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03 August 2012 No.26 Ventilator Associated Pneumonia A Awath Behari Commentator: C Mitchell Moderator: L Pillay Department of Anaesthetics CONTENTS INTRODUCTION ................................................................................................... 3 DEFINITION .......................................................................................................... 3 INCIDENCE AND ETIOLOGY ............................................................................... 3 DIAGNOSIS .......................................................................................................... 6 Clinical................................................................................................................ 6 Microbiological.................................................................................................... 7 Clinical Pulmonary Infection Score (CPIS).......................................................... 8 Biomarkers ......................................................................................................... 8 MANAGEMENT .................................................................................................... 9 RESPONSE TO MANAGEMENT ........................................................................ 10 PREVENTION ..................................................................................................... 11 General Measures ............................................................................................ 11 Specific Measures ............................................................................................ 13 CONCLUSION .................................................................................................... 15 REFERENCES.................................................................................................... 16 Page 2 of 19 INTRODUCTION Ventilator associated pneumonia (VAP) is the commonest cause of hospital morbidity and mortality 1. Despite being a preventable disease, the high ICU incidence rate bears to the fact that traditional approaches and techniques to prevent, diagnose, and manage the disease have not been effective. Knowledge of risk factors, study proven preventative measures, diagnostic methods, and management options is vital not only for critical care specialists but for all clinicians involved in a patient's perioperative management. DEFINITION Ventilator associated pneumonia refers to pneumonias developing in patients who have been receiving mechanical ventilation for at least 48 hours 2. This time frame has been acknowledged to exclude community acquired infections by the United States National Nosocomial Infection Surveillance (NNIS) and was retained for bacterial infections because of their typical incubation period. Early onset VAP is defined as confirmed infection within 96 hours of initiation of mechanical ventilation and those diagnosed after 96 hours are defined as late onset VAP 1. INCIDENCE AND ETIOLOGY Prevalence ranges from 10% to 65% in tertiary care hospitals and can reach 76% in some specific settings which will be dicussed later on. Incriminating pathogens vary among hospitals3. Gram-negative organisms were the most incriminating microbial flora. The most common offending organism isolated in cases with early onset VAP is Pseudomonas aeroginosa followed by Hemophilus influenzae and Eschericia coli. In patients with late onset VAP, the most common organism isolated was Staphylococcus aureus followed closely by Pseudomonas aeroginosa, Klebsiella, Eschericia coli, and Acinetobacter 3. Page 3 of 19 Clinical Analysis of Patients Requiring Long-term Mechanical Ventilation of Over Three Months: Ventilator-associated Pneumonia as a Primary Complication Yoshihiro Kobashi and Toshiharu Matsushima* Prior antimicrobial use and late onset VAP are risk factors for methicillin resistant staphylococcus aureus (MRSA) infection. Unusual pathogens such as Aspergillus species, Candida species, Legionella pneumophilia, Pneumocystis jiroveci, and Cytomegalovirus are causes of VAP in patients who are immunocompromised 4. Page 4 of 19 Risk Factors Biolayer formation In 1986, Sotile et al described the presence of a biofilm or biolayer, which consists of an aggregate of bacteria on the inner surface of the endotracheal tube that protects the organisms from the action of antibiotics and the patient's defences4. Feldman et al found that all tubes had a biofilm in the distal third. Fragments of biofilm can detach spontaneously or dislodged by suction catheters and enter the lungs 5 . This pathological process is known as microaspiration. Adair et al concluded that 70% of patients with VAP had the same organism in the biofilm of the tube as in tracheal secretions5. Risk factors for the development of VAP can be divided into modifiable and non modifiable factors: Non-Pharmacological Prevention of Ventilator Associated Pneumonia Luis Aurelio Díaza; Mireia Llauradób; Jordi Rellob; Jordi Relloc; Marcos I. Restrepod Page 5 of 19 Modifiable factors are based on contribution to the above pathophysiological process. Duration of mechanical ventilation days Gadari et al concluded that mean duration of ventilator days is an important risk factor for the development of VAP. Non modifiable factors include age, severity (score) at admission to ICU , comorbidity (heart failure, chronic obstructive pulmonary disease, diabetes mellitus, neurological disease, neoplasms, trauma, and post op recovery6. Reintubation results in an increased incidence of VAP. This may be due to impaired reflexes following prolonged intubation or due to altered level of consciousness resulting in an increased aspiration risk. Twenty two to fourty percent of patients who have severe head and neck trauma develop VAP 7. DIAGNOSIS Clinical The fundamental problem with the diagnosis of ventilator associated pneumonia is the lack of an internationally accepted gold standard. Diagnosis of pneumonia can be made clinically using Johanson’s criteria if: new lung infiltrates are present, and 2 of the following: - temperature > 38 degrees - leukocytosis/ leukopaenia - purulent secretions If diagnosis is made using the above criteria, prompt empiric treatment should be initiated. Treatment can be modified on day 2-3 based on clinical parameters and semi-quantitative cultures. However, these criteria are non specific and of little utility in the diagnosis of VAP. An autopsy investigation showed that only 52 % of patients with pneumonia at autopsy had a localised infiltrate on their chest radiograph 8. Furthermore, fever and leukocytosis may be caused by other foci of infection in the ICU setting. The advantage of this approach is that it limits the possibility of a missed infection. The disadvantage is that antibiotic use increases and there is a high likelihood of treating non-infection due to the similar clinical picture of other pathologies commonly occurring in a critically ill patient (atelactasis, pulmonary embolism, pulmonary drug reaction, ARDS , etc). Page 6 of 19 Microbiological Diagnosis can also be made on a bacteriological basis using either quantitative endotracheal aspirate (ETA) or bronchoalveolar lavage (BAL). Here, if growth above a threshold is found, a diagnosis of VAP whereas growth below a threshold is considered colonisation. The Canadian Critical Care Trial group demonstrated no significant differences in mortality, other clinical outcomes, or the use of antibiotics between the two groups undergoing either a quantitative endotracheal aspirate (ETA) or bronchoalveolar lavage (BAL) as a diagnostic test in suspected VAP infected patients9. This finding, coupled with the fact that bronchoscopy is invasive and not without its complications especially in patients on high repiratory support, have rendered this diagnostic tool unpopular in most ICU settings. The advantage of the bacteriological approach to diagnosis is that it decreases antibiotic overuse, a narrower spectrum of drug is used, and results in a shorter duration of treatment. However studies have shown that length of ICU stay and duration of mechanical ventilation is not decreased. The disadvantage of this approach is that results are not always consistent and reproducible, risk of contamination of specimens, the delay in obtaining results, and the diagnostic threshold to differentiate infection from colonisation varies between the different techniques. In an attempt to increase the likelihood of diagnosing VAP, Pugin et al created the Clinical Pulmonary Infection Score (CPIS) based on sputum smear microscopy and tracheal aspirate culture, as well as on the clinical findings at the time of diagnostic suspicion. 6 Page 7 of 19 Clinical Pulmonary Infection Score (CPIS) Diagnosis of ventilator associated pneumonia: Critical care 2008 In that study, the authors concluded that there was a good correlation between clinical score and quantitative bacteriology. A CPIS threshold of 6 was found to be a fairly accurate measure of the presence or absence of pulmonary infection, as signified by bacterial culture. Biomarkers 10,11,12,13 The major potential advantage of biomarkers is not to diagnose VAP in isolation, but to improve the rapidity and performance of current diagnostic tools. Markers of alveolar infection, either endogenous mediators released locally by alveolar macrophages or those produced by parenchymal destruction, are assayed. A number of biomarkers, including soluble triggering receptor expressed on myeloid cells - 1 (STREM- 1), procalcitonin (PCT), copeptin, C- reactive protein (CRP), plasminogen activation inhibitor-1 , midregional proatrial natriuretic peptide, and endotoxin or elastin fibres , have been tested recently for use in diagnosing and prognosticating patients with suspected or confirmed VAP. Bloos et al found that the severity of illness as reflected by the degree of organ dysfunction may be a more important determinant of PCT levels than the type or cause of pneumonia13. The results of recent studies suggest that the measurement of biomarkers in bronchoalveolar lavage fluid appears to have minimal value for VAP diagnosis. Page 8 of 19 MANAGEMENT Prompt delivery of empirical therapy is a priority for patients with VAP as delay in appropriate antibiotic therapy has been associated with poor outcomes. Choice of appropriate antibiotics depends on variability of microbes amongst different hospitals. An important consideration when selecting empirical therapy is the agent’s ability to penetrate the infected site and achieve sufficient concentrations for the desired endpoint1. De-escalation of treatment should be opted for when results of investigations become available. Few studies have focused on the penetration of B-lactam agents into the epithelial lining fluid (ELF) and those done have produced a wide variation in results. Studies where ELF and serum were sampled at steady state showed that Ertapenem has an ELF penetration of about 30%. Ceftazadine produced an ELF penetration of26approximately 21%14. Lodise et al studied the penetration of Meropenem into epithelial lining fluid using mass spectrometry to compare serum and ELF levels. They found that high exposure targets for ELF are required to kill or suppress resistant emergence for bacteria like Pseudomonas aeroginosa and that combination chemotherapy may be necessary14. Based on the above, for early onset VAP and those deemed low risk for MDR organisms such as infection with Heamophilus influenzae and antibiotic sensitive enteric gram negatives such as Proteus sp, Enterobacter, E .Coli, and Klebsiella, recommended treatment include ceftriaxone, or levoflox, or ampicillin, or ertapenem26. Treatment options recommended for Pseudomonas, legionella, acinetobacter and klebsiella include: anti-pseudo cephalosporin (cefepime, ceftazidime) or, anti-pseudo carbapenem (impipenem, meropenem), or B-lactamase inhibitor (pipericillin-tazobactam) + anti-pseudo floroquinolone (ciproflox, levoflox) or an aminoglycoside (amikacin, gentamycin, tobramycin) 26. Page 9 of 19 Management of Methicillin Resistant Staphylococcus Aureus (MRSA) MRSA is considered to be a 'superbug' due to its enhanced antibiotic resistance and greater mortality compared to methicillin sensitive Staph aureus strains. This is due to characteristics such as the presence of the mecA gene that encodes a penicillin-binding protein, PBP2a, which is intrinsically insensitive to methicillin and all Beta lactam antibiotics that have been developed. Available studies examining the treatment of MRSA pneumonia with vancomycin have found treatment to be successful in only 35 to 57% of patients .15 A meta-analysis of two studies performed by the same group of investigators using the same study protocol found that patients with MRSA VAP treated with linezolid had a statistically greater survival compared to patients treated with vancomycin .16 Newer cephalosporin antibiotics with MRSA activity hold promise for improved treatment of MRSA pneumonia .1 RESPONSE TO MANAGEMENT26 This depends on patient factors (age, co-morbidities, etc) and bacterial factors (virulence and resistance). Response to management can be: 1. Eradication 2. Superinfection (new organism) 3. Recurrence 4. Persistence Factors attributable to non response to treatment include: a) Incorrect diagnosis (atelectasis, pulmonary embolism, ARDS, neoplasia, CCF, chemical pneumonitis, trauma) b) Treating for an incorrect organism c) Complications (empyaema, lung abscess, sinusitis, catheter related infections) d) Host factors (prolonged ventilation, renal failure, advanced age, prior antibiotic therapy, and chronic lung disease) Management of non-response to treatment include broadening of antimicrobial cover while waiting for results of investigations, repeating septic screen, line change, and biopsy of the lung. Page 10 of 19 PREVENTION General Measures a) Hand Hygiene The common VAP causing organisms, particularly gram negative bacilli and staphylococcus aureus, are of the hospital environment and infection occurs due to transmission from the hands of healthcare workers. The Centers for Disease Control and Prevention have found that the compliance with hand washing recommendations among healthcare workers is low, around 40%. However, the use of alcoholic solutions has increased comlpliance and has decreased the rate of nosocomial infections17. b) Avoiding unnecessary in-patient transfers Studies have reported that of patients who had at least one transfer out of ICU, 24-26% had VAP, while only 4-10% of non transferred patients had VAP (p=0.001) 17. However, no pathophysiological cause for these results has been established. c) Use of Non-Invasive Ventilation (NIV) The use of non-invasive ventilation for amenable conditions, such as acute exacerbations of chronic obstructive pulmonary disease, decreases the incidence and mortality of nosocomial pneumonia. d) Early disconnection from mechanical ventilation 18 As discussed previously, decreasing the duration of mechanical ventilation can reduce the incidence of VAP significantly. Daily interruption of sedation and protocols for early extubation shorten the duration of mechanical ventilation. e) FASTHUG 19 Papadimos et al studied the VAP incidence rate before implementation of the FASTHUG concept (daily evaluation of feeding, analgesia, sedation, thromboembolic prophylaxis, elevation of the head of bed, ulcer prophylaxis, and glucose control) compared to the incidence rate after implementation over a 54 month period. Page 11 of 19 The first twelve months was the historical period. The FASTHUG concept was initiated at the beginning of year 2 of the study (month 25). A time series analysis showed a significant difference in VAP rates between months 1-24 and 25-54 , P= 0.004. f) SDD (Selective Decontamination of the Digestive tract)27 Modulates oropharyngeal colonisation by organisms normally occurring in the digestive tract thereby decreasing biofilm formation. This is done by administration of non-absorbable antibiotics such as tobramycin, polymixin, amphotericin, gentamicin, nystatin and intavenous cefotaxime. This modality has been associated with decreased mortality in ICU and decreased infection with MDR organisms. These findings are based upon meta-analysis and two single centre studies in MRSA-naive settings. Larger and preferably multicentre studies are needed to confirm these observations and SDD is therefore not a widely used modality at present. Page 12 of 19 Specific Measures a) Dental brushing Consistent evidence has shown that oropharyngeal colonisation is the most pathogenic mechanism for VAP development. The 2004 Centers for Disease Control and Prevention guidelines for the prevention of health care associated pneumonia and the 2005 American Thoracic Society guidelines for management of VAP made no recommendation regarding chlorhexidine use, and no evidence based recommendations for oral care are yet available. However, many authors have suggested that establishing and maintaining good oral hygiene should be part of the VAP protective bundle due to the pathogenic mechanism28. b) Head up Critically ill patients frequently suffer from depressed levels of consciousness and impaired vomiting reflex. Thus, keeping the head elevated at 30 - 45 degrees represents benefits to reduce the risk of gastric content reflux and aspiration in patients undergoing mechanical ventilation.20 Interestingly, Hiner et al 21 found only a 50% accuracy of perceived head of bed angle compared with the actual angle among nurse and physician providers based on 'eyeballing' head of bed elevation levels. They found that nurses tended to underestimate the angle whereas clinicians tended to overestimate. They advised the routine use of goniometers for accurate head of bed elevation. c) Prone positioning Prone positioning of patients was initially introduced to improve oxygenation in critically ill patients. It was then hypothesised to prevent the development of VAP based on the movement of tracheal mucus due to gravitational forces. Mounier et al found that prone positioning did not decrease VAP occurrence in a large controlled study. A higher incidence of circuit disconnection and tube dislodgement, together with nursing difficulties have rendered prone positioning as an unpopular means of VAP prevention in most ICUs22. d) Tracheotomy Liberation of the vocal cords in tracheotomised patients results in normal closure of the vocal cords and reduces the risk of aspiration of secretions from the oropharyngeal cavity 23. In addition, the inner surface of the endotracheal tube is known to be a nidus of bacterial biofilm formation. Nseir et al 23 found that early tracheotomy was associated with lower rates of VAP and mortality as compared with later tracheotomy. Early tracheotomy was defined as tracheotomy performed within 48 hours of ICU admission. Duration of mechanical ventilation and ICU stay was significantly shorter in patients with early tracheotomy versus late tracheotomy. Page 13 of 19 Intermittent subglottic secretions drainage (ISSD) 24 Aspiration of subglottic secretions can prevent bacterial contamination of the respiratory tract by decreasing leakage of secretions around the endotracheal tube cuff. It has been shown to reduce the incidence of VAP by nearly 50 percent. In addition, ISSD has been shown to shorten the duration of mechanical ventilation and the length of ICU stay. e) Prevention of bacterial biofilm formation Endotracheal tubes designed to decrease bacterial colonisation and biofilm have been introduced. The NASCENT trial, a prospective, randomised, multicentre study comparing standard and coated endotracheal tubes showed a significant reduction in the incidence of ventilated associated pneumonia (4.8% versus 7.5% , p= 0.03) in patients intubated with a silver coated tube. However, duration of ventilation and ICU length of stay were unchanged between the control and intervention groups 25. f) Mucus Shaver 5 The standard method of cleaning ETT's in intubated patients is via insertion of a small, flexible plastic suction catheter into the ETT. This method has been shown to be suboptimal as residual contaminated secretions may organise into bacterial biofilms, possibly spreading to the lower respiratory tract causing ventilator associated pneumonia. Furthermore, accumulated secretions increase the work of breathing and resistance to airflow, prolonging the weaning process. The mucus shaver is a novel device consisting of a concentric inflatable silicone rubber balloon to shave the ETT lumen. In a study using a sheep model, it was showed that in a single pass, all visible mucus was removed from the internal surface of the ETT. g) Miscellaneous The use of open versus closed suctioning devices and routine change of circuit has not been shown to decrease the incidence of VAP. Page 14 of 19 CONCLUSION Ventilator associated pneumonia is the most common nosocomial infection occurring in patients receiving mechanical ventilation. Patients developing VAP have high mortality rates ranging from 33 to 70% and patients developing VAP are twice as likely to die as those without VAP 4. The biggest obstacle to early diagnosis and initiation of appropriate treatment is the lack of a gold standard for diagnosis. New diagnostic tools such as the use of biomarkers are still in the trial stages and have, as yet, not provided a definitive answer to the diagnostic conundrum. A high degree of vigilance and suspicion for mechanically ventilated patients should always be present. However, study proven methods to prevent the development of the infection has facilitated the decline incidence of VAP with adherence to the so called 'VAP bundle'. While there is a current focus on the development of novel devices to prevent biofilm formation and microaspiration, it is important to remember that lower respiratory tract colonisation is multi factorial. Prevention of VAP cannot be achieved solely by eliminating bacterial biofilm on respiratory devices, and more comprehensive care of intubated patients should be implemented. Page 15 of 19 REFERENCES 1. Clinical practice guidelines for hospital-acquired pneumonia and ventilatorassociated pneumonia in adults Coleman Rotstein, Gerald Evans, Abraham Born, Ronald Grossman, R Bruce Light, MD, Sheldon Magder, Barrie McTaggart, Karl Weiss, and George G Zhanel Can J Infect Dis Med Microbiol. 2008 January;19 (1): 19-53. 2. Early-onset ventilator-associated pneumonia incidence in intensive care units: a surveillance-based study Philippe Vanhems, Thomas Bénet, Nicolas Voirin, Jean-Marie Januel, Alain Lepape, Bernard Allaouchiche, Laurent Argaud, Dominique Chassard, and Claude Guérin BMC Infect Dis. 2011; 11: 236. 3. Rakshit P, Nagar VS, Deshpande AK. Incidence, clinical outcome, and risk stratification of ventilator-associated pneumonia-a prospective cohort study. Indian J Crit care med 2005;9:211-6 4. Non-Pharmacological Prevention of Ventilator Associated Pneumonia Luis Aurelio Díaz, a Mireia Llauradó, b Jordi Rello, b,c and Marcos I. Restrepo d,* Arch Bronconeumol. 2010;46(4):188-195 5. Alternative approaches to ventilator-associated pneumonia prevention L Berra, J Sampson, J. Fumagalli, M Panigada, t Kolobow. Minerva Anesthesiol 2011;77:322-33) 6. Ventilator-associated pneumonia. Carlos Roberto Ribeiro de Carvalho J.bras.pneumonol 2006;32:4-11 7. Ventilator-Associated Pneumonia: Problems with Diagnosis and Therapy Jeanine P. Wiener-Kronish Best Pract Res Clin Anaesthesiol. 2008 September 1; 22(3): 437–449. 8. An Evidence-Based Approach to the Diagnosis of Ventilator-Associated Pneumonia Respiratory Care • November 2009 Vol 54 No 11 9. Nair S, Sen N, Peter JV, Raj JP, Brahmadathan KN. Role of quantitative endotracheal aspirate and cultures as a surveillance and diagnostic tool for ventilator associated pneumonia: A pilot study. Indian J Med Sci 2008;62:304-13 10. Update of the consensus document on ventilator-associated pneumonia: part I. Diagnostic aspects Fica C A, Cifuentes D M, Hervé E B. Rev Chilena Infectol. 2011 Apr;28(2):130-51 11. Comparing the accuracy of predictors of mortality in ventilator-associated pneumonia Renato Seligman; Beatriz Graeff Santos Seligman; Paulo José J.bras pnemol Vol 37 no.4 1590 12. Biological markers and diagnosis of ventilator-associated pneumonia JeanYves Fagon Crit Care. 2011; 15(2): 130. Page 16 of 19 13. Multinational, observational study of procalcitonin in ICU patients with pneumonia requiring mechanical ventilation: a multicenter observational study Frank Bloos, John C Marshall, Richard P Dellinger, Jean-Louis Vincent, Guillermo Gutierrez, Emanuel Rivers, Robert A Balk, Pierre-Francois Laterre, Derek C Angus, Konrad Reinhart, and Frank M Brunkhorst Crit Care. 2011; 15(2): R88 14. Penetration of Meropenem into Epithelial Lining Fluid of Patients with Ventilator-Associated Pneumonia T. P. Lodise,F. Sorgel, D. Melnick B. Mason,M. Kinzig, and G. L. Drusano Antimicrob Agents Chemother. 2011 April; 55(4): 1606–1610. 15. Marin H. Kollef and Scott T. Micek Staphylococcus Aureus Pneumonia : A ''Superbug'' Infection in Community and Hospital Settings Chest 2005;128;1093-1097 16. Wunderlink RG, Rello J, cammarata SK, et al. Linezolid vs Vancomycin: analysis of two double-blind studies of patients with methicillin resistant staphylococcus aureus nosocomial pneumonia. Chest 2003;124:1789-1797 17. Study of prone positioning to reduce ventilator-associated pneumonia in hypoxaemic patients. Mounier R, Adrie C, Français A, Garrouste-Orgeas M, Cheval C, Allaouchiche B, Jamali S, Dinh-Xuan AT, Goldgran-Toledano D, Cohen Y, Azoulay E, Timsit JF, Ricard JD; OUTCOMEREA Study Group Eur Respir J. 2010 Apr;35(4):795-804. Epub 2009 Sep 9. 18. A study of ventilator-associated pneumonia: Incidence, outcome, risk factors and measures to be taken for prevention Hina Gadani, Arun Vyas, and Akhya Kumar Indian J Anaesth. 2010 Nov-Dec; 54(6): 535–540 19. Implementation of Fasthug concept decreases the incidence of ventilator associated pneumonia in a surgical care unit. Thomas J. Papadimos, sandra J Heasley, Joan M Duggan, Sadik A Khuder, marilyn J Borst, john J Faith, Lauri R oakes, Debra Buchman Patient Saf Surg 2008;2-3 20. Evaluation of prevention and control measures for ventilator-associated pneumonia Silvia Rita Marin da Silva Canin; Miyeko Hayashida Rev. LatinoAm. Enfermagem vol.19 no.6 Ribeirão Preto Nov./Dec. 2011 21. Clinicians Perception of Head of Bed Elevation Chad Hiner, Tomoyo Kasuya, Christine Cottingham, joanne Whitney Crit Care Pham 1994;22:206-208 22. Study of prone positioning to reduce ventilator-associated pneumonia in hypoxaemic patients. Mounier R, Adrie C, Français A, Garrouste-Orgeas M, Cheval C, Allaouchiche B, Jamali S, Dinh-Xuan AT, Goldgran-Toledano D, Cohen Y, Azoulay E, Timsit JF, Ricard JD; OUTCOMEREA Study Group. Eur Respir J. 2010 Apr;35(4):795-804 23. Relationship between tracheotomy and ventilator-associated pneumonia: a case–control study S.Nseir, C Di Pompeo, E. Jozefowicz, B. Cavestri, H. Brisson, M. Nyunga Euro Resp Journal July 2006 Page 17 of 19 24. Comparing influence of intermittent subglottic secretions drainage with/without closed suction systems on the incidence of ventilator associated pneumonia Deven Juneja, Yash Javeri, Omender Singh, Prashant Nasa, Rameshwar Pandey, and Bhupesh Uniyal Indian J Crit Care Med. 2011 JulSep; 15(3): 168–172. 25. Prevention of ventilator-associated pneumonia in adults Hallie C Prescott and James M O’Brien Med Rep. 2010; 2: 15 26. Guidelines for the management of adults with HAP, VAP & HCAP - American Journal of Respiratory and Critical Care MedicineFeb 15, 2005 vol. 171 no. 4, pages 388-416. 27. The Prevention of VAP - Review article, NEJM, Feb 25, 1999, Vol. 340, no. 8. Marin, H. Kollef, M.D 28. Update in VAP - COIA 2006, 19, 117-121. William L. Jackson & Andrew F. Shorr Page 18 of 19 NOTES Page 19 of 19