Year : 2008 | Volume
: 52 | Issue : 2 | Page : 148--158
Pneumonia in Intensive Care Unit
Vinay Joshi1, Gurjar Mohan2,
1 Professor, Department of Anaesthesiology & Critical Care, S.N. Medical College, Jodhpur (Raj.), India
2 Assistant Professor, Department of Anaesthesiology & Critical Care, S.N. Medical College, Jodhpur (Raj.), India
Q.N.21, MG Hospital Campus, In front of Sanghi Petrol Pump, Station Road, Jodhpur (Raj) 342001
No large data based, or randomized controlled studies are available in reference to pneumonia in ICU especially in adult population, in India. Moreover the types of ICU infrastructure, sterilization& disinfection protocols, empirical antibiotics and antibiotics policy are standardized in the country. Hence this review article has mainly utilized available literature from developed countries. This review article briefly discusses the definition of various pneumonia, epidemiology, causative organism, pathogenesis, risk factors, diagnostic strategies and management modalities. By this article, authors hope that a certain guidelines or standardization of protocols in India will be formulated.
|How to cite this article:|
Joshi V, Mohan G. Pneumonia in Intensive Care Unit.Indian J Anaesth 2008;52:148-158
|How to cite this URL:|
Joshi V, Mohan G. Pneumonia in Intensive Care Unit. Indian J Anaesth [serial online] 2008 [cited 2021 Jan 18 ];52:148-158
Available from: https://www.ijaweb.org/text.asp?2008/52/2/148/60613
In intensive care unit (ICU), a significant number of beds are occupied by the patients suffering from pneumonia whether it is community or hospital acquired. The important factor is that pneumonia adds significantly to morbidity and mortality. The etiopathogenesis, pre-disposing factors, selection of the empirical antibiotics, antibiotic protocol in the ICU, diagnostic facility in the ICU, training of paramedical and treating physicians, causative organisms, non adherence to aseptic precautions, lack of monitors and specific ventilators, type of ICU (open or close) are the important factors posing specific challenges in developing countries than in developed countries. Unfortunately, no large randomized, prospective or retrospective literatures on this topic, especially for adults are available in context of India. The guidelines provided by American Thoracic Society (ATS) , are the major source for the content in this article.
Differentiations of different types of pneumonia are important as they differ in terms of predominance of causative organism, selection of antibiotic, and course and prognosis of the disease. To be more precise, the pneumonia has been broadly categorized as community acquired pneumonia (CAP) and hospital acquired pneumonia (HAP).
Pneumonia: infection of the lung that is most commonly caused by bacteria but occasionally caused by viruses, fungi, parasites, and other infectious organisms.
Nosocomial pneumonia (NP) / Hospital acquired pneumonia (HAP): pneumonia that occurs 48 hours or more after admission, which was not incubating at the time of admission.
ICU-acquired pneumonia: pneumonia that arise more than 48 hours after ICU admission.
Ventilator-associated pneumonia (VAP): pneumonia that arises more than 48-72 hours after endotracheal intubation.
Early onset HAP& VAP: occurring within the first 4 days of hospitalization.
Late onset HAP& VAP: at 5 days or more of hospitalization.
Healthcare-associated pneumonia (HACAP): This includes any patient who was hospitalized in an acute care hospital for two or more days within 90 days of the infection; resided in a nursing home or long-term care facility; received recent intravenous antibiotic therapy, chemotherapy or wound care within the past 30 days of the current infection; or attended a hospital or hemodialysis clinic.
The incidence of pneumonia has been reported to be 5-10 cases per 1000 hospital admissions ,, , while in general ICU population incidence has ranged from 820%  . The risk of pneumonia increases by 6 to 20 folds in mechanically ventilated patients ,, . The risk of pneumonia increases maximum during first five days. During first 5 days of ventilation, risk increases by 3%/day; during 5-10 days of ventilation it increases by 2%/day and after 10 days of ventilatory support it increases by 1%each day  . In a recent PGI Chandigarh study, VAP was found to be 30.7% per 1,000 ventilator days.
Gram negative bacilli (Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Acinetobacter species) are the main culprits for HAP (more than 60%). In patients with diabetes and trauma, Gram positive cocci such as Staphylococus aureus are emerging more common  . Anaerobic organism may be responsible following aspiration in non-intubated patient but is rare in VAP  .
In VAP, MRSA and K. pneumoniae are more common in non ventilated rather than intubated patients  . S. pneumoniae and H. influenzae are frequently found in CAP and in early onset HAP in patients without other risk factors, but are uncommon in late onset HAP. Legionella may be mainly responsible organism in immunocompromised patients. Fungal pathogens as Candida species and Aspergillus fumigatus may also occur in immunocompromised and organ transplanted patients. Influenza A is probably the most common viral cause of HAP.
In HAP, the major sources of infection are through healthcare devices, environment (air, water, equipment& fomites), and transfer of microorganism from health care provider to the patient ,,,,,, .
The major potential reservoirs for organisms in a human body are stomach and sinuses. From these potential sites, the bacteria get entry into the trachea via aspiration of oropharyngeal pathogens or via leakage of bacteria around endotracheal tube cuff , . From trachea, the microbial pathogens migrate to lower respiratory tract and here organisms are being colonized.
Against the invasion entry or migration of microbial pathogen, host defenses in the form of mechanical (ciliated epithelium and formation of mucus favoring expulsion of microorganism), in the form of humoral mechanism (formation of antibody and activation of compliment system) or in the form of cellular protection (through polymorphonuclear leucocyte, macrophages, lymphocytes and their cytokines) to expel the microorganism out or to kill them or to make them inactive ,. However if the defense mechanism is weak due to any factor or is insufficient to deal with the number of organisms, infection at lower respiratory tract takes place.
Certain risk factors have been identified which makes the patient more vulnerable for HAP:
General: H/O smoking, advanced age, male sex
Disease: COPD, ARDS, burn, trauma, coma or impaired consciousness, multiple organ failure, longer surgical procedure, thoracic or upper abdominal operations, immunosuppression (including systemic corticosteroids,) hypoalbuminemia, high APACHE II score and etc.
Intervention: H2 blockers or antacids, mechanical ventilation more than three days, previous antibiotics, use of paralytic agents or continuous sedation, re-intubations, bronchoscopy, nasogastric tube, ICP monitoring etc.
Modifiable risk factors
The risk of HAP in patients who are intubated and mechanical ventilated, is increased by 6 to 21 fold ,. Incidence of VAP can be reduced by maintaining endotracheal cuff pressure at greater than 20 cm H2O and by continuous aspiration of subglottic secretions ,,.
Possibly, incidence of HAP can be reduced by limiting the use of sedative& paralytic agents that depress cough and other host-protective mechanism and also by use of oral endotracheal& orogastric tubes, rather than nasotracheal& nasogastric tubes ,, . On the other side, incidence of VAP is not affected by frequent changing of ventilatory circuit and also by use of passive humidifiers or heat-moisture exchangers , .
A significant threefold reduction occurred in the incidence of ICU-acquired HAP in patients treated in the semirecumbent position  . Postpyloric feeding as well as strategy of late administration (i.e. day 5 of intubation ) of enteral feeding is associated with significant reduction in ICU-acquired HAP , .
In a randomized trial of post surgical patients, the use of oral antiseptic chlorhexidine was to be found with significantly reduction in rates of nosocomial infection  . Now a days routine prophylactic use of antibiotics as a selective decontamination of the digestive tract (SDD), to reduce HAP, is avoided due to high level of antibiotic resistance 1 . Unnecessary liberal use of allogenic blood products and old stored blood are found to be a risk factor for increased incidence of HAP and in a prospective randomized trial comparing liberal and conservative "triggers" to transfusion in ICU patients not exhibiting active bleeding and without underlying cardiac disease demonstrated that awaiting a haemoglobin level of 7.0 g/dl as opposed to a level of 9.0 g/dl before initiating transfusion resulted in no adverse effects on outcome  .
A large, double blind, randomized trial comparing ranitidine with sucralfate demonstrated a trend towards lower rates of VAP with sucralfate, but clinically significant gastrointestinal bleeding was 4% higher in the sucralfate group  . Aggressive treatment of hyperglycemia has both theoretical and clinical support, but may not lead to significant benefit in patient with VAP  .
A great emphasis should be to ensure effective infection control measure, which includes staff education, compliance with alcohol-based hand disinfection, and isolation to reduce cross-infection with MDR pathogens, as these means reduce incidence of HAP by around half ,,, . Surveillance of ICU infections, to identify and quantify endemic and new MDR pathogens, and preparation of timely data for infection control and to guide appropriate, antimicrobial therapy in patients with suspected HAP or other nosocomial infections, are recommended (Level II)  .
Clinical and bacteriological strategy
The diagnosis of HAP is suspected if the patient has a radio-graphic infiltrate that is new or progressive, along with fever, purulent sputum, leukocytosis, and decline in oxygenation. The diagnostic criteria of a radiographic infiltrate and at least one clinical feature (fever, leukocytosis, or purulent tracheal secretions) have high sensitivity but low specificity (especially for VAP) . Combinations of signs and symptoms may increase the specificity. When three clinical variables were used, the sensitivity declined, whereas the use of only one variable led to decline in specificity  .
All patients should have chest radiography, preferably postero-anterior and lateral if not intubated. The radiography can help to define the severity of pneumonia and the presence of complications, such as effusions or cavitations  .
The clinical approach is overly sensitive, and it could be difficult to differentiate from other non-infectious conditions like congestive heart failure, atelectasis, pulmonary thromboembolism, pulmonary drug reactions, pulmonary hemorrhage, or ARDS  .
The clinical pulmonary infection score (CPIS) scoring system grades the severity of pneumonia and this include six features  . Each of these six features scores on a scale from 0 to 2, as follows: tracheal secretion: 0= rare, 1= abundant, 2= purulent; radiographic infiltrates: 0= absent, 1= patchy or diffuse 2= localized; fever (°C): 0=≥36.5 and ≤38.4, 1= >38.4 and ≥ 38.9, 2= > 38.9 or 11000, 2= 11000 and > 500 band forms; PaO2/FiO2: 0= >240 or acute respiratory distress syndrome (ARDS), 2= ≤ 240 and no ARDS; microbiology 0= negative, 2= positive.
The absence of a "gold standard" for HAP diagnosis is a major problem, with which diagnostic results can be compared.
Although an etiologic diagnosis is made from a respiratory tract culture, colonization of the trachea precedes development of pneumonia in almost all cases of VAP, and thus a positive culture cannot always distinguish a pathogen from a colonizing organism. However, a sterile culture from the lower respiratory tract of an intubated patient, in the absence of a recent change in antibiotic therapy, is strong evidence that pneumonia is not present, and an extra pulmonary site of infection should be considered (Level II) ,.
Samples of lower respiratory tract secretions should be obtained from all patients with suspected HAP, and should be collected before antibiotic changes. Samples can include an endotracheal aspirate, bronchoalveolar lavage (BAL) sample, or protected specimen brush (PSB) sample (Level II)  . A negative tracheal aspirate (absence of bacteria or inflammatory cells) in a patient without a recent (within 72 hours) change in antibiotics has a strong negative predictive value (94%) for VAP (Level II)  .
In a prospective study by Gibot and coworkers used a rapid immunoblot technique on BAL fluid in whom infectious pneumonia suspected, and found that levels of soluble triggering receptor expressed on myeloid cells (sTREM-1) were the strongest independent predictor of pneumonia  .
Being multifocal nature of VAP, BAL and endotracheal aspirates can provide more representative samples than the protected specimen brush (PSB), which samples only a single bronchial segment  .
Endotracheal aspirates can be cultured quantitatively, and with a threshold of 106cfu/ml or more, the sensitivity of this method for the presence of pneumonia has a mean of 76± 9% and specificity with a mean of 75±28% .
Bronchoscopic BAL studies have typically used a diagnostic threshold of 104cfu/ml. A review literature of 23 prospective studies of BAL in suspected VAP showed a sensitivity with a mean of 73± 18%, and a specificity with a mean of 82±19% .
Quantitative cultures of PSB samples have used a diagnostic threshold of 103cfu/ml or more. The sensitivity and specificity for PSB have a mean 66±19%) and 90±15%, respectively , . PSB appears to be more specific than sensitive for the presence of pneumonia  .
If bronchoscopic sampling is not immediately available, non bronchoscopic sampling can reliably obtain lower respiratory tract secretions for quantitative cultures, which can be used to guide antibiotic therapy decisions (Level II)  .
Semi quantitative cultures of tracheal aspirates cannot be used as reliably as quantitative cultures to define the presence of pneumonia and the need for antibiotic therapy (Level I). 
Approximately 10% of hospitalized patients with CAP require ICU admission. Direct admission to an ICU or high-level monitoring unit is recommended for patients either with any one of the major criteria or 3 of the minor criteria for severe CAP (Level II) as listed in [Table 1]  . Summary of the recommended management of HAP as a algorithm is given in [Figure 1]  .
Major points and recommendations for antibiotic therapy : A major goal of therapy is eradication of the infecting organism, and so, antimicrobials are a mainstay of treatment. Delays in the initiation of appropriate antibiotic therapy can increase the mortality of VAP and thus, therapy should not be postponed for the purpose of performing diagnostic studies in patients who are clinically unstable (level II) ,.
Recommended empirical antibiotics for community acquired pneumonia who admitted to ICU are given in [Table 2]  . While, use the algorithm in [Figure 2] for HAP to select an initial empiric therapy based on the absence or presence of risk factors for MDR pathogens [Table 3]& [Table 4] (Level III)  .
These risk factors include prolonged duration of hospitalization (5 days or more), admission from a healthcare-related facility, and recent prolonged antibiotic therapy (Level II)  .
A reliable tracheal aspirate Gram stain can be used to direct initial empiric antimicrobial therapy and may increase the diagnostic value of the CPIS (Level II)  . Therapy is modified on the basis of the clinical response on Days 2 and 3  .
Choice of specific agents should be dictated by local microbiology, cost, availability, and formulary restrictions (Level II) , . Patients with healthcare-related pneumonia should be treated for potentially drug-resistant organisms, regardless of when during the hospital stay the pneumonia begins (Level II)  . Inappropriate therapy (failure of the etiologic pathogen to be sensitive to the administered antibiotic) is major risk factor for excess mortality and length of stay for patients with HAP, and antibiotic-resistant organisms are the pathogens most commonly associated with inappropriate therapy (Level II)  .
To achieve adequate therapy, it is necessary not only to use the correct antibiotic, but also the optimal dose and the correct route of administration (oral, intravenous, or aerosol) to ensure that the antibiotic penetrates to the site of infection, and to use combination therapy if necessary. Most b lactam antibiotics achieve less than 50% of their serum concentration in the lung, whereas fluoroquinolones and linezolid equal or exceed their serum concentration in bronchial secretions  .
The mechanism of action of certain agents can also affect dosing regimens, efficacy, and toxicity. Some antimicrobials are bactericidal whereas others are bacteriostatic. Bactericidal agents may act in a concentration dependent fashion (aminoglycosides and quinolones) or in a time dependent fashion (vancomycin and b lactam). Some antibiotics do have postantibiotic effect (PAE), as seen with aminoglycoside and quinolones while b lactam antibiotics lack this effect against gram negative bacilli with the exception of carbapenem  .
There is a lot of debate over the use of antibiotics as monotherapy versus combination therapy. A metaanalysis has evaluated all prospective randomized trials of -lactam monotherapy compared with b lactamaminoglycoside combination regimens in patients with sepsis, of whom at least around 15% patients had either HAP or VAP, showed clinical failure was more common with combination therapy and there was no advantage in the therapy of P. aeruginosa infections, compared with monotherapy . In addition, combination therapy did not prevent the emergence of resistance during therapy, but did lead to a significantly higher rate of nephrotoxicity.
Combination therapy should be used if patients are likely to be infected with MDR pathogens (Level II) ,, though no data documented the superiority of this approach compared with monotherpay, except to enhance the likelihood of initially appropriate empiric therapy (Level I)  . If patients receive combination therapy with an aminoglycoside-containing regimen, the aminoglycoside can be stopped after 5-7 days in responding patients (Level III) .
Monotherapy should be used and preferred over combination therapy whenever possible because combination therapy is often expensive and exposes patients to unnecessary antibiotics, thereby increasing the risk of MDR pathogens and adverse outcomes  . Patients who develop nosocomial pneumonia with no risk factors for drug-resistant organisms are likely to respond to monotherapy with the antibiotics listed in [Table 3]. Monotherapy is also the standard when gram-positive HAP, including MRSA, is documented  . Monotherapy with ciprofloxacin has been successful in patients with mild HAP (defined as a CPIS of 6 or less) but is less effective in severe HAP  .
To use monotherapy in patients with severe VAP, the ATS committee believed that patients should initially receive combination therapy as described in [Table 4], but therapy could be changed to a single agent if cultures did not shown a resistant pathogen  .
Monotherapy with selected agents can be used for patients with severe HAP and VAP in the absence of resistant pathogens (Level I) , . Patients in this risk group should initially receive combination therapy until the results of lower respiratory tract cultures are known and confirm that a single agent can be used (Level II).
If P. aeruginosa pneumonia is documented, combination therapy is recommended, mainly because of the high frequency of development of resistance on monotherapy  . Although combination therapy will not necessary prevent the development of resistance, combination therapy is more likely to avoid inappropriate and ineffective treatment of patients. (Level II)  .
In case of Acinetobacter species are to be present, the most active agents are the carbapenems, sulbactam, colistin, and polymyxin. There are no data documenting an improved outcome if these organisms are treated with a combination regimen. (Level II)  . If ESBL+ Enterbacteriaceae are present, then monotherapy with a third-generation cephalosporin should be avoided. The most active agents are the carbapenems (Level II) .
Duration of therapy
If patients receive an initially appropriate antibiotic regimen, efforts should be made to shorten the duration of therapy from the traditional 14 to 21 days to periods as short as 7 days, provided that the etiologic pathogen is not P. aeruginosa, and that the patient has a good clinical response with resolution of clinical features of infection (Level I)  . Patients with a low clinical suspicion of VAP (CPIS of 6 or less) can have antibiotics safely discontinued after 3 days  .
Data support the promise that most patients with VAP, who receive appropriate antibiotic therapy, have a good clinical response within first 6 days. Prolonged therapy leads to colonization with antibiotic resistants.
Aerosolized antibiotics have not been proven to have value in the therapy of VAP (Level I)  . But may be considered as adjunctive therapy with an inhaled amingolycoside or polymyxin for MDR gram negative pneumonia, especially in patients who are not improving with systemic therapy (Level III)  . More studies of this type of therapy are needed.
Preference of particular antibiotic
Linezolide is an alternative to vancomycin for the treatment of MRSA VAP (Level II) and may also be preferred if patients have renal insufficiency or are receiving other nephrotoxic agents, but more data are needed (Level III) ,
Antibiotic rotation or restriction or holiday
Antibiotic restriction can limit epidemics of infection with specific resistant pathogens. Heterogeneity of antibiotic prescriptions, including formal antibiotic cycling, may be able to reduce the incidence of antibiotic resistance. But, the long-term impact of this practice is unknown. (Level II) , .
Continuous versus intermittent infusion
Standard administration is by intermittent infusion; however, continuous infusion may be advantageous. Efficacy of drug with bactericidal activity increases with the exposure time that could be well maintained above minimum inhibitory concentration (MIC) by the continuous infusion. However, sufficient evidence of its clinical efficacy is limited.
Although supportive therapy like chest physiotherapy, postural drainage, humidification and aerosolisation with bronchodilators, mucolytic agents are crucial but with little documentation of efficacy in the management of pneumonia.
Patients with VAP had a longer duration of mechanical ventilation and longer hospital stay. VAP has its own attributable mortality. The crude mortality rate has ranged from 25-70% in late onset HAP/VAP. The increased mortality rates were associated with aerobic gram negative bacteria (Pseudomonas aeruginosa, Acinetobacter species), associated with medical rather than surgical illness, inadequate& ineffective antibiotic therapy and also in patients who had acute respiratory distress syndrome ,.
|1||American Thoracic Society Documents. Gudelines for the management of adults with hospital-acquired, ventilator-acquired, and healthcare associated pneumonia. Am J Respir Crit Care Med 205; 171:388-416.|
|2||Mandell LA, Wunderink RG, Anzueto et al. Infectious Diseases Society of American/ American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44:27-72.|
|3||Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002; 165:867-903.|
|4||Celis R, Torres A, Gatell JM, Almela M. Rodriguez-Roisin R, Agusti-Vidal A. Nosocomial pneumonia: a multivariate analysis of risk and prognosis. Chest 1988; 93:318-324.|
|5||Torres A. Aznar R, Gatell JM, Jimenez P, Gonzalez J, Ferrer A, Celis R, Rodriguez-Roisin R. Incidence, risk, and prognosis factors of nosocomial pneumonia in mechanically ventialated patients. Am Rev Respir Dis 1990;142:523-528.|
|6||Richards MJ, Edwards JR, Culver DH, Gaynes RP. Nosocomial infections in medical ICUs in the United States: National Nosocomial Infections Surveillance System. Crit Care Med. 1999; 27:887-892.|
|7||Cook DJ, Walter SD, Cook RJ, Griffith LE, Guyatt GH, Leasa D, Jaeschke RZ, Brun-Buisson C. Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients. Ann Intern Med.1998;129:440.|
|8||Rello J, Torres A, Ricart M, Valles J, Gonzalez J, Artigas A, Rodriguez-Roisin R. Ventilator-associated pneumonia by Staphylococcus aureus: comparision of methicillin-resistant and methicillin-sensitive episodes. Am J Respir Crit Care Med 1994; 150:1545-1549.|
|9||Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia: a prospective study. Chest 1999;115:178-183.|
|10||Tablan OC, Anderson LJ, Besser R, Bridges C, Hajjeh R. Healthcare Infection Control Practices Advisory Committee, Centers for Disease Control and Prevention. Guidelines for preventioning health-care-associated pneumonia, 2003; recommendations of the CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep 2004;53(RR-3):1-36.|
|11||Craven DE, Steger KA. Epidemiology of nosocomial pneumonia: new perspectives on an old disease. Chest 1995:108:1S-16S.|
|12||Pittet D, Hugonnet S, Harbarth S, Mourouga P, Sauvan V, Touveneau S, Perneger TV. Effectiveness of a hospital-wide programme to improve compliance with hand hygiene:Infection control programme. Lancet 2000:356:1307-1312.|
|13||Kollef MH. The prevention of ventilator-associated pneumonia. N Engl J Med. 1999:340:627-634.|
|14||du Maulin GC, Paterson DG, Hedley-Whyte J, Lisbon A. Aspiration of gastric bacteria in antacid-treated patients: a frequent cause of postoperative colonisation of the airway. Lancet 1982;1:242-245.|
|15||Valles J, Artigas A, Rello J, Bonsoms N, Fontanals D, Blanch L, Fernandez R, Baigorri F, Mestre J. Continuous aspiration of subglottic secretions in preventing ventilator-associated pneumonia, Ann Intern Med 1995;122:179-186.|
|16||Craven DE, Steger KA. Nosocomial pneumonia in mechanically ventilated adult patients:epidemiology and prevention in 1996. Semin Respir Infect 1996;11:32-53.|
|17||Cook D, De Jonghe B, Brochard L, Brun-Buisson C. Influence of airway management on ventilator-associated pneumonia:evidence from randomized trials. JAMA 1998:279:781-787.|
|18||Rello J. Sonora R, Jubert P, Artigas A, Rue M, Valles J. Pneumonia in intubated patients: role of respiratory airway care. Am J Respir Crit Care Med 1996:154:111-115.|
|19||Holzapfel L, Chastang, C, Demingeon G, Bohe J, Piralla B, Coupry A. A randomized study assessing the systematic search for maxillary sinusitis in nasotracheally mechanically ventilated patients. Influence of nosocomial maxillary sinusitis on the occurrence of ventilator associated pneumonia. Am J Respir Crit Care Med. 1999;159;695-701.|
|20||Hess D. Prolonged use of heat and moisture exchangers: why do we keep changing things. Crit Care Med 2000;28:16671668.|
|21||Kirton OC, De-Haven B, Morgan J, Morejon O. Civetta J. A prospective randomized comparison of an in-line heat moisture exchange filter and heated wire humidifiers: rates of ventilator-associated early-onset (community-acquired) or late-onset (hospital-acquired pneumonia and incidence of endotracheal tube occlusion. Chest 1997; 112:1055-1059.|
|22||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 trial. Lancet 1999;354:1851-1858.|
|23||Heyland DK, Drover GW, MacDonald S, Novak F. Lam M. Effect of postpyloric feeding on gastroesophageal regurgitation and pulmonary microaspiration: results of a randomized controlled trial. Crit Care Med 2001;29:1495-1501.|
|24||Ibrahim EH, Mehringer L, Prentice D, Sherman G, Schaiff R, Fraser V, Kollef MH. Early versus late enteral feeding of mechanically ventilated patients: results of a clinical trial. J. Parenter Enteral Nutr 2002;26:174-181.|
|25||De-Reiso AJ II, Ladowski JS, Dillon TA, Justice JW, Peterson AC. Chlorhexidine gluconate 0.12% oral rinse reduces the incidence of total nosocomial respiratory infection and nonprophylactic systemic antibiotic use in patients undergoing heart surgery. Chest 1996;109:1556-1561.|
|26||Hebert PC, Wells G, Blachman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. A multicenter, randomized. Controlled clinical trial of transfusion requirements in critical care. N. Engl J Med 1999; 340:409-417.|
|27||Prod'hom G, Leuenberger P, Koerfer J, Blum A, Chiolero R, Schaller MD, Perret C, Spinnler O, Blondel J, Siegrist H. Nosocomial pneumonia in mechanically ventilated patients receiving antacid, ranitidine, or sucralfate as prophylaxis for stress ulcer: a randomized controlled trial. Ann Intern Med 1994: 120:653-662.|
|28||Bonten MJ. Controversies on diagnosis and prevention of ventilator associated pneumonia. Diagn Microbiol Infect Dis 1999, 34:199-204.|
|29||Weinstein RA. Epidemiology and control of nosocomial infections in adult intensive care units. Am J Med 1991;91:179S-184S.|
|30||Wunderink RG, Woldenberg LS, Zeiss J, Day CM, Ciemins J, Lacher DA. The radiologic diagnosis of autopsy-proven ventilator-associated pneumonia. Chest 1992;101:458-463.|
|31||Calandra T, Cohen J. The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med 2005; 33: 1538-1548.|
|32||Souweline B, Veber B, Bedos JP, Gachot B, Dombret MC, Regnier B, Wolff M. Diagnostic accuracy of protected specimen brush and bronchoalveolar lavage in nosocomial pneumonia:impact of previous antimicrobial treatments. Crit Care med.1998;26:236-244.|
|33||Blot F, Raynard B, Chachaty E, Tancrede C, Antoun S, Nitenberg G. Value of Gram Stain examination of lower respiratory tract secretions for early diagnosis of nosocomial pneumonia. Am J Respir Crit Care med 2000; 162:1731-1737.|
|34||Gibot S, Cravoisy A, Levy B, Bene MC, Faure G, Bollaert PE. Soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia. N Engl J Med 2004;350:451-458.|
|35||Cook D, Mandell L. Endotracheal aspiration in the diagnosis of ventilator-associated pneumonia,. Chest 2000;117:195S-197S.|
|36||Torres A, El-Ebiary M. Bronchoscopic BAL in the diagnosis of ventilator-associated pneumonia. Chest 2000;117:198S-202S.|
|37||Marquette CH, Herengt F, Mathieu D, Saulnier F, Courcol R, Ramon P. Diagnosis of pneumonia in mechanically ventilated patients: repeatability of the protected specimen brush. Am Rev Respir Dis 1993; 147:211-214.|
|38||Campbell GD, Blinded invasive diagnostic procedures in ventilator-associated pneumonia. Chest 2000;117:207S-211S.|
|39||Sanchez-Nieto JM. Torres A, Garcia-Cordoba F, El-Ebiary M, Carrillo A, Ruiz J, Nunez ML, Niederman M. Impact of invasive and noninvasive quantitative culture sampling on outcome of ventilator-associated pneumonia: a pilot study. Am J Respir Crit Care Med. 1998;157:371-376.|
|40||Luna CM, Vujacich P, Niederman MS, Vay C, Gherardi C, Matera J, Jolly EC. Impact of BAL data on the therapy and outcome of ventilator associated pneumonia. Chest 1997;111:676-685.|
|41||Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999;115:462-474.|
|42||Trouillet JL, Chastre J, Vuagnat A, Joly-Guillou ML, Combaux D, Dombret MC, Gibert C. Ventilator-associated pneumonia caused by potentially drug-resistant bacteria. Am J Respir Crit Care Med. 1998; 157:531-539.|
|43||Fartoukh M, Maitre B, Honore S, Cerf C, Zahar JR, BrunBuisson C. Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited. Am J Respir Crit Care Med. 2003;168:173-179.|
|44||Ibrahim EH, Ward S, Sherman G, Schaiff R, Fraser VJ, Kollef MH. Experience with a clinical guideline for the treatment of ventilator associated pneumonia. Crit Care Med 2001;29:1109-1115.|
|45||Namias N, Samiian L, Nino D, Shirazi E, O' Neill K, Kett DH, Ginzburg E, Mc-Kenney MG, Sleeman D, Cohn SM. Incidence and susceptibility of pathogenic bacteria vary between intensive care units within a single hospital:implications for empiric antibiotic strategies. J. Trauna 2000;49:638-645 [discussion 645-646].|
|46||Gaynes R. Health-care associated bloodstream infections: a change in thinking. Ann Intern Med. 2002; 137:850-851.|
|47||Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis 2000;31: S131-S138.|
|48||Conte JE Jr, Golden JA, Kipps J. Zurlinden E. Intrapulmonary pharmacokinetics of linezolid. Antimicrob Agents Chemother 2002;46:1475-1480.|
|49||Craig WA. The pharmacology of meropenem, a new carbapenem antibiotic. Clin Infect Dis 1997; 24: S266-S275.|
|50||Paul M, Benuri-Silbiger I, Soares-Weiser K, Liebovici L. - Lactam monotherapy versus -Lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomized trials. BMJ, doi:10.1136/bmj.bmjjournals.com/cgi/reprint/bmj. 38028.520995.63v1.pdf?ck=nck.|
|51||Gruson D, Hilbert G, Vargas F, et al. Rotation and restricted use of antibiotics in a medical intensive care unit: impact on the incidence of ventilator-associated pneumonia caused by antibiotic resistant gram negative bacteria. Am J Respir Crit Care Med 2000; 162: 837-843.|
|52||Singh N, Rogers P, Atwood CW et al. Short course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000; 162: 505-511.|
|53||Fink MP, Snydman DR, Niederman MS et al. Severe pneumonia study group. Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized double blind trial comparing intravenous ciprofloxacin with imipenemcilastatin. Antimicrob Agents Chemother 1994; 38: 547-557.|
|54||Jaccard C, Troillet N, Harbarth S et al. Prospective randomized comparison of imipenem-cilastatin and piperacillintazobactam in nosocomial pneumonia or peritonitis. Antimicrob Agents Chemother 1998; 42:2966-2972.|
|55||Garnacho-Montero J, Ortiz-Leyba C, Jimenez-Jimenez FJ et al. Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-succeptible VAP. Clin Infect Dis 2003;36:1111-1118.|
|56||Paterson DL, Ko WC, Von Gattberg A, Casellas JM, Mulazimoglu L, Klugman KP, Bonomo RA, Rice LB, Mc Cormack JG, Yu VL. Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum ?-lactamases: implications for the clinical microbiology laboratory. J Clin Microbiol 2001;39:2206-2212.|
|57||Chastre J. Wolff M. Fagon JY, Chevret S, Thomas F, Wermert D, Clementi E, Gonzalez J, Jusscrand D. Asfar P, et al, Comparison of 8 vs 15 days of antibiotic therapy for ventilatorassociated pneumonia in adults: a randomized trial. JAMA 2003;290:2588-2598.|
|58||Brown RB, Kruse JA, Counts GW, Russel JA Christou NV, Sands ML. Endotracheal Tobramycin Study Group. Doubleblind study of endotracheal tobramycin in the treatment of gram-negative bacterial pneumonia. Antimicrob Agents Chemother 1990;34:269-272.|
|59||Hamer DH. Treatment of nosocomial pneumonia and tracheobronchitis caused by multidurg-resistant Pseudomonas aeruginosa with aerosolized colistin. Am J Respir Crit Care Med. 2000:162:328-330|
|60||Wunderink RG, Rello J, Cammarata SK. Cross-Dabrera RV, Kollef MH. Linezolid vs Vancomycin: analysis of two doubleblind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 2003; 124:1789-1797|
|61||Wunderink RG, Cammarata SK, Oliphant TH, Kollef MH. Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther 2003;25:980-992.|
|62||Kollef MH, Ward S, Sherman G et al. Inadequate treatment of nosocomial infection is associated with certain empiric antibiotic choices. Crit Care Med 2000; 28: 3456-3464.|
|63||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: 1908-1914.|
|64||Rello J. Ausina V. Ricart M, Castella J, Prats G. Impact of previous antimicrobial therapy on the etiology and outcome of ventilator associated pneumonia. Chest 1993;104:1230-1235.|
|65||Heyland DK, Cook DJ, Griffith L, Keenan SP, Brun-Buisson C, Canadian Critical Trials Group. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. Am J Respir Crit Care Med 1999;159:1249-1256.|