Prevalence, Risk Factors, and Mortality for Ventilator-Associated Pneumonia in Middle-Aged, Old, and Very Old Critically Ill Patients* Stijn Blot, PhD1; Despoina Koulenti, PhD2,3; George Dimopoulos, PhD2; Claude Martin, PhD4; Apostolos Komnos, MD5; Wolfgang A. Krueger, PhD6; Giuseppe Spina, MD7; Apostolos Armaganidis, PhD2; Jordi Rello, PhD8; and the EU-VAP Study Investigators
Objective: We investigated the epidemiology of ventilator-associated pneumonia in elderly ICU patients. More precisely, we assessed prevalence, risk factors, signs and symptoms, causative bacterial pathogens, and associated outcomes. Design: Secondary analysis of a multicenter prospective cohort (EU-VAP project). Setting: Twenty-seven European ICUs. Patients: Patients who were mechanically ventilated for greater than or equal to 48 hours. We compared middle-aged (45–64 yr; n = 670), old (65–74 yr; n = 549), and very old patients (≥ 75 yr; n = 516).
*See also p. 742. 1 Department of Internal Medicine, Ghent University, Ghent, Belgium. 2 Attikon University Hospital, Athens, Greece. 3 Critical Care Department, The Burns, Trauma, and Critical Care Research Center, The University of Queensland, Brisbane, QLD, Australia. 4 Critical Care Department, Nord University Hospital, Marseille, France. 5 Critical Care Department, General Hospital of Larisa, Larisa, Greece. 6 Critical Care Department, Clinics of Constance, Constance, Germany. 7 Department of Intensive Care, Mauriziano Hospital, Turin, Italy. 8 Critical Care Department, Vall d’Hebron University Hospital, CIBERES, Universitat Autonoma de Barcelona, Barcelona, Spain. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ ccmjournal). Supported, in part, by Generalitat de Catalunya grant (SGR 05/920), CIBER Enfermedades Respiratorias, and Carlos III Health Institute grants (PI05/2410 and AI/07/90031). Dr. Blot is an associate board member for the prevention of postoperative pulmonary complications. Dr. Blot received grant support from Ghent University (Special Research Fund) and received support for educational development of slide kit on endotracheal tube management. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected] Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.ccm.0000435665.07446.50
Critical Care Medicine
Measurements and Main Results: Ventilator-associated pneumonia occurred in 103 middle-aged (14.6%), 104 old (17.0%), and 73 very old patients (12.8%). The prevalence (n ventilator-associated pneumonia/1,000 ventilation days) was 13.7 in middle-aged patients, 16.6 in old patients, and 13.0 in very old patients. Logistic regression analysis could not demonstrate older age as a risk factor for ventilator-associated pneumonia. Ventilator-associated pneumonia in elderly patients was more frequently caused by Enterobacteriaceae (24% in middle-aged, 32% in old, and 43% in very old patients; p = 0.042). Regarding clinical signs and symptoms at ventilator-associated pneumonia onset, new temperature rise was less frequent among very old patients (59% vs 76% and 74% for middle-aged and old patients, respectively; p = 0.035). Mortality among patients with ventilator-associated pneumonia was higher among elderly patients: 35% in middle-aged patients versus 51% in old and very old patients (p = 0.036). Logistic regression analysis confirmed the importance of older age in the risk of death (adjusted odds ratio for old age, 2.1; 95% CI, 1.2–3.9 and adjusted odds ratio for very old age, 2.3; 95% CI, 1.2–4.4). Other risk factors for mortality in ventilator-associated pneumonia were diabetes mellitus, septic shock, and a high-risk pathogen as causative agent. Conclusions: In this multicenter cohort study, ventilator-associated pneumonia did not occur more frequently among elderly, but the associated mortality in these patients was higher. New temperature rise was less common in elderly patients with ventilatorassociated pneumonia, whereas more episodes among elderly patients were caused by Enterobacteriaceae. (Crit Care Med 2014; 42:601–609) Key Words: elderly; geriatric; infection; intensive care; mortality; outcome; pneumonia; risk factors
I
n the 20th century, population aging has emerged as a major demographic trend worldwide. As a consequence of the average increase in life expectancy, the number of elderly patients admitted to hospitals is growing fast. As older age is associated with a higher occurrence rate of chronic conditions www.ccmjournal.org
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and substantial functional impairment, ICUs are also confronted with a steadily growing proportion of elderly critically ill patients. In a European center, the proportion of elderly ICU patients (≥ 75 yr) increased from 7% to 17% between the periods 1992–1996 and 2002–2006 (1). Data from the Australian and New Zealand Intensive Care Society Adult Database indicated that in the period 2000 to 2005 13% of all adult patients admitted to ICUs were at least 80 years old (2), and in a French cohort study, 36% of ICU patients appeared to be 70 years old or older (3). The average increase in age of the ICU population has substantial clinical implications. Elderly patients are more vulnerable to the development of healthcare-associated infection because of their immunologic involution, age-associated physiological and anatomical alterations, increasingly severe chronic diseases, and malnutrition (4–6). As a consequence, in a general population, severe infections such as pneumonia and bloodstream infection occur more frequently in elderly compared with younger adults (7). In addition, severe infections in elderly are associated with more complications, as well as with a worse prognosis. Studies concerning the epidemiology of severe nosocomial infections in elderly ICU patients remain scarce and are mainly focused on risk factors and outcome associated with healthcare-associated bloodstream infection (1, 8–10). Yet, despite the availability of evidence-based guidelines and ongoing innovations in prevention and management (11–13), ventilator-associated pneumonia (VAP) remains the most important infectious challenge in the ICU (14, 15). Indeed, the impact of VAP in terms of occurrence rate and clinical and health economic burden is particularly worrisome. A systematic review indicated that VAP is likely to occur in 10–20% of patients who are ventilated for at least 48 hours (15). These patients face a mortality risk estimated to be twice as high compared with similar ICU patients without VAP (pooled odds ratio [OR], 2.0; 95% CI, 1.2–3.6). Furthermore, VAP results in an average excess length of ICU stay of 6 days (95% CI, 5.3–6.8), adding up to an excess hospital cost of $10,000–$13,000 (15). More recent estimates are less dramatic, reporting attributable mortalities ranging 1–6% and an added length of hospitalization of 4 days (95% CI, 1.5–7.0) (14, 16, 17). Despite being more optimistic, these figures still reflect the heavy impact of VAP on healthcare systems (17). It is uncertain if these figures substantially differ with age within adult patients. Given the above-mentioned age-associated physiological alterations and the presence of multiple underlying conditions, it seems plausible that the general epidemiology of VAP in elderly deviates from VAP in younger adults in at least some aspects such as risk profile, causative bacterial pathogens, and outcomes. The objective of this study is to investigate the epidemiology of VAP in elderly ICU patients who are mechanically ventilated for at least 48 hours. More precisely, comparisons between middle-aged, old, and very old ICU patients are performed concerning occurrence rate and prevalence of VAP, risk factors for the acquisition of VAP, clinical signs and symptoms at VAP onset, causative bacterial pathogens, associated mortality, and risk factors for death. 602
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PATIENTS AND METHODS The current study is a secondary analysis of the EU-VAP database (18). The EU-VAP/CAP project was a prospective, observational survey conducted in 27 ICUs from nine European countries: Belgium, France, Germany, Greece, Italy, Ireland, Portugal, Spain, and Turkey. All patients requiring admission for a diagnosis of pneumonia or on invasive mechanical ventilation for more than 48 hours, irrespective of the admission diagnosis, were included. The target was the collection of data on 100 consecutive admissions in each ICU. Patient demographics, primary diagnosis, comorbidities, McCabe classification (19) and Simplified Acute Physiology Score (SAPS) II score at admission (20), ICU and hospital length of stay, duration of mechanical ventilation, and ICU mortality were recorded for all patients. For patients with a clinical diagnosis of pneumonia, data collection included pneumonia type, clinical signs, subjective confidence in diagnosis by the attending physician, sepsis severity (sepsis/ severe sepsis/septic shock) (21), SAPS II score on the previous day and the day of clinical suspicion for VAP, Sequential Organ Failure Assessment score (22) on the day of clinical suspicion of pneumonia, other suspected or concurrent infections, diagnostic procedures performed, microbiologic data, treatment data, clinical response, and pneumonia’s contribution to death as estimated by the attending physician. Because of the specific purpose of the study, we additionally reported an age-adjusted SAPS II score in which points attributed to older age were subtracted from the total score. Each clinical episode of pneumonia was described separately. The participating centers received ethical approval from their institutions. Informed consent was waived because of the observational nature of the study. Full details of the methods have been presented elsewhere (18). In this secondary analysis of the EU-VAP database, patients were classified as “middle aged” (45–64 yr), “old” (65–74 yr), and “very old” (≥ 75 yr) in accordance with previous studies on elderly critically patients (1). Patients younger than 45 years were excluded to avoid possible bias. For the same reason, trauma patients were excluded from the current analysis because of their strong relationship with younger age. Definitions VAP was defined as a pulmonary infection arising in greater than or equal to 48 hours after endotracheal intubation with no evidence of pneumonia at the time of intubation or the diagnosis of a new pulmonary infection if the initial admission to ICU was for pneumonia (11). Early-onset VAP was defined as VAP with onset more than 48 hours but less than 5 days after intubation (11). Late-onset VAP was defined as VAP with onset 5 or more days after intubation (11). Definite pathogen was defined as a microorganism isolated in a patient with suspicion of pneumonia from blood sample and respiratory sample or indicated by serology and judged as definite by the attending physician. Prevalence (expressed per 1,000 patients mechanically ventilated for at least 48 hr) and occurrence rate of VAP (expressed per 1,000 mechanical ventilation days) were calculated for the predefined age groups. In addition, prevalence calculations March 2014 • Volume 42 • Number 3
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were performed with censoring patient days after VAP onset (mechanical ventilation days “at risk” or exposure time). For patients who developed more than one episode of VAP, only the first episode was considered in the analyses. Statistical Analysis Statistical analysis was conducted using SPSS version 20.0 for Windows (SPSS, Chicago, IL). Descriptive data are expressed as n (%) or median (25th–75th percentile). Chi-square test was used for the comparison of categorical variables and the Mann-Whitney U test or Kruskal-Wallis test for the comparison of continuous variables. Cox proportional-hazard regression analysis was performed to identify risk factors for VAP with sensoring on ICU discharge. In an unadjusted model, age categories were the only independent variable included. Two adjusted models were performed with forced entry of age categories in one model and age as a continuous variable in the other. Other independent variables entered into each adjusted model were those with a logical relationship with risk of VAP (e.g., SAPS II score) or variables with VAP in bivariate analysis (p < 0.25). Variables assessed for their relationship with VAP acquisition included the sex, age-adjusted SAPS II score, the primary organ failure leading to ICU admission (respiratory, cardiovascular, neurological, metabolic, renal or hepatic failure, gastrointestinal disorder, and sepsis), and underlying conditions (chronic heart failure, chronic kidney failure, chronic obstructive pulmonary
disease, diabetes, malignancy, immunosuppression, cirrhosis, and alcoholism). Variables with a p value more than 0.15 were stepwise removed from the model. Logistic regression analysis was also used to assess adjusted and unadjusted relationships with mortality and age among patients with VAP. Results of the regression models are reported as OR and 95% CI. Survival curves are prepared by means of the Kaplan-Meier method. Unadjusted survival distributions are compared with use of the log rank test (Fig. 1). Statistical significance is defined as p value less than 0.05.
RESULTS
According to the inclusion criteria, 1,735 patients from 24 centers were eligible for inclusion. The study cohort included 670 middle-aged patients, 549 old patients, and 516 very old patients. Patient characteristics for the distinct age groups are shown in Supplemental Table 1 (Supplemental Digital Content 1, http://links.lww.com/CCM/A753). Very old patients were more likely to be female. Important differences in underlying conditions were observed. Compared with middle-aged adults, old and very old patients had more chronic heart failure, more underlying respiratory disease, more chronic renal failure, more diabetes, and more non-metastatic cancer. Cirrhosis, solid organ transplantation, and alcoholism were more common among middle-aged patients. Severity of disease as assessed by the SAPS II score significantly increased with age category (p < 0.001). However, age-adjusted SAPS II scores were slightly lower among very old patients (p = 0.027). Mortality increased with age category. No differences between the age groups were observed in length of mechanical ventilation and length of ICU stay. Total length of hospitalization was longer in elderly patients, but this difference was no longer significant when only survivors were taken into account. The prevalence of VAP in the total cohort (patients aged ≥ 45 yr) was 14.4 VAP/1,000 ventilation days at risk. The occurrence rate and prevalence of VAP in the distinct age groups are described in Table 1. No important differences were noted between the groups, either when all VAP episodes or only early or late episodes were considered. Also logistic regression analysis could not demFigure 1. Survival curves of patients with ventilator-associated pneumonia according to age category. Solid onstrate a higher risk for VAP black line represents middle-aged patients; solid gray line represents old patients; dashed black line represents among elderly patients (Table very old patients. Log rank test: p = 0.211.
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Table 1. Occurrence Rate and Prevalence of Ventilator-Associated Pneumonia According to Age Age 45–64 Yr
65–74 Yr
≥ 75 Yr
pa
103 (15.4)
104 (18.9)
73 (14.1)
0.082
Early VAP
48 (7.2)
39 (7.1)
25 (4.8)
0.206
Late VAP
55 (8.2)
65 (11.8)
48 (9.3)
0.102
11.5
12.6
10.5
0.130
Early VAP
5.3
4.7
3.6
0.349
Late VAP
6.1
7.9
6.9
0.368
13.7
16.6
13.0
0.202
Early VAP
6.4
6.2
4.4
0.292
Late VAP
7.3
10.4
8.5
0.155
Occurrence rate of VAP, n (%)
Prevalence of VAP, n/1,000 ventilation days
Prevalence of VAP, n/1,000 ventilation days “at risk”
VAP = ventilator-associated pneumonia. a p value for differences between age groups.
Table 2.
Independent Risk Factors for Ventilator-Associated Pneumonia
Potential Risk Factors
Hazard Ratio (95% CI)
P
Unadjusted analysis Middle agea (45–64 yr)
—
—
Old age (65–74 yr)
1.20 (0.91–1.58)
0.191
Very old age (≥ 75 yr)
0.89 (0.66–1.21)
0.456
Adjusted analysis Middle agea (45–64 yr)
—
—
Old age (65–74 yr)
1.20 (0.91–1.58)
0.191
Very old age (≥ 75 yr)
0.89 (0.66–1.21)
0.456
Neurological failure at admission
1.94 (1.41–2.66)
< 0.001
Cardiovascular failure at admission
2.69 (2.02–3.59)
< 0.001
Metabolic, renal, or hepatic failure at admission
1.75 (1.14–2.71)
0.011
0.453 (0.187–0.96)
0.038
0.99 (0.985–1.00)
0.038
0.997 (0.986–1.008)
0.542
Immunosuppression Age-adjusted SAPS II score (per point increase) Adjusted analysis with age as continuous variable Age (per year increase) Neurological failure at admission
1.95 (1.42–2.67)
< 0.001
Cardiovascular failure at admission
2.67 (2.00–3.57)
< 0.001
Metabolic, renal, or hepatic failure at admission
1.72 (1.11–2.65)
0.015
Immunosuppression
0.42 (0.19–0.95)
0.037
Age-adjusted SAPS II score (per point increase)
0.99 (0.98–1.00)
0.041
SAPS = Simplified Acute Physiology Score. a Reference category for older age groups.
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2). The only variable recognized as an independent risk factor for VAP appeared to be length of mechanical ventilation. Bacterial pathogens causing VAP are shown in Table 3. Compared with middle-aged patients, VAP in elderly patients was more frequently caused by Enterobacteriaceae, particularly Escherichia coli and Klebsiella species. No differences were observed in VAP caused by high-risk pathogens or polymicrobial pneumonia. We compared clinical signs and symptoms associated with VAP in the distinct age groups (Table 4). No differences were noted, with the exception of new temperature rise, which was less frequently observed among very old patients. Characteristics of patients with VAP were compared between the age groups (Supplemental Table 2, Supplemental Digital Content 1, http://links.lww.com/CCM/A753). Very Table 3.
old patients more frequently had diabetes mellitus, whereas chronic alcoholism was more common among middle-aged patients with VAP. Mortality among patients with VAP was higher among elderly patients: 35% in middle-aged patients versus 51% in old and very old patients. Logistic regression analysis confirmed the importance of older age as an independent risk factor for death following VAP (Table 5). In this analysis, being old or very old resulted in an identical risk for death. Other risk factors for mortality in patients with VAP were diabetes mellitus as underlying condition, septic shock, and a high-risk pathogen as causative agent. Survival curves of patients with VAP in distinct age groups are illustrated in Figure 1. Curves of middle-aged versus old and very old patients start to diverge after approximately 2 weeks of ICU stay, reaching a maximum after about 1 month. Curves of old
Etiology in Ventilator-Associated Pneumonia According to Age Category Age 45–64 Yr (n = 103)
65–74 Yr (n = 104)
≥ 75 Yr (n = 73)
78 (75.7)
77 (74.0)
58 (79.5)
Methicillin-susceptible Staphylococcus aureus
12 (11.7)
8 (7.7)
8 (11.0)
Methicillin-resistant S. aureus
15 (14.6)
14 (13.5)
9 (12.3)
5 (4.9)
3 (2.9)
0 (0.0)
Enterobacteriaceaea
25 (24.3)a
33 (31.7)
31 (42.5)a
Escherichia colia
8 (7.8)a
11 (10.6)
15 (20.5)a
Klebsiella pneumonia
6 (5.8)
12 (11.5)
11 (15.1)
Proteus mirabilis
5 (4.9)
5 (4.8)
2 (2.7)
Enterobacter species
6 (5.8)
5 (4.8)
3 (4.1)
Serratia marscescens
2 (1.9)
3 (2.9)
3 (4.1)
Citrobacter species
2 (1.9)
0 (0.0)
2 (2.7)
Morganella species
0 (0.0)
2 (1.9)
0 (0.0)
Pseudomonas aeruginosa
20 (19.4)
20 (19.2)
10 (13.7)
Acinetobacter baumannii
15 (14.6)
14 (13.5)
8 (11.0)
2 (1.9)
1 (1.0)
2 (2.7)
6 (5.8)
4 (3.8)
5 (6.8)
45 (43.7)
42 (40.4)
28 (38.4)
24 (23.3)
24 (23.1)
18 (24.7)
Variables
Microbiologically documented ventilator-associated pneumonia, n (%) Gram-positive bacteria
Streptococcus pneumoniae Gram-negative bacteria
Non-fermenting Gram-negative bacteria
Stenotrophomonas maltophilia Gram-negative cocci Haemophilus influenzae/Moraxella catarrhalis High-risk pathogens
b
Polymicrobial episodes
c
p < 0.05 for middle-aged versus very old patients. High-risk pathogens: methicillin-resistant S. aureus, P. aeruginosa, A. baumannii, and S. Maltophilia. c Percentage calculated per total number of episode in each group. Data reported as n (%). The total of percentages may be more than the percentage of microbiologically documented ventilator-associated pneumonia because of the presence of polymicrobial episodes. a
b
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Table 4. Physical and Laboratory Findings in Patients With Ventilator-Associated Pneumonia According to Age Age 65–74 Yr (n = 104)
≥ 75 Yr (n = 73)
Clinical signs of consolidation
59 (57.3)
56 (53.8)
41 (56.2)
0.880
Worsening oxygenation
80 (77.7)
82 (78.8)
57 (78.1)
0.979
Purulent/changing respiratory secretions
79 (76.7)
80 (76.9)
60 (82.2)
0.632
New temperature rise
78 (75.7)
77 (74.0)
43 (58.9)
0.035
1 (1.0)
4 (3.8)
4 (5.5)
0.223
Pleural effusion
20 (19.4)
27 (26.0)
15 (20.5)
0.489
New or worsening chest radiograph infiltrate
74 (71.8)
74 (71.2)
47 (64.4)
0.521
Only peribronchial infiltrate
17 (16.5)
23 (22.1)
19 (26.0)
0.296
Cavitation on chest radiograph (infective cause)
5 (4.9)
13 (12.5)
7 (9.6)
0.152
> 25% increase or > 10,000/μL of WBC count
60 (58.9)
60 (57.7)
41 (56.2)
0.961
4 (1.4)
3 (1.1)
5 (1.8)
0.426
Hypothermia
> 10% immature WBCs a
pa
45–64 Yr (n = 103)
Variables
Indicating difference between middle-aged, old, and very old patients.
and very old patients never differ substantially throughout the ICU course.
DISCUSSION In this multicenter cohort study, we found that older age as such is not a risk factor for VAP. However, this respiratory infection is associated with a significantly higher mortality rate in older age groups. To the best of our knowledge, this is the first study to investigate the prevalence of VAP according to age in a multicenter approach. VAP occurrence rates ranged from 14.1% to 18.9% over the age groups (Table 1) and are as such in line with a systematic review that indicated an average VAP rate of 10–20% for critically ill patients ventilated for more than 48 hours (15). Also the prevalence, as expressed per 1,000 mechanical ventilation days, was not different between the distinct age groups. We assumed that elderly might have had a higher risk profile because of age-associated immunologic involution or—even more important—the presence of more underlying conditions. Indeed, in elderly patients, the number of comorbid conditions—as evidenced by a cumulative illness rating scale—is a better predictor of impaired immunity than chronological age as such (23). In our cohort, old and very old patients had significantly more underlying conditions compared with middle-aged patients. However, rather than underlying diseases, other factors such as noncompliance with evidence-based infection prevention measures (12) or severity of acute illness (24) seem to put patients at a higher risk for VAP. Unexpectedly, however, a higher index of severity of acute illness, as indicated by the age-adjusted SAPS II score, tends to be associated with a protective effect for VAP (p = 0.082) (Table 2). This observation is most probably due to survival bias because many patients with a high SAPS II score died early in the ICU course and as such did not have an equal risk for the 606
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acquisition of VAP in terms of exposure time. Indeed, although mortality at the end of observation was higher among patients with VAP (45.0% vs 37.7%; p = 0.021), survival curves demonstrated a higher mortality in the first month following ICU admission for patients without VAP (data not shown). In other words, in the present study cohort, VAP is a complication that preferably affects patients who survived their initial phase of critical illness while many other very sick patients died before the onset of VAP. A similar but even stronger case of survival bias has been described before. Myny et al (25) found that VAP appeared to be protective for mortality because many patients without VAP died early in the ICU course after which survival curves ran parallel over time. Yet, this difference was no longer significant after adjustment for severity of covariates (OR, 0.79; 95% CI, 0.41–1.53). Analogously, it is in this light that studies aiming to estimate the attributable mortality of VAP by means of causality models failed to demonstrate a substantial added fatality risk (16). Enterobacteriaceae, E. coli and Klebsiella species in particular, more frequently caused VAP in old and very old patients. E. coli has been repeatedly observed as a particular cause of pneumonia in elderly patients, frequently following aspiration (26–28). Transtracheal aspiration is common in neurologically impaired elderly. However, in the current study, neurological impairment was less frequently present in elderly patients. Recently, a laboratory-based study showed that extraintestinal isolates of the antimicrobial resistant E. coli sequence type 131 were independently associated with healthcare facilities and older age (29). In contrast with Enterobacteriaceae, no differences were observed in other high-risk Gram-negative pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii (Table 3). Martin et al (6) also reported Gramnegative bacteria to cause 34.1% of pneumonia in patients 65 March 2014 • Volume 42 • Number 3
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years old or older, whereas in younger patients only 20.5% of pneumonia was caused by such pathogens. Although, in general, the problem of multidrug resistance is more pronounced in elderly patients because of chronic conditions and increased exposure to antimicrobials (30, 31), this appeared not to be the case in the current study. In a study concerning nosocomial bloodstream infection in the ICU, no difference in multidrug resistant etiology was found (1). This may be explained through a similar exposure to antimicrobial use and risk of horizontal transmission of resistant pathogens as well-known risk factors for antimicrobial resistance in all age groups admitted to ICUs. An alternative explanation might be that the classic risk factors such as antimicrobial exposure have lost their stringent relationship with multidrug resistance involvement as resistance has become more and more widespread in the community irrespective of a specific risk profile (32). We compared clinical signs and symptoms of patients with VAP in distinct age categories. Very old patients had significantly less fever at VAP onset compared with old and middle-aged patients (Table 4). It is well known that fever may be blunted in elderly patients with pneumonia. Roughly 20–30% of severe infection will present with blunted or absent fever response (33, 34). In addition, there exists substantial evidence that absence of fever is associated with worse prognosis (35). In our series, absence of new onset of fever only demonstrated a slight trend toward unfavorable outcome (Table 5). Despite the fact that elderly patients do not have an increased risk for acquisition of VAP, their prognosis is substantially worse compared with their younger counterparts. This observation is in line with a large longitudinal observational study using U.S. national hospital discharge data indicating that patients with sepsis aged 65 years old or older had an increased mortality risk compared with patients 65 years old or younger (adjusted OR, 2.26; 95% CI, 2.17–2.36) (6). No difference in the risk for death was noticed between old and very old patients. The high mortality associated with VAP stresses the importance of vigorous application of evidence-based prevention measures such as antiseptic-based oral care and subglottic secretions drainage (36, 37) and further development of innovative strategies to further reduce the risk of VAP in critically ill patients (38). Several limitations of our study must be addressed. First, the study was a secondary analysis and thus was not specifically designed for the research question. As a consequence, neither data on preventive measures nor data on vaccination status were collected. Especially, the latter could have served as an explanation for the low number of pneumococcal pneumonia in elderly. As the primary objective of the EU-VAP project was to identify differences in diagnostic approaches, VAP could be diagnosed on the basis of a broad variety of clinical signs and symptoms, thereby including a potential risk of overdiagnosing. Second, patients were not followed up after hospital discharge, implying a lack of quality-of-life data among elderly survivors. Third, some variables reflecting a specific risk profile for elderly, such as nutritional status and functional disability level, were not included in the present database. On the other hand, data on underlying conditions were available while the Critical Care Medicine
Table 5. Independent Risk Factors for Mortality Among Patients With VentilatorAssociated Pneumonia With Special Emphasis on Age Category Potential Risk Factors for Mortality
OR (95% CI)
p
—
—
Unadjusted analysis Middle agea (45–64 yr) Old age (65–74 yr)
1.93 (1.11–3.38) 0.021
Very old age (≥ 75 yr)
1.91 (1.04–3.53) 0.038
Adjusted analysis Middle agea (45–64 yr)
—
—
Old age (65–74 yr)
2.13 (1.13–3.99) 0.019
Very old age (≥ 75 yr)
2.15 (1.07–4.36) 0.032
Septic shock
2.04 (1.15–3.60) 0.014
High-risk pathogen
2.25 (1.31–3.86) 0.003
Diabetes
2.23 (1.15–4.31) 0.017
Absence of fever at the onset of ventilator-associated pneumonia
1.65 (0.92–2.99) 0.095
Age-adjusted Simplified Acute Physiology Score II scoreb
1.01 (0.99–1.03) 0.192
Exposure timeb
1.02 (0.99–1.06) 0.275
OR = odds ratio. a Reference category for older age groups. b Forced in the model because of logical relationship with mortality. Excluding these variables from the model did not change the final result of the analysis. Hosmer and Lemeshow goodness-of-fit test: p = 0.315.
SAPS II score quantified severity of acute illness. This classification system covers the risk for death as well as the risk for infection in general ICU populations and elderly ICU patients (39, 40). Finally, we did not divide the study cohort into classic age categories used in articles reporting on geriatric patients, including an additional differentiation of patients 75–85 years old and patients 85 years old or older (41). There were several reasons for this. In the present cohort of 1,735 ICU patients 45 years old or older, only 61 were 85 years old or older; 7 of these patients developed VAP. This indicates a limited relevance of such a subgroup within the total ICU population as well as a restricted potential to perform valid statistical analyses. In conclusion, in this multicenter cohort study, VAP did not occur more frequently among elderly, but the associated mortality in these patients was higher. New temperature rise was less common in elderly patients with VAP, whereas more episodes among elderly patients were caused by Enterobacteriaceae.
ACKNOWLEDGMENTS We thank Dr. Joel Dulhunty (The Burns, Trauma and Critical Care Research Centre, Royal Brisbane and Women’s Hospital and The University of Queensland, Brisbane, Australia) for his valuable statistical advice. www.ccmjournal.org
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1. Blot S, Cankurtaran M, Petrovic M, et al: Epidemiology and outcome of nosocomial bloodstream infection in elderly critically ill patients: A comparison between middle-aged, old, and very old patients. Crit Care Med 2009; 37:1634–1641 2. Bagshaw SM, Webb SA, Delaney A, et al: Very old patients admitted to intensive care in Australia and New Zealand: A multi-centre cohort analysis. Crit Care 2009; 13:R45 3. Montuclard L, Garrouste-Orgeas M, Timsit JF, et al: Outcome, functional autonomy, and quality of life of elderly patients with a long-term intensive care unit stay. Crit Care Med 2000; 28:3389–3395 4. Gavazzi G, Krause KH: Ageing and infection. Lancet Infect Dis 2002; 2:659–666 5. Laupland KB, Church DL, Mucenski M, et al: Population-based study of the epidemiology of and the risk factors for invasive Staphylococcus aureus infections. J Infect Dis 2003; 187:1452–1459 6. Martin GS, Mannino DM, Moss M: The effect of age on the development and outcome of adult sepsis. Crit Care Med 2006; 34: 15–21 7. Yoshikawa TT: Epidemiology and unique aspects of aging and infectious diseases. Clin Infect Dis 2000; 30:931–933 8. Marra AR, Bar K, Bearman GM, et al: Systemic inflammatory response syndrome in nosocomial bloodstream infections with Pseudomonas aeruginosa and Enterococcus species: Comparison of elderly and nonelderly patients. J Am Geriatr Soc 2006; 54:804–808 9. Stéphan F, Cheffi A, Bonnet F: Nosocomial infections and outcome of critically ill elderly patients after surgery. Anesthesiology 2001; 94:407–414 10. Reunes S, Rombaut V, Vogelaers D, et al: Risk factors and mortality for nosocomial bloodstream infections in elderly patients. Eur J Intern Med 2011; 22:e39–e44 11. American Thoracic Society, Infectious Diseases Society of America: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388–416 12. Lorente L, Blot S, Rello J: Evidence on measures for the prevention of ventilator-associated pneumonia. Eur Respir J 2007; 30: 1193–1207 13. Blot S, Rello J, Vogelaers D: What is new in the prevention of ventilator-associated pneumonia? Curr Opin Pulm Med 2011; 17:155–159 14. Timsit JF, Zahar JR, Chevret S: Attributable mortality of ventilatorassociated pneumonia. Curr Opin Crit Care 2011; 17:464–471 15. Safdar N, Dezfulian C, Collard HR, et al: Clinical and economic consequences of ventilator-associated pneumonia: A systematic review. Crit Care Med 2005; 33:2184–2193 16. Bekaert M, Timsit JF, Vansteelandt S, et al; Outcomerea Study Group: Attributable mortality of ventilator-associated pneumonia: A reappraisal using causal analysis. Am J Respir Crit Care Med 2011; 184:1133–1139 17. Muscedere JG, Martin CM, Heyland DK: The impact of ventilatorassociated pneumonia on the Canadian health care system. J Crit Care 2008; 23:5–10 18. Koulenti D, Lisboa T, Brun-Buisson C, et al; EU-VAP/CAP Study Group: Spectrum of practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European intensive care units. Crit Care Med 2009; 37:2360–2368 19. McCabe W, Jackson G: Gram-negative bacteremia. I. Etiology and ecology. Arch Intern Med 1962; 110:847–855 20. Le Gall JR, Lemeshow S, Saulnier F: A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993; 270:2957–2963 21. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ
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failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20:864–874 22. Vincent JL, Moreno R, Takala J, et al: The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22:707–710 23. Castle SC, Uyemura K, Rafi A, et al: Comorbidity is a better predictor of impaired immunity than chronological age in older adults. J Am Geriatr Soc 2005; 53:1565–1569 24. Rello J, Ollendorf DA, Oster G, et al; VAP Outcomes Scientific Advisory Group: Epidemiology and outcomes of ventilator-associated pneumonia in a large US database. Chest 2002; 122:2115–2121 25. Myny D, Depuydt P, Colardyn F, et al: Ventilator-associated pneumonia in a tertiary care ICU: Analysis of risk factors for acquisition and mortality. Acta Clin Belg 2005; 60:114–121 26. Jonas M, Cunha BA: Bacteremic Escherichia coli pneumonia. Arch Intern Med 1982; 142:2157–2159 27. Okimoto N, Hayashi T, Ishiga M, et al: Clinical features of Escherichia coli pneumonia. J Infect Chemother 2010; 16:216–218 28. Berk SL, Neumann P, Holtsclaw S, et al: Escherichia coli pneumonia in the elderly with reference to the role of E. coli K1 capsular polysaccharide antigen. Am J Med 1982; 72:899–902 29. Banerjee R, Johnston B, Lohse C, et al: Escherichia coli sequence type 131 is a dominant, antimicrobial-resistant clonal group associated with healthcare and elderly hosts. Infect Control Hosp Epidemiol 2013; 34:361–369 30. Yoshikawa TT: Antimicrobial resistance and aging: Beginning of the end of the antibiotic era? J Am Geriatr Soc 2002; 50:S226–S229 31. Yoshikawa TT: Resistant pathogens: Considerations in geriatrics and infectious disease. J Am Geriatr Soc 2002; 50:S225 32. Vogelaers D, De Bels D, Forêt F, et al; ANTHICUS Study Investigators: Patterns of antimicrobial therapy in severe nosocomial infections: Empiric choices, proportion of appropriate therapy, and adaptation rates—A multicentre, observational survey in critically ill patients. Int J Antimicrob Agents 2010; 35:375–381 33. Castle SC, Norman DC, Yeh M, et al: Fever response in elderly nursing home residents: Are the older truly colder? J Am Geriatr Soc 1991; 39:853–857 34. Norman DC: Fever in the elderly. Clin Infect Dis 2000; 31:148–151 35. Weinstein MP, Murphy JR, Reller LB, et al: The clinical significance of positive blood cultures: A comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. II. Clinical observations, with special reference to factors influencing prognosis. Rev Infect Dis 1983; 5:54–70 36. Labeau SO, Van de Vyver K, Brusselaers N, et al: Prevention of ventilator-associated pneumonia with oral antiseptics: A systematic review and meta-analysis. Lancet Infect Dis 2011; 11:845–854 37. Muscedere J, Rewa O, McKechnie K, et al: Subglottic secretion drainage for the prevention of ventilator-associated pneumonia: A systematic review and meta-analysis. Crit Care Med 2011; 39:1985–1991 38. Lorente L, Blot S, Rello J: New issues and controversies in the prevention of ventilator-associated pneumonia. Am J Respir Crit Care Med 2010; 182:870–876 39. Blot S, Depuydt P, Vandewoude K, et al: Measuring the impact of multidrug resistance in nosocomial infection. Curr Opin Infect Dis 2007; 20:391–396 40. Van Den Noortgate N, Vogelaers D, Afschrift M, et al: Intensive care for very elderly patients: Outcome and risk factors for in-hospital mortality. Age Ageing 1999; 28:253–256 41. Gavazzi G, Mallaret MR, Couturier P, et al: Bloodstream infection: Differences between young-old, old, and old-old patients. J Am Geriatr Soc 2002; 50:1667–1673
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APPENDIX 1. The EU-VAP Study Investigators Djilali Annane (Raymond Poincaré University Hospital, Garches, France); Rosario Amaya-Villar (Virgen de Rocio University Hospital, Seville, Spain); Apostolos Armaganidis (Attikon University Hospital, Athens, Greece); Stijn Blot (Ghent University Hospital, Ghent, Belgium); Christian BrunBuisson (Henri-Mondor University Hospital, Paris, France); Antonio Carneiro (Santo Antonio Hospital, Porto, Portugal); Maria Deja (Charite University Hospital, Berlin, Germany); Jan DeWaele (Ghent University Hospital, Ghent, Belgium); Emili Diaz (Joan XIII University Hospital, Tarragona, Spain); George Dimopoulos (Attikon University Hospital and Sotiria Hospital, Athens, Greece); Silvano Cardellino (Cardinal Massaia Hospital, Asti, Italy); Jose Garnacho-Montero (Virgen de Rocio University Hospital, Seville, Spain); Muhammet Guven (Erciyes University Hospital, Kayseri, Turkey); Apostolos Komnos (Larisa Hospital, Larisa, Greece); Despoina Koulenti (Attikon University Hospital, Athens, Greece; Rovira i Virgili University, Tarragona, Spain); Wolfgang Krueger (Tuebingen University Hospital, Tuebingen, Germany; Constance
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Hospital, Constance, Germany); Thiago Lisboa (Joan XIII University Hospital, Tarragona, Spain; CIBERES); Antonio Macor (Amedeo di Savoia Hospital, Torino, Italy); Emilpaolo Manno (Maria Vittoria Hospital, Torino, Italy); Rafael Mañez (Bellvitge University Hospital, Barcelona, Spain); Brian Marsh (Mater Misericordiae University Hospital, Dublin, Ireland); Claude Martin (Nord University Hospital, Marseille, France); Ignacio Martin-Loeches (Mater Misericordiae University Hospital, Dublin, Ireland; CIBERES, Corporacio Sanitaria Parc Tauli, Sabadell, Spain); Pavlos Myrianthefs (KAT Hospital, Athens, Greece); Marc Nauwynck (St Jan Hospital, Brugges, Belgium); Laurent Papazian (Sainte-Marguerite University Hospital, Marseille, France); Christian Putensen (Bonn University Hospital, Bonn, Germany); Bernard Regnier (Claude Bernard University Hospital, Paris, France); Jordi Rello (Joan XIII University Hospital, Tarragona, Spain; Vall d’Hebron University Hospital and CIBERES, Spain); Jordi Sole-Violan (Dr. Negrin University Hospital, Gran Canarias, Spain); Giuseppe Spina (Mauriziano Umberto I Hospital, Torino, Italy); Arzu Topeli (Hacettepe University Hospital, Ankara, Turkey); and Hermann Wrigge (Bonn University Hospital, Bonn, Germany).
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Objective: We investigated the epidemiology of ventilator-associated pneumonia in elderly ICU patients. More precisely, we assessed prevalence, risk factors, signs and symptoms, causative bacterial pathogens, and associated outcomes. Design: Secondary analysis of a multicenter prospective cohort (EU-VAP project). Setting: Twenty-seven European ICUs. Patients: Patients who were mechanically ventilated for greater than or equal to 48 hours. We compared middle-aged (45–64 yr; n = 670), old (65–74 yr; n = 549), and very old patients (≥ 75 yr; n = 516).
*See also p. 742. 1 Department of Internal Medicine, Ghent University, Ghent, Belgium. 2 Attikon University Hospital, Athens, Greece. 3 Critical Care Department, The Burns, Trauma, and Critical Care Research Center, The University of Queensland, Brisbane, QLD, Australia. 4 Critical Care Department, Nord University Hospital, Marseille, France. 5 Critical Care Department, General Hospital of Larisa, Larisa, Greece. 6 Critical Care Department, Clinics of Constance, Constance, Germany. 7 Department of Intensive Care, Mauriziano Hospital, Turin, Italy. 8 Critical Care Department, Vall d’Hebron University Hospital, CIBERES, Universitat Autonoma de Barcelona, Barcelona, Spain. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ ccmjournal). Supported, in part, by Generalitat de Catalunya grant (SGR 05/920), CIBER Enfermedades Respiratorias, and Carlos III Health Institute grants (PI05/2410 and AI/07/90031). Dr. Blot is an associate board member for the prevention of postoperative pulmonary complications. Dr. Blot received grant support from Ghent University (Special Research Fund) and received support for educational development of slide kit on endotracheal tube management. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected] Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.ccm.0000435665.07446.50
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Measurements and Main Results: Ventilator-associated pneumonia occurred in 103 middle-aged (14.6%), 104 old (17.0%), and 73 very old patients (12.8%). The prevalence (n ventilator-associated pneumonia/1,000 ventilation days) was 13.7 in middle-aged patients, 16.6 in old patients, and 13.0 in very old patients. Logistic regression analysis could not demonstrate older age as a risk factor for ventilator-associated pneumonia. Ventilator-associated pneumonia in elderly patients was more frequently caused by Enterobacteriaceae (24% in middle-aged, 32% in old, and 43% in very old patients; p = 0.042). Regarding clinical signs and symptoms at ventilator-associated pneumonia onset, new temperature rise was less frequent among very old patients (59% vs 76% and 74% for middle-aged and old patients, respectively; p = 0.035). Mortality among patients with ventilator-associated pneumonia was higher among elderly patients: 35% in middle-aged patients versus 51% in old and very old patients (p = 0.036). Logistic regression analysis confirmed the importance of older age in the risk of death (adjusted odds ratio for old age, 2.1; 95% CI, 1.2–3.9 and adjusted odds ratio for very old age, 2.3; 95% CI, 1.2–4.4). Other risk factors for mortality in ventilator-associated pneumonia were diabetes mellitus, septic shock, and a high-risk pathogen as causative agent. Conclusions: In this multicenter cohort study, ventilator-associated pneumonia did not occur more frequently among elderly, but the associated mortality in these patients was higher. New temperature rise was less common in elderly patients with ventilatorassociated pneumonia, whereas more episodes among elderly patients were caused by Enterobacteriaceae. (Crit Care Med 2014; 42:601–609) Key Words: elderly; geriatric; infection; intensive care; mortality; outcome; pneumonia; risk factors
I
n the 20th century, population aging has emerged as a major demographic trend worldwide. As a consequence of the average increase in life expectancy, the number of elderly patients admitted to hospitals is growing fast. As older age is associated with a higher occurrence rate of chronic conditions www.ccmjournal.org
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and substantial functional impairment, ICUs are also confronted with a steadily growing proportion of elderly critically ill patients. In a European center, the proportion of elderly ICU patients (≥ 75 yr) increased from 7% to 17% between the periods 1992–1996 and 2002–2006 (1). Data from the Australian and New Zealand Intensive Care Society Adult Database indicated that in the period 2000 to 2005 13% of all adult patients admitted to ICUs were at least 80 years old (2), and in a French cohort study, 36% of ICU patients appeared to be 70 years old or older (3). The average increase in age of the ICU population has substantial clinical implications. Elderly patients are more vulnerable to the development of healthcare-associated infection because of their immunologic involution, age-associated physiological and anatomical alterations, increasingly severe chronic diseases, and malnutrition (4–6). As a consequence, in a general population, severe infections such as pneumonia and bloodstream infection occur more frequently in elderly compared with younger adults (7). In addition, severe infections in elderly are associated with more complications, as well as with a worse prognosis. Studies concerning the epidemiology of severe nosocomial infections in elderly ICU patients remain scarce and are mainly focused on risk factors and outcome associated with healthcare-associated bloodstream infection (1, 8–10). Yet, despite the availability of evidence-based guidelines and ongoing innovations in prevention and management (11–13), ventilator-associated pneumonia (VAP) remains the most important infectious challenge in the ICU (14, 15). Indeed, the impact of VAP in terms of occurrence rate and clinical and health economic burden is particularly worrisome. A systematic review indicated that VAP is likely to occur in 10–20% of patients who are ventilated for at least 48 hours (15). These patients face a mortality risk estimated to be twice as high compared with similar ICU patients without VAP (pooled odds ratio [OR], 2.0; 95% CI, 1.2–3.6). Furthermore, VAP results in an average excess length of ICU stay of 6 days (95% CI, 5.3–6.8), adding up to an excess hospital cost of $10,000–$13,000 (15). More recent estimates are less dramatic, reporting attributable mortalities ranging 1–6% and an added length of hospitalization of 4 days (95% CI, 1.5–7.0) (14, 16, 17). Despite being more optimistic, these figures still reflect the heavy impact of VAP on healthcare systems (17). It is uncertain if these figures substantially differ with age within adult patients. Given the above-mentioned age-associated physiological alterations and the presence of multiple underlying conditions, it seems plausible that the general epidemiology of VAP in elderly deviates from VAP in younger adults in at least some aspects such as risk profile, causative bacterial pathogens, and outcomes. The objective of this study is to investigate the epidemiology of VAP in elderly ICU patients who are mechanically ventilated for at least 48 hours. More precisely, comparisons between middle-aged, old, and very old ICU patients are performed concerning occurrence rate and prevalence of VAP, risk factors for the acquisition of VAP, clinical signs and symptoms at VAP onset, causative bacterial pathogens, associated mortality, and risk factors for death. 602
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PATIENTS AND METHODS The current study is a secondary analysis of the EU-VAP database (18). The EU-VAP/CAP project was a prospective, observational survey conducted in 27 ICUs from nine European countries: Belgium, France, Germany, Greece, Italy, Ireland, Portugal, Spain, and Turkey. All patients requiring admission for a diagnosis of pneumonia or on invasive mechanical ventilation for more than 48 hours, irrespective of the admission diagnosis, were included. The target was the collection of data on 100 consecutive admissions in each ICU. Patient demographics, primary diagnosis, comorbidities, McCabe classification (19) and Simplified Acute Physiology Score (SAPS) II score at admission (20), ICU and hospital length of stay, duration of mechanical ventilation, and ICU mortality were recorded for all patients. For patients with a clinical diagnosis of pneumonia, data collection included pneumonia type, clinical signs, subjective confidence in diagnosis by the attending physician, sepsis severity (sepsis/ severe sepsis/septic shock) (21), SAPS II score on the previous day and the day of clinical suspicion for VAP, Sequential Organ Failure Assessment score (22) on the day of clinical suspicion of pneumonia, other suspected or concurrent infections, diagnostic procedures performed, microbiologic data, treatment data, clinical response, and pneumonia’s contribution to death as estimated by the attending physician. Because of the specific purpose of the study, we additionally reported an age-adjusted SAPS II score in which points attributed to older age were subtracted from the total score. Each clinical episode of pneumonia was described separately. The participating centers received ethical approval from their institutions. Informed consent was waived because of the observational nature of the study. Full details of the methods have been presented elsewhere (18). In this secondary analysis of the EU-VAP database, patients were classified as “middle aged” (45–64 yr), “old” (65–74 yr), and “very old” (≥ 75 yr) in accordance with previous studies on elderly critically patients (1). Patients younger than 45 years were excluded to avoid possible bias. For the same reason, trauma patients were excluded from the current analysis because of their strong relationship with younger age. Definitions VAP was defined as a pulmonary infection arising in greater than or equal to 48 hours after endotracheal intubation with no evidence of pneumonia at the time of intubation or the diagnosis of a new pulmonary infection if the initial admission to ICU was for pneumonia (11). Early-onset VAP was defined as VAP with onset more than 48 hours but less than 5 days after intubation (11). Late-onset VAP was defined as VAP with onset 5 or more days after intubation (11). Definite pathogen was defined as a microorganism isolated in a patient with suspicion of pneumonia from blood sample and respiratory sample or indicated by serology and judged as definite by the attending physician. Prevalence (expressed per 1,000 patients mechanically ventilated for at least 48 hr) and occurrence rate of VAP (expressed per 1,000 mechanical ventilation days) were calculated for the predefined age groups. In addition, prevalence calculations March 2014 • Volume 42 • Number 3
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were performed with censoring patient days after VAP onset (mechanical ventilation days “at risk” or exposure time). For patients who developed more than one episode of VAP, only the first episode was considered in the analyses. Statistical Analysis Statistical analysis was conducted using SPSS version 20.0 for Windows (SPSS, Chicago, IL). Descriptive data are expressed as n (%) or median (25th–75th percentile). Chi-square test was used for the comparison of categorical variables and the Mann-Whitney U test or Kruskal-Wallis test for the comparison of continuous variables. Cox proportional-hazard regression analysis was performed to identify risk factors for VAP with sensoring on ICU discharge. In an unadjusted model, age categories were the only independent variable included. Two adjusted models were performed with forced entry of age categories in one model and age as a continuous variable in the other. Other independent variables entered into each adjusted model were those with a logical relationship with risk of VAP (e.g., SAPS II score) or variables with VAP in bivariate analysis (p < 0.25). Variables assessed for their relationship with VAP acquisition included the sex, age-adjusted SAPS II score, the primary organ failure leading to ICU admission (respiratory, cardiovascular, neurological, metabolic, renal or hepatic failure, gastrointestinal disorder, and sepsis), and underlying conditions (chronic heart failure, chronic kidney failure, chronic obstructive pulmonary
disease, diabetes, malignancy, immunosuppression, cirrhosis, and alcoholism). Variables with a p value more than 0.15 were stepwise removed from the model. Logistic regression analysis was also used to assess adjusted and unadjusted relationships with mortality and age among patients with VAP. Results of the regression models are reported as OR and 95% CI. Survival curves are prepared by means of the Kaplan-Meier method. Unadjusted survival distributions are compared with use of the log rank test (Fig. 1). Statistical significance is defined as p value less than 0.05.
RESULTS
According to the inclusion criteria, 1,735 patients from 24 centers were eligible for inclusion. The study cohort included 670 middle-aged patients, 549 old patients, and 516 very old patients. Patient characteristics for the distinct age groups are shown in Supplemental Table 1 (Supplemental Digital Content 1, http://links.lww.com/CCM/A753). Very old patients were more likely to be female. Important differences in underlying conditions were observed. Compared with middle-aged adults, old and very old patients had more chronic heart failure, more underlying respiratory disease, more chronic renal failure, more diabetes, and more non-metastatic cancer. Cirrhosis, solid organ transplantation, and alcoholism were more common among middle-aged patients. Severity of disease as assessed by the SAPS II score significantly increased with age category (p < 0.001). However, age-adjusted SAPS II scores were slightly lower among very old patients (p = 0.027). Mortality increased with age category. No differences between the age groups were observed in length of mechanical ventilation and length of ICU stay. Total length of hospitalization was longer in elderly patients, but this difference was no longer significant when only survivors were taken into account. The prevalence of VAP in the total cohort (patients aged ≥ 45 yr) was 14.4 VAP/1,000 ventilation days at risk. The occurrence rate and prevalence of VAP in the distinct age groups are described in Table 1. No important differences were noted between the groups, either when all VAP episodes or only early or late episodes were considered. Also logistic regression analysis could not demFigure 1. Survival curves of patients with ventilator-associated pneumonia according to age category. Solid onstrate a higher risk for VAP black line represents middle-aged patients; solid gray line represents old patients; dashed black line represents among elderly patients (Table very old patients. Log rank test: p = 0.211.
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Table 1. Occurrence Rate and Prevalence of Ventilator-Associated Pneumonia According to Age Age 45–64 Yr
65–74 Yr
≥ 75 Yr
pa
103 (15.4)
104 (18.9)
73 (14.1)
0.082
Early VAP
48 (7.2)
39 (7.1)
25 (4.8)
0.206
Late VAP
55 (8.2)
65 (11.8)
48 (9.3)
0.102
11.5
12.6
10.5
0.130
Early VAP
5.3
4.7
3.6
0.349
Late VAP
6.1
7.9
6.9
0.368
13.7
16.6
13.0
0.202
Early VAP
6.4
6.2
4.4
0.292
Late VAP
7.3
10.4
8.5
0.155
Occurrence rate of VAP, n (%)
Prevalence of VAP, n/1,000 ventilation days
Prevalence of VAP, n/1,000 ventilation days “at risk”
VAP = ventilator-associated pneumonia. a p value for differences between age groups.
Table 2.
Independent Risk Factors for Ventilator-Associated Pneumonia
Potential Risk Factors
Hazard Ratio (95% CI)
P
Unadjusted analysis Middle agea (45–64 yr)
—
—
Old age (65–74 yr)
1.20 (0.91–1.58)
0.191
Very old age (≥ 75 yr)
0.89 (0.66–1.21)
0.456
Adjusted analysis Middle agea (45–64 yr)
—
—
Old age (65–74 yr)
1.20 (0.91–1.58)
0.191
Very old age (≥ 75 yr)
0.89 (0.66–1.21)
0.456
Neurological failure at admission
1.94 (1.41–2.66)
< 0.001
Cardiovascular failure at admission
2.69 (2.02–3.59)
< 0.001
Metabolic, renal, or hepatic failure at admission
1.75 (1.14–2.71)
0.011
0.453 (0.187–0.96)
0.038
0.99 (0.985–1.00)
0.038
0.997 (0.986–1.008)
0.542
Immunosuppression Age-adjusted SAPS II score (per point increase) Adjusted analysis with age as continuous variable Age (per year increase) Neurological failure at admission
1.95 (1.42–2.67)
< 0.001
Cardiovascular failure at admission
2.67 (2.00–3.57)
< 0.001
Metabolic, renal, or hepatic failure at admission
1.72 (1.11–2.65)
0.015
Immunosuppression
0.42 (0.19–0.95)
0.037
Age-adjusted SAPS II score (per point increase)
0.99 (0.98–1.00)
0.041
SAPS = Simplified Acute Physiology Score. a Reference category for older age groups.
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2). The only variable recognized as an independent risk factor for VAP appeared to be length of mechanical ventilation. Bacterial pathogens causing VAP are shown in Table 3. Compared with middle-aged patients, VAP in elderly patients was more frequently caused by Enterobacteriaceae, particularly Escherichia coli and Klebsiella species. No differences were observed in VAP caused by high-risk pathogens or polymicrobial pneumonia. We compared clinical signs and symptoms associated with VAP in the distinct age groups (Table 4). No differences were noted, with the exception of new temperature rise, which was less frequently observed among very old patients. Characteristics of patients with VAP were compared between the age groups (Supplemental Table 2, Supplemental Digital Content 1, http://links.lww.com/CCM/A753). Very Table 3.
old patients more frequently had diabetes mellitus, whereas chronic alcoholism was more common among middle-aged patients with VAP. Mortality among patients with VAP was higher among elderly patients: 35% in middle-aged patients versus 51% in old and very old patients. Logistic regression analysis confirmed the importance of older age as an independent risk factor for death following VAP (Table 5). In this analysis, being old or very old resulted in an identical risk for death. Other risk factors for mortality in patients with VAP were diabetes mellitus as underlying condition, septic shock, and a high-risk pathogen as causative agent. Survival curves of patients with VAP in distinct age groups are illustrated in Figure 1. Curves of middle-aged versus old and very old patients start to diverge after approximately 2 weeks of ICU stay, reaching a maximum after about 1 month. Curves of old
Etiology in Ventilator-Associated Pneumonia According to Age Category Age 45–64 Yr (n = 103)
65–74 Yr (n = 104)
≥ 75 Yr (n = 73)
78 (75.7)
77 (74.0)
58 (79.5)
Methicillin-susceptible Staphylococcus aureus
12 (11.7)
8 (7.7)
8 (11.0)
Methicillin-resistant S. aureus
15 (14.6)
14 (13.5)
9 (12.3)
5 (4.9)
3 (2.9)
0 (0.0)
Enterobacteriaceaea
25 (24.3)a
33 (31.7)
31 (42.5)a
Escherichia colia
8 (7.8)a
11 (10.6)
15 (20.5)a
Klebsiella pneumonia
6 (5.8)
12 (11.5)
11 (15.1)
Proteus mirabilis
5 (4.9)
5 (4.8)
2 (2.7)
Enterobacter species
6 (5.8)
5 (4.8)
3 (4.1)
Serratia marscescens
2 (1.9)
3 (2.9)
3 (4.1)
Citrobacter species
2 (1.9)
0 (0.0)
2 (2.7)
Morganella species
0 (0.0)
2 (1.9)
0 (0.0)
Pseudomonas aeruginosa
20 (19.4)
20 (19.2)
10 (13.7)
Acinetobacter baumannii
15 (14.6)
14 (13.5)
8 (11.0)
2 (1.9)
1 (1.0)
2 (2.7)
6 (5.8)
4 (3.8)
5 (6.8)
45 (43.7)
42 (40.4)
28 (38.4)
24 (23.3)
24 (23.1)
18 (24.7)
Variables
Microbiologically documented ventilator-associated pneumonia, n (%) Gram-positive bacteria
Streptococcus pneumoniae Gram-negative bacteria
Non-fermenting Gram-negative bacteria
Stenotrophomonas maltophilia Gram-negative cocci Haemophilus influenzae/Moraxella catarrhalis High-risk pathogens
b
Polymicrobial episodes
c
p < 0.05 for middle-aged versus very old patients. High-risk pathogens: methicillin-resistant S. aureus, P. aeruginosa, A. baumannii, and S. Maltophilia. c Percentage calculated per total number of episode in each group. Data reported as n (%). The total of percentages may be more than the percentage of microbiologically documented ventilator-associated pneumonia because of the presence of polymicrobial episodes. a
b
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Table 4. Physical and Laboratory Findings in Patients With Ventilator-Associated Pneumonia According to Age Age 65–74 Yr (n = 104)
≥ 75 Yr (n = 73)
Clinical signs of consolidation
59 (57.3)
56 (53.8)
41 (56.2)
0.880
Worsening oxygenation
80 (77.7)
82 (78.8)
57 (78.1)
0.979
Purulent/changing respiratory secretions
79 (76.7)
80 (76.9)
60 (82.2)
0.632
New temperature rise
78 (75.7)
77 (74.0)
43 (58.9)
0.035
1 (1.0)
4 (3.8)
4 (5.5)
0.223
Pleural effusion
20 (19.4)
27 (26.0)
15 (20.5)
0.489
New or worsening chest radiograph infiltrate
74 (71.8)
74 (71.2)
47 (64.4)
0.521
Only peribronchial infiltrate
17 (16.5)
23 (22.1)
19 (26.0)
0.296
Cavitation on chest radiograph (infective cause)
5 (4.9)
13 (12.5)
7 (9.6)
0.152
> 25% increase or > 10,000/μL of WBC count
60 (58.9)
60 (57.7)
41 (56.2)
0.961
4 (1.4)
3 (1.1)
5 (1.8)
0.426
Hypothermia
> 10% immature WBCs a
pa
45–64 Yr (n = 103)
Variables
Indicating difference between middle-aged, old, and very old patients.
and very old patients never differ substantially throughout the ICU course.
DISCUSSION In this multicenter cohort study, we found that older age as such is not a risk factor for VAP. However, this respiratory infection is associated with a significantly higher mortality rate in older age groups. To the best of our knowledge, this is the first study to investigate the prevalence of VAP according to age in a multicenter approach. VAP occurrence rates ranged from 14.1% to 18.9% over the age groups (Table 1) and are as such in line with a systematic review that indicated an average VAP rate of 10–20% for critically ill patients ventilated for more than 48 hours (15). Also the prevalence, as expressed per 1,000 mechanical ventilation days, was not different between the distinct age groups. We assumed that elderly might have had a higher risk profile because of age-associated immunologic involution or—even more important—the presence of more underlying conditions. Indeed, in elderly patients, the number of comorbid conditions—as evidenced by a cumulative illness rating scale—is a better predictor of impaired immunity than chronological age as such (23). In our cohort, old and very old patients had significantly more underlying conditions compared with middle-aged patients. However, rather than underlying diseases, other factors such as noncompliance with evidence-based infection prevention measures (12) or severity of acute illness (24) seem to put patients at a higher risk for VAP. Unexpectedly, however, a higher index of severity of acute illness, as indicated by the age-adjusted SAPS II score, tends to be associated with a protective effect for VAP (p = 0.082) (Table 2). This observation is most probably due to survival bias because many patients with a high SAPS II score died early in the ICU course and as such did not have an equal risk for the 606
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acquisition of VAP in terms of exposure time. Indeed, although mortality at the end of observation was higher among patients with VAP (45.0% vs 37.7%; p = 0.021), survival curves demonstrated a higher mortality in the first month following ICU admission for patients without VAP (data not shown). In other words, in the present study cohort, VAP is a complication that preferably affects patients who survived their initial phase of critical illness while many other very sick patients died before the onset of VAP. A similar but even stronger case of survival bias has been described before. Myny et al (25) found that VAP appeared to be protective for mortality because many patients without VAP died early in the ICU course after which survival curves ran parallel over time. Yet, this difference was no longer significant after adjustment for severity of covariates (OR, 0.79; 95% CI, 0.41–1.53). Analogously, it is in this light that studies aiming to estimate the attributable mortality of VAP by means of causality models failed to demonstrate a substantial added fatality risk (16). Enterobacteriaceae, E. coli and Klebsiella species in particular, more frequently caused VAP in old and very old patients. E. coli has been repeatedly observed as a particular cause of pneumonia in elderly patients, frequently following aspiration (26–28). Transtracheal aspiration is common in neurologically impaired elderly. However, in the current study, neurological impairment was less frequently present in elderly patients. Recently, a laboratory-based study showed that extraintestinal isolates of the antimicrobial resistant E. coli sequence type 131 were independently associated with healthcare facilities and older age (29). In contrast with Enterobacteriaceae, no differences were observed in other high-risk Gram-negative pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii (Table 3). Martin et al (6) also reported Gramnegative bacteria to cause 34.1% of pneumonia in patients 65 March 2014 • Volume 42 • Number 3
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years old or older, whereas in younger patients only 20.5% of pneumonia was caused by such pathogens. Although, in general, the problem of multidrug resistance is more pronounced in elderly patients because of chronic conditions and increased exposure to antimicrobials (30, 31), this appeared not to be the case in the current study. In a study concerning nosocomial bloodstream infection in the ICU, no difference in multidrug resistant etiology was found (1). This may be explained through a similar exposure to antimicrobial use and risk of horizontal transmission of resistant pathogens as well-known risk factors for antimicrobial resistance in all age groups admitted to ICUs. An alternative explanation might be that the classic risk factors such as antimicrobial exposure have lost their stringent relationship with multidrug resistance involvement as resistance has become more and more widespread in the community irrespective of a specific risk profile (32). We compared clinical signs and symptoms of patients with VAP in distinct age categories. Very old patients had significantly less fever at VAP onset compared with old and middle-aged patients (Table 4). It is well known that fever may be blunted in elderly patients with pneumonia. Roughly 20–30% of severe infection will present with blunted or absent fever response (33, 34). In addition, there exists substantial evidence that absence of fever is associated with worse prognosis (35). In our series, absence of new onset of fever only demonstrated a slight trend toward unfavorable outcome (Table 5). Despite the fact that elderly patients do not have an increased risk for acquisition of VAP, their prognosis is substantially worse compared with their younger counterparts. This observation is in line with a large longitudinal observational study using U.S. national hospital discharge data indicating that patients with sepsis aged 65 years old or older had an increased mortality risk compared with patients 65 years old or younger (adjusted OR, 2.26; 95% CI, 2.17–2.36) (6). No difference in the risk for death was noticed between old and very old patients. The high mortality associated with VAP stresses the importance of vigorous application of evidence-based prevention measures such as antiseptic-based oral care and subglottic secretions drainage (36, 37) and further development of innovative strategies to further reduce the risk of VAP in critically ill patients (38). Several limitations of our study must be addressed. First, the study was a secondary analysis and thus was not specifically designed for the research question. As a consequence, neither data on preventive measures nor data on vaccination status were collected. Especially, the latter could have served as an explanation for the low number of pneumococcal pneumonia in elderly. As the primary objective of the EU-VAP project was to identify differences in diagnostic approaches, VAP could be diagnosed on the basis of a broad variety of clinical signs and symptoms, thereby including a potential risk of overdiagnosing. Second, patients were not followed up after hospital discharge, implying a lack of quality-of-life data among elderly survivors. Third, some variables reflecting a specific risk profile for elderly, such as nutritional status and functional disability level, were not included in the present database. On the other hand, data on underlying conditions were available while the Critical Care Medicine
Table 5. Independent Risk Factors for Mortality Among Patients With VentilatorAssociated Pneumonia With Special Emphasis on Age Category Potential Risk Factors for Mortality
OR (95% CI)
p
—
—
Unadjusted analysis Middle agea (45–64 yr) Old age (65–74 yr)
1.93 (1.11–3.38) 0.021
Very old age (≥ 75 yr)
1.91 (1.04–3.53) 0.038
Adjusted analysis Middle agea (45–64 yr)
—
—
Old age (65–74 yr)
2.13 (1.13–3.99) 0.019
Very old age (≥ 75 yr)
2.15 (1.07–4.36) 0.032
Septic shock
2.04 (1.15–3.60) 0.014
High-risk pathogen
2.25 (1.31–3.86) 0.003
Diabetes
2.23 (1.15–4.31) 0.017
Absence of fever at the onset of ventilator-associated pneumonia
1.65 (0.92–2.99) 0.095
Age-adjusted Simplified Acute Physiology Score II scoreb
1.01 (0.99–1.03) 0.192
Exposure timeb
1.02 (0.99–1.06) 0.275
OR = odds ratio. a Reference category for older age groups. b Forced in the model because of logical relationship with mortality. Excluding these variables from the model did not change the final result of the analysis. Hosmer and Lemeshow goodness-of-fit test: p = 0.315.
SAPS II score quantified severity of acute illness. This classification system covers the risk for death as well as the risk for infection in general ICU populations and elderly ICU patients (39, 40). Finally, we did not divide the study cohort into classic age categories used in articles reporting on geriatric patients, including an additional differentiation of patients 75–85 years old and patients 85 years old or older (41). There were several reasons for this. In the present cohort of 1,735 ICU patients 45 years old or older, only 61 were 85 years old or older; 7 of these patients developed VAP. This indicates a limited relevance of such a subgroup within the total ICU population as well as a restricted potential to perform valid statistical analyses. In conclusion, in this multicenter cohort study, VAP did not occur more frequently among elderly, but the associated mortality in these patients was higher. New temperature rise was less common in elderly patients with VAP, whereas more episodes among elderly patients were caused by Enterobacteriaceae.
ACKNOWLEDGMENTS We thank Dr. Joel Dulhunty (The Burns, Trauma and Critical Care Research Centre, Royal Brisbane and Women’s Hospital and The University of Queensland, Brisbane, Australia) for his valuable statistical advice. www.ccmjournal.org
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APPENDIX 1. The EU-VAP Study Investigators Djilali Annane (Raymond Poincaré University Hospital, Garches, France); Rosario Amaya-Villar (Virgen de Rocio University Hospital, Seville, Spain); Apostolos Armaganidis (Attikon University Hospital, Athens, Greece); Stijn Blot (Ghent University Hospital, Ghent, Belgium); Christian BrunBuisson (Henri-Mondor University Hospital, Paris, France); Antonio Carneiro (Santo Antonio Hospital, Porto, Portugal); Maria Deja (Charite University Hospital, Berlin, Germany); Jan DeWaele (Ghent University Hospital, Ghent, Belgium); Emili Diaz (Joan XIII University Hospital, Tarragona, Spain); George Dimopoulos (Attikon University Hospital and Sotiria Hospital, Athens, Greece); Silvano Cardellino (Cardinal Massaia Hospital, Asti, Italy); Jose Garnacho-Montero (Virgen de Rocio University Hospital, Seville, Spain); Muhammet Guven (Erciyes University Hospital, Kayseri, Turkey); Apostolos Komnos (Larisa Hospital, Larisa, Greece); Despoina Koulenti (Attikon University Hospital, Athens, Greece; Rovira i Virgili University, Tarragona, Spain); Wolfgang Krueger (Tuebingen University Hospital, Tuebingen, Germany; Constance
Critical Care Medicine
Hospital, Constance, Germany); Thiago Lisboa (Joan XIII University Hospital, Tarragona, Spain; CIBERES); Antonio Macor (Amedeo di Savoia Hospital, Torino, Italy); Emilpaolo Manno (Maria Vittoria Hospital, Torino, Italy); Rafael Mañez (Bellvitge University Hospital, Barcelona, Spain); Brian Marsh (Mater Misericordiae University Hospital, Dublin, Ireland); Claude Martin (Nord University Hospital, Marseille, France); Ignacio Martin-Loeches (Mater Misericordiae University Hospital, Dublin, Ireland; CIBERES, Corporacio Sanitaria Parc Tauli, Sabadell, Spain); Pavlos Myrianthefs (KAT Hospital, Athens, Greece); Marc Nauwynck (St Jan Hospital, Brugges, Belgium); Laurent Papazian (Sainte-Marguerite University Hospital, Marseille, France); Christian Putensen (Bonn University Hospital, Bonn, Germany); Bernard Regnier (Claude Bernard University Hospital, Paris, France); Jordi Rello (Joan XIII University Hospital, Tarragona, Spain; Vall d’Hebron University Hospital and CIBERES, Spain); Jordi Sole-Violan (Dr. Negrin University Hospital, Gran Canarias, Spain); Giuseppe Spina (Mauriziano Umberto I Hospital, Torino, Italy); Arzu Topeli (Hacettepe University Hospital, Ankara, Turkey); and Hermann Wrigge (Bonn University Hospital, Bonn, Germany).
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