Concise Denitive Review

R. Phillip Dellinger, MD, Section Editor

Pneumonia in the intensive care unit

Jordi Rello; Emili Diaz
Objective: To update the state-of-the-art on pneumonia in adult patients in the intensive care unit (ICU), with special emphasis on new developments in management. Methods: We searched MEDLINE, using the following keywords: hospital-acquired pneumonia, ventilator-associated pneumonia and healthcare-associated pneumonia, diagnosis, therapy, prevention. Results: Interventions to prevent pneumonia in the ICU should combine multiple measures targeting the invasive devices, microorganisms, and protection of the patient. Once pneumonia develops, the appropriateness of the initial antibiotic regimen is a vital determinant of outcome. Three questions should be formulated: a) Is the patient at risk of methicillin-resistant Staphylococcus aureus?; b) Is Acinetobacter baumannii a problem in the institution?; and c) is the patient at risk of Pseudomonas aeruginosa? Antibiotic therapy should be started immediately and must circumvent pathogen-resistance mechanisms developed after previous antibiotic exposure. Therefore, antibiotic choice should be institution specic and patient oriented. Microbiologic investigation is useful on evaluating the quality of the respiratory sample and permits early modication of the regimen in light of the microbiologic ndings. Conclusion: A decision tree outlining an approach to the evaluation and management of ventilator-associated pneumonia is provided. (Crit Care Med 2003; 31:2544 2551)

ospital-associated pneumonia is dened as pneumonia occurring either after the rst 48 hrs of hospital admission or in intubated patients. An articial airway is associated with a 21-fold increase in the risk of developing pneumonia (1). Ventilator-associated pneumonia (VAP) represents 80% of episodes of hospital-associated pneumonia, and the term is applied to episodes developed in intubated or acutely tracheotomized patients under mechanical ventilation. Overall, VAP is the most frequent nosocomial infection in the intensive care unit (ICU) (2) and is responsible for more than half of antibiotic prescription in the ICU. Patients with VAP present a high mortality rate, although the question of whether these patients would survive in the absence of the complication is controversial (3). This article reviews VAP in adult patients, placing particular emphasis on recent investigations. Immunocompromised patients and children will not be considered because these patients may have different pathogens and require specic diagnostic and therapeutic approaches.

EPIDEMIOLOGICAL FEATURES
In the National Nosocomial Infections Surveillance system (4), rates of VAP varied from ve cases per 1000 ventilatordays in pediatric patients to 16 cases per 1000 ventilator-days in patients with thermal injury or trauma. Rates of VAP are generally higher in surgical than in medical ICU patients. Kollef (5) reported an incidence of 21.6% in cardiothoracic patients, compared with 14% in other surgical patients and 9.3% in medical patients. The cumulative risk of developing VAP is around 1% per day of mechanical ventilation, but it is concentrated within the rst days postintubation (6). Intubation is the most important risk factor for developing nosocomial pneumonia (7). Documented massive aspiration is associated with an extremely high incidence of VAP (8). Large study populations provide the best opportunity to identify variables associated with a small increase in probability (i.e., odds ratios [OR] 2) as risk factors for VAP. A prospective cohort study of 1,014 ventilated patients in Canada (9) identied burns (OR 5.09), trauma (OR 5.0), central nervous system disease (OR 3.4), witnessed aspiration (OR 3.25), respiratory disease (OR 2.79), cardiac comorbidity (OR 2.72), ventilation in the last 24 hrs (OR 2.28), administration of paralyzing agents (1.57), and antibiotic exposure (OR 0.37). In a matched cohort study (10) with 9,080 patients in 100 U.S. hospitals,

From the Critical Care Department, Joan XXIII University Hospital, University Rovira i Virgili, Tarragona, Spain. Supported, in part, by grants from Comissio Interdepartamental de Ciencia i Tecnologia (CIRIT) SGR2001/414 and Distincio a la Recerca Universitaria (JR). Copyright 2003 by Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000089928.84326.D2

independent risk factors associated with VAP were male gender (OR 1.58), trauma (1.75), and, interestingly, intermediate deciles of severity on admission (OR 1.471.70 for deciles 31 80%). In lowseverity patients, the time of exposure to mechanical ventilation may not be long enough to acquire VAP, whereas highseverity patients may die before developing pneumonia. The recent consensus conference on VAP (11) concluded that risk factors vary depending on the time of exposure to intubation. For example, in a study (6) investigating pneumonia occurring within 48 hrs after intubation, antibiotic exposure had a protective effect (OR 0.29). In contrast, antibiotic exposure signicantly increased the risk of VAP (OR 1.42) for episodes developed later than 48 hrs. The study by Cook et al. (9) supports this observation (Fig. 1). Survival in patients with VAP is determined primarily by the degree of severity of illness at the time of diagnosis (12). In a recent cohort study (10), 842 patients with VAP (mean interval between intubation and VAP of 3.3 days) were matched with 2,243 control subjects, and hospital mortality rate did not differ (30.5% vs. 30.4%). This does not rule out the possibility that certain subgroups of patients, such as patients with VAP caused by Pseudomonas aeruginosa (1315) or methicillin-resistant Staphylococcus aureus (MRSA) (16) may have had extra attributable mortality rate. Nevertheless, patients with VAP (10) had a signicantly
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longer duration of mechanical ventilation (10 extra days), ICU stay (6 extra days), and hospital stay (11 extra days). The average excess hospital charges for nosocomial pneumonia were estimated to be U.S. $1255 per patient in 1982 in a study by Pinner et al. (17) and $2863 per patient in 1985 in another study by Beyt et al. (18). The largest U.S. study (10) performed to date estimated the cost of VAP per patient in 1999 at $40,000.

PATHOPHYSIOLOGICAL FEATURES AND IMPLICATIONS FOR PREVENTION

There are only four routes through which bacteria can reach the lower respiratory tract to cause VAP: contiguous spread, hematogenous spread, inhalation, and aspiration. Hematogenous or contig-

Figure 1. Probability of developing ventilatorassociated pneumonia according to the exposure to antibiotics and days of intubation. OR, odds ratio.

uous routes of invasion are very rare. Contamination of the ventilator circuits is universal and has no clinical implications. Therefore, the ventilator circuit change interval does not affect the incidence of VAP (19). However, improper manipulation of the circuits may allow condensate from the warm humidied air that ventilates patients to precipitate, and aerosolization of bacteria is possible. This means that great care must be taken during manipulation of circuits. Aspiration is the main route used by bacteria to invade the lower airways and cause VAP. The endotracheal tube holds the vocal cords open, facilitating aspiration. Most patients are sedated, or even paralyzed, and cannot cough efciently. The magnitude of aspiration of gastric content is decreased in patients in a semiupright position, particularly when enterally fed (20, 21). Once aspirated, the secretions pool above the inated endotracheal tube cuff. Maintenance of the upper airway by early tracheotomy (22) or effective drainage of subglottic secretions (23) signicantly reduces the incidence of VAP. The pressure in the endotracheal tube cuff changes (24), deforming it and allowing the secretions to be transported around the inated cuff by capillary action (23, 24). Routine checking of the cuff pressure to maintain it 25 cm of water, but 30 cm of water to prevent tracheal injury, is essential to ensure that subglottic drainage is effective (25). Failure to avoid cuff leak is

associated with introduction of organisms into the distal airspaces. The defense mechanisms attempt to eliminate these organisms, and the outcome will depend on the nature, bacterial burden, and virulence of the organisms and on the biological status of the host. If the tube is left in the trachea for several days, an infected biolm develops on the inner surface of the endotracheal tube. Preclinical studies (26) suggest that the silver coating used in endotracheal tubes delays the onset and decreases the magnitude of lung colonization by P. aeruginosa. Critical steps in the prevention and control of nosocomial infections in the ICU are continuous application of effective infection control, including hand washing and microbiological surveillance. However, the rate of implementation of evidence-based preventive measures (27) for VAP is low, and the reasons for barriers to implementing these measures are varied (28, 29). Educating healthcare professionals and heightening their awareness are the keys to success (30, 31). Indeed, it is vital that all healthcare professionals participate in these programs and that these programs are customized to each ICU to ensure continuous improvement in the provision of care to critically ill intubated patients. Potential measures of control (Table 1) should focus on the patient, the microorganisms, and the device.

MICROBIOLOGICAL FEATURES
The American Thoracic Society (32) and a further report from France (33) described the distribution of causative organisms for VAP according to easily identiable risk factors. These studies suggested that classifying patients according to prior duration of mechanical ventilation and prior exposure or nonexposure to antibiotics provided a rational basis for anticipating the pathogens. However, in a retrospective multiple-center study comparing four treatment sites (34), we concluded that the causes of VAP varied markedly across different institutions. These differences can be explained by differences in patients demographics, strategies for prophylaxis, methods of diagnosis, and, particularly, local patterns of resistant organisms. A further report from Namias et al. (35) in different ICUs from the same hospital conrmed that decisions regarding initial antibiotic choices should consider local patterns.
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Table 1. Evidence-Based Measures to Prevent Ventilator-Associated Pneumonia Strategy Protection of the patient Use of gowns and gloves Adequate nutritional support Avoidance of gastric overdistension Postural changes Semirecumbent positioning Limitation of stress-ulcer prophylaxis Measures targeting microorganisms Hand washing Clorhexidine oral rinse Formal infection control program Avoidance of unnecessary antibiotics Selective digestive decontamination Routine parenteral antibiotics in comatose patients Interventions targeting invasive devices Adequate pressure endotracheal cuff Removal of nasogastric/endotracheal tubes Humidication with head moisture exchangers Drainage of condensate from ventilator circuits Subglottic drainage Oral intubation Modied from Refs. 2729 Evidence Degree

B C B B B B B B C C A B C C A C A D

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Table 2. Microorganisms Causing Ventilator-Associated Pneumonia Trouillet (33) (n 245) 32 (13.1) 20 (8.2) 3 (1.2) 33 (13.5) 23 (19.4) 39 (15.9) 22 (9.0) 15 (6.1) 7 (2.4) 4 (1.6) 9 (3.7) 21 (8.6) 6 (2.4) NR NR Rello (34) (n 301) 38 (12.6) 10 (3.3) 25 (8.3) 10 (3.3) 24 (7.8) 102 (33.9) 38 (12.6) 26 (8.6) NR NR NR 23 (7.6) NR NR NR Ibrahim (36) (n 420) 62 (14.7) 81 (19.3) 6 (1.4) NR NR 130 (30.9) 16 (3.8) 19 (4.5) 9 (2.1) 13 (3.1) 25 (5.6) 28 (6.6) NR 28 (6.6) 5 (3.1)

Pathogen Aerobic Gram-positive MSSA MRSA Streptococcus pneumoniae Other streptococci Other Aerobic Gram-negative Pseudomonas aeruginosa Acinetobacter baumannii Hemophilus inuenzae Proteus species Serratia species Klebsiella species Other Anaerobic ora Fungi Virus

retrospective (culture of tracheal aspirate), and the value given to each element of the score was arbitrary. Obviously, the value of the presence of tracheal secretions should be different from that assigned to the number of blood leukocytes or oxygenation changes. On these grounds, pneumonia should be suspected in the presence of purulent respiratory secretions plus an abnormal chest radiograph. In a critically ill patient in this setting, empirical broad spectrum agents should be administered immediately. Microbiological testing should be performed to rule out other sources and to identify the causative pathogen. This would permit prompt modication of therapy if resistant or de-escalation if several agents are sensitive.

MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus; NR, not reported. Adapted from Refs. 33, 34, 76. Values are no. (%).

DIAGNOSIS
Decisions regarding initiation of empirical therapy can be improved if a cytospin is available in the laboratory and initial antibiotic choices are based on direct staining of respiratory samples. Direct stains, available within 1 hr, can be done from protected specimen brush (41), bronchoalveolar lavage (50), or tracheal aspirates (51). Mertens et al. (52) reported that a gure of 10% neutrophils in bronchoscopic samples is uniformly associated with negative cultures and should be followed by a careful search for alternative diagnoses. Moreover, the cellular product of the sample can be used to evaluate its quality. The presence of 1% of epithelial cells in bronchoscopic samples suggests heavy oropharyngeal contamination, and the interpretation of cultures is unreliable (53). The level may increase to ten squamous epithelial cells per low-power eld (magnication, 100) for tracheal aspirates (51). Unfortunately, Morris et al. (51) reported that 85% of tracheal aspirate specimens should be rejected from analysis because they contained more than ten squamous epithelial cells per low-power eld. So the bacterial burden should be interpreted considering the quality of the sample, the specic clinical setting of the patient (days of intubation and presence of comorbidities), and the potential interference of antibiotics in cultures (44, 54). Figure 2 summarizes the probability of having pneumonia according to the bacterial concentration in respiratory samples. Quantitative bronchoscopic samples are more accurate (55) but are timeCrit Care Med 2003 Vol. 31, No. 10

Table 2 summarizes the distribution of organisms in some major studies (33, 34, 36) of VAP. Haemophilus inuenzae, Streptococcus pneumoniae, and methicillin-sensitive S. aureus should be considered in patients without antibiotic exposure. Compared with patients with VAP caused by methicillin-sensitive S. aureus, patients with MRSA are often older and signicantly more likely to have previous lung disease, steroid therapy, and a longer period of mechanical ventilation. Nearly all MRSA cases were exposed to antibiotics (37). Bacteremia, shock, and mortality rate are signicantly higher in MRSA pneumonia. In a study on VAP (38), nonfermenting Gram-negative bacilli accounted for 25% of the pathogens isolated by protected specimen brush, but they caused up to 80% of deaths related to pneumonia. P. aeruginosa and MRSA are the leading pathogens associated with death by pneumonia. Interpreting the clinical relevance of a positive respiratory culture for fungi in an intubated patient is a major problem. Candida sp. are very commonly isolated. Except in neutropenic or transplant patients, yeasts are isolated from the respiratory tract in the apparent absence of disease (39, 40). Other pathogens such as anaerobes (41), Legionella (42), viruses (43), or Pneumocystis carinii are uncommon.

CLINICAL FEATURES
If an intubated patient develops clinical signs of sepsis (particularly fever and
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leukocytosis), the source should be investigated. Pneumonia is the result of an invading organism overwhelming lung defenses. A local inammatory response follows, which is always manifested by purulent respiratory secretions. In the absence of purulent respiratory secretions, the diagnosis of VAP is unlikely (44). However, the only way to differentiate tracheobronchitis from VAP is by the presence of a radiologic opacity. Radiologic diagnosis, therefore, is mandatory for diagnosis. Unfortunately, Wunderink et al. (45) reported that no single radiographic sign had a diagnostic accuracy 68%. In patients with acute lung injury, this correlation was particularly poor. In addition, many other entities in intubated patients can mimic VAP, such as atelectasis, pulmonary edema, or thromboembolic disease (46, 47). The clinical pulmonary infection score was created to predict the pretest probability of pneumonia (48). It combines information on body temperature, volume and appearance of tracheal secretions, chest radiograph, white blood cell count, oxygenation, and tracheal aspirate culture. Serial measurements of clinical pulmonary infection score (49) are useful to monitor clinical resolution during VAP therapy. A persistent low score after 3 days of therapy in patients in whom pneumonia was unlikely based on the clinical pulmonary infection score allowed a substantial reduction in antibiotic use (47). Unfortunately, some variables were subjective and others

should combine multiple measures targeting the invasive devices, microorganFigure 2. Probability of having presence/absence of pneumonia across the range of colony counts (colony-forming units, CFU) in cultures of protected specimen brush diluent. Reprinted with permission (68).

nterventions to prevent pneumonia in the intensive care unit

isms, and protection of the patient.

consuming, labor intensive, and expensive, and they may not be practical for many laboratories (11, 56) that do not have microbiologists on duty around the clock. Contraindications exist, and management of the ventilator setting should be performed by an expert, maintaining positive end-expiratory pressures in hypoxemic patients, as detailed elsewhere (44). If bronchoalveolar lavage is performed to guide modication of initial resistant therapy in patients with poor resolution (57), the impact on outcome is minimal. In contrast (58), modication of the antimicrobial regimen based on early diagnostic testing (i.e., within 12 hrs of VAP suspicion) has been associated with resolution of 63% of episodes. What we have learned in the past decade (54, 56 59) is that avoiding delay in sampling and starting therapy quickly are more important than the type of quantitative technique used.

MANAGEMENT
Antimicrobial therapies may not benet individuals in whom cardiovascular support is inadequate. Thus, supportive measures to improve hemodynamics and oxygenation are critical. Septic shock and refractory hypoxemia (often in a context of organ dysfunction) are the most frequent mechanisms of death. Marked increases in intrapulmonary shunt combined with mild to moderate ventilationperfusion inequalities are the predominant mechanisms of abnormal gas exchange in patients with VAP. Shunt predominates in the early phase, whereas areas with ventilation-perfusion inequalities are more noticeable during recovery. VAP can be facilitated by a previous lung damage due to an alveolar overdistension by using high tidal volumes during meCrit Care Med 2003 Vol. 31, No. 10

chanical ventilation or by other noninfectious mechanisms (60). Ventilator-induced lung injury also may disseminate local pulmonary infection (61) to the bloodstream, producing bacteremia, systemic inammatory response, and multiple organ dysfunction. Delay in administration of effective therapy for intubated patients with VAP is associated with increases in mortality rate (5759, 62, 63), morbidity rate, and cost (64). Optimizing survival and costs in patients with VAP is based on prompt, adequate therapy (65, 66). The choice of the initial antibiotic should be based on prior antibiotic exposure (67) (Fig. 3), the patients comorbidities (32, 68), the length of hospitalization (33, 36), and local sensitivities (34). In patients with severe sepsis, there is not a second opportunity. Therefore, initial narrowspectrum antibiotic regimens should not be used because they increase the risk of death due to inadequate therapy if resistant pathogens are implicated. The key questions to address in a specic patient with VAP are as follows: a) when to start antibiotics; b) how microbiological tests determine antibiotic changes (de-escalate); c) dose and duration; d) what microorganisms should be covered; and e) the choice of the initial agent. Table 3 summarizes the points that determine the management of VAP in our institution (68). Knowledge of the local microbial epidemiology and susceptibility patterns is crucial in the clinicians choice of antibiotics (34). Heterogeneous use of antibiotics (Fig. 3) removes selective pressure (69). Years of clinical study of antibiotics suggest that a heterogeneous pattern of prescription reduces the likelihood of resistances (69, 70) compared with protocols that main-

Figure 3. Heterogeneous use of antibiotic and choices based on prior exposure.

tain a standard option over a long period of time. The optimal duration of antibiotic therapy is controversial. Most clinical trials, and some guidelines based on expert opinion, recommend a minimum course of 2 wks of therapy for uncomplicated respiratory infections (32). Shorter antibiotic regimens have been used by some authors to reduce antimicrobial costs, adverse events, and the emergence of antibiotic-resistant pathogens (71). Longer courses of antibiotics can increase costs, side effects, and resistant phenotypes and did not prevent recurrences (47). We recommend a patient-based approach that recently was reported elsewhere (68). The antibiotic penetration into lung tissues is of vital importance in therapy. Septic ventilated patients have increased volumes of distribution, which expose them to poor clinical resolution if standard doses are prescribed. This suggests that adequate therapy should no longer be dened on microbiological grounds alone. Breakpoints for pathogens should be customized to respiratory infections, as in the 2002 National Committee on Clinical Laboratory Standards recommendations for pneumococci. The unac2547

Table 3. Tarragona Strategy Antibiotic therapy should be started immediately. Antibiotic choice can be targeted, in same cases, on direct staining. The prescription should be modied in the light of microbiologic ndings. Prolonging antibiotic treatment does not prevent recurrences. Patients with chronic obstructive pulmonary disease or 1 wk of intubation should receive combination therapy, due to the risk of ventilatorassociated pneumonia caused by Pseudomonas aeruginosa. 6. Methicillin-resistant Staphylococcus aureus is not expected in the absence of antibiotic exposure, whereas methicillin-sensitive S. aureus should be strongly suspected in comatose patients. 7. Therapy against yeast is not required, even in presence of Candida species colonization. 8. Vancomycin administration for Gram-positive pneumonias is associated with a very poor outcome. 9. The specic choice of agent should be based on the regimen to which each patient has been exposed previously. 10. Guidelines should be regularly updated and customized to local patterns. ed from Ref. 59. 1. 2. 3. 4. 5.

Figure 4. Flow diagram for guidance in management decisions in ventilator-associated pneumonia. ATB, antibiotic therapy; CBP, carbapenem; PS, Pseudomonal; MRSA, methicillin-resistant Staphylococcus aureus; ARDS, acute respiratory distress syndrome.

ceptably high attributable mortality rate of patients with pneumonia caused by S. aureus treated with vancomycin (16, 72,
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73) when compared with cloxacillin (16, 72) or linezolid (73, 74) illustrates this problem. This difference is probably due

to the poor lung penetration of vancomycin, with epithelial lining uid concentration 4 mg/kg in 36% of ventilated patients (75) and with a plasma/epithelial lining uid ratio of drug penetration of 6:1. Therefore, in our opinion, vancomycin is often a poor choice for MRSA pneumonia, and better alternatives are either linezolid or other antibiotics based on measured sensitivities of the organism (such as trimethoprim-sulfametoxazol or teicoplanin). The effectiveness of a regimen of imipenem plus rifampin in pneumonia caused by imipenem-resistant Acinetobacter baumannii conrms the differences in the concept of adequate therapy when clinical outcomes or in vitro sensitivity is used as the criterion of effectiveness (76). The synergy between both drugs and the excellent penetration to lung tissues may explain why two resistant drugs become effective in vivo. Optimal therapy depends on maintaining a concentration above the minimal inhibitory concentration in lung tissue (68). Opportunities for therapeutic improvement (77) include optimizing dosing, considering pharmacokinetics and pharmacodynamics, and calculating the area under the inhibitory curve. The area under the inhibitory curve allows comparisons between drugs of different classes, regardless of their pharmacokinetics and pharmacodynamic responses. We have recently learned that strains of P. aeruginosa have different expressions of virulence. Secretion of type III proteins has been associated with worse outcomes (relapse or death) in patients with VAP (78, 79). This suggests that antibodies against the PcrV antigen might be used in prevention and therapy of VAP caused by P. aeruginosa. As newer antimicrobial agents are developed, management of VAP in the next decade may conceivably be based on a combination of
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newer antibiotics (79a), different principles of prescription (77), and immunotherapy (80). As for now, prevention based on old (27, 81 84) and new (22, 25, 26, 85, 86) principles should be the cornerstone in the ght against VAP.

SUMMARY
Interventions to prevent pneumonia in the ICU should combine multiple measures targeting the invasive devices, microorganisms, and protection of the patient. Once pneumonia develops, the appropriateness of the initial antibiotic regimen is a vital determinant of outcome. Three questions should be asked: a) Is the patient at risk of MRSA? b) Is A. baumannii a problem in the institution? c) Is the patient at risk of P. aeruginosa? Antibiotic therapy should be started immediately and must circumvent pathogen-resistance mechanisms developed after previous antibiotic exposure. Therefore, antibiotic choice should be institution specic and patient oriented. Microbiological investigation is useful in evaluating the quality of the respiratory sample and permits early modication of the regimen in the light of the microbiological ndings. Figure 4 displays a decision tree outlining the approach to the work-up of VAP.

ACKNOWLEDGMENTS
We thank Dr. Maria Bodi and Alejandro Rodriguez for insightful critique of the manuscript.

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