VENTILATOR-ASSOCIATED PNEUMONIA CURRENT STATUS AND FUTURE RECOMMENDATIONS

VENTILATOR-ASSOCIATED PNEUMONIA:CURRENT STATUS AND FUTURE RECOMMENDATIONSShai Efrati,MD 1,Israel Deutsch,BSc 1,Massimo Antonelli,MD 2,Peter M.Hockey,MD 3,Ronen Rozenblum,PhD,MPH 4and Gabriel M.Gurman,MD 5Efrati S,Deutsch I,Antonelli M,Hockey PM,Rozenblum R,Gurman GM,Ventilator-associated pneumonia:current status and future rec-ommendationsJ Clin Monit Comput 2010;24:161–168ABSTRACT .Objective.Ventilator-associated pneumonia (VAP)is a common hazardous complication in ICU patients.The aim of the current review is to give an update on the current status and future recommendations for VAP prevention.Methods.This article gives an updated review of the current literature on VAP.The first part briefly reviews pathogenesis and epidemiology while the second includes an in-depth review of evidence-based practice guidelines (EBPG)and new technologies developed for prevention of VAP.Results.VAP remains a frequent and costly complication of critical illness with a pooled relative risk of 9–27%and mortality of 25–50%.Strikingly,VAP adds an estimated cost of more than $40,000to a typical hospital admission.An important aetiological mechanism of VAP is gross or micro-aspiration of oropharyngeal organisms around the cuff of the endotracheal tube (ETT)into the distal bronchi.Prevention of VAP is preferable.Preventative measures can be divided into two main groups:the implemen-tation of EBPGs and use of device-based technologies.EBPGs have been authored jointly by the American Thoracic Society and the Infectious Diseases Society of America.The Canadian Critical Care Trials group also published VAP Guidelines in 2008.Their recommendations are detailed in this review.The current device-based technologies include drainage of subglottic secretions,silver coated ETTs aiming to influence the internal bio-layer of the ETT,better sealing of the lower airways with ultrathin cuffs and loops for optimal cuff pressure control.Conclusions.EBPG consensus includes:elevation of the head of the bed,use of daily ‘‘sedation vacations’’and decontamination of the oropharynx.Technological solutions should aim to use the most comprehensive combination of subglottic suction of secretions,optimization of ETT cuff pressure and ultrathin cuffs.VAP is a type of hospital-acquired pneumonia that develops more than 48h after endotracheal intubation.Its incidence is estimated to be 9–27%,with a mortality of 25–50%[Am J Respir Crit Care Med 171:388–416(2005),Am J Med 85:499–506(1988),Chest 122:2115–2121(2002),Intensive Care Med 35:9–29(2009)].The most important target in VAP handling is its prevention.The aim of this article is to review the pathogenesis,epidemiology and the different strategies/technologies for prevention of VAP.KEY WORDS.ventilator-associated pneumonia,pathogenesis,epi-demiology,clinical practice guidelines,prevention,technologies.DEFINITION AND EPIDEMIOLOGYVentilator-associated pneumonia (VAP)should be con-sidered in any mechanically ventilated patient who develops new or increased fever,alveolar infiltrate,From the Shai Efrati,Israel Deutsch and Ronen Rozenblum are shareholders in Hospitech Respiration,Ltd.The AnapnoGuard system developed by Hospitech Respiration is being presented in the manuscript.From the 1Research &Development Unit,Assaf Harofeh Medical Center,Affiliated with the Sackler School of Medicine,Tel-Aviv University,Zerifin 70300,Israel;2Department of Intensive Care and Anesthesiology,Policlinico Universitario A.Gemelli,Univer-sita`Cattolica del Sacro Cuore,Largo A,Rome,Italy;3General and Respiratory Medicine,Hampshire Community Health Care,Hampshire,UK;4The Center for Patient Safety Research and Practice,Division of General Medicine,Brigham &Women’s Hospital and Harvard Medical School,Boston,MA,USA;5Faculty of Health Sciences,Beer-Sheva,and Myney Hayesuah Medical Center,Ben-Gurion University of the Negev,Bnei Brak,Israel.Received 8January 2010.Accepted for publication 4March 2010.Address correspondence to S.Efrati,Research &Development Unit,Assaf Harofeh Medical Center,Affiliated with the Sackler School of Medicine,Tel-Aviv University,Zerifin 70300,Israel.E-mail:efratishai@Journal of Clinical Monitoring and Computing (2010)24:161–168DOI:10.1007/s10877-010-9228-2ÓSpringer 2010respiratory secretions,leukocytosis,or respiratory abnor-malities.Diagnostic testing is required whenever VAP is suspected because clinicalfindings alone are nonspecific [1–3].The purpose of diagnostic testing is to confirm VAP and identify the likely pathogen.Diagnostic testing involves radiographic imaging and microbiologic analysis of lower respiratory tract secretions,including gram stain and culture.A clinical pulmonary infection score(CPIS) combining clinical,radiographic,physiologic,and microbiologic data into a numerical result has been sug-gested as a standard for VAP diagnosis.Initial validation of the CPIS found that a score greater than six correlated with VAP[4].VAP remains a frequent and costly complication of critical illness with a pooled relative risk of9–27%and mortality of25–50%[5–8].Strikingly,VAP adds an estimated cost of more than$40,000to a typical hospital admission[7,9].Clearly,the combination of the need to improve patient outcomes,thefinancial impact of improving throughput,and the proposed cut in VAP medicare reimbursement,is serving as a strong impetus to implement practices and policies aimed at reducing the risk of VAP.PATHOGENESISAn important contributing factor to the development of VAP is gross-or micro-aspiration of oropharyngeal organisms into the distal bronchi,followed by bacterial proliferation and parenchymal invasion[5,10–12].In the mechanically ventilated patient,a number of factors conspire to compromise host defenses:critical illness,co morbidities,H2-blockers and antacid therapy,malnutri-tion impairing the immune system.Endotracheal intuba-tion thwarts the cough reflex,compromises mucociliary clearance,injures the tracheal epithelial surface,and pro-vides a direct conduit for rapid access of bacteria from above into the lower respiratory tract[11,13–17].Intu-bation increases the risk of pneumonia6-to20-fold[5], and it would probably be more accurate to rename VAP as‘‘endotracheal-intubation-related pneumonia’’.In order for microorganisms to cause VAP,they must first gain access to the normally sterile lower respiratory tract,where they can adhere to the mucosa and produce sustained infection.Microorganisms gain access by one of four mechanisms:[5]the most common is by aspiration of microbe-laden secretions around the ETT cuff(Figure1). The source of the secretions is either from the oropharynx directly or,secondarily,by reflux from the stomach into the oropharynx;[6]by direct extension of a contiguous infection,such as a pleural space infection;[7]through inhalation of contaminated air or medical aerosols;or[8] by hematogenous carriage of microorganisms to the lung from remote sites of local infection,such as vascular or urinary catheter-related bloodstream infection[10–12, 18–21].PREVENTION OF VAPPrevention of VAP is the gold standard.Preventative measures can be divided into two main groups:clinical practices guidelines and device-based technologies.All measures are aiming at altering at least one of the parameters playing a role in the pathogenesis of VAP: bacterial proliferation and shift of oropharyngeal/GIflora, aspiration of secretions around the ETT cuff,and injury to tracheal epithelium.The standard procedures needed to keep the ventilator circuits disinfected are beyond the scope of this review.Clinical practice guidelinesAn evidence-based practice guideline(EBPG)has been authored jointly by the American Thoracic Society and the Infectious Diseases Society of Americasynthesizing Fig.1.Aspiration of microbial laden secretions around the ETT cuff.162Journal of Clinical Monitoring and Computingand appraising all of the available evidence in this disease state[22].The Canadian Critical Care Trials group also published VAP guidelines in2008[23].In all recom-mendations it is clear that the risk of VAP is related to the use of the ETT and non-invasive mechanical ventilation (NIMV)is recommended whenever possible.If ETT is needed,orotracheal intubation and orogastric tubes should be preferred to nasotracheal intubation and naso-gastric tubes in order to prevent nosocomial sinusitis and to reduce the risk of VAP[8,24].The Boston-based Institute for Healthcare Improve-ment(IHI),has been instrumental in supporting organi-zations to implement EBPGs for the prevention of VAP.[9].The standard component of IHI’s approach is‘‘bun-dles’’of care,defined as‘‘a small,straightforward set of practices—generally three tofive—that,when performed collectively and reliably,have been proven to improve patient outcomes’’[9].The IHI’s ventilator bundle was originally aimed at reducing complications of mechanical ventilation,and not specifically at VAP prevention[9].Of the four components in this bundle,three—head of the bed elevation,daily sedation interruption and daily screening for readiness to extubate—are aimed specifically at VAP prevention[9].Each of these three IHI bundle elements has behind it either a level I(head of the bed elevation and stress bleeding prophylaxis)or level II(use of sedation holidays)evidence individually.In view of this,it is difficult to argue that implementing each of the proposed measures does not amount to good care of pa-tients on mechanical ventilation,supporting the original intent of the mechanical ventilation bundle development [9].‘‘Elevation of the head of the bed’’is an integral part of the ventilator bundle and has been correlated with reduction in the rate of VAP.The recommended eleva-tion is30–45°[9,25].While it is not immediately clear whether the intervention aids in the prevention of VAP by decreasing the risk of aspiration of gastrointestinal contents or oropharyngeal and nasopharyngeal secretions, this was the ostensible reason for the initial recommen-dation.Even though elevation of the head seems to be effective,some studies have indicated that a variety of reasons preclude this goal from being achieved85%of the time,and even call its effectiveness into question[26]. The fourth component of the IHI bundle is stress ulcer bleeding prophylaxis.Stress ulcerations are the most common cause of gastrointestinal bleeding in intensive care unit patients,and the presence of gastrointestinal bleeding due to these lesions is associated with afivefold increase in mortality compared to ICU patients without bleeding[9].Applying peptic ulcer disease prophylaxis is therefore a necessary intervention in critically ill patients.A concern about prophylactic therapy for stress ulceration has been the potential for increased risk of nosocomial pneumonia[9].Agents that raise gastric pH may promote the growth of bacteria in the stomach,particularly gram-negative bacilli that originate in the duodenum.One randomized trial comparing antacids,H2blockers and sucralfate reported no differences in rates of early-onset VAP,while rates of late-onset VAP were reduced in pa-tients treated with sucralfate[27].However,another large, double-blind,randomized study comparing ranitidine with sucralfate reported a clinically significant increase in gastrointestinal bleeding among patients receiving sucral-fate[28].Consequently,if stress ulcer prophylaxis is indicated,the risk and benefits of each therapeutic strategy should be carefully considered[8].Using daily‘‘sedation vacations’’and assessing the pa-tient’s readiness to extubate is an integral part of the ventilator bundle[9,29].It appears that lightening seda-tion decreases the amount of time spent on mechanical ventilation and therefore the risk of ventilator-acquired pneumonia[9].In addition,weaning patients from ven-tilators becomes easier when patients are able to assist themselves at extubation with coughing and control of secretions[9].However,sedation vacations are not without risks.Patients who are not sedated as deeply will have an increased potential for self-extubation.Therefore, the maneuver must be conducted in a careful fashion[9]. In addition,there may be an increased potential for pain and anxiety associated with lightening stly, increased tone and poor synchrony with the ventilator during the maneuver may risk episodes of desaturation[9]. Decontamination of the oropharynxGingival and dental plaque rapidly becomes colonized with aerobic pathogens in ICU patients due to poor oral hygiene and lack of mechanical elimination.Results from a meta-analysis of11trials of3,242mechanically venti-lated adults who were treated with oral application of antibiotics or antiseptics or with placebo or standard oral care alone[30],showed that the incidence of VAP was significantly reduced by oral antiseptics such as chlorh-exidine(relative risk[RR]0.56,95%CI0.39–0.81)but not oral applications of antibiotics(RR0.69,95%CI 0.41–1.18).Technologies and devicesSubglottic drainageDrainage of subglottic secretions may lessen the risk of aspiration and thereby decrease the incidence of VAP. Specially designed endotracheal tubes have been devel-oped to provide continuous aspiration of subglottic secretions(CASS)[31–34].However,even though the Efrati et al.:VAP Status and Future Recommendations163CASS system can lower bacterial colonization of the respiratory tract,there is a risk of severe tracheal mucosal damage at the level of the suction port [35].The aetiology of mucosal damage is suction performed in a relatively small space (the boundaries are the vocal cords,tracheal mucosa,ETT and ETT cuff)creating a vacuum that ad-heres the tracheal mucosa to the suction port.The vacuum created in the subglottic area is responsible for the severe macroscopic and microscopic damage of the tracheal mu-cosa and is also responsible for the inability to perform effective suction in many patients intubated with the Hi-Lo Evac (Mallinckrodt Inc.,Athlone,Ireland)(Table 1).Silver-coated endotracheal tubeSilver-coated ETTs reduce the incidence of VAP.This was demonstrated in a prospective,randomized,single-blinded trial in which a silver-coated ETT was compared to an uncoated ETT in 2003patients requiring mechan-ical ventilation [36].Among patients intubated for more than 24h,the rate of microbiologically confirmed VAP was significantly lower with the silver-coated ETT.The silver-coated ETT was also associated with a significant delay in the occurrence of VAP,suggesting the main beneficial effect was during the relatively early days of intubation.There were no differences between the groups in the duration of intubation,intensive care unit stay,or hospital stay;mortality;or the frequency or severity of adverse events [36].It should be noted that the silver coated ETTs may influence the internal bio-layer of the ETT but they do not have any significant effect on the aspiration around the ETT.Ultrathin cuffThe high-volume low-pressure cuffs developed to pro-vide tracheal sealing at lower cuff pressures may leak due to folds created when the cuff is inflated in a lower diameter trachea [37,38].To overcome this,a new generation of high-volume low-pressure thin walled cuffs was developed.Wall thickness reduction shrinks voids created by folds and cuff vulnerability to leakage [38].Recently,two versions of ultrathin cuffs have been approved for clinical use:the Microcuff äETT of Kim-berly-Clark Ltd and the SealGuard äETT of Covidien Ltd.In both cases the cuff is made of polyurethane.The use of endotracheal tubes with ultra-thin cuffs and inter-mittent subglottic secretion drainage were shown to reduce VAP.The better sealing of the new generation of ultra thin cuffs,should be accompanied with continuous or intermittent aspiration of subglottic secretions [39].As detailed above,it should again be noted that CASS or intermittent aspiration of secretions may be dangerous while using a single lumen for suction (due to the vacuum created below the vocal cords).T a b l e 1.C o m p a r i s o n b e t w e e n t h e c u r r e n t a v a i l a b l e t e c h n o l o g i e sT e c h n o l o g yD e v i c e s i n t h e m a r k e tC u f f p r e s s u r e c o n t r o lL o w i n t r a c u f f p r e s s u r eL e a k a g e d e t e c t i o n S e c r e t i o n s e v a c u a t i o nD i l u t i o n o f s e c r e t i o n sS t a f f r e d u c e d o v e r l o a d A u t o m a t i c o p e n -l o o p p r e s s u r e c o n t r o l T r a c o eÖU l t r a t h i n c u f f sT a p e r e d E v a c (C o v i d i e n )M i c r o c u f f (K i m b e r l a y )ÖÖC A S S -s u c t i o n t u b e s T a p e r e d E v a c (C o v i d i e n )ÖÖC o m p r e h e n s i v e s e a l i n g c o n t r o lA n a p n o G u a r d (H o s p i t e c h )ÖÖÖÖÖÖ164Journal of Clinical Monitoring and ComputingAutomatic open loop pressure controlA critical component in the management of mechanically ventilated patients is to avoid complications related to inappropriate ETT cufffilling[15,40–42].An appropri-ately inflated ETT cuff should achieve isolation of the lower airways,thus reducing the risk of aspiration around the cuff and possible VAP.However,an over-inflated cuff may cause local mechanical complications such as mucosal ulcerations,granulomas,tracheal stenosis,and tracheoe-sophagealfistulae[15,40,41,43].The tracheal tissue/ mucosa is especially sensitive to mechanical complications in patients with low blood pressure since thetissue parison between the Hi-Lo Evac and the new Hospitech endotracheal tube used for subglotic aspiration of secretions.(a)Photos of the Hi-Lo Evac and the new endotracheal tube of Hospitech.(b)Hospitech endotracheal tube:the position of the extra subglotic opening for vacuum prevention and CO2 sampling.Efrati et al.:VAP Status and Future Recommendations165perfusion pressure is low.As a general guideline,the cuff pressure should be maintained between18and 25mmHg.A cuff pressure above18mmHg is expected to prevent leakage around the ETT cuff[44].However, since the relation between the patient tracheal anatomy and the ETT cuff are hard to predict,and since there are more dynamic parameters that may affect the minimal cuff pressure needed to prevent leakage(e.g.ETT location, maximal ventilation pressure,mucosal edema)it is very difficult to predict the optimal cuff pressure for an indi-vidual patient.Accordingly,it was demonstrated that an ETT with a device that sets the cuff pressure automatically by an open loop pressure controller does not have a beneficial effect with regards to VAP,ICU mortality,or hospital mortality[45].A comprehensive continuous sealing control systemOptimal ETT cufffilling is defined as the minimal pres-sure required for airway isolation.It is influenced by airway anatomy,cuff location,cuff compliance,size and volume,and by peak inspiratory pressure[46,47].The common clinical practice of optimizing cufffilling by auscultation or by assessing inhaled/exhaled volume dif-ference is imprecise,and evaluating leak by dye infusion is impractical.It has been demonstrated that even with optimal conditions in elective surgical patients,and the use of an automatic cuff pressure controller,anesthesiol-ogists only set the optimal cuff pressure in15%of patients [48].In order to confirm complete sealing of the ETT cuff, maintain baseline cuff pressure,and monitor the cyclic changes in the intra-cuff pressures during the respiration cycle,the AnapnoGuard system was developed(Hospi-tech Respiration Ltd,Petach Tikva,Israel).In brief,The AnapnoGuard system has been developed to detect any leak around the ETT cuff during the respiratory cycle.As detailed elsewhere[48],the optimal tracheal sealing by ETT cuff is based on closed loop control of the CO2 levels above the cuff and of intra cuff-pressure.Any leakage sensed above the cuff expressed by an increase of CO2level marks non-optimal sealing of the trachea and the system sets the optimal pressure accordingly[48]. Moreover,the system automatically performs cyclic sub-glottic suction of secretions.However,unlike the CASS system,in order to prevent the resultant vacuum in the subglottic space and the related mucosal damage,the AnapnoGuard system uses a specially designed ETT that has an extra lumen,in addition to the suction lumen (Figure2).When the subglottic suction is activated the extra lumen is open and thereby avoiding the creation of a hazardous vacuum.The AnapnoGuard system has recently gained CE approval and is currently in use in clinical trials.IN CONCLUSIONMuch effort is being made in order to prevent VAP and the combination of new technologies and better clinical practices holds promise for better results in this arena. Practical clinical recommendations are for:elevation of the head of the bed,use of daily‘‘sedation vacations’’and decontamination of the oropharynx.Technological rec-ommendations should aim to use the most comprehensive combination of solutions:subglottic suction of secretions, optimization of ETT cuff pressure and ultrathin cuffs. REFERENCES1.Andrews CP,Coalson JJ,Smith JD,Johanson WG Jr.Diag-nosis of nosocomial bacterial pneumonia in acute,diffuse lung injury.Chest1981;80:254–258.2.Fagon JY,Chastre J,Hance AJ,Domart Y,Trouillet JL,GibertC.Evaluation of clinical judgment in the identification andtreatment of nosocomial pneumonia in ventilated patients.Chest1993;103:547–553.3.Fagon JY,Chastre J,Hance AJ,Guiguet M,Trouillet JL,Domart Y,Pierre J,Gibert C.Detection of nosocomial lung infection in ventilated e of a protected specimen brush and quantitative culture techniques in147patients.Am Rev Respir Dis1988;138:110–116.4.Wood AY,Davit AJ II,Ciraulo DL,Arp NW,Richart CM,Maxwell RA,Barker DE.A prospective assessment of diag-nostic efficacy of blind protective bronchial brushings com-pared to bronchoscope-assisted lavage,bronchoscope-directed brushings,and blind endotracheal aspirates in ventilator-asso-ciated pneumonia.J Trauma2003;55:825–834.5.America ATSIDSo.Guidelines for the management of adultswith hospital-acquired,ventilator-associated,and healthcare-associated pneumonia.Am J Respir Crit Care Med2005;171: 388–416.6.Chastre J,Fagon JY,Soler P,Bornet M,Domart Y,TrouilletJL,Gibert C,Hance AJ.Diagnosis of nosocomial bacterial pneumonia in intubated patients undergoing ventilation: comparison of the usefulness of bronchoalveolar lavage and the protected specimen brush.Am J Med1988;85:499–506. 7.Rello J,Ollendorf DA,Oster G,Vera-Llonch M,Bellm L,Redman R,Kollef MH.Epidemiology and outcomes of ventilator-associated pneumonia in a large US database.Chest 2002;122:2115–2121.8.Torres A,Ewig S,Lode H,Carlet J.Defining,treating andpreventing hospital acquired pneumonia:European perspec-tive.Intensive Care Med2009;35:9–29.9.IHI Ifhci-.Implement the Ventilator Bundle.2008.10.Estes RJ,Meduri GU.The pathogenesis of ventilator-associ-ated pneumonia:I.Mechanisms of bacterial transcolonization and airway inoculation.Intensive Care Med1995;21:365–383.11.Safdar N,Crnich CJ,Maki DG.The pathogenesis of ventila-tor-associated pneumonia:its relevance to developing effective166Journal of Clinical Monitoring and Computingstrategies for prevention.Respir Care2005;50:725–739dis-cussion39–41.12.Alcon A,Fabregas N,Torres A.Hospital-acquired pneumonia:etiologic considerations.Infect Dis Clin North Am2003;17: 679–695.13.Bone DK,Davis JL,Zuidema GD,Cameron JL.Aspirationpneumonia.Prevention of aspiration in patients with trach-eostomies.Ann Thorac Surg1974;18:30–37.14.Gal TJ.Effects of endotracheal intubation on normal coughperformance.Anesthesiology1980;52:324–329.15.Klainer AS,Turndorf H,Wu WH,Maewal H,Allender P.Surface alterations due to endotracheal intubation.Am J Med 1975;58:674–683.16.Levine SA,Niederman MS.The impact of tracheal intubationon host defenses and risks for nosocomial pneumonia.Clin Chest Med1991;12:523–543.17.Kollef MH.Ventilator-associated pneumonia.A multivariateanalysis.JAMA1993;270:1965–1970.18.de Latorre FJ,Pont T,Ferrer A,Rossello J,Palomar M,PlanasM.Pattern of tracheal colonization during mechanical venti-lation.Am J Respir Crit Care Med1995;152:1028–1033.19.Ewig S,Torres A,El-Ebiary M,Fabregas N,Hernandez C,Gonzalez J,Nicolas JM,Soto L.Bacterial colonization patterns in mechanically ventilated patients with traumatic and medical head injury.Incidence,risk factors,and association with ven-tilator-associated pneumonia.Am J Respir Crit Care Med 1999;159:188–198.20.Meduri GU,Estes RJ.The pathogenesis of ventilator-associ-ated pneumonia:II.The lower respiratory tract.Intensive Care Med1995;21:452–461.21.Hamill RJ,Houston ED,Georghiou PR,Wright CE,KozaMA,Cadle RM,Goepfert PA,Lewis DA,Zenon GJ, Clarridge JE.An outbreak of Burkholderia(formerly Pseudomo-nas)cepacia respiratory tract colonization and infection associ-ated with nebulized albuterol therapy.Ann Intern Med1995;122:762–766.22.Kollef MH,Morrow LE,Baughman RP,Craven DE,McGowan JE Jr,Micek ST,Niederman MS,Ost D,Paterson DL,Segreti J.Health care-associated pneumonia(HCAP):a critical appraisal to improve identification,management,and outcomes—proceedings of the HCAP summit.Clin Infect Dis 2008;46(Suppl4):S296–S334quiz5–8.23.Muscedere J,Dodek P,Keenan S,Fowler R,Cook D,Hey-land prehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia:prevention.J Crit Care2008;23:126–137.24.Rouby JJ,Laurent P,Gosnach M,Cambau E,Lamas G,Zouaoui A,Leguillou JL,Bodin L,Khac TD,Marsault C,et al.Risk factors and clinical relevance of nosocomial maxillary sinusitis in the critically ill.Am J Respir Crit Care Med1994;150:776–783.25.Drakulovic MB,Torres A,Bauer TT,Nicolas JM,Nogue S,Ferrer M.Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients:a randomised ncet1999;354:1851–1858.26.van Nieuwenhoven CA,Vandenbroucke-Grauls C,van TielFH,Joore HC,van Schijndel RJ,van der Tweel I,Ramsay G, Bonten MJ.Feasibility and effects of the semirecumbent po-sition to prevent ventilator-associated pneumonia:a random-ized study.Crit Care Med2006;34:396–402.27.Prod’hom G,Leuenberger P,Koerfer J,Blum A,Chiolero R,Schaller MD,Perret C,Spinnler O,Blondel J,Siegrist H, SaghafiL,Blanc D,Francioli P.Nosocomial pneumonia in mechanically ventilated patients receiving antacid,ranitidine, or sucralfate as prophylaxis for stress ulcer.A randomized controlled trial.Ann Intern Med1994;120:653–662.28.Cook D,Guyatt G,Marshall J,Leasa D,Fuller H,Hall R,Peters S,Rutledge F,Griffith L,McLellan A,Wood G,KirbyA.A comparison of sucralfate and ranitidine for the preventionof upper gastrointestinal bleeding in patients requiring mechanical ventilation.Canadian Critical Care Trials Group.N Engl J Med1998;338:791–797.29.Kress JP,Pohlman AS,O’Connor MF,Hall JB.Daily inter-ruption of sedative infusions in critically ill patients undergoing mechanical ventilation.N Engl J Med2000;342:1471–1477.30.Chan EY,Ruest A,Meade MO,Cook DJ.Oral decontami-nation for prevention of pneumonia in mechanically ventilated adults:systematic review and meta-analysis.BMJ2007;334: 889.31.Smulders K,van der Hoeven H,Weers-Pothoff I,Van-denbroucke-Grauls C.A randomized clinical trial of inter-mittent subglottic secretion drainage in patients receiving mechanical ventilation.Chest2002;121:858–862.32.Kollef MH,Skubas NJ,Sundt TM.A randomized clinical trialof continuous aspiration of subglottic secretions in cardiac surgery patients.Chest1999;116:1339–1346.33.Bouza E,Perez MJ,Munoz P,Rincon C,Barrio JM,Hortal J.Continuous aspiration of subglottic secretions in the prevention of ventilator-associated pneumonia in the postoperative period of major heart surgery.Chest2008;134:938–946.34.Dezfulian C,Shojania K,Collard HR,Kim HM,Matthay MA,Saint S.Subglottic secretion drainage for preventing ventilator-associated pneumonia:a meta-analysis.Am J Med2005;118: 11–18.35.Berra L,Panigada M,De Marchi L,Greco G,ZX Y,BaccarelliA,Pohlmann J,Costello KF,Appleton J,Mahar R,Lewan-dowski R,Ravitz L,Kolobow T.New approaches for the prevention of airway infection in ventilated patients.Lessons learned from laboratory animal studies at the National Institutes of Health.Minerva Anestesiol2003;69:342–347.36.Kollef MH,Afessa B,Anzueto A,Veremakis C,Kerr KM,Margolis BD,Craven DE,Roberts PR,Arroliga AC, Hubmayr RD,Restrepo MI,Auger WR,Schinner R.Silver-coated endotracheal tubes and incidence of ventilator-associ-ated pneumonia:the NASCENT randomized trial.JAMA 2008;300:805–813.37.Asai T,Shingu K.Leakage offluid around high-volume,low-pressure cuffs apparatus A comparison of four tracheal tubes.Anaesthesia2001;56:38–42.38.Dullenkopf A,Schmitz A,Gerber AC,Weiss M.Trachealsealing characteristics of pediatric cuffed tracheal tubes.Paediatr Anaesth2004;14:825–830.39.Lorente L,Lecuona M,Jimenez A,Mora ML,Sierra A.Influence of an endotracheal tube with polyurethane cuff and subglottic secretion drainage on pneumonia.Am J Respir Crit Care Med2007;176:1079–1083.40.Stauffer JL,Olson DE,Petty plications and conse-quences of endotracheal intubation and tracheotomy.A pro-spective study of150critically ill adult patients.Am J Med 1981;70:65–76.Efrati et al.:VAP Status and Future Recommendations167。