Respirology (2009) 14 (Suppl. 2) S51 S58 doi: 10.1111/j.1400-1843.2009.01577.x CHAPTER VIII Ventilator-associated pneumonia SUMMARY Ventilator-associated pneumonia is a pneumonia that develops initially more than 48 h from the start of tracheal intubation and mechanical ventilation. The route of infection is almost always through the respiratory tract. Intake of contaminants from outside the tracheal tube (silent aspiration) is considered a key route, and suctioning of secretions that have accumulated above the cuff of the endotracheal tubes is effective in preventing infection. The circuit is managed and heated-wire humidifiers and suction are manipulated based on appropriate infection control measures. To diagnose pathogens, efforts should be made to collect specimens from the pneumonia focus. Realistically, however, diagnosis can also be achieved based on the clinical course and from the results of culture of samples from tracheal aspirate. Use of prophylactic antimicrobials is not recommended, but once a diagnosis is made, antimicrobials are administered that combat the causative microorganism. DEFINITION Ventilator-associated pneumonia (VAP) is defined as a pneumonia that occurs more than 48 h after the start of artificial respiration with tracheal intubation, in cases where no pneumonia was present before the tracheal intubation and artificial respiration management. By convention, the cause of inflammation is limited to bacterial infection. Non-infectious inflammation is not considered, and infections from fungi and viruses are in fact rare. Onset within 4 5 days after tracheal intubation is taken to be early-onset VAP and onset after 5 days as late-onset VAP. The most common causative microorganisms differ between these two types. EPIDEMIOLOGY Pneumonia is an infectious disease that occurs with a very high frequency in ICU, with an incidence of 9 24% after 48 h from the start of artificial respiration management. No recent improvements have been seen in this incidence. 1 In ICU, for patients with internal medicine conditions, the incidence of VAP has risen to 1%/day (Fig. VIII-1). 2 Factors related to the onset of VAP are the host, period of mechanical ventilation and virulence of the causative bacteria. Risk factors include long-term respiratory management with a mechanical ventilator, repeat intubation, admini stration of antimicrobials before onset, underlying disease (burns, trauma, central nervous system disease, respiratory disease, heart disease), clear aspiration of foreign materials and the use of muscle relaxants. Other factors that are thought to be related to VAP are low tracheal tube cuff pressure, transfer from ICU and a supine position (Table VIII-1). 3 PATHOGENESIS OF VENTILATOR- ASSOCIATED PNEUMONIA (Fig. VIII-2) The alveoli are essentially aseptic spaces, and so it is necessary to think about how bacteria arrives. In common experience, the route of bacterial invasion is almost always the respiratory tract, but in rare cases, invasion may be haematogenous or lymphogenous. In patients who have undergone tracheal intubation, prevention strategies can best be developed by considering contamination from inside and outside the tracheal tube separately. Contamination from inside the tracheal tube will not occur if obvious procedures have been properly implemented. 4,5 These include: (i) sterilization of the mechanical ventilator and circuit in the prescribed manner after use; (ii) clean assembly; (iii) not putting water into the humidifier if it has been left sitting for a long time after the first use; (iv) use of a separate nebulizer drug solution for each patient; (v) exchange of the connector at the mouth when it becomes visibly dirty; and (vi) washing hands and wearing gloves during aspiration procedures. The cause of VAP in nearly all cases is understood to be pathogens present in the oropharynx that make their way into the trachea through the cuff from the outside of the tracheal tube (silent aspiration).
S52 Respirology (2009) 14 (Suppl. 2) (%) 40 Cumulative incidence of pneumonia 30 20 10 (408) (567) (224) (124) (82) (53) (33) 0 3 5 10 15 20 25 30 Number of days of mechanical ventilation Numbers in parentheses indicate number of patients (from Reference 2) Figure VIII-1 Relationship between days of mechanical ventilation and cumulative incidence of pneumonia. Mechanical ventilator Plaque Nasal cavity (sinusitis, nasotracheal intubation, gastric tube) Accumulation of secretions Gastric content reflux Mechanical ventilator circuit Suctioning Figure VIII-2 Mechanism of ventilator-associated pneumonia (VAP) development various bacterial infection routes through the respiratory tract. Table VIII-1 Independent risk factors for ventilator-associated pneumonia (VAP) Host factors Treatment factors Other factors Serum albumin <2.2 g/dl H 2 blocker administration ± antacids Season: fall, winter Age 60 years Continuous administration of muscle relaxants, Acute respiratory distress syndrome (ARDS) analgesics Chronic respiratory disease (bronchiectasis, Administration of 4 units + (USA) of blood products pulmonary emphysema, pulmonary Intracranial pressure monitor tuberculosis sequela etc) Mechanical ventilation >2 days Coma or impaired consciousness PEEP load Burn injury, trauma Frequent changes of mechanical ventilator circuit Organ failure Contaminated respirator, nebulizer Disease severity Repeat intubation Aspiration of large amounts of gastric juice Nasogastric tube insertion Colonization by gastric bacteria and Horizontal supine position (vs semi-fowler position) elevated ph Discharge from ICU Bacterial colonization of the upper Past long-term administration of antimicrobials, no respiratory tract antimicrobial treatment Sinusitis + USA 1 unit = 400 cc. From Reference 3. ICU, intensive care unit; VAP, ventilator-associated pneumonia. Concept: Lesions exist in alveoli Those lesions represent inflammation (bacterial infection) Clinical findings: Fever, leukocytosis, decreased PaO 2 Emergence and progression of alveolar infiltrative shadows on chest radiography Purulent respiratory secretion Diagnosis of ventilator-associated pneumo- Figure VIII-3 nia (VAP). Possibility of VAP Close examination: BAL (>10 4-5 cfu/ml) or PSB (>10 3 cfu/ml) Blood culture is positive and corresponds to bacteria from the lower respiratory tract Culture of pleural effusion is positive and corresponds to bacteria from the lower respiratory tract Colonization of pathogenic bacteria in the oral cavity is important in the onset of VAP. In nasotracheal intubation and nasogastric tubes, colonization of the paranasal sinuses plays an important role. Subglottic oral secretions presumably enter along the outside of the tracheal tube, a biofilm forms on the surface of the tracheal tube and pathogens are carried to the distal respiratory tract by air flow. In addition, reflux materials from the stomach are also transported to the respiratory tract through the same mechanism. Finally, whether infection will occur is determined by the balance between the host defence capacity of the patient and the infectious capacity of the bacteria. Administration of antimicrobials and various other medical interventions affect this balance.
JRS Guidelines for Management of Hospital-Acquired Pneumonia S53 DIAGNOSIS 6 (Fig. VIII-3) As pneumonia is an infection of the alveoli, two conditions must be satisfied simultaneously: (i) lesions are present in the alveoli; and (ii) those lesions represent infections (bacterial infections). Symptoms of (i) are the appearance and progression of abnormal shadows on chest radiography and decreased oxygenation capacity in the lungs. Symptoms of (ii) are fever, leukocytosis, elevated CRP and purulent respiratory secretions. As none of the symptoms or tests are specific, results of multiple tests should be considered when making a diagnosis. 1. Radiographs Radiographs are taken over time during the course of mechanical ventilation assistance. Radiographs are interpreted with the awareness that they are taken front to back with the patient in a supine position. Differentiation from other diseases that cause infiltrative shadows is necessary. CT images can be useful when radiographical images are difficult to interpret, but a decision must be made as to whether the advantage to be obtained from such images outweighs the risk of transporting the patient under mechanical ventilation. 2. Blood gas Differentiation from other diseases (pulmonary oedema, atelectasis etc) that cause decreased oxygenation capacity (PaO 2 /FiO 2 ) is necessary. 3. Fever, leukocytosis, elevated CRP A search was made for other infection sites. Assessment is difficult if postoperative trauma or burn injuries are present. 4. Purulent respiratory secretions If no infiltrative shadows are apparent in the lung fields, the probability of tracheitis or bronchitis is high. alveoli is thought to be via the respiratory tract in nearly all cases, so bacteria detected in the trachea and bronchial tubes may be assumed with a high degree of probability to be the causative bacteria. However, if the clinical course or treatment effect do not correspond to those bacteria, tests must be actively conducted to detect bacteria from the lower respiratory tract using the methods described below. 5.1 Clinical diagnosis A clinical diagnosis of VAP is made for symptoms, such as appearance and progression of abnormal shadows on chest radiography, breathing difficulty in the patient, decreased oxygenation capacity (PaO 2 / FiO 2 ) in the lungs, fever, leukocytosis or purulent respiratory secretion. 5.2 Pathogen diagnosis The VAP pathogen can be diagnosed if any of the below apply in addition to the clinical signs described above. Histological evaluation with biopsy and quantitative bacterial culture are needed for definitive diagnosis, but are not practical and are thus omitted from this discussion. 1 Bronchoalveolar lavage (BAL) by bronchoscopy and quantitative bacterial culture by protected specimen brush (PSB) are 10 4 5 cfu/ml and >10 3 cfu/ml, respectively. 2 Blood culture is positive and matches results for bacteria from the lower respiratory tract. 3 Culture of pleural effusion is positive and corresponds to bacteria from the lower respiratory tract. The sensitivity and specificity of respiratory secretions collected by various methods are shown in Table VIII-2. Specificity of 95% is reported for bacterial macrophage counts of 2% or more in BAL. Direct endotracheal aspiration has low specificity, but can be performed quickly at any time because the technique is simple and safe. Early administration of appropriate antimicrobials is important in improving the outcome for VAP, so the first recommendation is that such treatment be started. The goal is quantitative culture of 10 6 cfu/ml. Bacteria that are most likely to cause VAP are shown in Figure VIII-4. 5. Culture of endotracheal secretions As colonization in patients with tracheal intubation is common, treatment is not necessary, even when bacteria are detected, unless findings of inflammation are identified. 4,7 Cultures that are negative, even though the antimicrobials have not been changed within 72 h, are strong predictors (94%) for ruling out VAP. 8 Although there is no assurance that bacteria cultured from specimens taken from the level of the trachea and bronchial tubes are actually present in the alveoli, the route by which bacteria invade the Table VIII-2 Methods of collecting respiratory secretions, with sensitivity and specificity Collection method Sensitivity (%) Specificity (%) PSB (quantitative) 82 (62 100) 92 (60 100) BAL (quantitative) 86 (72 100) 87 (69 100) Suctioned sputum 69 (38 91) 80 (59 92) (quantitative) Suctioned sputum (non-quantitative) 78 (57 88) 19 (0 33) PSB, protected specimen brush.
S54 Respirology (2009) 14 (Suppl. 2) Coagulase-negative staphylococcus Stenotrophomonas maltophilia 1.4% 1.7% Neisseria 2.6% Pneumococcus 4.1% Other 3.8% Anaerobes 0.9% Fungus 0.9% Pseudomonas aeruginosa 24.4% *1 MRSA 55.7% MSSA 44.3% Klebsiella 15.6% Escherichia coli 24.1% Proteus 22.3% Enterobacter 18.8% Staphylococcus aureus* 1 Serratia 12.1% Hemophilus 20.4% Citrobacter 5.0% 9.8% Hafnia 2.1% Acinetobacter 7.9% Streptococci 8.0% Enterobacteria* 2 14.1% *2 (from Reference 3) Figure VIII-4 Bacterial species representing likely causes of ventilator-associated pneumonia (VAP) analysis of 2490 specimen strains from 1689 specimens in 24 studies. HOST DEFENSE MECHANISMS Tracheal intubation and artificial respiration can interfere with host defence mechanisms. (i) Factors in cough suppression include sedatives, opioid analgesics, and muscle relaxants; while (ii) factors in mucosal ciliary clearance suppression are inhalation of highly concentrated oxygen, decreased moisture for inhalation, tracheal intubation itself and dehydration; (iii) tracheal intubation damages the respiratory tract, delays tissue repair and promotes bacterial colonization; and (iv) biofilm forms on the surface of the tracheal tube. TREATMENT 1. Morbidity and mortality In a comparison of groups in which VAP did and did not occur among patients of the same severity, mortality rates were 23.7% and 17.9%, respectively. Outcomes were thus clearly poorer in the VAP group. The mortality rate is affected by whether appropriate antibacterial agents were administered for VAP. Significant results were not obtained in an investigation of whether VAP was directly involved in these deaths. However, the number of days in the ICU was longer in the VAP group regardless of survival or death. 9 2. Bacteriological investigation A broad range of bacteria cause VAP, and differences are seen between each hospital and ICU. Surveillance of the normally isolated bacteria in an institution is thus essential. Causative bacteria in VAP diagnosed invasively to date are often Gram-negative bacilli, and several species of causative bacteria are present in many cases. In the past, anaerobes were emphasized in VAP pathology, but this has come into question in recent years, 10,11 and anaerobes are rarely identified even in post-mortem biopsy. 12 Legionella infection from contaminated water in the heated-wire humidifiers of mechanical ventilators has been reported, 13 and care is needed to prevent this situation. 3. Selection of antibacterial agents As a rule, an adequate dose of antimicrobial is given to eliminate the causative bacteria. In assessing culture results, neutrophil counts 25 and squamous epithelial cell counts 10/field (magnification 100) on smear specimens are taken to indicate respiratory secretions derived from the lower respiratory tract (see Chapter III). When VAP is suspected, the earliest possible administration of antibacterial agents for the presumed causative bacteria is desirable. If patients have been assisted with mechanical ventilation for a
JRS Guidelines for Management of Hospital-Acquired Pneumonia S55 long period or have received a wide range of antimicrobials before VAP onset, the possibility of drugresistant bacteria as the causative bacteria must be considered. Pseudomonas aeruginosa, Acinetobacter and Stenotrophomona maltophilia are the most important. MRSA is also considered in patients who have been on a ventilator for >5 days, patients receiving steroids and patients who have an organic lung disease or who have been receiving immunosuppressants. In such cases, anti-mrsa drugs may be necessary in addition to the drugs being administered. In any event, patients in whom the risk of drugresistant bacteria as the causative agent of VAP is high should be treated with a combination of two types of antimicrobials that have different action mechanisms. A greater number of drug-resistant bacteria have been identified in ICU than in other wards, and the trends in drug-resistant bacteria differ in each hospital. Monitoring prevalent strains is thus very important. To minimize the occurrence of drug-resistant bacteria, narrow-spectrum antibiotics should be changed based on culture results, and discontinuation should be considered when infection is ruled out. 1.4 Tracheal intubation A high incidence of sinusitis is seen with nasotracheal intubation and represents a cause of VAP. From the perspective of prevention, therefore, tracheal intubation is done orally as a rule. As mentioned in (1.7) below, a tube with a port that can suction the hilar region (above the cuff) is preferable (Fig. VIII-5). However, since tracheal intubation itself is a cause of VAP, the basic policy is to avoid tracheal intubation. Measures to achieve this include not performing unnecessary intubation or mechanical ventilation, selecting non-invasive artificial respiration when possible, and switching to tracheotomy if longterm artificial respiration for more than 2 weeks is predicted. The incidence of VAP is thought to decrease with non-invasive positive-pressure ventilation (NPPV). Excessive administration of sedatives and muscle relaxants and mechanical ventilation without a clearly defined purpose needlessly prolongs the intubation time and increases the risk of VAP, and thus should be avoided. 1.5 Tracheotomy PREVENTION 1. Preventive measures without the use of drugs 1.1 Hand cleanliness, gloves and gowns The standard precautions of the Centers for Disease Control and Prevention (CDC) and equivalent hygienic control are strictly observed. Thorough awareness among medical staff and preparation of a prevention programme are important, and continuous educational activities are essential to achieving this. If a patient has healthy laryngeal function, tracheotomy can theoretically be expected to prevent aspiration equally as well as non-intubation. In the ICU of single hospitals for trauma patients, early tracheotomy reduced the number of days of mechanical ventilation, the number of days in the ICU and the occurrence of VAP in a number of reports from prospective and retrospective studies conducted since 2000. 18 20 A multicenter prospective study reported in 1997, however, found no significant differences. 21 Methodological flaws have been indicated in these studies, and judgment remains suspended for the present. 22 1.2 Patient position Due to the high risk of aspiration in patients in a supine position, a semi-fowler position (upper body raised 30 45%) is preferable. This is particularly true for patients receiving tube feeding. 14,15 Risk of aspiration is mitigated by total parenteral nutrition, but in that case there are risks of catheter infection, bacterial translocation and other complications. Arrangements to avoid accidental or self-extubation are important. 1.3 Gastric contents Aspiration of gastric contents has been shown to be one mechanism in the occurrence of VAP. Abdominal fullness should thus be avoided and medications that suppress intestinal movement limited. In patients receiving enteral feeding, the feeding tube should be placed distal to the ligament of Treitz if possible. 16 The size of the nasogastric tube does not affect the frequency of aspiration of gastric contents. 17 Figure VIII-5 upper cuff. Tracheal tube with suction port on the
S56 Respirology (2009) 14 (Suppl. 2) 1.6 Management of mechanical ventilator and circuit Sterilization and disinfection are not necessary every time a mechanical ventilator is used. Sterilized circuits are used and exchanged when contamination is visible. Regular changes are not necessary for the same patient. In randomized controlled trials to date, the incidence of VAP has not increased, even when exchange time was extended. In fact, a decreasing trend was seen in the infection rate. No consensus has been reached regarding the optimum frequency of replacement, but the risk of VAP has been shown not to increase, even with circuit changes every other week. 23 1.7 Effectiveness of subglottic suction and tube cuff pressure Tracheal tubes with suction ports on the cuff are commercially available. Good results have been reported with either continuous or intermittent suction (reduction from 29% to 13% with continuous suction, and from 32.5% to 18.5% with intermittent suction), and the risk of VAP is reduced by half with subglottic suction according to a comprehensive meta-analysis. 24 This prevention is especially strong for early-onset VAP. To make this suction effective, the tube cuff pressure needs to be maintained at 25 30 cm H 2 O, 25 but attention is needed, as excessive pressure can induce ischemic impairment. 1.8 Suction catheter Aspiration of respiratory secretions is currently done with either closed-system catheters or open-system disposable catheters, but no significant difference in VAP incidence is seen between these two types. From considerations of cost and respiratory management, however, closed-system catheters are recommended. 1.9 Heated-wire humidifiers and artificial noses The use of artificial noses has increased in recent years, but these do not necessarily reduce the incidence of VAP. 26,27 Blockage can be a problem in artificial noses, but use for up to 1 week is reportedly safe. 1.10 Changing patient position Prevention of VAP by postural drainage has been reported and special beds have been introduced for this purpose, but no conclusion has been reached as to their effectiveness. The occurrence of hypoxemia in physical therapy is also a problem. However, whether feasibility, safety and cost concerns may be barriers to implementation is unclear. 1.11 Continuing education and surveillance Continual education is needed to raise staff awareness and spread knowledge. In addition, by understanding which bacteria are most often detected at each specific institution, causative bacteria can be more easily predicted and treatment plans developed. 2. Preventive measures with the use of drugs 2.1 Antibacterial agents Systemic administration of antibacterial agents before VAP occurs is problematic because of an increase in drug-resistant bacteria. Lower respiratory tract colonization by Pseudomonas aeruginosa and MRSA, in particular, has been shown to be very closely related to the development of VAP. To inhibit the emergence of drug-resistant bacteria, administration of unnecessary antibiotics should be avoided. 2.1.1 Combination therapy. Combination therapy should be limited to patients in whom multiple causative microorganisms or drug-resistant causative bacteria are strongly suspected. 2.1.2 Prophylactic administration of antimicrobials. The effectiveness of local administration of antimicrobials through inhalation has not been demonstrated, and the emergence of drug-resistant bacteria is also problematic. Similarly, some doubt exists as to the clinical effectiveness of selective digestive tract decontamination (SDD), and problems of drugresistant bacteria and side-effects have yet to be resolved. 13,28 However, some reports have described the effectiveness of SDD in ICU patients. 2.1.3 Drug selection. The first-choice antimicrobial is not given alone, and a strategy is set to achieve a balance in the use of antimicrobials. This approach is thought to reduce the emergence of drug-resistant bacteria, 29 31 although consensus on this issue has yet to be reached. 2.2 Adjunctive preventive measures 2.2.1 Measures against acute gastric mucosal lesions. Antacids and H2 blockers are often administered to patients undergoing mechanical ventilation with the aim of preventing so-called stress ulcer. Bacterial colonization, particularly by enterobacteria, cannot be stopped if the ph of gastric contents rises (acidity declines), and concern has been voiced that the risk of VAP may increase. At one time, the recommendation was that H2 blockers be avoided and sucralfate used. In reality, however, the results with regard to the involvement of gastric content ph are inconsistent and no conclusion has been reached. In any event, prevention of ulceration is necessary in all
JRS Guidelines for Management of Hospital-Acquired Pneumonia S57 cases without exception, and the advantages and disadvantages of each agent must be considered. In a multicenter prospective study of VAP in patients with ARDS, a higher incidence of VAP was reported among patients treated with sucralfate. 32 2.2.2 Rinsing the oral cavity. Chlorhexidine has been shown to be effective in controlling dental plaque and other oral conditions, and in preventing the occurrence of VAP. This promising agent has been shown to be effective in preventing VAP in patients who have undergone cardiovascular surgery. However, the concern is that colonization or infection by chlorhexidine-resistant bacteria will lead to a higher risk of VAP. Moreover, the use of chlorhexidine in the oral cavity has yet to be approved in Japan. Daily oral hygiene must be performed, regardless of whether such care is related to VAP. 2.2.3 Blood glucose control. High blood sugar levels have been confirmed to decrease the immune function of leukocytes. Strict blood glucose control is reported to significantly decrease mortality and the number of days spent in the ICU. 33 Blood sugar levels are monitored in the Surviving Sepsis Campaign, and administration of regular insulin in continuous microdoses is recommended. 34 The target blood sugar level is about 150 mg/dl. 2.2.4 Transfusions. Several studies have suggested that transfusions decrease immune function. A Hb level of 7.0 g/dl has been thought to provide no impediment to oxygen transport capacity. In fact, good treatment results have been reported using transfusions kept to that level. 35 2.2.5 Immunoglobulin preparations. Administration of immunoglobulin preparations in adult patients after surgery is reported to clearly decrease postoperative infection, but administration should be limited because of the problems of expense and side-effects. 36 Conflict of Interest No conflict of interest has been declared by The Committee for the Japanese Respiratory Society guidelines for the management of respiratory infections. REFERENCES 1 Papazian L, Bregeon F, Thirion X et al. Effect of ventilator-associated pneumonia on mortality and morbidity. Am. J. Respir. Crit. Care Med. 1996; 154: 91 7. 2 Fagon JY, Chastre J, Domart Y et al. Nosocomial pneumonia in patients receiving continuous mechanical ventilation. Prospective analysis of 52 episodes with use of a protected specimen brush and quantitative culture techniques. Am. Rev. Respir. Dis. 1989; 139: 877 84. 3 Chastre J, Fagon JY. Ventilator-associated pneumonia. Am. J. Respir. Crit. Care Med. 2002; 165: 867 903. 4 Niederman MS. Gram-negative colonization of the respiratory tract: Pathogenesis and clinical consequences. Semin. Respir. Infect. 1990; 5: 173 84. 5 Bergmans DC, Bonten MJ, van Tiel FH et al. Crosscolonisation with Pseudomonas aeruginosa of patients in an intensive care unit. Thorax 1998; 53: 1053 8. 6 Pingleton SK, Fagon JY, Leeper KV Jr. Patient selection for clinical investigation of ventilator-associated pneumonia. Criteria for evaluating diagnostic techniques. Chest 1992; 102 (Suppl. 1): 553S 556S. 7 Johanson WG Jr, Pierce AK, Sanford JP et al. Nosocomial respiratory infections with Gram-negative bacilli. The significance of colonization of the respiratory tract. Ann. Intern. Med. 1972; 77: 701 6. 8 Blot F, Raynard B, Chachaty E et al. Value of Gram stain examination of lower respiratory tract secretions for early diagnosis of nosocomial pneumonia. Am. J. Respir. Crit. Care Med. 2000; 162: 1731 7. 9 Craig CP, Connelly S. Effect of intensive care unit nosocomial pneumonia on duration of stay and mortality. Am. J. Infect. Control 1984; 12: 233 8. 10 Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia: A prospective study. Chest 1999; 115: 178 83. 11 Doré P, Robert R, Grollier G et al. Incidence of anaerobes in ventilator-associated pneumonia with use of a protected specimen brush. Am. J. Respir. Crit. Care Med. 1996; 153: 1292 8. 12 Torres A, el-ebiary M, Padró L et al. Validation of different techniques for the diagnosis of ventilator-associated pneumonia. Comparison with immediate postmortem pulmonary biopsy. Am. J. Respir. Crit. Care Med. 1994; 149: 324 31. 13 La Scola B, Boyadjiev I, Greub G et al. Amoeba-resisting bacteria and ventilator-associated pneumonia. Emerg. Infect. Dis. 2003; 9: 815 21. 14 Torres A, Serra-Batlles J, Ros E et al. Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: The effect of body position. Ann. Intern. Med. 1992; 116: 540 3. 15 Drakulovic MB, Torres A, Bauer TT et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: A randomised trial. Lancet 1999; 354: 1851 8. 16 Heyland DK, Drover JW, MacDonald S et al. Effect of postpyloric feeding on gastroesophageal regurgitation and pulmonary microaspiration: Results of a randomized controlled trial. Crit. Care Med. 2001; 29: 1495 501. 17 Ferrer M, Bauer TT, Torres A et al. Effect of nasogastric tube size on gastroesophageal reflux and microaspiration in intubated patients. Ann. Intern. Med. 1999; 130: 991 4. 18 Arabi Y, Haddad S, Shirawi N et al. Early tracheostomy in intensive care trauma patients improves resource utilization: A cohort study and literature review. Crit. Care 2004; 8: R347 52. 19 Möller MG, Slaikeu JD, Bonelli P et al. Early tracheostomy versus late tracheostomy in the surgical intensive care unit. Am. J. Surg. 2005; 189: 293 6. 20 Ahmed N, Kuo YH. Early versus late tracheostomy in patients with severe traumatic head injury. Surg. Infect. 2007; 8: 343 7. 21 Sugerman HJ, Wolfe L, Pasquale MD et al. Multicenter, randomized, prospective trial of early tracheostomy. J. Trauma 1997; 43: 741 7. 22 Dodek P, Keenan S, Cook D et al. Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia. Ann. Intern. Med. 2004; 141: 305 13.
S58 Respirology (2009) 14 (Suppl. 2) 23 Kollef MH, Shapiro SD, Fraser VJ et al. Mechanical ventilation with or without 7-day circuit changes. A randomized controlled trial. Ann. Intern. Med. 1995; 123: 168 74. 24 Dezfulian C, Shojania K, Collard HR et al. Subglottic secretion drainage for preventing ventilator-associated pneumonia: A meta-analysis. Am. J. Med. 2005; 118: 11 18. 25 Diaz E, Rodríguez AH, Rello J. Ventilator-associated pneumonia: Issues related to the artificial airway. Respir. Care 2005; 50: 900 6. 26 Davis K Jr, Evans SL, Campbell RS et al. Prolonged use of heat and moisture exchangers does not affect device efficiency or frequency rate of nosocomial pneumonia. Crit. Care Med. 2000; 28: 1412 18. 27 Thomachot L, Leone M, Razzouk K et al. Randomized clinical trial of extended use of a hydrophobic condenser humidifier; 1 vs 7 days. Crit. Care Med. 2002; 30: 232 7. 28 Gastinne H, Wolff M, Delatour F et al. A controlled trial in intensive care units of selective decontamination of the digestive tract with nonabsorbable antibiotics. The French study group on selective decontamination of the digestive tract. N. Engl. J. Med. 1992; 326: 594 9. 29 Kollef MH, Vlasnik J, Sharpless L et al. Scheduled change of antibiotic classes: A strategy to decrease the incidence of ventilator-associated pneumonia. Am. J. Respir. Crit. Care Med. 1997; 156: 1040 8. 30 Gruson D, Hilbert G, Vargas F et al. Strategy of antibiotic rotation: Long-term effect on incidence and susceptibilities of Gram-negative bacilli responsible for ventilator-associated pneumonia. Crit. Care Med. 2003; 31: 1908 14. 31 Sandiumenge A, Diaz E, Rodriguez A et al. Impact of diversity of antibiotic use on the development of antimicrobial resistance. J. Antimicrob. Chemother. 2006; 57: 1197 204. 32 Markowicz P, Wolff M, Djedaïni K et al. Multicenter prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome. Incidence, prognosis, and risk factors. ARDS study group. Am. J. Respir. Crit. Care Med. 2000; 161: 1942 8. 33 van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in the critically ill patients. N. Engl. J. Med. 2001; 345: 1359 67. 34 Dellinger RP, Carlet JM, Masur H et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit. Care Med. 2004; 32: 858 73. 35 Hébert PC, Wells G, Blajchman MA et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion requirements in critical care investigators, Canadian critical care trials group. N. Engl. J. Med. 1999; 340: 409 17. 36 The Intravenous Immunoglobulin Collaborative Study Group. Prophylactic intravenous administration of standard immune globulin as compared with core-lipopolysaccharide immune globulin in patients at high risk of postsurgical infection. N. Engl. J. Med. 1992; 327: 234 40.