Patient Selection for Clinical Investigation of Ventilator-Associated Pneumonia* Criteria for Evaluating Diagnostic Techniques Susan K. Pingleton, M.D., F.C.C.P.; Jean-Yves Fagon, M.D.; and
KlnMth V. l.nt>M: ]f'., M.D., F.C.C.P.
N
osocomial pneumonia in patients receiving ventilation is a common ICU occurrence. The exact frequency is not known because of the lack of specificity of the clinical diagnosis and existing standard diagnostic techniques. We have attempted to come to consensus in identifying a patient population with a clinical suspicion of nosocomial pneumonia and establishing a definition of pneumonia by which new diagnostic techniques can be compared. DAYS ON MECHANICAL VENTILATION
Background Virtually all recent evaluations of diagnostic methods for nosocomial pneumonia require some defined time period on mechanical ventilation for inclusion into the study. The implied rationale results from the attempt to differentiate pneumonia present at or developing very soon after intubation. This differentiation is based on the work of Johanson et al•, who found that 50 percent of patients required at least 4 days before colonization occurred. Therefore, atime criterion has been used to separate community-acquired pneumonia from nosocomial pneumonia. Controversy
The majority of studies required the patient to have at least 48 h of mechanical ventilation before study inclusion. w Other studies required >72 h.""u Salata et al 13 defined a time period of 4 days) had a different pathogenesis and microbiologic spectrum.
Recommendations Limited data are available to specifically define the difference in frequency of nosocomial pneumonia based on 48 vs 72 vs 96 h of mechanical ventilation. Until such studies are performed, recommendations related to studies for evaluation of diagnostic techniques are made on the basis of *From the Pulmonary and Critical Care Division, University of Kansas Medical Center, Kansas City; Hopital Service de Reanimation Medicale, Broussais, Paris, France; and the Division of Pulmonary and Critical Care Medicine, The University ofTennessee, Memphis. Contributors: Chmtian Brun-Buisson, M.D.; Deborah J Cook, M.D.; Jean-Jacques Garaud, M.D .; R. J Kahn, M.D.; Michael B. Iarkptitrick, M.D .; H. Lode, M.D. ; Richard J Maunder; M.D.; Jerome ftlgjn, M.D.; Michael Wolfj M.D .
time required for colonization to occur. Using 48 h after intubation and initiation of mechanical ventilation, two groups of patients with ventilator-associated pneumonia (VAP) should be studied: (1) early-onset VAP (48 h). Areas of fUture Investigation
Studies evaluating rates of nosocomial pneumonia and microbiologic characterization of nosocomial pneumonia at 48, 72, and 96 h after intubation should be performed. TYPES oF REsPIRATORY FAILURE
Background Respiratory failure, which is defined as the need for mechanical ventilation, is caused by many disease processes. Virtually all recent studies evaluating nosocomial pneumonia have defined nosocomial pneumonia in patients receiving mechanical ventilation. Therefore, the terms "nosocomial pneumonia" and "ventilator-associated pneumonia" are for the most part used interchangeably. However, the disease process and therefore the patient population requiring mechanical ventilation vary in all reported studies. For example, Fagon et alo.t• described their patient population as an ICU population (mostly cardiac) comprised primarily (79 of 145 =54 percent) of postoperative respiratory insufficiency. Only 23 percent of patients had respiratory insufficiency secondary to chronic obstructive pulmonary disease (COPD), and only 8 percent had adult respiratory distress syndrome (ARDS). 10 Other studies have described a medicalsurgical,• a medical;• a surgical,•·•• and a respiratory ICU population. •• In many instances, these studies did not include the specific diagnosis of the study population. Controversy
There are no data to define the risk or frequency of nosocomial pneumonia in specific patient populations (eg, ARDS) requiring mechanical ventilation. Also, limited data are available to describe coexisting primary disease (eg, COPD) in patients receiving ventilation for another reason, such as postoperative respiratory insufficiency. Different patient populations could conceivably have different risks of nosocomial pneumonia, which may have an impact on the diagnostic approach.
Recommendations Studies of homogeneous patient populations are encouraged. The classification presented in Table 1, which categorizes patients by type of respiratory failure leading to CHEST I 102 I 5 I NOVEMBER, 1992 I Supplement
553S
Acute Respiratory Process Acute difl'use lung disease
Noncardiogenic pulmonary edema Cardiogenic pulmonary edema
Acute focal disease
Pneumonia Nonpneumonia Acute airways disease Acute hypoventilation
Deterioration of Chronic Conditions Pulmonary Obstructive Restrictive
Extrapulmonary Neuromuscular disease Altered level of consciousness Other
mechanical ventilation, is recommended. The circumstances leading to respiratory failure should be classified as medical, postoperative, or traumatic. The type of artificial airway (le, tracheostomy or endotracheal intubation) should be described. Areas of Alture Investigation
Future investigations should be conducted to determine the risk factors and incidence of VAP in different patient populations requiring mechanical ventilation. In addition, criteria for evaluating the severity of underlying lung disease should be developed. DEFINmoN oF CLINICAL PNEuMONIA
Background Most researchers have adopted or modified the definition of pneumonia originally used by Johanson et al:• (1) radiographic appearance of a new or progressive pulmonary in6ltrate; (2) fever; (3) leukocytosis; and (4) purulent tracheobronchial secretions. Some investigators have required a sputum Gram stain showing >25 leukocytes and 38°C or >38.3"C) increases the diagnostic sensitivity or specificity.
Becommendations Clinical criteria used to define a population with a clinical suspicion of VAP who require diagnostic tests include new and persistent infiltrates and grossly purulent tracheobron-
chial secretions. In addition, the clinical suspicion is enhanced with the presence of fever >38.3°C, leukocytosis, and deterioration of gas exchange. These criteria may not apply to the neutropenic patient. Areas of Alture Investigation
In future studies, criteria for the clinical suspicion of VAP should be tabulated and correlated with evidence for or absence of definite and probable pneumonia to enable a rigorous assessment of the sensitivity and specificity of these clinical criteria. ANTIBIOTIC TREATMENT BEFORE DIAGNOSTIC PROCEDURE
Background Antibiotic therapy can affect both the sensitivity and specificity of microbial studies. Chastre et al10 compared protected specimen brush (PSB) quantitative cultures to postmortem quantitative cultures in patients receiving ventilation. In diagnosing pneumonia, the PSB culture had an overall specificity of 60 percent. The specificity increased to 87 percent in patients without antibiotics compared to 42 percent in patients receiving antibiotics. 10 Therefore, antibiotic therapy can result in false-negative results by precluding the recovery of organisms at a significant concentration in respiratory secretions. False-positive results can also occur because antibiotics may predispose to colonization of the lower airway. The frequency with which antibiotics affect sensitivity and specificity and therefore cause false-negative and falsepositive results has been described infrequently. While many studies define the percentage of patients receiving antibiotics,....a.a.e.u.u.••·15 only a few report duration of antibiotic therapy prior to the diagnostic procedure. Chastre et al10 described results of PSB quantitative culture and histologic examination in 26 patients, 14 of whom received antibiotics and 12 of whom did not. The false-positive rate was 8 of 20 (40 percent); 7 of the patients with false-positive results received antibiotics. No false-negative results were noted. More recently, Pham et al 18 evaluated quantitative PSB cultures in 17 patients with proven pneumonia, 9 of whom received antibiotics. No false-positive results were identified. Of six false-negative results, however, four of the patients were receiving antibiotics. To avoid the effect of antibiotics on culture results, antibiotics are frequently discontinued before the procedure. Essentially no information is available to validate this practice or to determine the minimum number of hours required without antibiotic therapy before samples can be taken with maximum cultural yield.
Recommendations The effect of antibiotics on nosocomial pneumonia should be evaluated by recording and reporting the following: (1) no prior antibiotic therapy for at least 48 h; (2) the institution of or change in antibiotic therapy within 48 h; (3) antibiotic therapy >48 h; (4) topical antibiotics, including inhalation, oropharyngeal, or gastric routes of administration. Areas of Alture Investigation
Rigorous evaluation of the effect of withholding or disconPatient Selection (Pingleton, Fegon, Llleper)
tinuing antibiotics on the basis of a negative diagnostic study is required. The important outcome measures include mortality, morbidity, duration of stay in the ICU, and cost. DEFINmON OF PRESENCE OR ABsENCE OF PNEUMONIA
Background Clinical manifestations of pneumonia are inaccurate for the diagnosis oflung infection in patients receiving mechanical ventilation. Nosocomial pneumonia may be underdiagnosed when compared to histologic findings at autopsy. •u• The opposite is also true. Several prospective studies have
shown that pneumonia, as diagnosed by quantitative culture
either of PSB or with BAL and verified with stringent criteria, occurs much less frequently than is clinically suspected. uue
Controversy: Criteria for the Diagoosis of Nosocomial Pneumonia Because the clinical diagnosis of nosocomial pneumonia is inaccurate, various objective criteria to define pneumonia have been proposed. The definitions have included several categories: definite, probable, and inconclusive criteria.'3 •18 Specific criteria to define the presence or absence of pneumonia have also been developed. 18 The criteria of four researchers are presented below. For Salata et al, 13 the diagnosis of nosocomial pneumonia is definite if there is development of new or progressive pulmonary infiltrate with (1) positive pleural fluid or blood cultures for the same organism as in tracheal aspirate, or (2) radiographic cavitation, or (3) histopathologic demonstration of pneumonia or necrosis, or (4) new fever and leukocytosis and purulent tracheal aspirate. Diagnosis is probable if there is development of new or progressive pulmonary infiltrate associated with two of the following three criteria: (1) purulent tracheal aspirate; (2) a rise in body temperature (~1°C, or ~38.3°C) ; or (3) ~25 percent increase in circulating leukocytes. The diagnosis is uncertain if two of the following four criteria are met: (1) purulent tracheal aspirate; (2) increased temperature ~1°C and ~38 . 3°C ; (3) ~25 percent increase in circulating leukocytes; (4) new or progressive infiltrate. According to Chastre et al, 11 the diagnosis of pneumonia is definite if one of these three criteria are met: (1) positive pleural fluid cultures; (2) rapid cavitation of lung infiltrates; (3) histopathologic demonstration of pneumonia. Pneumonia is absent if there is full recovery with complete resolution of fever and pulmonary infiltrates without antimicrobial therapy or 1f there are no signs of bacterial pneumonia at autopsy performed within 8 days ofbronchoscopy in patients not receiving antibiotics. The diagnosis is uncertain for patients who could not be classified into one of the two preceding categories. For Pham et al, 18 diagnosis of pneumonia is definite if one of these four criteria are met: (1) positive blood cultures unrelated to another source and obtained within 48 h before or after bronchial sampling; (2) culture of empyema fluid; (3) CT evidence of pulmonary abscess; (4) pathologic evidence of pneumonia on postmortem study (within 3 days after sampling) demonstrating abscess formation or area of consolidation with intense polymorphonuclear (PMN) leu-
kocyte accumulation. In the absence of criteria for definite infection, diagnosis is probable if quantitative culture samples (PSB) are ~10' and the clinical course is consistent with pulmonary bacterial infection. Diagnosis is uncertain if antibiotics were administered after sampling because of strong clinical suspicion of pneumonia, which would obscure interpretation of subsequent samples. Also according to these investigators, results are false-negative when sample yields are ~10' cfu/ml of either PSB or YI'C in the presence of one of the definitive criteria for infection. Results are false-positive when (I) samples yield
KlnMth V. l.nt>M: ]f'., M.D., F.C.C.P.
N
osocomial pneumonia in patients receiving ventilation is a common ICU occurrence. The exact frequency is not known because of the lack of specificity of the clinical diagnosis and existing standard diagnostic techniques. We have attempted to come to consensus in identifying a patient population with a clinical suspicion of nosocomial pneumonia and establishing a definition of pneumonia by which new diagnostic techniques can be compared. DAYS ON MECHANICAL VENTILATION
Background Virtually all recent evaluations of diagnostic methods for nosocomial pneumonia require some defined time period on mechanical ventilation for inclusion into the study. The implied rationale results from the attempt to differentiate pneumonia present at or developing very soon after intubation. This differentiation is based on the work of Johanson et al•, who found that 50 percent of patients required at least 4 days before colonization occurred. Therefore, atime criterion has been used to separate community-acquired pneumonia from nosocomial pneumonia. Controversy
The majority of studies required the patient to have at least 48 h of mechanical ventilation before study inclusion. w Other studies required >72 h.""u Salata et al 13 defined a time period of 4 days) had a different pathogenesis and microbiologic spectrum.
Recommendations Limited data are available to specifically define the difference in frequency of nosocomial pneumonia based on 48 vs 72 vs 96 h of mechanical ventilation. Until such studies are performed, recommendations related to studies for evaluation of diagnostic techniques are made on the basis of *From the Pulmonary and Critical Care Division, University of Kansas Medical Center, Kansas City; Hopital Service de Reanimation Medicale, Broussais, Paris, France; and the Division of Pulmonary and Critical Care Medicine, The University ofTennessee, Memphis. Contributors: Chmtian Brun-Buisson, M.D.; Deborah J Cook, M.D.; Jean-Jacques Garaud, M.D .; R. J Kahn, M.D.; Michael B. Iarkptitrick, M.D .; H. Lode, M.D. ; Richard J Maunder; M.D.; Jerome ftlgjn, M.D.; Michael Wolfj M.D .
time required for colonization to occur. Using 48 h after intubation and initiation of mechanical ventilation, two groups of patients with ventilator-associated pneumonia (VAP) should be studied: (1) early-onset VAP (48 h). Areas of fUture Investigation
Studies evaluating rates of nosocomial pneumonia and microbiologic characterization of nosocomial pneumonia at 48, 72, and 96 h after intubation should be performed. TYPES oF REsPIRATORY FAILURE
Background Respiratory failure, which is defined as the need for mechanical ventilation, is caused by many disease processes. Virtually all recent studies evaluating nosocomial pneumonia have defined nosocomial pneumonia in patients receiving mechanical ventilation. Therefore, the terms "nosocomial pneumonia" and "ventilator-associated pneumonia" are for the most part used interchangeably. However, the disease process and therefore the patient population requiring mechanical ventilation vary in all reported studies. For example, Fagon et alo.t• described their patient population as an ICU population (mostly cardiac) comprised primarily (79 of 145 =54 percent) of postoperative respiratory insufficiency. Only 23 percent of patients had respiratory insufficiency secondary to chronic obstructive pulmonary disease (COPD), and only 8 percent had adult respiratory distress syndrome (ARDS). 10 Other studies have described a medicalsurgical,• a medical;• a surgical,•·•• and a respiratory ICU population. •• In many instances, these studies did not include the specific diagnosis of the study population. Controversy
There are no data to define the risk or frequency of nosocomial pneumonia in specific patient populations (eg, ARDS) requiring mechanical ventilation. Also, limited data are available to describe coexisting primary disease (eg, COPD) in patients receiving ventilation for another reason, such as postoperative respiratory insufficiency. Different patient populations could conceivably have different risks of nosocomial pneumonia, which may have an impact on the diagnostic approach.
Recommendations Studies of homogeneous patient populations are encouraged. The classification presented in Table 1, which categorizes patients by type of respiratory failure leading to CHEST I 102 I 5 I NOVEMBER, 1992 I Supplement
553S
Acute Respiratory Process Acute difl'use lung disease
Noncardiogenic pulmonary edema Cardiogenic pulmonary edema
Acute focal disease
Pneumonia Nonpneumonia Acute airways disease Acute hypoventilation
Deterioration of Chronic Conditions Pulmonary Obstructive Restrictive
Extrapulmonary Neuromuscular disease Altered level of consciousness Other
mechanical ventilation, is recommended. The circumstances leading to respiratory failure should be classified as medical, postoperative, or traumatic. The type of artificial airway (le, tracheostomy or endotracheal intubation) should be described. Areas of Alture Investigation
Future investigations should be conducted to determine the risk factors and incidence of VAP in different patient populations requiring mechanical ventilation. In addition, criteria for evaluating the severity of underlying lung disease should be developed. DEFINmoN oF CLINICAL PNEuMONIA
Background Most researchers have adopted or modified the definition of pneumonia originally used by Johanson et al:• (1) radiographic appearance of a new or progressive pulmonary in6ltrate; (2) fever; (3) leukocytosis; and (4) purulent tracheobronchial secretions. Some investigators have required a sputum Gram stain showing >25 leukocytes and 38°C or >38.3"C) increases the diagnostic sensitivity or specificity.
Becommendations Clinical criteria used to define a population with a clinical suspicion of VAP who require diagnostic tests include new and persistent infiltrates and grossly purulent tracheobron-
chial secretions. In addition, the clinical suspicion is enhanced with the presence of fever >38.3°C, leukocytosis, and deterioration of gas exchange. These criteria may not apply to the neutropenic patient. Areas of Alture Investigation
In future studies, criteria for the clinical suspicion of VAP should be tabulated and correlated with evidence for or absence of definite and probable pneumonia to enable a rigorous assessment of the sensitivity and specificity of these clinical criteria. ANTIBIOTIC TREATMENT BEFORE DIAGNOSTIC PROCEDURE
Background Antibiotic therapy can affect both the sensitivity and specificity of microbial studies. Chastre et al10 compared protected specimen brush (PSB) quantitative cultures to postmortem quantitative cultures in patients receiving ventilation. In diagnosing pneumonia, the PSB culture had an overall specificity of 60 percent. The specificity increased to 87 percent in patients without antibiotics compared to 42 percent in patients receiving antibiotics. 10 Therefore, antibiotic therapy can result in false-negative results by precluding the recovery of organisms at a significant concentration in respiratory secretions. False-positive results can also occur because antibiotics may predispose to colonization of the lower airway. The frequency with which antibiotics affect sensitivity and specificity and therefore cause false-negative and falsepositive results has been described infrequently. While many studies define the percentage of patients receiving antibiotics,....a.a.e.u.u.••·15 only a few report duration of antibiotic therapy prior to the diagnostic procedure. Chastre et al10 described results of PSB quantitative culture and histologic examination in 26 patients, 14 of whom received antibiotics and 12 of whom did not. The false-positive rate was 8 of 20 (40 percent); 7 of the patients with false-positive results received antibiotics. No false-negative results were noted. More recently, Pham et al 18 evaluated quantitative PSB cultures in 17 patients with proven pneumonia, 9 of whom received antibiotics. No false-positive results were identified. Of six false-negative results, however, four of the patients were receiving antibiotics. To avoid the effect of antibiotics on culture results, antibiotics are frequently discontinued before the procedure. Essentially no information is available to validate this practice or to determine the minimum number of hours required without antibiotic therapy before samples can be taken with maximum cultural yield.
Recommendations The effect of antibiotics on nosocomial pneumonia should be evaluated by recording and reporting the following: (1) no prior antibiotic therapy for at least 48 h; (2) the institution of or change in antibiotic therapy within 48 h; (3) antibiotic therapy >48 h; (4) topical antibiotics, including inhalation, oropharyngeal, or gastric routes of administration. Areas of Alture Investigation
Rigorous evaluation of the effect of withholding or disconPatient Selection (Pingleton, Fegon, Llleper)
tinuing antibiotics on the basis of a negative diagnostic study is required. The important outcome measures include mortality, morbidity, duration of stay in the ICU, and cost. DEFINmON OF PRESENCE OR ABsENCE OF PNEUMONIA
Background Clinical manifestations of pneumonia are inaccurate for the diagnosis oflung infection in patients receiving mechanical ventilation. Nosocomial pneumonia may be underdiagnosed when compared to histologic findings at autopsy. •u• The opposite is also true. Several prospective studies have
shown that pneumonia, as diagnosed by quantitative culture
either of PSB or with BAL and verified with stringent criteria, occurs much less frequently than is clinically suspected. uue
Controversy: Criteria for the Diagoosis of Nosocomial Pneumonia Because the clinical diagnosis of nosocomial pneumonia is inaccurate, various objective criteria to define pneumonia have been proposed. The definitions have included several categories: definite, probable, and inconclusive criteria.'3 •18 Specific criteria to define the presence or absence of pneumonia have also been developed. 18 The criteria of four researchers are presented below. For Salata et al, 13 the diagnosis of nosocomial pneumonia is definite if there is development of new or progressive pulmonary infiltrate with (1) positive pleural fluid or blood cultures for the same organism as in tracheal aspirate, or (2) radiographic cavitation, or (3) histopathologic demonstration of pneumonia or necrosis, or (4) new fever and leukocytosis and purulent tracheal aspirate. Diagnosis is probable if there is development of new or progressive pulmonary infiltrate associated with two of the following three criteria: (1) purulent tracheal aspirate; (2) a rise in body temperature (~1°C, or ~38.3°C) ; or (3) ~25 percent increase in circulating leukocytes. The diagnosis is uncertain if two of the following four criteria are met: (1) purulent tracheal aspirate; (2) increased temperature ~1°C and ~38 . 3°C ; (3) ~25 percent increase in circulating leukocytes; (4) new or progressive infiltrate. According to Chastre et al, 11 the diagnosis of pneumonia is definite if one of these three criteria are met: (1) positive pleural fluid cultures; (2) rapid cavitation of lung infiltrates; (3) histopathologic demonstration of pneumonia. Pneumonia is absent if there is full recovery with complete resolution of fever and pulmonary infiltrates without antimicrobial therapy or 1f there are no signs of bacterial pneumonia at autopsy performed within 8 days ofbronchoscopy in patients not receiving antibiotics. The diagnosis is uncertain for patients who could not be classified into one of the two preceding categories. For Pham et al, 18 diagnosis of pneumonia is definite if one of these four criteria are met: (1) positive blood cultures unrelated to another source and obtained within 48 h before or after bronchial sampling; (2) culture of empyema fluid; (3) CT evidence of pulmonary abscess; (4) pathologic evidence of pneumonia on postmortem study (within 3 days after sampling) demonstrating abscess formation or area of consolidation with intense polymorphonuclear (PMN) leu-
kocyte accumulation. In the absence of criteria for definite infection, diagnosis is probable if quantitative culture samples (PSB) are ~10' and the clinical course is consistent with pulmonary bacterial infection. Diagnosis is uncertain if antibiotics were administered after sampling because of strong clinical suspicion of pneumonia, which would obscure interpretation of subsequent samples. Also according to these investigators, results are false-negative when sample yields are ~10' cfu/ml of either PSB or YI'C in the presence of one of the definitive criteria for infection. Results are false-positive when (I) samples yield
