Ventilator-associated pneumonia is a well-acknowledged complication after hospitalization for injury or surgical emergency. The contribution to the literature on this topic by Dr Timothy Fabian and the Memphis group at the Elvis Presley Trauma Center resulted in the contemporary recognition that the diagnosis and management of pneumonia is an essential component of surgical critical care. During three decades, the Memphis group, under Dr Fabian’s leadership, performed numerous clinical studies that led to the publication of over 40 articles concerning the epidemiology, diagnosis, and treatment of pneumonia after injury. The purpose of this review is to survey the consecutive studies from Memphis specifically that led to the development of a clinical pathway that has stood the test of time. Examination of the research output during this period provides a case study in how bedside clinical research can inform clinical practice and is a model for applied science in the intensive care unit.
- critical care
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Ventilator-associated pneumonia (VAP) is a well-acknowledged complication after hospitalization for injury or surgical emergency. Thirty years ago, that was not the case. At the Southern Surgical Association annual meeting in 1997, in his discussion of one of the first major pneumonia studies conducted at the Elvis Presley Trauma Center in Memphis, Tennessee, Dr Hiram Polk lamented that ‘pneumonia is a far more common cause of death in a surgical patient than pulmonary embolism and, yet, the surgical community has not taken any interest in this.’1 The subsequent output of literature on this topic by Dr Timothy Fabian and the Memphis group contributed to the contemporary recognition that the diagnosis and management of pneumonia is an essential component of surgical critical care. During three decades, surgeons and intensive care unit (ICU) pharmacists at the Elvis Presley Trauma Center, under Dr Fabian’s leadership, performed numerous clinical studies that led to the publication of over 40 articles concerning the epidemiology, diagnosis, and treatment of pneumonia after injury (table 1). As stated by former Memphis trauma and surgical critical care fellow Dr Robert Maxwell at the Southern Surgical Association annual meeting in 2014, ‘the data produced by the group in Memphis … are responsible in large part for establishing a standard of care for the diagnosis of VAP in the surgical and trauma ICUs.’2 The purpose of this review is to survey the consecutive studies from Memphis specifically that led to the development of a clinical pathway that has stood the test of time. The applied clinical science during this period is a case study in how bedside clinical research can inform clinical practice.
Nearing the close of the 20th century, nosocomial pneumonia, now more often referred to as VAP, was a clinical diagnosis suspected by the onset of a new or changing pulmonary infiltrate on X-ray, fever, leukocytosis, and purulent tracheobronchial secretions. Although the development of this clinical picture in a patient previously free of pulmonary disease indicates bacterial pneumonia with a high likeliness, many existing conditions in a mechanically ventilated patient present a similar clinical picture, including chemical pneumonitis, acute respiratory distress syndrome, systemic inflammatory response syndrome (SIRS), pulmonary contusion, atelectasis, pulmonary edema, and pleural effusion. In addition, intubated patients often have proximal airway colonization by potentially pathogenic organisms and often have purulent secretions because of either tracheobronchitis or oropharyngeal secretions that escape the barrier of the endotracheal tube cuff. As a result, patients were often assumed to have pneumonia and treated for such with empiric antibiotics. Investigations performed in the 1980s began to illuminate this deficiency in diagnostic accuracy.3–5 Taken together, these studies suggested that no combination of clinical variables was accurate in the prediction of nosocomial pneumonia and the misdiagnosis of nosocomial pneumonia was a common occurrence.
Stimulated by their medical colleagues at the University of Tennessee Health Sciences Center who were among the early proponents of fiberoptic bronchoscopy diagnosis of pneumonia,6 Dr Fabian and his surgical colleagues embarked on the first of many studies that would subsequently confirm and refine the efficacy of a lower-respiratory culture-driven approach to the diagnosis of pneumonia in trauma patients.7 In 107 trauma patients with clinical suspicion of pneumonia, respiratory cultures were obtained in triplicate—the first by routine sputum collection, the second by fiberoptic bronchoscopy-guided protected specimen brushing, and the third by fiberoptic bronchoscopy-guided bronchoalveolar lavage (BAL). They observed that the incidence of pneumonia according to culture positivity was 73% by sputum culture, 34% by protected brush specimen, and 25% by BAL. Importantly, this article included the details of a provocative pilot study to determine if empiric therapy could be stopped safely should the lower respiratory tract cultures be negative. It is important to note that it was common practice at that time to continue antibiotics irrespective of culture results should the clinical picture resemble pneumonia, and cessation of antibiotics would have been perceived as putting the patient at risk. Ten patients were studied and seven did not meet the prespecified lavage criteria for diagnosis of pneumonia of ≥105 colony-forming units (cfu)/mL and antibiotics were discontinued. One of these patients subsequently died of their head injury, but the remaining six patients clinically improved without continuation of antibiotic therapy. From this observation, the Memphis group proposed that bronchoscopy with BAL was able to differentiate trauma patients with de facto lower respiratory tract infection from those with SIRS, paving the way for their next study.
The proof-of-concept study was completed in 1994 and presented at the Eastern Association of Trauma Annual Meeting in 1995.8 This study sought to answer two questions with respect to suspected pneumonia in mechanically ventilated trauma patients: (1) can quantitative BAL culture differentiate pneumonia from SIRS, and (2) can antibiotic therapy be based solely on quantitative BAL cultures? In this prospective study, patients with clinically suspected VAP (based on the presence of abnormal body temperature, leukocytosis, grossly purulent sputum, and new or changing infiltrate on chest X-ray) underwent fiberoptic bronchoscopy with BAL, and only those with significant bacterial colony counts (≥105 cfu/mL) were treated with a full course of therapeutic antibiotics. Forty-three patients underwent bronchoscopy 55 times, and 20 were identified to have pneumonia according to quantitative culture result (the remaining 23 were designated as having SIRS). For the patients with SIRS, antibiotics were stopped after culture result (average 3.3 days). Sixty-five percent of these patients clinically improved after antibiotic cessation. The remaining 35% continued to demonstrate clinical suspicion of pneumonia and underwent repeat bronchoscopy with BAL. Among these eight patients, three were identified to have developed pneumonia per quantitative culture result on repeat bronchoscopy; the remaining five ultimately had clinical improvement without continuation of antibiotics. From this study, it was concluded that bronchoscopy with quantitative culture from BAL could in fact distinguish pneumonia from SIRS and dictate the appropriateness of the continuation of antibiotic therapy. This approach to the diagnosis of pneumonia then became standard practice in the Memphis Trauma ICU.
A follow-up prospective study involving 232 patients during a 2-year period was presented at the annual meeting of the Southern Surgical Association in 1997 and served to establish a false negative rate of 7% when using a cut-off point of ≥105 cfu/mL to establish the diagnosis of pneumonia.1 In this study, empiric antibiotic therapy was instituted on all patients after BAL. A third-generation antipseudomonal cephalosporin, a quinolone, or a carbapenem was administered at the discretion of attending physician, and vancomycin was added if the gram stain demonstrated gram-positive organisms. This study revealed two important findings. Organisms identified by quantitative culture ≥105 cfu/mL were compared with the gram stain, and it was observed that the gram stain of the BAL effluent correlated poorly with the ultimate culture result and would therefore not be useful in guiding specific antibiotic empiric therapy. However, the investigators identified that duration of hospital stay could guide empiric therapy with respect to antibiotic choice. In the first week of ICU stay, BAL primarily identified Haemophilus influenzae and gram-positive organisms, whereas Acinetobacter and Pseudomonas were more common after the first week (figure 1).
The third study from Memphis related to the diagnosis of pneumonia among ventilated trauma patients was presented at the annual meeting of the American Association for the Surgery of Trauma (AAST) in 2003.9 The purpose of that study was to determine the optimal diagnostic threshold for pneumonia with respect to quantitative cultures. Based on their own mortality data, the Memphis group had chosen a threshold of 105 cfu/mL to distinguish pneumonia from SIRS. As derived from their first study, the mortality rate of all patients with 105 cfu/mL was significantly higher than patients with less than 105 cfu/mL (29% vs. 14%, p<0.04). Nonetheless, there was not a consensus at the time as to what diagnostic threshold was optimal and, in fact, a lower diagnostic threshold was generally recommended in the medical ICU setting. In this study of 526 patients who underwent 1372 bronchoscopies with BAL, the sensitivities, specificities, positive and negative predictive values were determined with respect to the diagnostic thresholds of 105 cfu/mL and 104 cfu/mL. As demonstrated in table, test performance was better at 105 cfu/mL with improved specificity and positive predictive value without any large reduction in either sensitivity or negative predictive value. This study solidified the diagnostic threshold of 105 cfu/mL for trauma patients and remains the diagnostic threshold in the Memphis trauma ICU today. In accordance with the theme of continuous performance improvement, the diagnostic threshold was re-evaluated a decade later, presented at the annual meeting of the AAST in 2014.10 This study comprised 1679 patients who underwent 3202 bronchoscopies with BAL, during a 9-year period. Using 105 cfu/mL as a diagnostic threshold, a low false negative rate continued to be achieved (2.3%), the false negative rate among those with 104 cfu/mL remained low (7.5%) as well. The current clinical pathway for initial diagnosis is demonstrated in figure 2.
Continuous querying of their own data led the Memphis group to refine the treatment of pneumonia as well as the diagnosis. At a time when most patients were treated for 14–21 days for hospital-acquired pneumonia, the Memphis group recognized that, in trauma patients, clinical resolution of pneumonia may be as difficult to determine as onset of pneumonia, given the often-present confounders of pulmonary contusion, atelectasis, ongoing SIRS from multiple injuries and or multiple operations to manage multiple injuries. Guidelines from the American Thoracic Society suggested that patients with VAP should respond clinically by day 3 of appropriate antibiotic treatment.11 The Memphis group demonstrated in a retrospective study of 126 trauma patients with VAP that neither temperature nor white cell count or the ratio of partial pressure arterial blood oxygenation to the fractional inspired oxygen changed significantly during the course of a 16-day follow-up suggesting that clinical and laboratory abnormalities in injured patients with pneumonia do not in fact resolve promptly.12
Dr Fabian and colleagues proposed a microbiological-based approach to treatment duration, first described in a study presented at the Critical Care Congress of the Society of Critical Care Medicine in 2004.13 The purpose of this pilot study was to determine if the duration of antibiotic therapy could be safely abbreviated in critically ill trauma patients who demonstrate a significant reduction in pulmonary bacterial growth on repeat quantitative BAL culture on day 4 of therapy. Significant reduction was defined as less than 104 cfu/mL quantitative culture growth. Ninety-six percent of early VAP isolates (ie, 7 days or less from admission) responded (ie, significant reduction) on repeat BAL compared with 71% of late-occurring VAP isolates (ie, beyond 7 days). It was therefore concluded that patients with early VAP (eg, less than 7 days and methicillin-sensitive Staphylococcus aureus, Haemophilus, or Streptococcus spp) could be treated for 7 days without need for repeat BAL. This prompted a clinical practice of treating early VAP for 7 days and late-occurring VAP according to repeat BAL as performed on day 4 and every 3 days thereafter as dictated by bacterial quantitative cultures.
This clinical practice was further refined as a result of a performance analysis presented in 2010 at the annual meeting of the Southern Surgical Association.14 The purpose of this study was to determine the appropriate duration of antimicrobial therapy for VAP in trauma patients secondary to hospital-acquired pathogens (ie, late pneumonia) based solely on the causative pathogen by using quantitative cultures on repeat BAL. The results of this study demonstrated that by using a bacteriologic response threshold on repeat quantitative BAL culture, the optimal duration of antimicrobial therapy for VAP in trauma patients secondary to hospital-acquired pathogens could be determined accurately. To achieve microbiologic resolution in patients with either methicillin-resistant S. aureus VAP or Pseudomonas sp VAP, the majority of patients (62% with methicillin-resistant S. aureus VAP and 81% with Pseudomonas sp VAP) required 14 days of appropriate antimicrobial therapy. Although up to one-third of patients with methicillin-resistant S. aureus VAP responded to shorter-course therapy (7 or 10 days), this abbreviated treatment would have resulted in an unacceptable number of undertreated patients. In contrast, nearly 60% of patients with Acinetobacter (60%), Stenotrophomonas (58%), or Enterobacter spp (62%) VAP achieved microbiologic resolution after 10 days of appropriate antimicrobial therapy. However, an additional 30% of these patients required prolonged therapy (for a total of 14 days). By performing repeat BAL on day 7 of appropriate therapy, both patients who have achieved microbiologic resolution (by day 10) and those requiring additional therapy could be identified. This study led to a change in practice whereby early community-acquired pneumonia would receive antibiotic treatment for 7 days and hospital-acquired pneumonia would receive antibiotic treatment according to microbiologic resolution with repeat bronchoscopy performed on day 7. This clinical pathway (figure 3) remains the current management algorithm in Memphis and has been demonstrated to be durably efficacious without contributing to antimicrobial resistance.15
The Memphis contribution to the diagnosis and management of pneumonia within the domain of surgical critical care is commendable. As can be understood from this review, it also is demonstrative as to how an iterative quality improvement process can both inform and influence the practice at a single institution and contribute to the body of clinical research so that other centers may learn from, implement, and further refine clinical pathways for the betterment of patient care. We often think of ‘bench to bedside’ when considering translational research. Without minimizing the importance of bench research, I hope to have illuminated the high yield of performing bedside research and applying it directly to bedside care. Dr Fabian applied this approach to clinical research across many domains; in fact, there is scarcely a topic related to trauma patient care that he and his Elvis Presley Trauma Center colleagues have not had influence. As a past trauma/critical care fellow and faculty member in Memphis, I am grateful to have had the privilege of Dr Fabian’s mentorship and the opportunity to participate in the clinical research that has shaped the contemporary care of the trauma patient (figure 4).
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Contributors JAW wrote the article.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.