1. VAP: what, how, and why ? Bradley J. Phillips, M.D. Critical Care Medicine Boston Medical Center Boston University School of Medicine TRAUMA-ICU NURSING EDUCATIONAL SERIES

2. Nosocomial Pneumonia Leading cause of death from hospital-acquired infections, with an associated mortality rate of 30 %. VAP is a sub-type of nosocomial pneumonia specifically referring to a bacterial source Kollef. NEJM 1999

3. “VAP” defined as parenchymal lung infection occurring more than 48 hrs after the initiation of mechanical ventilation Morehead & Pinto. Arch Int Med 2000

4. VAP: a framework (1) Early-onset VAP Early-onset VAP occurs within 48 – 72 hrs after tracheal intubation occurs within 48 – 72 hrs after tracheal intubation often from aspiration during the intubation process often from aspiration during the intubation process usually due to antibiotic-sensitive bacteria usually due to antibiotic-sensitive bacteria Oxacillin-sensitive Staph aureus Oxacillin-sensitive Staph aureus Haemophilus influenzae Haemophilus influenzae Strep pneumoniae Strep pneumoniae Kollef. NEJM 1999

5. VAP: a framework (2) Late-onset VAP Late-onset VAP occurs after 72 hrs of mechanical ventilation occurs after 72 hrs of mechanical ventilation multiple theories behind it’s actual development multiple theories behind it’s actual development usually due to antibiotic-resistant bacteria usually due to antibiotic-resistant bacteria Oxacillin-resistant Staph aureus (“MRSA”) Oxacillin-resistant Staph aureus (“MRSA”) Pseudomonas aeruginosa Pseudomonas aeruginosa Acinetobacter species Acinetobacter species Enterobacter species Enterobacter species Kollef. NEJM 1999

6. Why are we talking about VAP ? Single most common ICU nosocomial infection Single most common ICU nosocomial infection Incidence: 20 - 25% (though controversial !) Incidence: 20 - 25% (though controversial !) Mortality Mortality Differing reports throughout the world… Differing reports throughout the world… range 20 - 80% range 20 - 80% depends on type of ICU and organism depends on type of ICU and organism difficult to ascertain actual incidence difficult to ascertain actual incidence Varying definitions Varying definitions Varying populations Varying populations Varying techniques & diagnostic methods Varying techniques & diagnostic methods

7. Epidemiology Mechanically ventilated patients Mechanically ventilated patients 9 – 24 % incidence 9 – 24 % incidence some authors report as high as 44% some authors report as high as 44% Morbidity Morbidity increased ICU length of stay (5x longer) increased ICU length of stay (5x longer) increased total length of stay (2x longer) increased total length of stay (2x longer) increased ventilator days (7x longer) increased ventilator days (7x longer) Costs Costs Additional $8,800 for VAP Additional $8,800 for VAP Papazian et al. Am J Res CCM 1996. Craven et al. Am Rev Res Dis. 1996. Kollef. JAMA 1993. Torres et al. Am Rev Res Dis 1990.

8. Pathogenesis of VAP Kollef, NEJM 1999 2 Key Steps a.Bacterial colonization of the aerodigestive tract b.Aspiration of contaminated secretions into the lower airway

9. Pathophysiology (1) Bacterial entry into the lower airway Bacterial entry into the lower airway Inhalation Inhalation Hematogeneous (“seeding”) Hematogeneous (“seeding”) Contributing factors Contributing factors impaired gastric and intestinal motility impaired gastric and intestinal motility altered LOC altered LOC diminished gag reflex diminished gag reflex decreased mucociliary clearance decreased mucociliary clearance

10. Pathophysiology (2) the endotracheal tube creates an abnormal continuum between the upper airway and the trachea as well as establishing a subglottic reservoir of secretions rich in bacterial pathogens… those secretions, over time, become part of a biofilm that lines the ET tube – allowing distal aerosolization of particulate matter via the ventilatory cycle Morehead et al. Arch Intern Med 2000

11. The Airway

12. Intubation (1) Greatest risk factor !! Greatest risk factor !! increased incidence 7 - 21 fold increased incidence 7 - 21 fold reintubation reintubation 47% compared to 10% in matched controls 47% compared to 10% in matched controls ICU stay and crude mortality higher ICU stay and crude mortality higher Etiology Etiology Microaspiration Microaspiration Oral and gastric bacteria colonize subglottic area Oral and gastric bacteria colonize subglottic area ET quickly invested with biofilm above and below cuff ET quickly invested with biofilm above and below cuff

13. Intubation (2) Mechanical factors Mechanical factors Glottis is eliminated Glottis is eliminated primary barrier to aspiration lost primary barrier to aspiration lost Balloon cuff erodes tracheal epithelium Balloon cuff erodes tracheal epithelium Allows direct bacterial invasion Allows direct bacterial invasion Role of low-pressure cuffs…? Role of low-pressure cuffs…? Airway desiccation Airway desiccation loss of mucus/antibody production in oral cavity loss of mucus/antibody production in oral cavity Role of humidified circuits…? Role of humidified circuits…?

14. Role of the Gastric Tube Intubated patients have gastric tubes Intubated patients have gastric tubes Decrease gastric distension Decrease gastric distension Access for enteral feedings Access for enteral feedings Provides a conduit for bacterial migration Provides a conduit for bacterial migration Higher rate of reflux and sinusitis (NGT vs. OGT) Higher rate of reflux and sinusitis (NGT vs. OGT)

15. H-2 Blockers Gastric alkalinization Gastric alkalinization Promotes bacterial overgrowth Promotes bacterial overgrowth Presumably higher rates of significant aspiration Presumably higher rates of significant aspiration Gastric pH > 4 predisposition to GNR/S. aureus Gastric pH > 4 predisposition to GNR/S. aureus Use of sulcrafate associated with lower rates of VAP Use of sulcrafate associated with lower rates of VAP ( Am J med 1987 and 1991, Ann Int Med, 1995 Infec Control Hosp Epidemiol 1994) VAP: sulcrafate 5%, antacid 10%, ranitidine 21% VAP: sulcrafate 5%, antacid 10%, ranitidine 21% Benefit: lack of gastric alkalinization and lower bacterial colonization Benefit: lack of gastric alkalinization and lower bacterial colonization

16. Stress Ulcer Prophylaxis and VAP Controversial Topic ! Controversial Topic ! A Meta-analysis of previous studies found no significant difference A Meta-analysis of previous studies found no significant difference Prospective randomized trials Prospective randomized trials Simms et al, J Trauma, 1991 Simms et al, J Trauma, 1991 99 trauma patients on antacids, cimetidine, or sulcralfate 99 trauma patients on antacids, cimetidine, or sulcralfate No difference in nosocomial pneumonia or gastric bacteria No difference in nosocomial pneumonia or gastric bacteria Thomason et al, J Trauma, 1996 Thomason et al, J Trauma, 1996 242 intubated ICU patients on antacid, ranitidine, or sulcralfate 242 intubated ICU patients on antacid, ranitidine, or sulcralfate No difference in rates of VAP or GI bleeding No difference in rates of VAP or GI bleeding Markowicz et al, Am J Respir Crit Care Med, 2000 Markowicz et al, Am J Respir Crit Care Med, 2000 Multicenter, prospective trial Multicenter, prospective trial Found sulcrafate significantly associated with pneumonia in ARDS Found sulcrafate significantly associated with pneumonia in ARDS ? mechanism ? mechanism

17. Diagnosis: Nosocomial Pneumonia Difficult in ventilated patient Difficult in ventilated patient Typical criteria Typical criteria Clinical Clinical Radiographic Radiographic Laboratory Laboratory Statistically, a specific combination of clinical diagnostic criteria has not been identified to reliably diagnose bacterial pneumonia

18. What is “VAP” ?

19. Reliability of Clinical Signs Signs Signs Fever, pulmonary infiltrate, and purulent tracheal secretions Fever, pulmonary infiltrate, and purulent tracheal secretions Fagon et al, Am J Med, 1993 Fagon et al, Am J Med, 1993 23 patients with tracheobronchitis 23 patients with tracheobronchitis clinical “pneumonia” criteria, but negative protected brushings and BAL clinical “pneumonia” criteria, but negative protected brushings and BAL Matched with patients unsuspected to have pneumonia Matched with patients unsuspected to have pneumonia Mortality rates were similar (26% vs. 27%) Mortality rates were similar (26% vs. 27%) Lower than patients with a “proven” pneumonia ( BAL) Lower than patients with a “proven” pneumonia ( BAL)

20. Diagnosis: Nosocomial Pneumonia Objective tests can be unreliable Objective tests can be unreliable After 48 hrs, endogenous flora of aerodigestive tract replaced by hospital microflora After 48 hrs, endogenous flora of aerodigestive tract replaced by hospital microflora Antibiotic usage allows for selection and overgrowth of resistant organisms Antibiotic usage allows for selection and overgrowth of resistant organisms CXR has been notoriously inaccurate CXR has been notoriously inaccurate No single radiographic sign has > 68% accuracy No single radiographic sign has > 68% accuracy Due to high incidence of SIRS and ARDS in ICU, the validity of a radiographic infiltrate becomes less reliable Due to high incidence of SIRS and ARDS in ICU, the validity of a radiographic infiltrate becomes less reliable

21. Differential Diagnosis Pulmonary Edema Pulmonary Edema Cardiogenic Cardiogenic Non-cardiogenic Non-cardiogenic Atelectasis Atelectasis Infarction Infarction Nosocomial pneumonia Nosocomial pneumonia Hemorrhage Hemorrhage Systemic Inflammatory Response Syndrome Systemic Inflammatory Response Syndrome Adult Respiratory Distress Syndrome (ARDS) Adult Respiratory Distress Syndrome (ARDS)

22. Diagnosis Remember, VAP is a sub-type of nosocomial pneumonia defined specifically in relation to a bacterial etiology ? Role of Candida species…

23. Why an accurate diagnosis ? Inappropriate treatment of pneumonia has been shown to correlate directly with an increased mortality Inappropriate treatment of pneumonia has been shown to correlate directly with an increased mortality Indiscriminate use of antibiotics leads to the development of multi-resistant strains Indiscriminate use of antibiotics leads to the development of multi-resistant strains Empiric antibiotic therapy predisposes to infection with more virulent strains Empiric antibiotic therapy predisposes to infection with more virulent strains Fagon et al, Am Rev Respir Dis, 1989 Fagon et al, Am Rev Respir Dis, 1989 Increased proportion of pneumonias due to Pseudomonas and Acinetobacter from 19% to 65% when antibiotics were administrated before the development of an actual pneumonia Increased proportion of pneumonias due to Pseudomonas and Acinetobacter from 19% to 65% when antibiotics were administrated before the development of an actual pneumonia Increased mortality in previously-treated group (48% vs. 83%) Increased mortality in previously-treated group (48% vs. 83%)

24. Diagnostic Tests Tracheal aspirations Tracheal aspirations Selective airway sampling Selective airway sampling Bronchoalveolar lavage (BAL) Bronchoalveolar lavage (BAL) Protected specimen brush Protected specimen brush Direct airway visualization Direct airway visualization

25. Quantitative Cultures Becoming a mainstay in the “academic diagnosis” of VAP Becoming a mainstay in the “academic diagnosis” of VAP However, regardless of technique, laboratory standardization is essential However, regardless of technique, laboratory standardization is essential Cumbersome Cumbersome Labor intensive Labor intensive Associated Costs Associated Costs

26. Tracheal Aspirates (TA) Gram stains plagued by low specificity Gram stains plagued by low specificity Tracheal colonization Tracheal colonization Correlate with cultures in only 46% (EAST Study) Correlate with cultures in only 46% (EAST Study) GNR better predictive, whereas gram positive or no bacteria was unreliable GNR better predictive, whereas gram positive or no bacteria was unreliable Quantitative cultures and TA Quantitative cultures and TA Probably comparable to invasive procedures Probably comparable to invasive procedures Sensitivity (82% vs. 64%) and specificity (83% vs. 96%) Sensitivity (82% vs. 64%) and specificity (83% vs. 96%) Overall more cost-effective than invasive procedures Overall more cost-effective than invasive procedures

27. Diagnostic Tests: TA Presence of elastin fibers in TA Presence of elastin fibers in TA Specific indicator of pulmonary necrosis Specific indicator of pulmonary necrosis Increased specificity to 73-100% Increased specificity to 73-100% Shlaes et al, Chest, 1984 Shlaes et al, Chest, 1984 Sputum samples strongly correlated to radiographic evidence of pulmonary necrosis Sputum samples strongly correlated to radiographic evidence of pulmonary necrosis Histologically proven positive in 9 cases without radiographic findings Histologically proven positive in 9 cases without radiographic findings Can be non-specific for noninfectious causes of necrotizing lung diseases Can be non-specific for noninfectious causes of necrotizing lung diseases

28. Bronchoaveolar Lavage (BAL) Performed by bronchoscopy Performed by bronchoscopy BAL samples larger portion of lung than TA BAL samples larger portion of lung than TA Sensitivity 72-100%, specificity 69-100% Sensitivity 72-100%, specificity 69-100% Increased with protected catheter Increased with protected catheter Sens 92%, Spec 97% Sens 92%, Spec 97% Recommend threshold of 10 4 CFU/ ml Recommend threshold of 10 4 CFU/ ml Blind mini-BAL Blind mini-BAL Can be done by respiratory technicians Can be done by respiratory technicians Protected catheter-approach Protected catheter-approach Compares favorably to bronchoscopic BAL Compares favorably to bronchoscopic BAL

29. Protected Specimen Brush Performed via bronch or non-bronchoscopic Performed via bronch or non-bronchoscopic Sensitivity and specificity varies Sensitivity and specificity varies Sensitivity 70-100% Sensitivity 70-100% Specificity 60-92% Specificity 60-92% Sensitivity drops with antibiotic use (13%) Sensitivity drops with antibiotic use (13%) Threshold 10 3 CFU/ml Threshold 10 3 CFU/ml

30. Combination of Test Inherent drawback with BAL and PSB Inherent drawback with BAL and PSB Delays in cultures of 24-48 hrs. Delays in cultures of 24-48 hrs. Lower than acceptable sens. and spec. when either method used alone Lower than acceptable sens. and spec. when either method used alone Combined BAL and PSB Combined BAL and PSB BAL recovered cells determine empiric antibiotic if more than 5% of infected cells BAL recovered cells determine empiric antibiotic if more than 5% of infected cells Therapy is altered based on PSB with 10 3 CFU cutoff Therapy is altered based on PSB with 10 3 CFU cutoff Improves sensitivity 100% and specificity 96% Improves sensitivity 100% and specificity 96%

31. Prevention is Critical… Intubation Intubation Intubate only if necessary Intubate only if necessary Early extubation if criteria meet…though need to minimize the risk of re-intubation ! Early extubation if criteria meet…though need to minimize the risk of re-intubation ! ? Semi-upright positioning ? Semi-upright positioning ? Subglottic continuous aspiration ? Subglottic continuous aspiration ? Use of oral gastric tubes instead of NGT ? Use of oral gastric tubes instead of NGT ? Limited use of gastric alkalinization ? Limited use of gastric alkalinization ? Selective digestive decontamination ? Selective digestive decontamination

32. Subglottic Continuous Aspiration Valles et al, Ann Int Med, 1995 Valles et al, Ann Int Med, 1995 Randomized blinded study Randomized blinded study Reduction of VAP Reduction of VAP Controls 39.6 episodes /1000 vent days Controls 39.6 episodes /1000 vent days Intervention 19.9 episodes / 1000 vent days Intervention 19.9 episodes / 1000 vent days Increased time to developing VAP Increased time to developing VAP (control) 5.9 days to (intervention) 12 days (control) 5.9 days to (intervention) 12 days Drawbacks Drawbacks Expensive specialized ET tubes Expensive specialized ET tubes

33. Semi-Upright Positioning Evidence For: (Torres et al, Ann Int Med, 1992) Evidence For: (Torres et al, Ann Int Med, 1992) Used radioactive labeling of gastric contents Used radioactive labeling of gastric contents Significantly less aspiration with 45 degree elevation Significantly less aspiration with 45 degree elevation Magnitude of supine aspiration time-dependent Magnitude of supine aspiration time-dependent Evidence Against: (Ibanez et al, JPEN, 1992) Evidence Against: (Ibanez et al, JPEN, 1992) Similar study in 70 patients Similar study in 70 patients No statistical difference in supine vs. upright No statistical difference in supine vs. upright Significant difference of reflux in patients with NGT Significant difference of reflux in patients with NGT

34. Use of Oral Gastric Tubes Use significantly reduces Use significantly reduces Incidence of infectious sinusitis Incidence of infectious sinusitis Incidence of VAP Incidence of VAP Recommendations Recommendations Convert NGT to OG Convert NGT to OG Consider gastrostomy if long term use necessary Consider gastrostomy if long term use necessary

35. Sample Current Practice ?

36. Empirical Antibiotics: VAP

37. Why such a concern: Abx-Resistance MMWR – July 5, 2002 MMWR – July 5, 2002 VRSA in Michigan VRSA in Michigan MMWR - October 11, 2002 MMWR - October 11, 2002 VRSA in Pennsylvania VRSA in Pennsylvania Wake-up Call….

38. Antibiotics & VAP what is the “appropriate use” of antibiotics in either suspected or “proven” VAP ?

39. Mortality related to Abx-Coverage

40. VAP: Summary of Approach Critical Care Medicine Boston Medical Center Boston University School of Medicine

41. Nonpharm. Prevention Measures Kollef, NEJM 1999.

42. Pharm. Prevention Measures Kollef, NEJM 1999.

43. VAP: Conclusions Most common nosocomial infection in the ICU Most common nosocomial infection in the ICU Most significant risk is intubation/reintubation Most significant risk is intubation/reintubation ? Preventable Disease ? Preventable Disease Treatment should be rationale Treatment should be rationale Hospital-based patterns of infection (i.e. biograms) Hospital-based patterns of infection (i.e. biograms) Unit-specific protocols validated through time Unit-specific protocols validated through time Accurate & accepted diagnosis of VAP Accurate & accepted diagnosis of VAP Clinical, radiographic, and laboratory findings Clinical, radiographic, and laboratory findings Such a diagnosis may be most accurate with quantitative cultures via either TA, BAL, PSB Such a diagnosis may be most accurate with quantitative cultures via either TA, BAL, PSB

44. VAP: Questions Critical Care Medicine Boston Medical Center Boston University School of Medicine

45. Ventilator-Associated Pneumonia Critical Care Medicine Boston Medical Center Boston University School of Medicine Bradley J. Phillips, M.D.