RESPIRATORY INFECTIOUS COMPLICATIONS IN THE INTENSIVE CARE UNIT

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INTENSIVE CARE UNIT COMPLICATIONS

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RESPIRATORY INFECTIOUS COMPLICATIONS IN THE INTENSIVE CARE UNIT Antoni Torres, MD, Mustafa El-Ebiary, MD, and Ana RaA6, MD

Nosocomial pneumonia (NP) accounts for approximately 10% to 15% of all hospitalacquired infections. It is currently the second leading type of nosocomial infection, after urinary tract infections. The overall risk of acquiring nosocomial pneumonia is approximately 6 to 8.6 infections per 1000 admissions. The incidence of nosocomial pneumonia is greatly increased for all patients in intensive care units (ICUs),where respiratory infections have been reported to be the most frequent type of nosocomial infection. The reported incidence in ICUs has ranged from 12% to 29%.*' Patients receiving mechanical ventilation have a risk as much as 20-fold higher, with rates as high as 25% to 70%.1p19 Ventilator-associated pneumonia (VAP) is a frequent complication of mechanical ventilation, with an incidence ranging from 9% to 70% depending on the period of mechanical ventilation, the type of population studied, and the diagnostic methods employed.', l9 The crude mortality of VAP is around 50%, but the attributable mortality accounts for 30% of total mortality.20 A crucial feature in the etiopathogenesis of VAP is the abnormal colonization of the oropharynx and its contiguous structures Supported in part by grant: FISS 981096, and Grant SGR 00086 from the Comisionat for a Univesitats i Recesca de la Generalitat de Catalumya 1997 and by the Fundacid Clinic/CIRIT, IDIBAPS.

such as sinuses, dental plaque, trachea, and gastric re~erv0ir.l~ Efforts regarding prevention of VAP should be directed to the different steps of its etiopathogenesis-abnormal oropharyngeal and gastric colonization, aspiration, exogenous inoculation, and bacterial transl~cation.~~ The antibiotic treatment of VAP usually is empiric. It has been shown that the inadequacy of initial empiric antibiotic regimens is related to poor prognosis. Recent standardized guidelines have been published to improve the adequacy of empiric antibiotic treatment for VAP.7 The severity of pneumonia, duration of hospital stay, and presence of risk factors for acquisition of particular microorganisms are the factors upon which the clinician should base his or her therapeutic ~trategy.~ Nosocomial sinusitis is a not infrequent infectious complication in intubated patients8 An association between maxillary sinusitis and VAP has been suggested.= In patients with fever not responding adequately to antibiotic treatment, nosocomial sinusitis has to be searched for, particularly in the presence of nasal intubation and nasogastric tubess1 This article mainly deals with the respiratory infectious complications in patients admitted to the ICU, particularly VAP and nosocomial sinusitis. Epidemiology, etiopathogenesis, prevention, diagnosis, and treatment are discussed thoroughly.

From the Servei de Pneumologia, Institut Clinic de Malalties Respiratbries, Hospital Clinic, Barcelona, Spain ~~

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Table 1. MICROORGANISMS ISOLATED IN VENTILATOR-ASSOCIATED PNEUMONIA* Pathogen

Rello et al' n = 129

Torres et a P n = 78

Fagon et a P n = 52

25 4 2

9

NR

20 3

4 4

NR 14

Aerobic gram-positive S. aureus Streptococcus pneumoniae Enterococcus spp. Other Aerobic gram-negative Haemophilus injuenme l? aeruginosa Acinetobacter spp. Proteus spp. Serratia spp. Klebsiella spp. Escherichin coli Other Anaerobic flora Fllngi

2

18 21 3 3 4 NR 3 7 3 3

NR 22 39 4 4

NR NR 8 NR 4

6

19 9 9 9 2 5 9 1

NR

NR

= not reported. *Figuresrepresent percentages of studied patients.

VENTILATOR-ASSOCIATED

Incidence The incidence of VAP in mechanically ventilated patients ranges between 9% and 70%.'* l9 The average incidence is 20% to 25%. In other words, one of every four mechanically ventilated patients acquires pulmonary infection during the period of mechanical ventilation. The incidence depends on several factors, although the most important are those related to the host and the duration of intubation. The latter is a risk factor exponentially related to the acquisition of VAP9Using the ratio of "cases per 1000 ventilator days,'' the rates of VAP are around 15 per 1000 ventilator days. This figure is often higher in surgical units compared with medical ICU patients. Crude rates of VAP range from 1% to 3% per day of intubation and mechanical ventilation. Causes

The bacterial pathogens most frequently associated with VAP are enteric gram-negative bacilli and Staphylococcus aureus, although the cause is polymicrobial in 50% of mechanically ventilated patients.14 Anaerobic microorganisms and fungi are infrequent causes. Table 1 illustrates the different microorganisms isolated in VAP from three published epidemiologic series.19, The most comprehensive classification of

pathogens causing nosocomial pneumonia (NP) and VAP was published recently in the American Thoracic Society (ATS) official ~tatement.~ This classification could be useful in starting empirical antibiotic treatment. The spectrum of potential pathogens can be classified according to three variables, as follows: (1) Is VAP mild to moderate, or is it severe? (Definition of severity is shown in Table 2.) (2) Are specific host or therapeutic factors, predisposing to specific pathogens, present? (3) Is the pneumonia early-onset (occurring within <5 days of admission), or late-onset (occurring >5 days of admission)? Accordingly, patients can be classified into three groups: (1) Group 1: patients without risk factors who present with either mild to moderate NP occurring any time during hospitalTable 2. CRITERIA FOR DEFINING SEVERE NOSOCOMIAL PNEUMONIA

Any two of the following criteria: 1. Respiratory rate >30/min while receiving supplemental oxygen 2. Arterial partial pressure of oxygen <60 mm Hg while receiving >35% oxygen, arterial carbon dioxide pressure >48 mm Hg and pH <7.3 3. Urine output <80 mL/4 hours, unless other explanation exists or the patient is on dialysis 4. Change in mental status (acute delirium) Admit to intensive care unit if one of the following criteria is present: 1. Need for mechanical ventilation 2. Patient suffering from shock (systolic blood pressure <90 mm Hg, or diastolic blood pressure <60 mm Hg) 3. Pharmacologic blood pressure support >4 hours

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Table 3. SPECIFIC RISK FACTORS FOR THE EMERGENCE OF CERTAIN MICROORGANISMS ~~

Risk Factor

Agent

Witnessed gross aspiration Abdominal surgery Coma, intravenous drug abuse Diabetes mellitus Chronic renal failure Corticosteroids Prolonged hospital stay Prolonged intensive care unit stay Prior antibiotics Structural lung diseases

Anaerobic bacteria Enterococcus spp., anaerobes S. aureus (methicillin-sensitive) S. aureus (methicillin-sensitive) S. aureus (methicillin-sensitive) Legionella spp., Aspergillus spp. P. aeruginosa, Enterobacter spp., Acinetobacter spp. P. aeruginosa, Enterobacter spp., Acinetobacter spp. P. aeruginosa, Enterobacter spp., Acinetobacter spp. P. aeruginosa

ization, or severe nosocomial pneumonia of early onset. (2) Group 2: patients with mild to moderate nosocomial pneumonia and risk factors (Table 3), who develop pneumonia at any time. (3) Group 3: patients with severe early-onset nosocomial pneumonia and without risk factors, or patients with severe pneumonia occurring at any time and risk factors. Bacterial agents causing NP in patients in group 1 are defined as core and include (Table 4) gram-negative bacilli such as Enterobacter spp., Escherichia coli, Klebsiella spp., Proteus spp., and Serratia marcescens. Microorganisms such as Haemophilus influenzae, methicillinsensitive Staphylococcus aureus, and Streptococcus pneumoniue should also be included. Microorganisms causing NP in group 2 are the same as those in group 1. In addition, specific risk factors present in this group might influence the presence of some agents (Table 3). In the same group, if mild to moderate NP is of early onset (<5 days of hospitalization), H. influenzae, s. pneumoniae, and s. aureus (methicillin-sensitive) are more common than other core microorganisms.” The

Table 4. CORE ORGANISMS IN PATIENTS WITH GROUP 1* NOSOCOMIAL PNEUMONIA

Enteric gram-negative (nonpseudomonal) Enterobacter spp. Escherichia coli Klebsiella spp. Proteus spp. Serratia marcescens Haemophilus influenzae Methicillin-sensitiveS. aureus Streptococcus pneumoniae *Mild-to-moderate nosocomial pneumonia, no unusual risk factors, onset any time or patients with severe nosocomial pneumonia with early onset. Adapted from Campbell D, Niederman Ms, Broughton WA, et al: ATS Official Statement. Hospital-acquired pneumonia in adults: Diagnosis, assessment of severity, initial antimicrobial therapy, and preventive strategies. A Consensus Statement. Am J Respir Crit Care Med 153:771-1725, 1996.

specific microorganisms (non-core) related to particular risk factors are anaerobes: methi~ pneucillin-sensitive S. a ~ r e u s , 4Legionella mophila: Pseudomonus aeruginosa, and Aspergillus spp.49 Group 3 patients are those presenting with severe pneumonia at any time or late-onset (>5 days of hospitalization) pneumonia. The definition of severe NP is adapted from the guidelines for the management of community-acquired pneumonia and is summarized in Table 2A3 Severe NP may occur in patients already admitted to ICUs or may predispose to ICU admission. Although core organisms are frequently found in this setting, additional pathogens (P. aeruginosa, Acinetobacter spp., and methicillin-resistant S. aureus [if endemic in the hospital]) should be considered, particularly when the patient has been hospitalized for more than 5 days. Patients corresponding to this category are at risk for being infected with potentially multiresistant organisms. They could have received certain therapies predisposing to gram-negative multi-resistant bacteria, or they may have a number of severe coexisting impairments, allowing infection by these agents. In mechanically ventilated patients, VAP is polymicrobial in approximately 40% of cases. If these patients have received prior antibiotic treatment, the risk of pneumonia by P. aeruginosa or Acinetobacter spp. is increased. Other multiresistant microorganisms such as Stenotrophomonas maltophilia and Citrobacter freundii have to be taken into account. A recent study from Trouillet et a F has found that multi-resistant microorganisms are linked to mechanical ventilation lasting more than 7 days as well as prior and broad antibiotic treatment. ETIOPATHOGENESIS AND PREVENTION

Understanding the pathogenesis and the pathophysiology of VAP is an important step

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toward providing preventive and curative measures. Microorganisms can reach the lung by the following routes: (1) spread to the lung from contiguous structures such as the pleura or the mediastinum, (2) hematogenous spread from distal foci, (3) inoculation by aerosols, or (4)aspiration of colonized oropharyngeal and gastric contents. The oropharynx may be colonized from contiguous structures such as dental plaque, paranasal sinuses, the trachea, and the upper gastrointestinal tract (transcolonization; Fig. 1).Furthermore, a possible mechanism that might occur in critically ill patients is the translocation of bacteria from the ischemic gut to the systemic circulation and the lung. Most episodes of VAP are caused by the aspiration of oropharyngeal contents into the distal airways and the subsequent proliferation of bacteria in patients who already have an impaired mechanical, humoral, or cellular lung defense me~hanisrn.~~ If the proliferation

of bacteria overcomes the defense mechanisms, inflammation spreads from bronchioles to more distal airways, leading to bronchopneumonia. The main etiopathogenic mechanisms for the development of VAP therefore are the following: (1) oropharyngeal colonization, (2) gastric colonization, (3) bacterial translocation, (4)aspiration to lower airways, and (5) inoculation of aerosols (see Fig. 1). Prevention of VAP has to be guided by the steps of the etiopathogenesis in relation to the different risk factors described in the literature. Table 5 summarizes the main risk factors found in selected studies, and many of the recognized preventive methods are related to these risk factors. This table excludes specifically L. pneumophila, which can be endemic in some hospitals, contaminating cooling towers and water supplies. Inhalation of aerosols from respiratory therapy equipment and aspiration of contaminated potable water are

Figure 1. Pathogenesis of ventilator-associated pneumonia. Transcolonization of the oropharynx occurs with contiguous structures such as the sinuses, trachea, gastric contents, and periodontal areas. (From Meduri GU, Estes RJ: The pathogenesis of ventilator-associate& pneumonia: II. The lower respiratory tract. Intensive Care Med 21:452461, 1992; with permission.)

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Table 5. RISK FACTORS FOR BACTERIAL NOSOCOMIAL PNEUMONIA THAT HAVE BEEN IDENTIFIED IN SELECTED STUDIES* ~~

~

Ventilator-associatedpneumonia Independent risk factors Age >60 years COPD/PEEP/pulmonary disease Comahmpaired consciousness Therapeutic interventions Intracranial pressure monitor Organ failure Large volume gastric aspiration Prior antibiotics H,-blocker + antacids Gastric colonization and pH Season-fall, winter Ventilator circuit changes 24 versus 48 hours Reintubation Mechanical ventilation >2 days Tracheostomy Supine head position Ventilated and nonventilated patients Independent risk factors Age >60 years APACHE I1 >16 Trauma/head injury Impaired airway reflexes Coma Bronchoscopy Nasogastric tube Endotracheal intubation Upper abdominal/thoracic surgery Low serum albumin Neuromuscular disease

~~

Univariate risk factors for pneumonia Age > 60 years Smoking Underlying disease (RF vs NF/UF) SAPS >9 ASA class N Forced inspiratory oxygen >50 Prior care facility Alcohol intake Renal failure/dialysis Intra-aortic balloon pump COPD Chemical paralysis Airway instrumentation Aspiration before intubation Mechanical ventilation >2 days No prior surgery H2-Blockersor antacids versus sucralfate Coma Head trauma Cascade humidifier versus HME Tracheostomy Continuous enteral feeding Prior antibiotics Nosocomial maxillary sinusitis

*Excludes risk factors for pneumonia due to Legionella pneumophila. COPD = Chronic obstructive pulmonary disease; PEEP = positive end-expiratory pressure; RF = rapidly fatal; NF = nonfatal; UF = ultimately fatal; SAPS = Simplified Acute Physiological Score; ASA = American Society of Anaesthesia; Hz = histamine type 2; APACHE = Acute Physiology and Chronic Health Evaluation; HME = heat-moisture exchanger. Interventions were markers of severe underlying disease and included dopamine, dobutamine >5 pg/min, barbiturate therapy for increased intracranial pressure, continuous intravenous antiarrhythmic or antihypertensive therapy. Modified in part from Craven DE, Steger KA: Nosocomial pneumonia in mechanically ventilated adult patients: Epidemiology and prevention in 1996. Semin Respir Infect 11:32-53,1996.

methods of transmission of L. pneumophila in critically ill patients. The potential preventive measures against oropharyngeal and gastric colonization include the following: 1. judicious antibiotic policy because antibiotic treatment is a key factor for abnormal oropharyngeal colonization, 2. selective digestive decontamination (SDD), including parenteral and topical (oropharyngeal and gastric) antibiotics. SDD has been found effective in reducing nosocomial pulmonary infections by several authors, but it is still controversial. SDD probably is only effective in selected populations (young trauma patients, transplant recipients), and it imperatively requires microbiologic surveillance. In addition, there is concern regarding the appearance of multiresis-

tance (e.g., methicillin-resistant S.

aureus). All metanalyses published until now have systematically shown a reduction of respiratory infections rate using SDD without decreasing mortality. A recent meta-analysis by DAmico and coworkersI6of 15 years of clinical research, however, shows that antibiotic prophylaxis with a combination of topical and systemic drugs can reduce respiratory tract infections and overall mortality in critically ill patients. In view of the results of this meta-analysis, the recommendation of SDD for prevention of VAP probably has to be reviewed. 3. Although the role of gastric reservoir is still debated, the use of sucralfate instead of H, blockers is not recommended. In a recent extensive trial, Cook

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and colleag~es.'~ demonstrated that there was no difference in VAP incidence between patients receiving sucralfate versus ranitidine. The incidence of gastric bleeding was higher in patients receiving sucralfate. 4. In selected populations (i.e., coma with high risk of VAP), the use of high doses of antibiotics during short periods (<24 h) has been shown to reduce the incidence of VAP by almost 50%. Prevention of aspiration to lower airways probably includes the following methods: (1)head positioning at semirecumbency (45"), preventing aspiration of gastric contents to lower airways; (2) the use of endotracheal tube cuffs with supraglottic glottic aspiration; (3) avoiding reintubations whenever possible because reintubation introduces high levels of bacterial inocula into lower airways. Exogenous inoculation has to be prevented via the following issues57:(1) hand washing policy to avoid cross-infections, (2) careful management and manipulation of respiratory therapy equipment (mechanical ventilators, circuit tubing, nebulizers and humidifiers, and portable devices such as manual spirometers or bag resuscitators that can be easily transferred from unit to unit). It is clear that circuit tubing should not be changed because this measure does not decrease the incidence of VAP; (3) correct policy for suction of secretions; (4) adequate disinfection of fiberoptic bronchoscopes. The mechanical defenses are very difficult to improve because they are importantly altered in intubated patients, but adequate drainage by means of physiotherapy is clearly a highly recommended method. There is some evidence that using rotational beds (rocking bed) can lead to a decrease of respiratory infections in intubated patients. These beds are very expensive, however, and the cost-effectiveness of this method is not clearly confirmed. Finally, there are no clinically confirmed methods that prevent alterations in humoral and cellular defenses. Most of the work done in this field is experimental or under clinical investigation.

sistent pulmonary infiltrates, fever greater than 38.3"C,leukocytosis, and purulent secret i o n ~ ?Others ~ have added to these criteria the presence of a positive gram-stain in respiratory secretions. Although these parameters are fairly straightforward in nonventilated patients, they frequently present false-positive and false-negative results in patients undergoing mechanical ventilation. Andrews and colleagues,' using autopsy results as their gold standard, demonstrated that clinical parameters had a 29% misdiagnosis in patients with acute respiratory distress syndrome (ARDS). Bell and coworkers,5 studying similar populations, found 10% false-positive and 62% false-negatives rates. Wunderink et al?6 using necropsy results as their gold standard, did not find a single roentgenographic sign that had a diagnostic efficiency higher than 68%. In an immediate postmortem study in which the author@ performed histologic analysis of multiple pulmonary biopsies the best clinical parameter was pulmonary infiltrates, with a sensitivity of 70% and a specificity of 71%. An effort to improve the diagnostic yield of clinical parameters was made by Pugin et a1,& who designed a score that combines clinical, physiologic, and microbiologic parameters. A score higher than six was related to the presence of pneumonia. Studies using postmortem lung biopsies are warranted to clarify the exact value of this score. Major explanations for false-negative results of clinical parameters rely on the quality deficiencies of portable chest radiographs and the histologic pattern of VAP (diffuse bronchopneumonia), which is not easily detected in the initial periods by portable chest radiographs.5O False-positive results are explained by the frequent presence of other pulmonary lesions such as alveolar hemorrhage, pulmonary fibrosis, atelectasis, and diffuse alveolar damage. Meduri and colleague^^^ for example, observed that the fibroproliferative phase of ARDS may mimic pneumonia, presenting with fever and leukocytosis and great difficulty in ascertaining the presence of new pulmonary infiltrates. In view of this information, it seems clear that the clinical diagnosis of VAP is not an easy task for the ICU physician.

CLINICAL DIAGNOSIS OF VENTILATOR-ASSOCIATED PNEUMONIA

MICROBIOLOGICAL DIAGNOSIS

The clinical diagnosis of NP has been classically based on the presence of new and per-

The introduction of the flexible fiberoptic bronchoscope in the late 1960s resulted in the

Bronchoscopic Methods

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ability to directly access the lower airway. The most commonly used bronchoscopic methods are the protected specimen brush (PSB) and bronchoalveolar lavage (BAL). Both techniques have been described in the context of an intent to reduce contamination of lower airway secretions by upper airway flora. Protected Specimen Brush

This technique involves positioning the bronchoscope next to the orifice of the Sampling area and advancing the PSB catheter 3 cm out of the fiberoptic bronchoscope to avoid collection of pooled secretions on the catheter tip. An inner cannula is protruded to eject a distal carbon wax plug into the airway, and the catheter is advanced to the desired subsegment. If purulent secretions are visualized, the brush is rotated into them. After sampling, the brush is retracted into the inner cannula, the inner cannula is retracted into the outer cannula, and the catheter is removed from the bronchoscope. A small quantity of brushed secretions may then be used for Gram’s stain. After wiping the catheter and cutting with sterile scissors, the brush is placed in 1 mL of diluent and immediately submitted for quantitative bacterial culture. The volume retrieved is approximately 0.001 mL (range 0.01-0.001) of lower respiratory secretions and, as a result of dilution in the holding medium, results in a 100 to 1000-fold dilution on the culture plate. Quantitative bacterial cultures of PSB are imperative to distinguish colonization from infection. A growth of >lo3 cfu/mL is considered significant and corresponds to an initial concentration of lo3 to lo6bacterial/mL in the retrieved secretions. The diagnostic threshold of this method could be influenced by several factors. The first is the lack of standardization of sampling technique used by different investigators. If the original method of Wimberley is usedG for PSB, then the brush is rotated in areas of visualized purulent secretions. This technique increases sensitivity, but peripheral wedging of the brush can increase sampling error. The choice of a specific segment for sampling does not appear to affect the sensitivity of the PSB method.34Recent information from histologic studiesls,52 that have shown that VAP is a multifocal process, however, suggests that some of the sensitivity problems of the technique could be related to its inherent particularities, such as the seg-

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mental sampling. Broad sampling techniques could overcome this problem. Second, prior antibiotic therapy is another explanation for false-negative results. Montravers et a141have shown antibiotics can rapidly sterilize samples collected by PSB after 3 days of treatment. A recent histologic study confirmed that the bacterial burden of the lung is importantly decreased in the presence of antibiotic treatment.18 This effect is obviously minimized when prior antibiotic treatment was ineffective against the microorganisms causing Third, another possible explanation for false-negative results is that they are not really negative but rather borderline results because the infection is in an early stage. At this stage, withholding antibiotics could be deleterious to patient outcome. Dreyfuss and colleag~es’~ followed up borderline cultures (between lo2 and lo3 cfu/mL) and observed that some of these cultures evolved to positive cultures (above the threshold), therefore representing an early stage of infection. A final explanation for false-positive results is the presence of bronchiolitis without pneumonia. Although the bacterial concentrations can be low at this stage and there is no pneumonia, patients need to be treated with antibiotics. Bronchiolitis, with or without pneumonia, is a frequent finding in recent postmortem studies regarding the histology of VAP.”, 52 The sensitivity of PSB varies among studies,’2 from 33% to 369’0~. to more than 95%.” On the other hand, the calculated specificity12 ranges from 50%62 to lOO%,’O, 40, 56 with the median specificity 95%.12 The PSB may be more specific than sensitive. Bronchoalveolar Lavage

BAL is performed by advancing the bronchoscope distally into a subsegmental bronchus (generally a third- or fourth-generation bronchus) until the airway is occluded proximally. The next step is the instillation of 20 to 50 mL aliquots of sterile saline into the lung periphery, followed by gentle aspiration. As yet, there is no consensus about the total volume instilled, but it is believed that at least 100 mL are required to retrieve secretions from the periphery of the subsegment. Investigators have used from 100 to 240 mL in the diagnostic evaluation of pneumonia.35The sampling area is selected based on the loca-

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tion of the infiltrate on chest radiograph or by direct visualization of a subsegment containing purulent secretions. Other methods using protected systems have been designed to avoid contamination of the retrieved BAL fluid. These methods, however, are more expensive because they use catheters that are inserted into the bronchoscope channel in addition to the rest of equipment used in performing conventional BAL.37 Quantitative bacterial cultures of BAL fluid are imperative to distinguish colonization from infection. The currently accepted threshold is lo4 cfu/mL. Most of the information regarding bronchoscopic BAL in this population refers to patients with VAP. Several studies have been published in the literature regarding BAL technique performed via fiberoptic bronchoscopy for the diagnosis of VAP. Interestingly, there were four studies performed immediately after death that included lung tissue 32, 62 sampling with histologic examination.26, The diagnostic value of sampling methods, other than BAL, was compared with BAL in histologic and nonhistologic studies. The techniques compared were endotracheal aspirates, PSB, and other types of BAL. Sensitivity of BAL varies among the different studies and ranges from as low as 22% in one study61 to 100% in The calculated mean k SD sensitivity among different studies was 73kl8Y0.l~As regards specificity of BAL, in the same review the mean -+SD calculated specificity among 23 studieslZwas 82 k 19%. This variability depends on prior antibiotic treatment, type of study population, and the reference test used. Another factor that can influence variability is the repeatability of the method, as shown in a recent ~tudy.2~ Examination of Bronchoalveolar Lavage Fluid. The examination of BAL fluid for intracellular organisms (KO) has been suggested as a useful means of establishing an early diagnosis of pneumonia and guiding initial antibiotic treatment. This requires using a threshold value of infected cells, usually around YO.^, lo,56, Several studies applied the detection of ICO to assess the diagnostic yield. Sensitivities ranged from as low as 37%32to 100%;specificities ranged from 89%11 to 100%. Nonbronchoscopic Sampling

Nonbronchoscopic methods have the advantage of being more readily achievable

prior to administration of antibiotics. Like bronchoscopic techniques, the nonbronchoscopic methods use quantitative culture thresholds to improve their overall diagnostic accuracy. Unlike simple quantitative cultures of tracheal aspirates, however, these nonbronchoscopic methods can also be used to diagnose nonbacterial infections, particularly in immunocompromised hosts. Most of the studies involving nonbronchoscopic techniques have been performed in mechanically ventilated patients. At least four studies have shown that PSB used blindly through an endotracheal tube has an accuracy similar to its use via bron30, 63, 67 One of these used chosc~py.~~, the Metras catheter for introducing the PSB and obtaining lower respiratory samples. Pham and colleagues45reported that the quantitative cultures blindly aspirated through a plugged telescoping catheter have a similar diagnostic value to those obtained using a PSB via fiberoptic bronchoscopy. The method described by these authors is interesting because of its simplicity and low cost. A theoretical advantage of the visualized over the blind methods is that the former (persistence of distal secretions surging from distal bronchi during exhalation) can help in the prediction of pneumonia, as suggested by Timsit et al.59 Blind BAL has also been tested by several authors using different approaches. These approaches use c ~ n v e n t i o n a methods, l~~ protected catheters using mini-BAL procedure~,5~ Swan-Ganz catheters,= or, more recently, protected catheters that can be directed to one or the other side of the lungs, depending upon where the infiltrates are locatedz8 (Fig. 2). Overall, these methods have also shown accuracies very similar to or even better thanwhen protected-those obtained by guided methods. This information, although apparently surprising, is explained by the histologic pattern of VAP described in recent studies18,52: bilateral, diffuse, and preferentially affecting the dependent zones of the lower lobes (Fig. 3). Consequently, the accuracy of each method does not depend completely on the visual guide of the sampling. This latter statement is very important in practical terms for units that cannot have fiberoptic bronchoscopy available 24 hours per day. The side effects of these techniques, although not completely described, are hypothetically similar to those alluded to previously but with the advantage of avoiding

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Figure 2. Ballard catheter for bronchoalveolar lavage. Note that the inner catheter’s end is mushroom-shaped helping to wedge it in a subsegmentary bronchus. The inner catheter is also numerically marked from 16 to 50 cm to match it with the length of the orotracheal tube.

those inherent to the use of fiberoptic bronchoscopy. Moreover, the validation of these diagnostic methods has not been extensively performed using postmortem lung examination. ANTIBIOTIC TREATMENT FOR VENTILATOR-ASSOCIATED PNEUMONIA

The core organisms of group 1patients (i.e., patients without risk factors who present with either mild to moderate NP occurring any time during hospitalization or severe nos-

Figure 3. Ventilator-associated pneumonia. This is a multifocal bilateral process affecting predominantly the lower lobes. Different degrees of evolution and severity coexist at the same time. (From Fabregas N, Torres A: New histopathological aspects of human ventilator-associated pneumonia. In Vincent JL (ed): Yearbook 1996 of Intensive Care and Emergency Medicine. Berlin, Springer-Verlag, 1996, pp 520-530; with permission.)

ocomial pneumonia of early onset) are the enteric gram-negative bacilli and should be treated with second- or nonpseudomonal third-generation cephalosporin (see Table 4). The p-lactam/ p-lactamase-inhibitor combination also can be used. In case of penicillin allergy, fluoroquinolones or clindamycin/aztreonam can be given. Monotherapy is usually appropriate in this setting. In patients from group 2 (i.e., patients with mild to moderate NP and risk factors who develop pneumonia at any time), certain bacteria in addition to the core organisms, such as anaerobes, S. auyeus, Legionella spp., and P. aeyuginosa, should be considered according to the presence or absence of specific risk factors for these organisms (see Table 3). All of these patients should be treated for the core organisms as discussed, but usually require the addition of other antimicrobial agents to provide coverage for other likely pathogens. Clindamycin and metronidazole are active against anaerobes, for example, and can be added to the core antibiotics in witnessed or suspected cases of gross aspiration, although a p-lactam/ p-lactamase inhibitor combination may be sufficient. Vancomycin should be added in cases with coma or head trauma until multiresistant S. auyeus (MRSA) is ruled out. Upon suspicion of Legionella infection (e.g., patients on high doses of steroids), erythromycin and/or rifampicin should be administered. In patients from group 3 (i.e., patients with severe early-onset NP and without risk fac-

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tors, or patients with severe pneumonia occurring at any time and risk factors), treatment should be directed against the core organisms as well as more resistant and virulent gram-negative bacilli such as Acinetobacter spp. and P. aeruginosa. S. maltophila also occasionally is detected. This requires the use of combination antimicrobial therapy. This can be done with an aminoglycoside or ciprofloxacin plus an antipseudomonal penicillin, a p-lactam/ p-lactamase inhibitor, ceftazidime or cefoperazone, imipenem, meropenem, or aztreonam. The treatment of patients from group 3 requires the use of combination antimicrobial therapy, although it may be able to complete therapy using a single agent in some cases. The decision to continue combination therapy can be made after 2 or 3 days of treatment and based on the clinical response and microbial cultures. If P. aeruginosa, Acinetobacter spp., Enterobacter spp., or MRSA is not isolated, for instance, monotherapy can be given confidently because there are data showing good efficacy using monotherapy in severe nonpseudomonal NP. If one of the microorganisms just mentioned is present, however, antibiotic combination therapy has to be continued to improve mortality in bacteremic cases and to avoid the emergence of resistant mutants. It is important to keep in mind that risk factors for the acquisition of these microorganisms are mechanical ventilation period greater than 7 days, prior antibiotic therapy, and inadequate antibiotic treatment. The information regarding the use of monotherapy in severe NP is scanty. In one studyIz1monotherapy with imipenem was compared with monotherapy with ciprofloxacin in 78% of 405 cases of severe NP. Both monotherapy regimens were effective if P. aeruginosa was not present, but the therapy with ciprofloxacin was associated with a better clinical efficacy and a better rate of eradication of Enterobacter spp. In another study,13 comparing imipenem to imipenem plus netilmycin in patients with severe NP or sepsis, however, the clinical efficacies were similar (80% and 86%, respectively). The emergence of P. aeruginosa resistant to imipenem occurred in eight patients receiving monotherapy and in 13 patients receiving combination therapy. In that particular study, imipenem monotherapy appeared as effective as the combination of imipenem plus netilmycin for the treatment of severe NP. Another recent randomized compared intravenous

meropenem (1000 mg/8 h) with intravenous ceftazidime (2 g/12 h) plus tobramycin. Satisfactory clinical response occurred in 56 of the 63 meropenem-treated patients and in 42 of 58 of the ceftazidime/tobramycin-treated patients (P = 0.04). The bacteriologic response rates were 89% and 6770, respectively (P= 0.06). The authors concluded that meropenem is well tolerated and more efficacious than the combination of ceftazidime/tobramycin for the initial empiric treatment of hospital-acquired pneumonia. Nevertheless, the ceftazidime dosage given in this study was only 2 g/12 h. The authors’ personal view tends to be conservative in patients with severe NP and start with combination antipseudomonal therapy until the results of cultures are available. There are several possibilities regarding antipseudomonal therapy. First is a combination of a p-lactam with an aminoglycoside, which, in theory, increases the synergism against P. aeruginosa. The existence of this synergism in vivo is not clear, however, because aminoglycosides do not penetrate well in pulmonary tissue and are inactivated by the acidic environment:* A second possibility is the combination of two p-lactam antibiotics. Using that approach, it may result in antagonism in some cases or even induction of p-lactamases for one or both antibiotics. Finally, the association of ciprofloxacin and a p-lactam antibiotic may provide synergy, good parenchymal penetration, and lower toxicity than aminoglycosides.6 Antibiotic Issues When Choosing Empirical Treatment Against Nosocomial Pneumonia

The choice of antibiotic regimens in a certain hospital depends on the following: (1)the sensitivity pattern of the predominant flora in the unit; (2) patients’ underlying conditions, type and degree of immunosuppression, and the type of antibiotics received for prophylaxis or treatment; and (3) antibiotic-related aspects such as the ability to produce endotoxins and select mutant strains. A penicillin plus a p-lactamase inhibitor is active against gram-positive cocci, including Enterococcus spp. (except ticarcillin/clavulanate), enterobacteria, P. aeruginosa (except ampicillin/sulbactam), and anaerobic microorganisms, including Bacteroides frasilis. Cefotaxime, ceftriaxone, and ceftizoxime have a

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similar spectrum, but their intrinsic activity is higher. They are inactive against Enterococcus spp. and P. aeruginosa. Ceftazidime is less active than other third-generation cephalosporins against gram-positive cocci; on the other hand, it is active against P. aeruginosa. Fourth generation cephalosporins have a similar spectrum to third-generation ones. They also are active against P. aeruginosa, with slighter higher minimum inhibitory concentrations (MICs) than ceftazidime. Carbapenems have a spectrum similar to the association of piperacillin/tazobactam, with MICs against P. aeruginosa two to four times lower. Meropenem has been shown to be more potent than imipenem-cilastatin in experimental models of gram-negative infections, including P. aeruginosa lung infection. In addition, in animal models and clinical trials in high-risk patients, the seizure-inducing properties of meropenem were less than those of imipenem with or without cilastatin. Aminoglycosides have a rapid bactericidal dose-dependent effect. The production of endotoxins induced by aminoglycosides is lower than that observed with cephalosporins, however. Glycopeptides such as vancomycin and teicoplanin possess a slow bactericidal and almost null postantibiotic effect. These are active against gram-positive cocci, including MRSA, S. pneumoniae, and penicillin-resistant enterococci. If using fluoroquinolones, it is preferable to administer them adjusted by their half-lives to avoid the selection of resistant mutants. Generally, they produce fewer endotoxins than cephalosporins. They are inactive against anaerobes. New antibiotic groups such as streptogramins (eg., Synercid) or new-generation quinolones are very active against gram-positive and maintain activity against gram-negative bacteria, respectively, and should be added to the hospital actual armamentarium.

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of 14 to 21 days to reduce the chances of relapse. In contrast, cure rates exceeding 95% have been noted for NP caused by methicillin-sensitive S. aureus or H . influenzae. For these pathogens, a 7- to 10-day course of treatment may be adequate. Nonresponse to Treatment

There are several possible causes for rapid deterioration or failure to improve. These include the possibility that the process is not pneumonia, or that certain host, bacterial, and therapeutic factors have not been considered. Noninfectious processes that may be mistakenly labeled as NP include atelectasis, congestive heart failure, pulmonary embolism with infarction, lung contusion in trauma patients, and chemical pneumonitis from aspiration. Patients with ARDS can have fibroproliferative diffuse alveolar damage, whereas mechanically ventilated patients can have pulmonary hemorrhage. Host factors associated with nonresponse to treatment include underlying fatal conditions, superinfection, chronic obstructive pulmonary disease, and immunosuppression. Again, bacterial variables can be associated with an adverse outcome of initial therapy. The infecting pathogen can be resistant at the outset to the chosen therapy or can acquire resistance during therapy, particularly in the case of P. aeruginosa. Finally, pneumonia can be caused by another pathogen (i.e., Mycobac-

terium tuberculosis). Certain complications during therapy can also lead to failure to respond to therapy. Some patients with NP have other sources of fever, such as sinusitis, vascular catheterrelated infection, urinary tract infections, or pseudomembranous enterocolitis. Complications of the original pneumonia can lead to failure, including the development of lung abscess or empyema.

Duration of Treatment NOSOCOMIAL SINUSITIS

Prospective studies assessing optimal duration of antibiotic therapy for NP have not been reported. Duration of therapy should be individualized based on the severity of illness, rapidity of clinical response, and infecting agent. Although carefully controlled studies documenting duration of therapy have not been reported, in these settings, antibiotics should be continued for a minimum

Sinusitis is present not infrequently in critically ill patients. The most important risk factors for sinusitis are nasal intubation and the presence of nasogastric tubes.51Paranasal sinusitis is a commonly overlooked source of sepsis in ventilated patients. Sinusitis was first noted as a frequent problem in neurosurgical patients because of the frequent use of

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brain CT scans, which include the paranasal sinuses (Fig. 4). An epidemiologic study in an ICU orally intubated population found that the incidence of sinusitis, as diagnosed by cultures of maxillary sinus secretion, was 1OYo.B

The microbial flora of patients with nosocomial sinusitis are mainly polymicrobial or composed of gram-negative bacilli. Sinus colonization is also related to oropharyngeal colonization and probably with VAP acquired by mechanically ventilated patients. Recent work from Rouby and coworkers51demonstrated the importance of nosocomial sinusitis as an occult focus of sepsis in critically ill patients and its relationship to the incidence of VAP in patients who developed sinusitis compared with those patients who did not. The incidence of sinusitis in this study was higher in patients intubated nasotracheally versus those intubated by the orotracheal ~ route (95.5%versus 22.5%;P < O . O O ~ . ~Furthermore, there was a coincidence between microorganisms causing sinusitis and NP. Etiopathogenesis

The presence of a foreign object in the nasopharynx appears to be a n important risk factor for the development of sinusitis. Foreign bodies in the nares can cause mucosal edema

and inflammation that may obstruct the sinus ostia, thereby impeding the drainage of the more than 500 mL of fluid produced by the paranasal sinuses daily. Stagnant secretions in a closed space, contaminated by hospitalacquired pathogens, may lead to sinusitis and systemic signs of sepsis. Once established in the maxillary sinuses, inflammation and infection can spread to the ethmoid and sphenoid sinuses. Intracranial spread via diploic veins can have devastating consequences such as meningitis, brain abscess, osteomyelitis, and cavernous sinus thrombosis. Additional factors play a role and may account for cases of sinusitis in patients without nasal tubes. The supine position and limitation of head movements prevent the natural sinus drainage caused by gravity. In addition, this position causes decreased venous blood return from the head and neck, resulting in increased nasal congestion and narrowing of .~ ventimaxillary sinus o ~ t i aPositive-pressure lation, by raising central venous pressure, may compound this problem. Impaired ability to cough or sneeze, and the simple absence of airflow through the nares in mechanically ventilated patients, may also predispose to infection. Clinical Findings

In intubated patients, localized signs of infection are difficult to elicit, and the first man-

Figure 4. Radiologic maxillary sinusitis in a patient with left nasotracheal intubation and right nasogastric tube. Left maxillary sinus demonstrates a complete opacification whereas right maxillary sinus demonstrates a characteristic fluid level. (From Rouby JJ, Laurent P, Gosnach M, et al: Risk factors and clinical relevance of nosommial maxillary sinusitis in the critically ill. Am J Respir Crit Care Med 150:776-783,1994; with permission.)

RESPIRATORY INFECTIOUS COMPLICATIONS IN THE INTENSIVE CARE UNIT

ifestation of nosocomial sinusitis is often fever or even sepsis without an obvious source. A purulent nasal discharge may be absent in up to 73% of cases. Infected purulent secretions, when present, may appear in the proximal trachea because of aspiration, simulating tracheobronchitis and pneumonia.

Microbiology Sinusitis in ICU patients is most commonly caused by gram-negative bacilli and S. uureus and is often polymicrobial. In a recent study using nasal disinfection with povidone-iodine solution before transnasal puncture to avoid contamination with colonizing organisms, gram-negative bacilli accounted for 47% of infections, with P. aeruginosa being the most common, S. aureus representing 209'0, and, surprisingly, yeasts were found in 18% of the causes. Twenty percent of infections were polymicrobial.8

Diagnosis CT scan provides the best visualization of the paranasal sinuses. Mucosal thickening, opacification, or air-fluid levels suggest the presence of infection. Because radiographic abnormalities do not always represent infection, microbiologic diagnosis is established with direct aspiration and culture of material from the maxillary sinus. Using a nasal disinfection protocol before aspiration and a diagnostic threshold equal to or greater than lo3 cfu/mL to diagnose infection, Rouby et alS1 found positive cultures in 38% of cases. Bacteremia with the same microorganisms occurred in 17% to 25% of patients with nosocomial sinusitis.

Treatment The first and most important step in treatment is to remove all tubes from the nares and replace them orally, if possible. Elevating the head of the bed may facilitate drainage of the sinuses. Topical decongestants may shrink the edematous mucosa, helping to re-establish patency of sinus ostia. Antibiotics should be directed toward organisms found in bacterial cultures. Maxillary sinus puncture is both diagnostic and therapeutic, in allowing drainage of infected material.

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