Ventilator-Associated Pneumonia: When to hold the breath?

Ventilator-associated pneumonia (VAP) is the most common infection in mechanically ventilated patients, and carries the highest mortality. An early diagnosis and definitive management not only reduces the overall mortality, but also brings down the burden of health care to the patient by reducing the cost, length of Intensive Care Unit (ICU) stay, duration of mechanical ventilation, and so on. Out of the various scoring systems, the Clinical Pulmonary Infection Score (CPIS) calculation for VAP has a good sensitivity (72%) and specificity (85%) and the targeted antibiotic therapy in the appropriate dosage is found to be more beneficial than empirical treatment. Although controversies persist on several issues, preventive strategies like head elevation by 30 degrees, cuff pressure monitoring, avoidance of sedatives and muscle relaxants, and so on, have been found to reduce the occurrence of VAP.

INTRODUCTION

Hospital-acquired pneumonia (HAP) is one of the most common nosocomial infections and the leading cause of death due to hospital-acquired infections (attributable to mortality 33-50%). Among HAP patients, ventilator-associated pneumonia (VAP) has the highest morbidity and mortality. VAP is the most common ICU (intensive care unit)-acquired infection in patients requiring mechanical ventilation for over 48 hours and its estimated incidence is 10-20%. The crude ICU mortality rates for VAP range from 24 to 76%, and these patients are twice as likely to die as those patients on ventilator without pneumonia.[1] Other than being an independent determinant of mortality; VAP is associated with longer ICU and hospital stays, prolonged mechanical ventilation, and higher costs.[2]

In the recent past, various advancements have taken place in the management of VAP. Several studies have provided important insights into the relationship of the histology and bacteriology of VAP, various epidemiological researches have allowed the establishment of concepts for empiric antimicrobial treatment, and various updates on state-of-the-art care have been outlined.[34] However, despite these measures, a majority of issues related to the management of VAP remain unresolved and are subject to controversy. This is particularly true for the diagnostic evaluation of a patient with suspected VAP. The lack of consensus regarding the best way to diagnose VAP largely explains why the incidence rates vary so widely from one study to another — from 5 to 50% of mechanically ventilated intensive care unit (ICU) patients.

The keywords, ‘ventilator-associated pneumonia,’ in PUBMED revealed a total of 2474 titles and 521 review articles within the search limit of 10 years, between 1990 and 2010. Only articles in English were chosen.

Definitions

According to the previous definitions, VAP was diagnosed on the presence of new and / or progressive pulmonary infiltrates on a chest radiograph, plus two or more of the following criteria: fever (≥ 38.5°C) or hypothermia (< 36°C), leucocytosis (≥ 12 × 109 / L), purulent tracheobronchial secretions or a reduction of partial pressure of arterial oxygen (PaO2) / fraction of inspired oxygen (FiO2) of 15% or greater, in the past 48 hours.[5]

As per the same guidelines, tracheobronchitis was defined as the presence of purulent tracheobronchial secretions plus two or more of the following criteria: fever (≥ 38.5°C) or hypothermia (< 36°C), leucocytosis (≥ 12 × 109 / L) or significant bacteriological counts in the respiratory secretions of patients without pulmonary infiltrates suggesting pneumonia on chest radiograph. Cases with either VAP or tracheobronchitis had to be microbiologically confirmed.

However, according to a more recent criteria, VAP is defined as pneumonia occurring in a patient within 48 hours or more after intubation, with an endotracheal tube or tracheostomy tube, which was not present before.[6]

Early onset of VAP occurs within 48 hours and late onset of VAP after 48 hours of tracheal intubation and mechanical ventilation.

Pathogenesis and Pathophysiology of Ventilator-Associated Pneumonia

There are several factors that potentially contribute to the high rates of VAP in ICU patients. First, ICUs contain clusters of highly vulnerable patients, many of whom have predisposing lung conditions that compromise with the defense mechanisms in their airways. Although the respiratory tract is designed to prevent the entry of pathogenic organisms into the lungs and to eradicate such pathogens if they bypass the upper airway host defenses, these defense mechanisms can be overwhelmed at times, for example, a large aspirated inoculum or an inherently virulent organism.

Second, the most common means of acquiring pneumonia is via aspiration.[7] Aspiration is promoted by supine position and by upper airway and nasogastric tube placement. In mechanically ventilated patients, aspiration occurs around the outside of the endotracheal tube rather than through the lumen. Leakage around the endotracheal cuff can be demonstrated in most patients. Given that as many as 45% of the healthy individuals aspirate during sleep, it is understandable that aspiration is even more common among patients with abnormal swallowing, impaired gag reflexes, compromised consciousness due to medication or anesthesia, delayed gastric emptying, or decreased gastric motility.

Third, the dominant organisms in nosocomial pneumonia are aerobic Gram-negative bacilli.[89] These bacteria presumably reach the lower airway via aspiration of gastric contents or of upper airway secretions. Oropharyngeal colonization with Gram-negative bacilli is unusual in otherwise healthy, non-hospitalized individuals. In moderately ill patients, however, the carriage rate is around 16%, rising to almost 75% in severely ill patients. [10] Thus, the propensity for colonization of the upper airway directly correlates with the severity of illness. In addition to the severity of illness, several other factors have been identified as being associated with Gram-negative colonization, as shown in Table 1.

Table 1

Risk factors for VAP following Gram-negative sepsis in critically ill patients

Other means by which pneumonia can be acquired include aspiration from the stomach or nose and paranasal sinuses. Aspiration of the gastric contents can be minimized by maintaining the patient in a semi-recumbent position, but this is not an effective measure for minimizing oropharyngeal aspiration.

How to Diagnose Ventilator-Associated Pneumonia

The most crucial task in VAP is to arrive at an early diagnosis. This is often difficult because many conditions common to ICU patients like sepsis, acute respiratory distress syndrome (ARDS) or pulmonary atelectasis may present with a similar clinical picture. It has been seen in some studies that more than 50% of the diagnosed patients do not have VAP and up to one-third of the patients may remain undiagnosed.[411]

The diagnosis of VAP is usually based on three components: Systemic signs of infection, new or worsening infiltrates seen on the chest X-ray, and bacteriological evidence of pulmonary parenchymal infection. The systemic signs of infection, such as, fever, tachycardia, and leukocytosis, are nonspecific findings and can be caused by any condition that releases cytokines. Although the plain (usually portable) chest X-ray remains an important component in the evaluation of hospitalized patients with suspected pneumonia, it is most helpful when it is normal and rules out pneumonia. In a review of 24 patients with autopsy-proven pneumonia, who were receiving mechanical ventilation (MV), no single radiographic sign had a diagnostic accuracy greater than 68%. The presence of air bronchograms was the only sign that corresponded well with pneumonia, accurately predicting a majority of the diagnosed cases of pneumonia.[12]

Fagon et al.[13] found that the clinical predictions of the presence or absence of definite and probable VAP were accurate in 62 and 84% of VAP patients, respectively. In another study assessing the clinical criteria for VAP in surgical patients, numerous clinical parameters distinguished patients with suspected VAP from others. However, the subsequent validation of this diagnosis by serial examination of clinical, microbiological, and radiographic data could not identify the predictors of patients truly having VAP.[14]

The controversy about the clinical diagnosis of VAP chiefly included the role of the clinical criteria in the assessment of suspected VAP. Although some authors have advocated an approach relying strictly on the results of invasive bronchoscopic diagnostic testing,[15] others have insisted on an approach that keeps the clinical and microbiological criteria in balance, not withholding antimicrobial treatment in the presence of cultures below the thresholds, but clinically suspected VAP.[16]

Although the limited diagnostic accuracy does not undermine the importance of clinical assessment, according to a large body of evidence derived from several validation studies, using strictly independent references, invasive and noninvasive microbiological testing ie also associated with 30-40% false-negative and false-positive results.[17]

A recommended approach to the clinical diagnosis of VAP is the Clinical Pulmonary Infection Score (CPIS), which was developed by Pugin et al.[18] This score includes the following six weighted clinical and microbiological variables: Temperature, white blood cell count, character and volume of the tracheobronchial aspirate, Gram stain and culture of the tracheobronchial aspirate, gas exchange ratio, and chest radiograph infiltrates [Table 2]. This score proved to achieve 72% sensitivity and 85% specificity at a threshold of six in a postmortem study.[19]

Table 2

Clinical pulmonary infection score (CPIS) calculation for VAP

A meta-analysis, including 23 studies of quantitative bronchoalveolar lavage (BAL), and a review of 18 studies evaluating quantitative protective specimen brush (PSB) confirmed the excellent diagnostic utility of these methods.[20] To minimize the false negative rate (10-40%), sampling should be performed prior to any antibiotic change in the preceding 24 to 72 hours. [21] Patients with negative quantitative BAL cultures collected prior to the antibiotic changes can have empiric antibiotics safely discontinued after 72 hours. Several guidelines integrate the clinical and microbiological criteria in a diagnostic algorithm to institute prompt empiric therapy in patients with a high suspicion for hospital-acquired pneumonia (HAP) and tailor therapy based on the reassessment of the clinical response and quantitative culture results.[22]

Are biological markers useful in ventilator-associated pneumonia?

There has been lot of speculation about the possible usefulness of the biological markers in VAP. C-reactive protein (CRP) and cytokine measurements in the serum or BAL of VAP patients have been tried, without any success.[23] The role of serum procalcitonin as a prognostic marker was evaluated in an observational study with 63 VAP patients. Those who failed treatment had higher procalcitonin levels from days one to seven.[24] A prospective study involving 96 ICU patients revealed the serum procalcitonin to be 100% specific for VAP, but not very sensitive (41%).[25] A prospective cohort study of 75 patients with clinical suspicion of VAP showed similar results. Non-survivors had significantly higher serum procalcitonin levels on days zero and four, and the decrease in levels by day four was predictive of survival (OR 4.43, P¼0.04).[26]

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a promising biomarker of pneumonia as well as VAP-related sepsis. TREM-1 belongs to the immunoglobin superfamily and is expressed on the surface of neutrophils, monocytes, and macrophages, during acute inflammatory responses. It increases during infectious processes, but not in inflammatory conditions (e.g., psoriasis, ulcerative colitis, vasculitis). TREM-1 exists in both a membranous and a soluble form (soluble triggering receptor expressed on myeloid cells-1; sTREM-1). Elevated levels of sTREM-1 have been detected in the plasma of septic patients;[27] in the BAL of patients with pneumonia,[28] and in the exhaled breath condensate in VAP patients.[29] In a recent study of VAP-related sepsis, the serum sTREM-1 levels remained elevated from days one to seven in non-survivors compared to serum cytokines. Another finding was that decreased ratios of sTREM-1 / TNFa seemed to identify the progression from sepsis to septic shock.[30]

Studies strongly support the potential role of alveolar sTREM-1 as a diagnostic biomarker for VAP and an indicator of the clinical outcomes. The advantage of measuring sTREM-1 in clinical practice, however, is unclear. A commercially available assay is unavailable and a high alveolar sTREM-1 does not preclude airway sampling and microbiological cultures to isolate the causative organism for pneumonia.

Antimicrobial treatment for ventilator-associated pneumonia

The routine use of prolonged courses of antibiotics, not supported by the results of microbiological cultures, should be discouraged, to minimize the risk of subsequent antibiotic-resistant infections. Elimination of unnecessary antibiotic administration for a prolonged period can reverse the trend of increasing antibiotic resistance among hospital-acquired infections.[31]

The use of aerosolized antibiotics has also been discouraged because of the inefficacy and propensity for the emergence of antibiotic-resistant infections.[32]

The routine use of selective digestive tract decontamination (SDD) has also not gained acceptance because of its lack of demonstrated effect on the mortality, emergence of antibiotic resistance infections, and additional toxicity. Moreover, some clinicians had a particular concern about the risk of infection with Clostridium difficile, as a result of SDD. As the mortality rate for patients with VAP on inadequate antibiotics treatment is also high (69.2 versus 46.0% if they are on the right antibiotics),[33] individual ICUs should develop empirical antibiotic policies targeting the pathogenic bacteria prevalent in their patient population. Antibiotic discontinuation policies (based on noninfectious causes for chest radiograph infiltrates and signs and symptoms suggesting that VAP has resolved) have been shown to reduce the antibiotic treatment duration without a significant deleterious effect on hospital mortality or recurrence of VAP.[34] A further curtailment of the multi-resistant bacteria may be possible with the rotation of antibiotics, particularly for gram-negative bacilli. Over a seven-year period, antibiotic rotation for empirical and therapeutic use was associated with a reduction in the VAP rate (23% before versus 16.3% following antibiotic rotation introduction) and an increase in the susceptibility of gram-negative organisms to the antibiotics commonly used.[35] Fowler et al.[36] treated 156 patients with suspected VAP and showed that patients who received empiric therapy with anti-pseudomonal penicillins plus beta-lactamase inhibitors had lower in-hospital mortality than those who did not receive these antibiotics. Also, their data suggested that aminoglycosides could improve survival. Namiduru et al.[37] retrospectively examined the microbiological sensitivities of 140 patients with VAP and determined that sulbactam and cefoperazone were the most appropriate antibiotics. If staphylococcal pneumonia was suspected, a glycopeptide (vancomycin or teicoplanin) or combined trimethoprim-sulfamethoxazole was recommended, until the sensitivity results were obtained.

Therefore, a targeted approach with an appropriate dose of the right antibiotic guided by evidence, as has been suggested in the Tarragona strategy,[38] is one of the logical approaches for VAP [Table 3].

Table 3

Tarragona Strategy

Prevention is better than cure in ventilator-associated pneumonia

Several measures to prevent VAP have proven to be effective and are generally recommended.

Precautions of pathogen transmission from patient to patient, including isolation.[39] The Euro-Nis study[40] (Moro and Jepsen) has described different practices that may reduce exogenous infections due to better surveillance and better staff education.

Hand-washing and disinfection: These are the most important measures to prevent patient to patient spread of pathogens, as well as to protect healthcare workers from potential infections.[41]

Change of the ventilator circuit not more than once per week: Daily change of ventilator circuits was shown to be a risk factor for VAP. Although the optimal exchange interval has not been determined, a policy of circuit change once a week as compared to a 48-hour interval has been shown to be safe.[42]

Orotracheal instead of nasotracheal intubation: Nasotracheal intubation increases the risk for sinusitis and VAP. Therefore, orotracheal intubation should be the preferred technique.[43]

Keeping the endotracheal tube cuff pressure optimized: The pressure of the endotracheal tube cuff should be optimized in order to prevent the leakage of colonized subglottic secretions into the lower airways.[44]

Semi-recumbent body position: A reduction of aspiration into the lower airways, in a semi-recumbent versus a supine body position, has been shown by scinitgraphic means.[45] Moreover, the effect of a semi-recumbent position on the reduction of VAP has been demonstrated.[46]

Avoidance of paralytic medication: Deeply sedated and relaxed patients clearly are at a higher risk of aspiration and VAP.[47] Therefore, relaxation should be avoided whenever possible.

Avoidance of reintubation: Reintubation was clearly demonstrated to represent a risk factor for VAP.[48] Furthermore, it seems obvious that non-invasive ventilation instead of intubation should reduce the incidence of VAP, particularly in patients who are immunocompromised.[49]

A meta-analysis examining 33 randomized SDD (selective digestive decontamination) trials involving 5,727 patients, demonstrated a significant reduction in the overall mortality (20%) and in the incidence of respiratory tract infections (65%).[50] A second systematic review in critically ill surgical patients showed an even greater benefit of SDD: Mortality was reduced by 30% and the rates of pneumonia by 80%. [51] SDD may be used in subsets of populations, such as, patients with trauma, pancreatitis, major burn injury, and those undergoing major elective surgery and transplantation. Some centers with experience are using SDD in all mechanically ventilated patients.

The Department of Health in the UK published the following ‘high impact interventions’ for ventilated patients in June 2007.[52]

Elevation of the head of bed to 35-40 degrees

Sedation holding

Deep vein thrombosis prophylaxis

Gastric ulcer prophylaxis

Appropriate humidification of inspired gas

Appropriate tubing management

Suctioning of respiratory secretions (including use of gloves and decontaminating hands before and after the procedure)

Routine oral hygiene as per local policy

Of all these interventions, elevation of the head, gastric ulcer prophylaxis, continuous suctioning of the subglottic secretions, chlorhexidine mouthwash, enteral feeding with a post-pyloric feeding tube, and daily sedation interruption are of particular importance to prevent VAP.

The NASCENT randomized trial explored the possibility of using a silver-coated endotracheal tube and found a statistically significant reduction in the incidence of VAP and delayed time to VAP when compared to a similar uncoated tube.[53] Although cost-effectiveness was a presumed hindrance, a more recent study has found that the silver-coated endotracheal tubes yielded persistent savings per case of VAP prevented.[54]

Many controversies still remain with regard to the epidemiology, diagnosis, prognosis, and therapy of ventilator-associated pneumonia. In particular, the proportion of ventilator-associated pneumonia that can be prevented by improving the quality of care is yet to be fully understood. To address these issues, a thorough understanding of the precise natural history of ventilator-associated pneumonia at a cellular level, and establishing the sequence of events between colonization and infection, is needed. Till such time, VAP will continue to present as a major therapeutic challenge to clinicians, particularly when patient management is complicated by the presence of underlying conditions. However, improvements in VAP management are possible and reduced mortality and morbidity attainable.