventive effects on ventilator-associated pneumonia and death.

On the basis of a meta-analysis of aggregated data from 53 randomised prevention studies including 58 comparisons, we estimated the attributable mortality of ventilator-associated pneumonia to be 9%.5 Yet, this approach was limited by the absence of individual patient data, which precluded subgroup analyses as well as applying any of the newer statistical methods that adjust for competing endpoints. We therefore did an individual patient data meta-analysis of studies of ventilator-associated pneumonia prevention, which offered the unique possibility to quantify attributable mortality of ventilator-associated pneumonia in predefined subgroups, while avoiding effects of confounding and adjusting for competing endpoints.

Section snippets

Search strategy and selection criteria

We searched for randomised trials assessing ventilator-associated pneumonia prevention measures in PubMed, Embase, the Cochrane library, and Web of Science using the terms and synonyms “ventilator-associated pneumonia” and “randomisation”. Eligible trials had to be published between January, 1998, and July, 2010. Inclusion criteria were that the studies had to include only patients who were mechanically ventilated and had to report both ventilator-associated pneumonia and mortality rates during

Results

Through our systematic search we identified 45 trials of ventilator-associated pneumonia prevention that were eligible for inclusion, and all corresponding authors were contacted. Individual patient data were provided from 26 studies (appendix). After screening of the individual patient data, 24 studies remained for further analyses yielding 6284 patients, of whom 3384 had been randomly assigned to a preventive measure (table 1).6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23

Discussion

On the basis of a meta-analysis of 6284 individual patient's data from 24 trials of ventilator-associated-pneumonia prevention, we estimate that the attributable mortality of the disorder is 13%. Yet, there are large differences between subgroups of patients, with attributable mortality rates of 69% in surgical patients and 36% in patients with an intermediate severity of illness score (ie, APACHE 20–29). The attributable mortality was close to zero in trauma and medical patients and in

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