neumonia asosiada a ventilador

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DOI:10.1378/chest.128.5_suppl_2.583S2005;128;583-591Chest

Andrew F. Shorr and Marin H. KollefVentilator-Associated Pneumonia: Insights From Recent Clinical Trials

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Ventilator-Associated Pneumonia*

Insights From Recent Clinical Trials

Andrew F. Shorr, MD, MPH, FCCP; and Marin H. Kollef, MD

Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in the ICU andcontributes disproportionately to both poor outcomes and the high cost of care in critically illpatients. While VAP has been the focus of extensive research, little consensus exists aboutmethods for diagnosis, treatment, or prevention. Delays in initiating appropriate therapy,antibiotic resistance due to indiscriminate and prolonged use of broad-spectrum antibiotics, andtreatment of patients with a low risk of VAP (based on clinical pulmonary infection scores)represent a sample of VAP-related issues that have been addressed in recent clinical trials.Educational programs for VAP prevention and other nonpharmacologic strategies aimed ateliminating VAP have also been explored in clinical investigations. This review highlights selectedareas of new clinical research on VAP treatment and prevention in order to place theirsignificance in context. (CHEST 2005; 128:583S591S)

Key words: antibiotic resistance; antibiotic therapy; ventilator-associated pneumonia

Abbreviations: CPIS clinical pulmonary infection score; MRSAmethicillin-resistant Staphylococcus aureus;NIV noninvasive mechanical ventilation; VAP ventilator-associated pneumonia

Learning Objectives: 1. To provide an update on the incidence of and potential consequences associated with ventilator-associated pneumonia. 2. To review current research on the topic of ventilator-associated pneumonia,including strategies for its treatment and prevention in critically ill patients.

Ventilator-associated pneumonia (VAP) remainsan area of active clinical investigation. Despite an

improved understanding of this disease, multiple

controversies remain about strategies for diagnosis,prevention, and management. There is, however,general agreement about the burden of VAP and itshigh cost.13 According to the National NosocomialInfection Surveillance system, one third of all noso-

comial infections in US ICUs are pneumonia4; ofthese, 83% are associated with mechanical ventila-tion. Financially, several estimates suggest that the

attributable costs of VAP approach $12,000 percase.5 The impact of VAP is also felt by society.Patients acquiring VAP have poorer outcomes,longer lengths of hospital and ICU stay,3 and highermortality rates.1,5,6

Changes in pathogen distribution and patterns ofantibiotic resistance have complicated care.7 Specif-ically, increased use of all classes of antibiotics overthe past 10 years has correlated with alarming de-clines in susceptibilities. This has simultaneouslyheightened the need to adopt multidrug regimensfor the initial treatment of nosocomial infections.7 In

turn, this creates additional selection pressure and,concomitantly, more resistance.

Several investigators8,9 have identified the initialantibiotic regimen as a key determinant of patientoutcome, and local microbiologic patterns are criticalto guide the choice of a suitable initial treatmentregimen. Observational studies10,11 suggest that cli-nicians primary antibiotic selections for VAP areinadequate (eg, the antibiotic administered does notcover the pathogen or the pathogen is resistant tothat antibiotic) in over one third of cases. The priceof making an incorrect anti-infective decision is high.

*From the Pulmonary Clinic (Dr. Shorr), Pulmonary and CriticalCare Medicine Service Department of Medicine, Walter ReedArmy Medical Center, Washington, DC; and Pulmonary andCritical Care Division (Dr. Kollef), Washington UniversitySchool of Medicine, Barnes-Jewish Hospital, St. Louis, MO.The honorarium for this article has been donated to the ArmyEmergency Relief Fund.

The following authors have disclosed financial relationships witha commercial party. Grant information and company namesappear as provided by the author: Andrew F. Shorr, MD, FCCP:Ortho Biotech - Consultant fee.The following authors have indicated to the ACCP that nosignificant relationships exist with any company/organization

whose products or services may be discussed in their article:Marin H. Kollef, MD, FCCP.This publication was supported by an educational grant fromOrtho Biotech Products, L.P.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Andrew F. Shorr, MD, MPH, FCCP, Pulmo-

nary and Critical Care Medicine, Washington Hospital Center,Washington, DC; e-mail: [email protected]

www.chestjournal.org CHEST / 128 / 5 / NOVEMBER, 2005 SUPPLEMENT 583S

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As with other infections encountered in the ICU,delayed treatment with appropriate antibiotics inde-pendently increases the risk for death from VAP.11 Inan effort to improve outcomes, trials have examinedmechanisms for ensuring adequate antimicrobialcoverage. One approach, the creation of VAP man-agement guidelines, has proven highly successful.12

Because of costs and the concern about overuse and

abuse of antibiotics, nonpharmacologic strategies forthe prevention of VAP have also attracted consider-able attention. Health-care worker hygiene (eg, handwashing), patient positioning techniques, ventilatordevice care, and noninvasive ventilation are someexamples of these strategies.13 Although preventioncan play a key role in reducing VAP incidence, thesemethods may require significant educational com-mitments and high rates of compliance in order toachieve success.14

Whether attempting to treat or prevent this costlycomplication of ICU care, intensivists are constantly

challenged to evaluate results from clinical trials andto keep abreast of current issues and trends in themanagement of VAP. The purpose of this manu-script is, therefore, to review key findings fromselected recent studies regarding VAP treatment andprevention.

Treatment Issues in VAP

Antibiotic Use and Rising Resistance

Few topics in intensive care medicine are as

heavily discussed and debated as antibiotic use. Priorantibiotic exposure together with duration of me-chanical ventilation represent important risk factorsfor development of VAP with resistant organisms.15

Antibiotic selection has the potential to influence thespectrum of bacteria endogenous to the hospital andcommunity,13 and health-care providers need toappreciate that their antibiotic choices have down-stream consequences. Although prompt identifica-tion of infection and isolation of the infecting organ-ism can pose considerable challenges in the ICU,choosing the appropriate antibiotic that will treat the

culprit pathogen and that simultaneously possessesthe narrowest spectrum of activity can be equallychallenging. A recent review of appropriate antibac-terial utilization with examples of successful de-escalation approaches underscores the importance ofthese strategies to contain costs, reduce morbidity,and control the spread of resistance.16

Prolonged and indiscriminate use of antibioticshas affected antibiotic resistance patterns and thesensitivities of organisms frequently encountered inthe ICU. Recent susceptibility data for Gram-nega-tive isolates from ICUs in 43 states show that

resistance of Pseudomonas aeruginosa to ciprofloxa-cin has risen from 17 to 32% between 1994 and 2000and has doubled for other Gram-negative bacilli aswell.7 This trend was coincident with a 2.5-foldincrease in fluoroquinolone utilization nationally(Fig 1). Moreover, Neuhauser and colleagues7 ob-served cross-resistance to cephalosporins and amino-glycosides with selected strains of bacteria, includingP aeruginosa, Enterobacter species, and Klebsiellapneumoniae. They and others17 have hypothesizedthat this has transpired because of the tendency forfluoroquinolones to select for bacteria with increasedefflux capacity for antibiotics. Although Gram-nega-tive pathogens have been implicated in 60% ofVAP cases, Gram-positive pathogens are increasinglyprevalent in the ICU.1 The incidence of VAP due toStaphylococcus aureus now rivals that caused by Paeruginosa. Additionally, methicillin-resistant S au-reus (MRSA) presently account for 50 to 70% of Saureus encountered in the ICU. This fact furthercomplicates antibiotic prescribing since broader useof vancomycin, as the prevalence of MRSA dictates,creates selection pressure for the development ofvancomycin-resistant enterococci.

Duration of Therapy

The duration of antibiotic therapy for VAP pre-sents another conundrum. Until recently, antibiotictreatment durations were based on expert opinionrather than randomized trials. Selecting a treatmentduration requires one to balance the risk of either

failure or relapse with short treatment coursesagainst the threat of antibiotic overuse with moreextended regimens.18 The belief that longer antibi-otic regimens pose no risk to the patient as long asthe specific agents used are effective against theinfecting organisms is false. For example, despiteinitial resolution of clinical parameters of infection within 6 days of instituting appropriate antibiotictherapy, Dennesen and co-workers19 noted thatGram-negative pathogens reemerged to colonize thetrachea during the second week of therapy. This ledto recurrence of VAP but now with strains that were

resistant to the original anti-infectives employed.19To discourage such colonization pressure, shorter

7-day courses of antibiotic therapy have been pro-posed for VAP.19 In a randomized 51-center trial,Chastre and colleagues18 tested the hypothesis thatshort courses (8 days) of initially appropriate antibi-otic therapy for VAP are as effective as traditionalcourses (15 days). The study18 included 401 patientsand was double blinded in the initial phase, throughday 8. Antibiotic selections were not protocolizedand were made at the physicians discretion based oncultures obtained following bronchoscopy (day 1).

584S Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management



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tibiotic prescribing was significant in this study inthat it independently increased the risk for deathnearly sevenfold.

One strategy for improving appropriate and timelyprescribing of anti-infectives for VAP is to adoptclinical guidelines to assist in antibiotic managementdecisions. Before and after implementation of a VAPtreatment guideline in one ICU, Ibrahim and col-

leagues20 demonstrated that initial administration ofappropriate therapy increased from 48.0 to 94.2%(p 0.001). The achievement of high rates of ini-tially appropriate coverage necessitated that theirguideline suggest starting with a broad-spectrummultidrug combination. Specifically, it included cov-erage not only for resistant Gram-negative pathogensbut also for MRSA. Although this approach mightraise concern about contributing further to selectionpressure for resistance, Ibrahim et al20 concomitantlyhypothesized that by guaranteeing correct coverageinitially they would be able to shorten the duration of

therapy. In fact, as a tradeoff for using multipleagents at the outset, they curtailed therapy at 8 daysif the patient was improving clinically. With imple-mentation of their practice guideline they found thatactual treatment durations decreased from14.8 8.1 days to 8.6 5.1 days (p 0.001). Thiswas also associated with a simultaneous reduction inVAP recurrence from 24.0 to 7.7% (p 0.03).

Pressure on physicians to ensure initially appropri-ate antibiotic therapy leads them to quickly initiatetherapy even in patients with a low likelihood ofinfection. Again, one can see the cost of this type of

practice in the rising rates of resistance in the ICU.Singh et al21 explored if it were possible to weanintensivists from the overuse of antibiotics and toguide them to be better antibiotic stewards. Using amodified version of the clinical pulmonary infectionscore (CPIS) [Table 1] proposed by Pugin andcolleagues22 to objectively stratify patients by likeli-hood of pneumonia, Singh and coworkers21 random-ized subjects less likely to have an infection (CPIS 6) to either standard care (10 to 21 days, at thediscretion of the health-care provider) or to a shortcourse of empiric therapy (ciprofloxacin for 3 days

followed by reevaluation, with discontinuation oftreatment if the CPIS remained 6). Outcomes forpatients treated with the short course were compa-rable to those receiving standard therapy. Thus, inpatients with an initial CPIS 6, longer antibioticregimens of 10 to 21 days may not be necessary. It isimportant to note that given the low CPIS coupledwith the rapid improvement in the patients studied,it is likely that few actually had pneumonia. Addi-tionally, the trial should not be viewed as an inves-tigation of the diagnostic value of the CPIS. Rather,these researchers explored if the CPIS could effec-

tively serve as a tool to limit antibiotic abuse. Theauthors22 were cautious to point out the limitationsof their pilot, unblinded, single-center study. Theyrecommended that each institution undertake itsown assessment of antibiotic utilization practicesbefore implementing ultrashort empiric therapy.Nevertheless, these researchers provide a provoca-tive solution for reducing antibiotic use in the settingof suspected VAP. Taken as a whole, the results fromall of these trials demonstrate that the responsibilityfor improvement rests with clinicians. Controllingthe duration of therapy to limit the spread of resis-

tance is indeed possible, if and when therapy isappropriate, initiated promptly, and administered tothe appropriate patients.

Prevention Strategies for VAP

Given cost-containment pressure and shrinkinghealth-care resources, efforts aimed at preventingVAP are of paramount importance. For the reasonsdiscussed above, namely, the emergence of multire-sistant bacteria, strategies employing prophylacticantibiotics such as selective decontamination of the

Table 1CPIS Calculation*

Parameters Points

Temperature, C 36.5 and 38.4 0 38.5 and 38.9 1 39.0 and 36.0 2

Blood leukocytes, L 4,000 and 11,000 0

4,000 or 11,000 (with band forms 50%) 1 (1)Tracheal secretions

None 0Nonpurulent secretions present 1Purulent secretions present 2

Oxygenation: Pao2 /fraction of inspired oxygen, mm Hg 240 or ARDS 0 240 and no ARDS 2

Pulmonary radiographyNo infiltrate 0Diffuse or patchy infiltrate 1Localized infiltrate 2

Progression of pulmonary infiltrateNo radiographic evidence of progression 0

Radiographic progression (congestive heart failure andARDS excluded) 2

Pathogenic bacteria cultured from tracheal aspirateRare or light quantity or no growth 0Moderate or heavy quantity (with same growth on

Gram stain)1 (1)

*Data are used with permission from Pugin et al22 as adapted bySingh etal.21

Defined as Pao2 /fraction of inspired oxygen 200, pulmonaryarterial wedge pressure 18 mm Hg, and acute bilateral infiltrates




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GI tract are controversial and not widely accepted inthe United States.23,24 Fortunately, multiple lesscontroversial nonpharmacologic strategies for VAPprevention exist. Most are well known25 but have notreceived the attention they merit.

Semirecumbency

One of the simplest and least expensive measuresis maintaining the patients head of bed in anelevated position. Increasing the head-of-bed angleis effective because it decreases the risk of aspirationof both gastric contents and of secretions from theupper aerodigestive tract. These secretions are oftencolonized with potentially pathogenic bacteria, andgenerally colonization precedes infection. In a ran-domized prospective study conducted by Drakulovicand colleagues26 in patients receiving mechanicalventilation, semirecumbent positioning to 45 sig-nificantly reduced the risk of clinically suspected

pneumonia by 25% compared to the supine posi-tion. Although a well-recognized, simple, and inex-pensive intervention, Helman et al27 noted duringinformal observation that the majority of patientsreceiving mechanical ventilation in their ICU hadhead-of-bed angles maintained at 30, consistentwith the findings of others.2729 These authors at-tempted to change behavior and practice in theirICU by creating a standardized order set that re-quired head-of-bed positioning at a 45 angle.With this tactic, investigators enhanced compliance,which climbed from 3% before intervention to 16%

(p 0.05). Supplemented with educational pro-grams, head-of-bed positioning compliance furtherimproved. In interviews with nurses, these research-

ers found that concerns about patients sliding in thebed,27 having reduced lateral movement, and patientdiscomfort were the most common reasons offeredfor noncompliance. Although Helman et al27 wereencouraged that head-of-bed angles increased anaverage of 11 over baseline, they emphasized thatsuch interventions, simple as they may seem, requireintense education, constant follow-up, and behavior

modification on the part of physician, nursing, andrespiratory therapy staff. Further research is neededto define whether head-of-bed positioning at 30or 45 prevents VAP to a different extent, sincelower angles were easier to achieve.

Educational Initiatives and Guidelines

The power of educational initiatives and theirpotential to lead to significant reductions in VAP isstriking. Zack and coworkers14 described the impactof a self-study instructional module on VAP preven-

tion strategies. A multidisciplinary task force com-prised of two physician leaders and members of thehospital infection control team developed the pro-gram. Their educational module targeted respiratorycare practitioners and critical care nurses. The in-tense but simple educational effort, involving beforeand after testing, facilitated the reduction of VAP by57.6%. ICUs with the highest initial rates of VAPaccounted for the largest decreases in VAP incidence(Fig 2). The authors14 estimated that their project yielded significant cost savings: up to $4 millionannually. The success of the initiative was, in part,

attributed to the participation of physician leadersand hospital administrators, as well as the generalacceptance of the common goal, preventing VAP.

Figure 2. Impact of educational efforts on reduction of VAP rates in individual ICUs. Data are fromZack et al14 *Significant decrease in VAP rates before and after intervention (p 0.001).




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Not all guidelines or educational initiatives haveachieved such success. Scarcity of resources, patientdiscomfort, disagreement with trial results, fear ofpotential adverse effects, and costs may impedeadoption of comprehensive preventive strategies.30

In a survey conducted by Ricart and colleagues,30

nurses tended to cite patient discomfort and safetyissues, whereas physicians were more likely to name

costs or differences in interpretation of clinical trialresults as reasons for nonadherence with evidence-based preventive strategies. Compliance with prevention recommendations also appears to vary be-tween countries. Cook et al31 compared Canadianand French ICUs regarding the use of seven strate-gies to control secretions and care for ventilatorcircuits to prevent VAP and reduce overall health-care costs. Adherence to specific prevention guide-lines for VAP was statistically more common amongFrench ICUs (64% vs 30%, p 0.002), althoughrates were low in both countries. These investigators

also found that published recommendations did notappear to substantially affect whether preventioninterventions were used within individual ICUs.Cook et al32 also surveyed clinicians to determinespecifically the reasons for the lack of use of semi-recumbency to prevent hospital-acquired pneumo-nia/VAP. Nurses perceived that the main determi-nant of semirecumbency was physicians orders,whereas intensivists perceived that the main deter-minant was nurses preferences. Participants identi-fied barriers to semirecumbency related to usefulalternative positions (eg, lateral position), contrain-

dications (eg, hemodynamic instability), risk of harm(eg, decubitus ulcers), safety (eg, sliding out of thebed), and available resources (eg, insufficient bedsfacilitating semirecumbency). When made aware ofthe evidence, all participants endorsed the use ofsemirecumbency. Armed with this information, clin-ical guidelines and educational programs can bebetter designed to address these issues in an effort toimprove compliance.

Noninvasive Ventilation

Several other nonpharmacologic strategies aimedat VAP prevention have been the subject of research.Noninvasive mechanical ventilation (NIV) has beenshown to reduce the incidence of VAP and mortalityin clinical trials of selected populations.33 By avoid-ing endotracheal intubation, NIV removes a majorrisk factor for the development of VAP. However,broader reliance on NIV has been limited. Girou and

colleagues34 have documented the value of NIV.Over the course of an 8-year longitudinal study inpatients with acute exacerbations of COPD or severecardiogenic pulmonary edema, they observed thatincreased utilization of NIV was associated withdecreased VAP rates and lower mortality (Fig 3).The relationships between NIV and improved sur-vival remained statistically significant after adjustingfor multiple potential confounding variables includ-ing severity of illness, bronchodilator use, and pro-pensity scores (eg, probability of receiving treatment with NIV over the years). In their multivariate

Figure 3. Trends in NIV and associated outcomes34: time-trend analysis of NIV use (p 0.001),nosocomial infections (p 0.01), and ICU mortality (p 0.04); p values are for 1994 vs 2001. Used

with permission from Girou et al.34




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analysis, NIV independently appeared to exert itseffect on improved outcomes mainly by preventingnosocomial infection. A meta-analysis completed byBurns et al35 contains information about noninvasive

positive pressure strategies for weaning from me-chanical ventilation and its impact on VAP.

Endotracheal Intubation

In addition to avoiding endotracheal intubation,redesigning the endotracheal tube has emerged as anintriguing option for VAP prevention. Frequently,the endotracheal tube becomes coated with a bio-film, which promotes upper airway and, in turn,lower airway colonization. Silver-coating urinarycatheters as a means for limiting the emergence of

colonized biofilm reduces urinary tract infections.36

A similar approach is currently being studied withendotracheal tubes. An animal model of mechanical ventilation and pneumonia revealed that silver-coated endotracheal tubes delay host colonization.This decreased propensity for colonization correlateswith histologic evidence of delayed alveolar neutro-phil infiltration and fewer cases of pneumonia.37

Continuous subglottic suctioning of endotrachealtubes represents another option for preventing VAPand is potentially attractive since it can be highlycost-effective.38 A recent study39 in which this tech-

nique was combined with semirecumbent position-ing, however, showed no clinical benefit.

Transfusion Practice

All efforts at preventing VAP initially require theidentification of factors that increase the risk for thiscondition. Hand-washing programs, patient position-ing, avoiding gastric overdistension and nasal intuba-tion, maintenance of ventilator and suction devices,and other VAP prevention strategies all arose fromobservations that these variables both correlated with the diagnosis of VAP and were, at the same

time, potentially modifiable. One issue that hasreceived little attention, specifically as it relates tonosocomial infection, is transfusion practice. Severalstudies4042 have suggested that in non-ICU pa-

tients, RBC transfusion heightens the risk for noso-comial infection. Similar data are emerging for VAP.In a secondary analysis43 of data from a large study(n 4,892) of transfusion practices in critically illpatients,44 RBC transfusions were found to be anindependent risk factor for VAP. Other factors asso-ciated with VAP included male gender, hospitaladmission following trauma, and treatment withheavy sedation (Table 2). Of these, RBC transfusionsmay represent an easily modifiable risk factor, espe-cially since, in a recent study by Levy et al,45 patients

receiving mechanical ventilation received transfu-sions at higher pretransfusion hemoglobin levelsthan patients not receiving mechanical ventilation(8.7 1.7 g/dL vs 8.2 1.7 g/dL, respectively;p 0.0001). Strikingly, there seemed to be no oneclear reason why patients needing mechanical venti-lation received transfusions more often.

Conclusions

VAP is a costly and common complication of

intensive care. Despite multiple studies investigatingthe diagnosis, treatment, and prevention of VAP,disagreement and controversy remain. Education ofpractitioners about VAP prevention, timing of anti-biotic treatment, appropriate selection and durationof antibiotic regimens, proper identification of pa-tients requiring therapy, and counseling against theoveruse of antibiotics represent several importantstrategies to reduce the burden of VAP.

ACKNOWLEDGMENT: The authors thank William Jackson,MD, and Gregory Susla, PharmD, for their helpful comments onearlier drafts of this article.

Table 2Risks of VAP Identified in a Secondary Analysis of Data from the CRIT Study*

VariablesAdjusted Odds Ratio

(95% Confidence Interval) p Value

Male gender 1.54 (1.152.07) 0.0042Trauma admission 1.68 (1.152.47) 0.0079Continuous sedation 1.43 (1.071.92) 0.0158Enteral nutrition within 48 h of mechanical ventilation 2.65 (1.933.63) 0.0001Parenteral nutrition 3.27 (2.244.75) 0.0001

Transfusion with 1 to 2 U of RBCs 1.90 (1.282.82) 0.0027Transfusion with 2 U of RBCs 1.87 (1.242.82) 0.0014Any transfusion 1.89 (1.332.68) 0.0004Duration of mechanical ventilation, d 1.50 (1.331.70) 0.0001

*Data are used with permission from Shorr et al.43 CRIT hematocrit and critical care study by Corwin et al.44

Estimates from a separate model in which any transfusion replaces the categorical transfusion variables.




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DOI:10.1378/chest.128.5_suppl_2.583S2005;128;583-591Chest

Andrew F. Shorr and Marin H. KollefVentilator-Associated Pneumonia: Insights From Recent Clinical Trials

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