Journal of Critical Care 30 (2015) 40–48

Contents lists available at ScienceDirect

Journal of Critical Care journal homepage: www.jccjournal.org

Aspiration pneumonia: A review of modern trends David M. DiBardino, MD a,⁎, Richard G. Wunderink, MD b a b

Department of Pulmonary, Allergy, and Critical Care Medicine, Columbia University, New York, NY Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL

a r t i c l e

i n f o

Keywords: Aspiration pneumonia Pneumonia Aspiration Microbiology of pneumonia Anaerobic infection Lung abscess

a b s t r a c t Purpose: The purpose was to describe aspiration pneumonia in the context of other lung infections and aspiration syndromes and to distinguish between the main scenarios commonly implied when the terms aspiration or aspiration pneumonia are used. Finally, we aim to summarize current evidence surrounding the diagnosis, microbiology, treatment, risks, and prevention of aspiration pneumonia. Materials and methods: Medline was searched from inception to November 2013. All descriptive or experimental studies that added to the understanding of aspiration pneumonia were reviewed. All studies that provided insight into the clinical aspiration syndromes, historical context, diagnosis, microbiology, risk factors, prevention, and treatment were summarized within the text. Results: Despite the original teaching, aspiration pneumonia is difficult to distinguish from other pneumonia syndromes. The microbiology of pneumonia after a macroaspiration has changed over the last 60 years from an anaerobic infection to one of aerobic and nosocomial bacteria. Successful antibiotic therapy has been achieved with several antibiotics. Various risks for aspiration have been described leading to several proposed preventative measures. Conclusions: Aspiration pneumonia is a disease with a distinct pathophysiology. In the modern era, aspiration pneumonia is rarely solely an anaerobic infection. Antibiotic treatment is largely dependent on the clinical scenario. Several measures may help prevent aspiration pneumonia. © 2014 Elsevier Inc. All rights reserved.

The word aspiration simply refers to the drawing in or out of a substance by suction. The term is commonly used in the patient care setting to denote that contents of the oral or upper gastrointestinal tract have passed through the trachea and larynx and entered the lung. The term aspiration does not itself indicate the nature of the inoculum or the consequences of the event [1]. Given this broad use of the term aspiration, classifying the majority of bacterial pneumonias as a consequence of aspiration is strictly correct based on known pathophysiology of community-acquired (CAP) and hospital-acquired pneumonia (HAP) [2–5]. However, when a clinician uses the term aspiration pneumonia, he or she is typically implying a subset of bacterial pneumonia that, although sharing the common pathophysiologic mechanism with most other pneumonias, represents a unique entity of a macroaspiration event resulting in pneumonia. The unique circumstance associated with this term has

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; AMS, altered mental status; ARDS, acute respiratory distress syndrome; BAL, bronchoalveolar lavage; BO, bronchiolitis obliterans; CAP, community-acquired pneumonia; COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disease; HAP, hospital-acquired pneumonia; ICD-9, International Classification of Diseases, Ninth Revision; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; RCT, randomized controlled trial; VAP, ventilator-associated pneumonia. ⁎ Corresponding author. 622 W 168th St, PH 8 East, Room 101, New York, NY 10032. Tel.: +1 212 305 1979; fax: +1 212 342 3144. E-mail address: [email protected] (D.M. DiBardino). http://dx.doi.org/10.1016/j.jcrc.2014.07.011 0883-9441/© 2014 Elsevier Inc. All rights reserved.

evolved over time and now may lead to confusion when physicians of different generations interact. The goal of this review is to describe classic aspiration pneumonias in the greater context of other lung infections and aspiration syndromes. We will attempt to distinguish between the main clinical scenarios commonly implied when the terms aspiration or aspiration pneumonia are used. We will then review current evidence surrounding its diagnosis, microbiology with implications for treatment, risk factors, and prevention. 1. Common consequences of aspiration It is important to understand that aspiration is a common event that may lie within the spectrum of normal physiology. A large proportion of healthy people with normal mental status aspirate during sleep based on the detection of radiolabeled oral dyes in the lungs of healthy volunteers [6–8]. The anesthesia literature began highlighting aspiration during ether anesthesia as early as 1950 based on case reports and animal studies carried out during the 19th century [9]. These reports continued with more modern anesthetic agents as well [10,11]. These studies used inert colored dyes ingested roughly 30 minutes before anesthesia and confirmed aspiration with bronchoscopy. These investigators astutely noted that younger, healthier patients almost always tolerated this aspiration without consequence and without respiratory morbidity. This was the first insight into the

D.M. DiBardino, R.G. Wunderink / Journal of Critical Care 30 (2015) 40–48

fact that pneumonia results from a complex interaction between host and inoculum, as opposed to an inoculum alone [12]. Therefore, one of the most common consequences of aspiration is actually to have no consequence—the inoculum is cleared by the normal airway and/or parenchymal host defenses without overt clinical syndromes. 2. Clinical syndromes Although occurring in otherwise healthy people, several important clinical consequences of aspiration can occur. The most clinically relevant are listed in Table 1. These various manifestations of aspiration can be distinguished by 3 main characteristics—whether the inoculum is infectious or not, the volume of the inoculum, and the acuity of onset of the clinical syndrome. Many of the aspiration syndromes are a result of noninfectious microaspiration, often due to gastroesophogeal reflux disease (GERD). These include chronic cough syndromes, exacerbation of asthma/ bronchospasm, bronchiolitis obliterans (BO) in lung transplant patients, and worsening of chronic fibrotic lung diseases, particularly idiopathic pulmonary fibrosis and systemic sclerosis (scleroderma). Chronic microaspiration itself has also been implicated as a cause of pulmonary fibrosis. The strongest evidence is with microaspiration of exogenous substances such as chronic lipoid pneumonia. Whether chronic microaspiration of refluxed stomach contents alone results in clinically significant pulmonary fibrosis is still unclear. Our review will concentrate on the lower respiratory tract consequences because chronic cough, exacerbation of asthma/bronchospasm, and BO would each require an extensive review [13,14]. 2.1. Chemical pneumonitis Chemical pneumonitis is characterized by macroaspiration of noxious liquids with immediate hypoxemia, fever, tachycardia, and abnormal chest radiograph and lung examination result. The most common noxious fluid is sterile gastric contents, although others such as bile and other agents instilled into the stomach may also result in this syndrome. This specific entity was first described in the anesthesia literature in the late 1940s by Mendelson [15] in a series of women who aspirated during obstetric anesthesia. In Mendelson’s series, all 61 young and otherwise healthy patients who aspirated liquid gastric contents recovered within 36 hours with no clear permanent sequelae (5 others aspirated solid material, resulting in 2 deaths by airway obstruction). Subsequently, the wide range of severity from transient hypoxemia to acute respiratory distress syndrome (ARDS) [15–19] has become apparent. Prospective studies of ARDS suggest that 16.5% of patients thought to have experienced Table 1 Aspiration syndromes

Airway syndromes Chronic cough Exacerbation of asthma/bronchospasm BO in lung transplant Lung parenchymal syndromes Exacerbation of fibrotic lung disease Chemical pneumonitis Bland aspiration Bacterial pneumonia Community acquired Anaerobic pleuropneumonia Hospital acquired Ventilator associated Aspiration pneumonia

41

aspiration developed ARDS [20]. If ARDS does occur, a particularly severe subtype with a high mortality ensues [18]. Animal experiments helped differentiate the pathophysiology of chemical pneumonitis from subclinical aspiration based on the pH and volume of gastric material needed to stimulate an immediate and severe inflammatory reaction. Based on experiments using human gastric secretions and rabbit lungs, a pH less than 2.4 was required to cause vigorous inflammation. At higher pH, the reaction seen microscopically was more similar to the changes caused by the instillation of water into the lungs [21]. In terms of quantity, experiments inducing chemical pneumonitis in a dog model required 2 mL of hydrochloric acid solution per kilogram to induce the clinical syndrome [22,23]. Similarly, studies done in rabbits by Mendelson required 20 mL of 0.1 mol/L hydrochloric acid per animal [15]. Based on these measurements, an average 70-kg patient would need to aspirate more than 120 mL of gastric contents to induce chemical pneumonitis assuming a gastric pH of 1. 2.2. Bland aspiration Not all noninfectious macroaspirations cause an inflammatory response in the lung; and therefore, to label these as pneumonitis would be inappropriate. Probably the 2 most common examples are aspiration of blood as a complication of severe epistaxis or hematemesis and the aspiration of enteral feedings. Twenty percent of patients undergoing esophagogastroduodenoscopy will have an infiltrate immediately after the procedure in the dependent lung [24,25]. Most resolve without antibiotic changes. Most episodes of aspiration with enteral nutrition are also uncomplicated [26]. Although bland aspiration may not initially be infectious, blood and enteral feedings represent excellent culture media for growth of either resident bacteria or the small aliquot of bacteria included in the inoculum. Generally, mucociliary clearance and the resident alveolar macrophages can clear the inoculum within hours. The major issue is confusion with an infectious aspiration pneumonia, particularly when the large-volume aspiration is not observed. Prolonged antibiotic treatment is unlikely to prevent this secondary pneumonia but may select for more multidrug-resistant (MDR) pathogens. 2.3. CAP and HAP Microaspiration has long been known to be the dominant pathophysiologic mechanism behind CAP. Supporting evidence includes the finding that most common CAP-causing microorganisms colonize the oropharynx or nasopharynx in nonhospitalized patients [2,27,28]. Similarly, the pathophysiology underlying HAP, including ventilator-associated pneumonia (VAP), has proved to be microaspiration of oropharyngeal, upper gastrointestinal, or subglottic contents [3,5,29–32]. The distinct microbiology of HAP stems from microaspiration occurring after hospitalized patients become colonized with the virulent organisms found in intensive care unit and hospital environments [4,33–36]. Given the above evidence of aspiration as a common event, development of a parenchymal lung infection depends largely on host defense factors [12,37] and the virulence of the aspirated pathogen. This interaction helps explain the phenomenon of subclinical aspiration without subsequent pneumonia described mostly in young healthy volunteers and surgical candidates.

Infectious inoculum

Acuity of onset

Volume

No No

Micro Micro

No

Chronic Acute or subacute Chronic

No

Chronic

Micro

No No

Acute Acute

Macro Macro

2.4. Anaerobic pleuropneumonia

Yes Yes Yes Yes Yes

Acute Subacute Acute Acute Acute

Micro Macro Variable Micro Macro

Anaerobic pleuropneumonia is probably the entity most commonly meant when the term aspiration pneumonia was initially used. Classically, subacute presentation with cough productive of purulent, foul-smelling sputum, and cavitary pneumonia with an associated complicated empyema characterized this syndrome. Patients usually

Micro

42

D.M. DiBardino, R.G. Wunderink / Journal of Critical Care 30 (2015) 40–48

had a history of loss of consciousness days to weeks earlier, most often associated with acute alcohol intoxication or seizure disorder. Severe gingivitis was another common clinical association. Invasive diagnostic procedures with careful microbiology documented that most of these pneumonias (and/or empyemas) were caused by anaerobes. The incidence of anaerobic pleuropneumonia is clearly decreasing, and many physicians have never seen a classic case. Anaerobes are the etiology in only 0.2% to 0.3% of all patients discharged from 2001 to 2010 with a pneumonia International Classification of Diseases, Ninth Revision (ICD-9) code [38]. Reasons for the marked decrease in this disease are multifactorial and likely societal rather than medical, such as better access to emergency medical services, fluorinated water, and greater social services. 2.5. Aspiration pneumonia Current use of this term most commonly refers to an acute lung infection developing after a large-volume aspiration of oropharyngeal or upper gastrointestinal contents with a high enough pH to avoid chemical pneumonitis (likely pH much greater than 2.5). This type of aspiration deposits a large bacterial load of pathogens from the oral cavity or upper gastrointestinal tract into the lungs. The possibility of infection with these normally nonvirulent, predominantly anaerobic organisms is partly because of the large inoculum [2,17,21,39–41]. Confusion surrounding this terminology and the exact definition continues despite attempts at clearer classifications [42]. Macroaspiration is the unique pathophysiologic component of what most clinicians call aspiration pneumonia. The challenge in specifically diagnosing aspiration pneumonia is that, for many patients in the community who are at risk for macroaspiration, the events in the days leading up to presentation with fever, cough, and chest radiograph infiltrate are unclear. A common risk for macroaspiration is decreased mental status, but this can be the result of CAP rather than the cause [43]. Because of this reality, substantial diagnostic overlap exists between aspiration, HAP, and CAP. Aspiration pneumonia represents 5% to 15% of pneumonias in the hospitalized population. The ICD-9 code–based reviews suggest an increasing incidence, making it the second most common diagnosis in Medicare patients who are hospitalized [2,44]. However, higher reimbursement rates for this ICD-9 code than for CAP ICD-9 codes may falsely increase the frequency in this population. 3. Risk factors for aspiration pneumonia Specific predisposing factors for aspiration pneumonia focus on the risk for high frequency and/or large volume of aspiration. Some risks may be more pertinent for the macroaspiration characteristic of aspiration pneumonitis or anaerobic pleuropneumonia than for microaspiration. Additionally, factors that influence the resident bacterial flora leading to colonization by more virulent pathogens, which are more likely to overwhelm the normal protective mechanisms, also play a role in development of clinical disease (Table 1). 3.1. Dysphagia/swallowing dysfunction Dysphagia, typically from neurologic disease (dementia, Parkinson disease, multiple sclerosis, poststroke), is considered the most important risk factor for aspiration pneumonia, given the abovedescribed pathogenesis. A host of literature, mostly in the elderly, stroke victims, and nursing home population, associates documented dysphagia and presence of dysphagia risk factors with pneumonia [7,40,45–47]. The patient population itself confounds analysis, as a number of studies associate age itself to aspiration pneumonia [48]. Furthermore, these data are generated from patients diagnosed with pneumonia with no discrimination between aspiration pneumonitis, as we have defined it, and traditional CAP. In fact, much of the

dysphagia literature examining pneumonia risk factors classifies all pneumonia with the term aspiration pneumonia and combines all patients with pneumonia to generate end points [49,50]. However, a significant portion of the cases used to generate this evidence are likely true aspiration pneumonia. It is important to remember that dysphagia itself is not definitive evidence of aspiration. Many high-risk patients will not complain of dysphagia but still aspirate based on advanced testing [51]. The poststroke population certainly has a higher prevalence of pneumonia with or without symptomatic dysphagia [52,53]. A lag time of more than 5 seconds between noxious stimuli and cough, as well as an increasing stimuli needed to produce a cough, has been linked to pneumonia in poststroke patients regardless of dysphagia [54]. The swallowing mechanism can also be affected by chest anatomy. Swallowing dysfunction is very common in chronic obstructive pulmonary disease (COPD) patients with hyperinflation [55]. Patients in this small series had a higher rate of dysphagia on questionnaire and frequently used protective swallowing strategies to prevent aspiration related to poor laryngeal elevation. Studies of aspiration pneumonia in the nursing home, veteran, and poststroke populations that find COPD is a risk factor also support the potential role of hyperinflation [49,56,57]. Certain medications interfere with the swallow reflex and may potentially lead to aspiration [58]. Although sedatives may suppress the patient’s mental status sufficiently to lead to aspiration, antipsychotic medications may actually affect the swallowing mechanism by inhibiting dopamine and therefore lead to aspiration. Accordingly, these drugs have been linked to pneumonia in a fairly large retrospective study [59]. 3.2. Altered mental status The association between acute altered mental status (AMS) and aspiration pneumonia has not been studied extensively despite the obvious connection. Adnet and Baud [60] demonstrated an association between the degree of AMS (as measured by Glasgow Coma Scale) and aspiration, supporting the pathophysiologic link between the entities. Most available case series focus on the association of acute AMS with chemical pneumonitis in the setting of sedation, poisoning, and trauma [15,61–63]. In these populations, vomiting and large-volume reflux of gastric contents may also increase the risk of aspiration pneumonia. Two specific types of AMS—acute alcohol abuse and seizures—are most likely to lead to the anaerobic pleuropneumonia syndrome. Probably the highest risk of aspiration pneumonia occurs in the severe alcohol abuse population. Acute alcohol ingestion has multifactorial risks for aspiration pneumonia including AMS, increased risk of vomiting, and direct effects of alcohol on normal neutrophil function. In the subset of patients without profound mental retardation, a relatively low postseizure aspiration pneumonia rate of 0.26% (4 of 1539) was observed [64]. The volume of aspiration is likely to be the reason for the lower rate. The common factor for these 2 risks for anaerobic pleuropneumonia syndrome is that patients frequently do not seek medical care acutely despite large-volume aspiration, leading to this subacute presentation. 3.3. Esophogeal motility disorders/vomiting Esophogeal motility disorders independent of GERD are also associated with aspiration and an increased risk of pneumonia. Many are a component of an underlying systemic disease, such as scleroderma or polymyositis, which may also compromise the host immune response itself or secondary to immunosuppressive treatment. Primary esophageal disorders, such as achalasia and esophageal strictures, increase the risk of aspiration of not only liquids but also solids. The latter are a unique form of aspiration risk in which

D.M. DiBardino, R.G. Wunderink / Journal of Critical Care 30 (2015) 40–48

bronchial impaction and postobstructive pneumonia result from the solid matter aspiration. Given the frequency of vomiting, the incidence of aspiration pneumonia/pneumonitis is actually very low. Protective laryngeal reflexes will prevent macroaspiration in the overwhelming majority of circumstances. Macroaspiration with vomiting almost always requires concomitant abnormal mental status, such as anesthesia induction, acute alcohol intoxication, or narcotics/sedatives. Another unique syndrome is vomiting associated with small bowel obstruction. In this situation, the stomach is no longer sterile but instead is filled with fluid that has significant overgrowth of bowel flora. Narcotics and antiemetics may compromise mental status at the time of vomiting. The result is a fulminant aspiration pneumonia due to gram-negative bowel pathogens, rather than the predominant gram-positive/anaerobic oral flora. 3.4. Enteral feeding The risk for aspiration pneumonia with enteral tube feeding has been extensively studied, especially in the more critically ill. Smalland large-bore nasogastric tubes, postpyloric tube feeds, gastric tube feeds, and jejunal tube feeds have all been associated with aspiration pneumonia in patients with and without endotracheal and tracheostomy tubes. Exact risk is difficult to characterize given the wide variety of incidences reported, small sample sizes, and lack of standard definitions regarding aspiration and aspiration pneumonia [65–75]. Regardless of the deficiencies in epidemiologic data, aspiration pneumonia is common enough in this population that it should be a consideration for all patients on tube feeds. Certain patients appear to be at greater risk. Intuitively, GERD and decreased gastric motility are implicated when tube feeds are aspirated. As evidence, Kitamura et al [70] demonstrated an association between endoscopically diagnosed reflux esophagitis and aspiration pneumonia. However, earlier, very similar studies failed to show a correlation [76]. Decreased gastric motility, typically defined by high gastric residual volume, has also been suggested as a risk factor for aspiration in tube-fed patients [65,67]. However, the criteria for high gastric residual volume vary widely between studies from 50 to greater than 500 mL at every 4-hour checks. A potentially independent risk factor is that patients with high gastric residuals may also be at increased risk of vomiting. 3.5. Oropharyngeal colonization Microbiologic factors also influence the risk of aspiration pneumonia. Pathophysiologically, risk of pneumonia relates to the body’s ability to combat the bacteria that routinely reach the lower respiratory tract. Unusual or more virulent microbes may be more difficult to eradicate by the normal host defenses. By far, the most important influence on alterations in normal oropharyngeal flora is use of systemic antibiotics. An independent association of poor oral hygiene with aspiration pneumonia is also supported by the literature [56,77]. The microbial density is increased in patients with gingival disease even if the spectrum has not shifted, increasing the likelihood of pneumonia developing in association with an episode of aspiration due to the greater inoculum. This suggests that edentulous patients are at lower risk for aspiration pneumonia. In edentulous patients, the tongue is more important as a focal point for colonization. Abe et al [78] associated tongue-coating scores in an edentulous elderly population with higher bacterial colonization and aspiration pneumonia. Many of the studies of oral hygiene have also demonstrated greater colonization by more virulent organisms in patients with poor oral hygiene. This is especially true for the colonization of gram negatives and respiratory pathogens in the intensive care unit [77]. As a further demonstration of this relationship, El-Solh et al [79] cultured respiratory

43

pathogens from dental plaques in critically ill patients. In those that developed pneumonia, bacteria from bronchoalveolar lavage (BAL) matched bacteria from the dental plaques by genetic testing. 3.6. Other risks General risk factors like male sex and smoking may increase risk for aspiration pneumonia based on case-controlled and cohort studies [48]. Diabetes mellitus has been repeatedly associated with pneumonia in patients who have had an acute stroke [48]. Much has been discussed regarding the increased risk of pneumonia as a whole in patients being treated with proton pump inhibitors and/or histamine receptor–2 antagonists [80,81]. Although these medications may not increase the risk of aspiration, they change the gastrointestinal environment such that natural host defenses, which include gastric acid secretion, cannot reduce bacterial burden. If a subsequent aspiration event occurs, patients appear more likely to deliver an inoculum of bacteria high enough to cause clinical infection. Conversely, the frequent use of proton pump inhibitors or histamine receptor–2 antagonist, particularly in the hospitalized population, may be associated with a lower incidence of aspiration pneumonitis. 4. Diagnosis Like all pneumonias, the diagnosis of aspiration pneumonia rests mostly on the history of presenting illness, medical history, vital signs, and chest radiograph. In clinical practice, aspiration pneumonia is most often coded as the diagnosis when a new chest radiograph infiltrate in a dependent pulmonary segment is found in patients with risk factors for aspiration. In a bed-bound patient, the dependent pulmonary segments are the posterior segments of the upper lobes and the superior segments of the lower lobes. In ambulatory patients, lower lobes are classically involved, especially the right [17,41]. Clinical features can help distinguish aspiration pneumonia from chemical pneumonitis and other lung infections. As opposed to chemical pneumonitis, the aspiration event in aspiration pneumonia is rarely witnessed [17]. The large volume of stomach contents required to cause chemical pneumonitis usually makes it a more obvious event. Furthermore, the clinical course of chemical pneumonitis is hyperacute hypoxemia, occurring almost immediately (within hours) and resulting in either devastating lung injury or resolution within 48 hours. These patients are likely to also have bronchospasm, frothy sputum, and chest radiographs with bilateral patchy infiltrates [15,17,18,41], including nondependent areas. Distinguishing anaerobic pleuropneumonia due to aspiration from classic CAP may be very difficult. Sophisticated molecular diagnosis of CAP etiology found that anaerobes are the etiology in 15% of cases [82]. In a series comparing clinical aspects of anaerobic aspiration pneumonia and pneumococcal pneumonia, few reliable predictors distinguished between the entities [83]. Absence of shaking chills and the development of lung abscess were 2 features more common in aspiration pneumonia. The classic teaching of putrid sputum was only present in 2 of 46 patients with aspiration pneumonia and may only become obvious after 1 to 2 weeks of infection when cavitation has begun. In fact, many of the older teachings involving clinical clues to anaerobic aspiration pneumonia involve the drastic findings that only result with cavitation and necrosis [84]. A slightly longer time before presentation to the hospital (4.5 vs 2.6 days) supports the common teaching that aspiration pneumonia has a more indolent course. Because of this difficulty, efforts have been made to use biomarkers to distinguish aspiration pneumonia from other aspiration syndromes. El-Solh et al [85] attempted to use procalcitonin to distinguish aspiration pneumonitis from aspiration pneumonia in the intensive care unit setting, given data to suggest that procalcitonin is a helpful marker for bacterial causes of sepsis [86]. Unfortunately,

44

D.M. DiBardino, R.G. Wunderink / Journal of Critical Care 30 (2015) 40–48

no difference between procalcitonin levels was demonstrated in culture-negative and culture-positive patients. Biomarkers more specific to aspiration have also been studied. Pepsinogen in tracheal secretions or BAL was very suggestive of aspiration as part of the pathogenesis of posttransplant BO and VAP. Bronchoalveolar lavage amylase levels have been demonstrated to correlate with clinical risk factors for aspiration, as well as with positive cultures [87–89]. This relationship may even be true in patients with VAP [90]. Bronchoalveolar lavage amylase can also function as an end point for studies of interventions to decrease risk of aspiration in ventilated patients [91]. 5. Microbiology The unique pathophysiology of aspiration pneumonia may lend itself to unique pathogens. However, the microbiology, and therefore the treatment, has seen significant changes over the last 40 to 50 years. The original teaching was that anaerobic bacteria were by far the most common pathogens in aspiration pneumonia based on well-done microbiology studies undertaken in patients with aspiration pneumonia acquired in and out of the hospital from the 1960s to 1980s. Bartlett and Gorbach [17] and Bartlett et al [92] reported on 2 cohorts of patients: one with aspiration pneumonia and a second with aspiration-induced pulmonary infections including pleural. In the initial study, 50 (93%) of 54 patients had anaerobes (25 cultures grew only anaerobes; 25 were a part of mixed flora). In the follow-up study, 61 (87%) of 70 patients with aspiration pneumonia had anaerobes in culture. Subsequent studies [93–96] seemed to confirm these results. These anaerobic infections commonly included greater than one pathogen, with Bacteroides species, Prevotella, Fusbacterium species, and peptostreptococci predominating (Table 2). Most of these patients had the anaerobic pleuropneumonia syndrome described above. As homogenous as these initial results appeared, evidence accumulated that aspiration pneumonia occurring after hospitalization had a microbiologic spectrum that included more Staphylococcus aureus, aerobes, and

gram-negative bacilli [17,84,92,94]. The pathogens that dominate aspiration pneumonia microbiology after a macroaspiration event after hospitalization are similar to those of many nosocomial infections. Although very limited, data from reliable cultures in nonintubated patients do suggest a higher frequency of anaerobes than in intubated patients; but the frequency is substantially lower than that of the prior era. Recent studies reveal much different results even for patients presenting from the community. El-Solh et al [97] reported a series of patients with suspected aspiration pneumonia who underwent bronchial sampling after intubation. Of the 54 patients with a bacterial diagnosis, 20% grew only anaerobes, with an additional 11% that included anaerobes as part of mixed flora. In contrast, common causative organisms in this study were Escherichia coli, S aureus, and Klebsiella pneumoniae. Tokuyasu et al [98] described this trend further in a series of elderly Japanese patients with clinically diagnosed aspiration pneumonia. Of 111 organisms isolated in 62 individuals, only 22 (20%) were anaerobes. Anaerobes were heavily outweighed by gram-negative bacilli (almost all enteric gramnegatives), found in 51.6% of patients. Even the etiology in patients with lung abscess has changed. Takayanagi et al [99] reported bacterial etiologies in 122 patients diagnosed with community-acquired lung abscess, likely a result of untreated aspiration. In this population, 74% grew aerobes only, 12% grew anaerobes only, and 14% grew mixed flora. Of the 107 aerobic cases, 79% were Streptococcus species. In a very similar study, Wang et al [100] reported that only 40 (44%) of 90 community-acquired lung abscesses grew any anaerobes, with only 13% purely anaerobic. Of the remaining cases, 33% were caused by K pneumoniae (almost all being pure K pneumoniae isolates). The latter finding suggests that aspiration may not even play a role in some cases of lung abscess, but rather more virulent CAP pathogens. The combination of lung abscess and empyema has also been reported with communityacquired methicillin-resistant S aureus (MRSA) pneumonia [101]. These 2 distinct bodies of literature, taken chronologically, reveal a fading importance of anaerobic bacteria in aspiration pneumonia and

Table 2 Pathogens involved Study

Year

Percent of patients with anaerobic infection (alone/mixed/total)

Most common anaerobes

Most common aerobes

Bartlett [17]

1975

46%/41%/87%

Bartlett [77]

1974

46%/46%/92%

-

Bacteroides sp Fusobacterium sp Peptostreptococcus sp Bacteroides sp Fusobacterium sp Peptostreptococcus sp

Cesar [78]

1975

35%/65%/100%

Lorber [79]

1974

32%/30%/62%

Brook [80]

1980

3%/91%/94%

El-Solh [82]

2003

20%/11%/31%

-

Bacteroides sp Fusobacterium sp Proprionibacterium Fusobacterium sp Peptostreptococcus sp Peptococcus sp Bacteroides sp Peptococcus sp Peptostreptococcus sp Fusobacterium sp Prevotella sp Fusobacterium sp

- Streptococcus pneumoniae - Staphylococcus aureus - K pneumoniae - S aureus - S pneumoniae - Klebsiella sp - Pseudomonas aeruginosa - E coli - S pneumoniae - Haemophilus influenza - α-Hemolytic Streptococcus - Streptococcus sp - P aeruginosa - E coli - α-Hemolytic Streptococcus - P aeruginosa - S pneumoniae

Tokuyasu [83]

2009

Not reported/not reported/27%

Takayanagi [84]

2010

12%/14%/26%

Wang [85]

2005

13%/44%/57%

-

Fusobacterium sp Streptococcus milleri Peptococcus sp Peptostreptococcus sp Prevotella sp Fusobacterium sp Veillonella sp Peptostreptococcus sp Prevotella sp Bacteroides sp

- E coli - K pneumoniae - S aureus - Streptococcus agalactiae - Methicillin-resistant S aureus - K pneumoniae - Streptococcus mitis - Streptococcus constellatus - Streptococcus salivarius - K pneumoniae - S milleri - Viridans streptococci

D.M. DiBardino, R.G. Wunderink / Journal of Critical Care 30 (2015) 40–48

even community-acquired lung abscess. A second implication of this etiologic shift is that the principles of typical nosocomial microbiology apply to patients with aspiration pneumonia if macroaspiration occurs after hospitalization. This etiologic overlap between aspiration pneumonia and HAP has been progressively evident since the 1970s. 6. Treatment As one would expect, empirical treatment of aspiration pneumonia has evolved, given the above changes in the microbiology of the infection [102]. Intravenous penicillin was the drug of choice in the past, as anaerobes constituted the vast majority of infections with few penicillinase-producing bacterial strains [103,104]. A randomized controlled trial (RCT) of 39 patients with lung abscesses compared penicillin with clindamycin in the early 1980s [105]. Although a small group of patients, the treatment failure rate and cure rate were much better for clindamycin, with all 13 followed patients being cured vs 8 of 15 in the penicillin group. The failure of penicillin to cure anaerobic infections was better characterized several years later in a Spanish RCT of confirmed anaerobic lung infections [106]. In this cohort of 37 patients, 47 anaerobes were isolated. Ten of these 47, all Bacteroides species, were penicillin resistant, whereas none were clindamycin resistant. None of the 5 patients with penicillin-resistant bacteria randomized to penicillin responded to therapy. Metronidazole has also been studied in anaerobic lungs infections. Sanders et al [107] described a poor cure rate in 13 patients with pleuropulmonary (11 of 13 being lung abscesses) infections with confirmed anaerobic bacteria. Similarly, Perlino [108] reported higher cure rates with clindamycin when compared to metronidazole in cases of lung abscess and pneumonia with confirmed anaerobic flora in a small RCT of 13 patients. It is important to understand that these studies included mainly classic anaerobic pleuropneumonia syndrome with anaerobes confirmed on culture and that most were completed decades ago. In the currently uncommon patient with aspiration resulting in classic anaerobic pleuropneumonia, prior results and the likely greater incidence of penicillin resistance suggest that clindamycin may be the optimal agent. Recent studies have focused on pneumonia in patients with risk factors for aspiration. Kadowaki et al [109] randomly assigned 100 elderly Japanese patients with suspected aspiration pneumonia to clindamycin, a carbapenem (penipenem/betamiprom), low-dose ampicillin/sulbactam (1.5 g twice daily), or high-dose ampicillin/ sulbactam (3 g twice daily). The investigators found little variance in efficacy (N 75% cure rate in all groups) and adverse events. Interestingly, no anaerobes were actually cultured. Of note, clindamycin was the cheapest treatment and associated with the lowest incidence (0/25 patients) of new MRSA infections. Another study of elderly Japanese with aspiration pneumonia [98] demonstrated a clinical efficacy rate of 61.3% with another carbapenem, meropenem. This lower efficacy than that found by Kadowaki et al [109] may be due to greater severity of illness in the study patients. Once again, nosocomial pathogens rather than anaerobes were the most common documented etiologies; and 33 of these 62 patients had MRSA growing in their postantibiotic sputum culture. A recent randomized German study compared high-dose ampicillin/sulbactam (3 g thrice times daily) to the standard CAP antibiotic moxifloxacin for the treatment of aspiration pneumonia and lung abscess in 96 elderly patients [110]. Clinical response rates were identical at 66.7%, and adverse reaction rates were very similar. Microbiology was consistent with the more recent data described above, with less than 10% of bacteria cultured being anaerobes. Of note, higher (although not statistically significant) mortality was seen in the ampicillin/sulbactam group, with 14 patients dying compared to 6 in the moxifloxacin group. These recent data from Japan and Germany have demonstrated effective treatment strategies for aspiration pneumonia in the face of

45

new microbiology patterns. Based on this limited evidence, clindamycin, a carbapenem, ampicillin/sulbactam, and moxifloxacin all appear to be reasonable first-line therapies in modern-day community-acquired aspiration pneumonia. For patients with hospital-acquired macroaspiration pneumonias, use of broad-spectrum combination therapy is recommended if MDR risk factors are present. Probably the single most important risk factor for MDR pathogens is prior antibiotic treatment. If none, the antibiotics listed for community-acquired aspiration pneumonia are adequate. The longer the prior course and the broader the spectrum of agent, the greater the likelihood of MDR pathogens. In nonventilated patients, anaerobes may still play a role; and cefepime should be avoided. For ventilated patients, the high oxygen tension is sufficient to kill anaerobes; and any β-lactam should be appropriate, although changing β-lactam class may be prudent. 7. Prevention Aspiration pneumonia can be a grave illness despite treatment, so prevention is important. Several randomized trials have been investigated to prevent aspiration pneumonia, but most are limited by enrollment. Dietary interventions have been studied in patients with dysphagia. In a small study involving patients with dysphagia secondary to neurodegenerative disease (pseudobulbar dysphagia) [111], more aspiration pneumonia occurred in those on a pureed diet compared to a mechanical soft diet with thickened liquids. However, the utility of dietary intervention has been questioned. Depippo et al [112] randomized 115 poststroke patients to 3 groups according to speech therapist intervention: Group A was given advice based on swallow testing, but the ultimate diet was determined by the patient and family; Group B was prescribed a specific diet based on swallow testing; and Group C was prescribed a specific diet and directly observed for compliance daily. No statistically significant differences between the groups were found in any end point. A number of small studies have reviewed pharmacologic intervention to protect the airway via the cough reflex. The most interesting drugs studied are angiotensin-converting enzyme inhibitors (ACEIs) because of their role in degrading substance P and bradykinin, stimulants of the cough reflex. A reduction in aspiration pneumonia in patients on an ACEI has been suggested in one casecontrol study [113] in elderly Japanese patients. Further, investigators have categorized an increased risk for pneumonia in patients with certain ACE gene polymorphisms that are associated with higher ACE levels: homozygous deletion of an alu repeat within intron 16 (ACE DD). The risk of pneumonia was markedly reduced in a case-control study of patients without this genotype who were taking an ACEI, whereas it was unaffected in patients with the genotype [114]. Because enteric tube feeding presents a risk for aspiration, there has been considerable effort to compare types of tube feeds to minimize this risk. The most important comparisons are between gastric and postpyloric feedings. Given the gastric dysmotility caused by critical illness, gastroparesis, and common medications, postpyloric feeds have been commonly postulated to be superior [65]. Two small prospective trials have found no difference [115,116] in pneumonia rates. To the contrary, a very small randomized trial, with almost no cases of aspiration pneumonia, and another prospective trial found advantages to jejunal feeds [117,118]. Comparisons have also been made between nasogastric tube and percutaneous endoscopic gastrostomy tube feeds in a variety of clinical settings. Several randomized controlled trials have failed in demonstrating a difference in pneumonia complication rates between the 2 feeding strategies. Percutaneous endoscopic gastrostomy tubes are more likely to achieve goal feeds but come at a much higher cost [119–121]. Many institutions monitor residual volumes from tube feeds to know when aspiration risk is increased. Residual volumes of 500 mL

46

D.M. DiBardino, R.G. Wunderink / Journal of Critical Care 30 (2015) 40–48

are considered high enough to hold tube feeds [65]. However, the inaccuracy of this method has been well documented [122]. Furthermore, results from a recent randomized clinical trial suggest that using strict residual volumes (250 mL) to understand when to hold nasogastric tube feeds does not affect the incidence of VAP [123]. Oral care has been shown to assist in preventing aspiration pneumonia as expected given the evidenced discussed above. Data are again limited, but encouraging quality oral care offers potential benefit with almost no morbidity [124]. For patients at risk of aspiration around the time of endotracheal intubation, several studies have shown that a short course (≤ 24 hours) of “prophylactic” β-lactam antibiotics may decrease the risk of subsequent VAP [125,126]. An extremely elevated BAL amylase may better select patients for this intervention. One very important preventative measure surrounds preventing aspiration in the hospitalized, critically ill patient. Increased aspiration in the supine position was evident after a Spanish study that detected enterically administered dye aspirated into the lungs of mechanically ventilated patients. Aspiration rates not only were higher in patients who were supine but were dependent on how much time was spent in the supine position [127]. The same investigators then confirmed the importance of this phenomenon by demonstrating drastically reduced rates of HAP in mechanically ventilated patients in the semirecumbent position compared to supine [128]. A subsequent study did not show a benefit of semirecumbant position when compared to elevation of as little as 10° from supine [129]. However, the risk benefit ratio of elevation of the head of the bed in ventilated patients is so favorable that it has become standard practice. 8. Conclusions Aspiration pneumonia is a common clinical syndrome with a distinct pathophysiology. Aspiration pneumonia must be distinguished from other aspiration syndromes that include similar risk factors including abnormalities in the cough reflex, oral microbiology, and the swallow mechanism. Despite the traditional teaching, aspiration pneumonia is difficult to distinguish from other pneumonia syndromes and therefore shares many features with CAP and HAP. In the modern era, aspiration pneumonia warrants consideration (and treatment) as solely an anaerobic infection only in the proper limited clinical setting. Antibiotic treatment is largely dependent on the clinical scenario, exposure to hospital-acquired pathogens, and local resistance patterns. Several measures may help prevent aspiration pneumonia without introducing morbidity that include diet interventions for dysphasia, oral care, postpyloric tube feedings, and the semirecumbent position for mechanically ventilated patient. References [1] Venes D, editor. Taber's cyclopedic medical dictionary. F. A. Davis Company; 2009. [2] Gorbach SLB, John G. In: Blacklow Neil R, editor. Infectious diseases. Philadelphia: Lippincott Williams & Wilkins; 2004. [3] Scheld WM. Developments in the pathogenesis, diagnosis and treatment of nosocomial pneumonia. Surg Gynecol Obstet 1991(172 Suppl.):42–53. [4] Winther FO, Horthe K, Lystad A, Vellar OD. Pathogenic bacterial flora in the upper respiratory tract of healthy students. Prevalence and relationship to nasopharyngeal inflammatory symptoms. J Laryngol Otol 1974;88:407–12. [5] Pugliese G, Lichtenberg DA. Nosocomial bacterial pneumonia: An overview. Am J Infect Control 1987;15:249–65. [6] Huxley EJ, Viroslav J, Gray WR, Pierce AK. Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am J Med 1978;64:564–8. [7] Kikuchi R, Watabe N, Konno T, Mishina N, Sekizawa K, Sasaki H. High incidence of silent aspiration in elderly patients with community-acquired pneumonia. Am J Respir Crit Care Med 1994;150:251–3. [8] Gleeson K, Eggli DF, Maxwell SL. Quantitative aspiration during sleep in normal subjects. Chest 1997;111:1266–72. [9] Weiss W. Regurgitation and aspiration of gastric contents during inhalation anesthesia. Anesthesiology 1950;11:102–9. [10] Culver GA, Makel HP, Beecher HK. Frequency of aspiration of gastric contents by lungs during anesthesia and surgery. Ann Surg 1951;133:289–92.

[11] Berson W, Adriani J. Silent regurgitation and aspiration during anesthesia. Anesthesiology 1954;15:644–9. [12] Wunderink RG, Waterer GW. Community-acquired pneumonia: Pathophysiology and host factors with focus on possible new approaches to management of lower respiratory tract infections. Infect Dis Clin North Am 2004;18:743–59[vii]. [13] King BJ, Iyer H, Leidi AA, Carby MR. Gastroesophageal reflux in bronchiolitis obliterans syndrome: A new perspective. J Heart Lung Transplant 2009; 28:870–5. [14] Tobin RW, Pope II CE, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;158:1804–8. [15] Mendelson CL. The aspiration of stomach contents into the lungs during obstetric anesthesia. Am J Obstet Gynecol 1946;52:191–205. [16] Bynum LJ, Pierce AK. Pulmonary aspiration of gastric contents. Am Rev Respir Dis 1976;114:1129–36. [17] Bartlett JG, Gorbach SL. The triple threat of aspiration pneumonia. Chest 1975; 68:560–6. [18] Doyle RL, Szaflarski N, Modin GW, Wiener-Kronish JP, Matthay MA. Identification of patients with acute lung injury. Predictors of mortality. Am J Respir Crit Care Med 1995;152:1818–24. [19] Fisk RL, Symes JF, Aldridge LL, Couves CM. The pathophysiology and experimental therapy of acid pneumonitis in ex vivo lungs. Chest 1970; 57:364–70. [20] Gajic O, Dabbagh O, Park PK, Adesanya A, Chang SY, Hou P, et al. Early identification of patients at risk of acute lung injury: Evaluation of lung injury prediction score in a multicenter cohort study. Am J Respir Crit Care Med 2011; 183:462–70. [21] Teabeaut II JR. Aspiration of gastric contents; an experimental study. Am J Pathol 1952;28:51–67. [22] Cameron JL, Sebor J, Anderson RP, Zuidema GD. Aspiration pneumonia. Results of treatment by positive-pressure ventilation in dogs. J Surg Res 1968;8:447–57. [23] Cameron JL, Caldini P, Toung JK, Zuidema GD. Aspiration pneumonia: Physiologic data following experimental aspiration. Surgery 1972;72:238–45. [24] Lipper B, Simon D, Cerrone F. Pulmonary aspiration during emergency endoscopy in patients with upper gastrointestinal hemorrhage. Crit Care Med 1991; 19:330–3. [25] Rudolph SJ, Landsverk BK, Freeman ML. Endotracheal intubation for airway protection during endoscopy for severe upper gi hemorrhage. Gastrointest Endosc 2003;57:58–61. [26] Mullan H, Roubenoff RA, Roubenoff R. Risk of pulmonary aspiration among patients receiving enteral nutrition support. JPEN J Parenter Enteral Nutr 1992; 16:160–4. [27] Mackowiak PA. The normal microbial flora. N Engl J Med 1982;307:83–93. [28] Tuomanen EI, Austrian R, Masure HR. Pathogenesis of pneumococcal infection. N Engl J Med 1995;332:1280–4. [29] Hessen MT, Kaye D. Nosocomial pneumonia. Crit Care Clin 1988;4:245–57. [30] Toews GB. Nosocomial pneumonia. Clin Chest Med 1987;8:467–79. [31] Safdar N, Crnich CJ, Maki DG. The pathogenesis of ventilator-associated pneumonia: Its relevance to developing effective strategies for prevention. Respir Care 2005;50:725–39[discussion 739–741]. [32] Rello J, Quintana E, Ausina V, Castella J, Luquin M, Net A, et al. Incidence, etiology, and outcome of nosocomial pneumonia in mechanically ventilated patients. Chest 1991;100:439–44. [33] Johanson WG, Pierce AK, Sanford JP. Changing pharyngeal bacterial flora of hospitalized patients. Emergence of gram-negative bacilli. N Engl J Med 1969; 281:1137–40. [34] Johanson Jr WG, Pierce AK, Sanford JP, Thomas GD. Nosocomial respiratory infections with gram-negative bacilli. The significance of colonization of the respiratory tract. Ann Intern Med 1972;77:701–6. [35] Saviteer SM, Samsa GP, Rutala WA. Nosocomial infections in the elderly. Increased risk per hospital day. Am J Med 1988;84:661–6. [36] Garrouste-Orgeas M, Chevret S, Arlet G, Marie O, Rouveau M, Popoff N, et al. Oropharyngeal or gastric colonization and nosocomial pneumonia in adult intensive care unit patients. A prospective study based on genomic DNA analysis. Am J Respir Crit Care Med 1997;156:1647–55. [37] Mason CM, Nelson S. Pulmonary host defenses and factors predisposing to lung infection. Clin Chest Med 2005;26:11–7. [38] Smith SRS, Waterer G, Wunderink R. Trends in pneumonia: Incidence, pathogens, and outcomes from 1993–2010. ATS International Conference, Philadelphia, PA, May 19, 2013; 2013. [39] Kikawada M, Iwamoto T, Takasaki M. Aspiration and infection in the elderly: Epidemiology, diagnosis and management. Drugs Aging 2005;22:115–30. [40] Marik PE, Kaplan D. Aspiration pneumonia and dysphagia in the elderly. Chest 2003;124:328–36. [41] Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001; 344:665–71. [42] Aspiration pneumonia. Respirology 2009;14(Suppl. 2):S59–64. [43] Waterer GW, Kessler LA, Wunderink RG. Delayed administration of antibiotics and atypical presentation in community-acquired pneumonia. Chest 2006; 130:11–5. [44] Baine WB, Yu W, Summe JP. Epidemiologic trends in the hospitalization of elderly medicare patients for pneumonia, 1991–1998. Am J Public Health 2001; 91:1121–3. [45] Cabre M, Serra-Prat M, Palomera E, Almirall J, Pallares R, Clave P. Prevalence and prognostic implications of dysphagia in elderly patients with pneumonia. Age Ageing 2010;39:39–45.

D.M. DiBardino, R.G. Wunderink / Journal of Critical Care 30 (2015) 40–48 [46] Loeb M, McGeer A, McArthur M, Walter S, Simor AE. Risk factors for pneumonia and other lower respiratory tract infections in elderly residents of long-term care facilities. Arch Intern Med 1999;159:2058–64. [47] Vergis EN, Brennen C, Wagener M, Muder RR. Pneumonia in long-term care: A prospective case–control study of risk factors and impact on survival. Arch Intern Med 2001;161:2378–81. [48] van der Maarel-Wierink CD, Vanobbergen JN, Bronkhorst EM, Schols JM, de Baat C. Risk factors for aspiration pneumonia in frail older people: A systematic literature review. J Am Med Dir Assoc 2011;12:344–54. [49] Langmore SE, Skarupski KA, Park PS, Fries BE. Predictors of aspiration pneumonia in nursing home residents. Dysphagia 2002;17:298–307. [50] Langmore SE, Terpenning MS, Schork A, Chen Y, Murray JT, Lopatin D, et al. Predictors of aspiration pneumonia: How important is dysphagia? Dysphagia 1998;13:69–81. [51] Smith Hammond CA, Goldstein LB. Cough and aspiration of food and liquids due to oral-pharyngeal dysphagia: Accp evidence-based clinical practice guidelines. Chest 2006;129:154S–68S. [52] Martino R, Foley N, Bhogal S, Diamant N, Speechley M, Teasell R. Dysphagia after stroke: Incidence, diagnosis, and pulmonary complications. Stroke 2005; 36:2756–63. [53] Ji R, Wang D, Shen H, Pan Y, Liu G, Wang P, et al. Interrelationship among common medical complications after acute stroke: Pneumonia plays an important role. Stroke 2013;44:3436–44. [54] Nakajoh K, Nakagawa T, Sekizawa K, Matsui T, Arai H, Sasaki H. Relation between incidence of pneumonia and protective reflexes in post-stroke patients with oral or tube feeding. J Intern Med 2000;247:39–42. [55] Mokhlesi B, Logemann JA, Rademaker AW, Stangl CA, Corbridge TC. Oropharyngeal deglutition in stable copd. Chest 2002;121:361–9. [56] Terpenning MS, Taylor GW, Lopatin DE, Kerr CK, Dominguez BL, Loesche WJ. Aspiration pneumonia: Dental and oral risk factors in an older veteran population. J Am Geriatr Soc 2001;49:557–63. [57] Masiero S, Pierobon R, Previato C, Gomiero E. Pneumonia in stroke patients with oropharyngeal dysphagia: A six-month follow-up study. Neurol Sci 2008; 29:139–45. [58] Ohrui T. Preventive strategies for aspiration pneumonia in elderly disabled persons. Tohoku J Exp Med 2005;207:3–12. [59] Knol W, van Marum RJ, Jansen PA, Souverein PC, Schobben AF, Egberts AC. Antipsychotic drug use and risk of pneumonia in elderly people. J Am Geriatr Soc 2008;56:661–6. [60] Adnet F, Baud F. Relation between glasgow coma scale and aspiration pneumonia. Lancet 1996;348:123–4. [61] Isbister GK, Downes F, Sibbritt D, Dawson AH, Whyte IM. Aspiration pneumonitis in an overdose population: Frequency, predictors, and outcomes. Crit Care Med 2004;32:88–93. [62] Christ A, Arranto CA, Schindler C, Klima T, Hunziker PR, Siegemund M, et al. Incidence, risk factors, and outcome of aspiration pneumonitis in icu overdose patients. Intensive Care Med 2006;32:1423–7. [63] Eizadi-Mood N, Saghaei M, Alfred S, Zargarzadeh AH, Huynh C, Gheshlaghi F, et al. Comparative evaluation of glasgow coma score and gag reflex in predicting aspiration pneumonitis in acute poisoning. J Crit Care 2009;24:470.e9–470.e15. [64] DeToledo JC, Lowe MR, Gonzalez J, Haddad H. Risk of aspiration pneumonia after an epileptic seizure: A retrospective analysis of 1634 adult patients. Epilepsy Behav 2004;5:593–5. [65] Metheny NA, Schallom ME, Edwards SJ. Effect of gastrointestinal motility and feeding tube site on aspiration risk in critically ill patients: A review. Heart Lung 2004;33:131–45. [66] Mizock BA. Risk of aspiration in patients on enteral nutrition: Frequency, relevance, relation to pneumonia, risk factors, and strategies for risk reduction. Curr Gastroenterol Rep 2007;9:338–44. [67] McClave SA, DeMeo MT, DeLegge MH, DiSario JA, Heyland DK, Maloney JP, et al. North american summit on aspiration in the critically ill patient: Consensus statement. JPEN J Parenter Enteral Nutr 2002;26:S80–5. [68] Gomes GF, Pisani JC, Macedo ED, Campos AC. The nasogastric feeding tube as a risk factor for aspiration and aspiration pneumonia. Curr Opin Clin Nutr Metab Care 2003;6:327–33. [69] Cogen R, Weinryb J. Aspiration pneumonia in nursing home patients fed via gastrostomy tubes. Am J Gastroenterol 1989;84:1509–12. [70] Kitamura T, Nakase H, Iizuka H. Risk factors for aspiration pneumonia after percutaneous endoscopic gastrostomy. Gerontology 2007;53:224–7. [71] Pannunzio TG. Aspiration of oral feedings in patients with tracheostomies. AACN Clin Issues 1996;7:560–9. [72] Pearce CB, Duncan HD. Enteral feeding. Nasogastric, nasojejunal, percutaneous endoscopic gastrostomy, or jejunostomy: Its indications and limitations. Postgrad Med J 2002;78:198–204. [73] Fox KA, Mularski RA, Sarfati MR, Brooks ME, Warneke JA, Hunter GC, et al. Aspiration pneumonia following surgically placed feeding tubes. Am J Surg 1995; 170:564–6[discussion 566–567]. [74] Sands JA. Incidence of pulmonary aspiration in intubated patients receiving enteral nutrition through wide- and narrow-bore nasogastric feeding tubes. Heart Lung 1991;20:75–80. [75] Carnes ML, Sabol DA, DeLegge M. Does the presence of esophagitis prior to peg placement increase the risk for aspiration pneumonia? Dig Dis Sci 2004; 49:1798–802. [76] Pace CC, McCullough GH. The association between oral microorgansims and aspiration pneumonia in the institutionalized elderly: Review and recommendations. Dysphagia 2010;25:307–22.

47

[77] Abe S, Ishihara K, Adachi M, Okuda K. Tongue-coating as risk indicator for aspiration pneumonia in edentate elderly. Arch Gerontol Geriatr 2008; 47:267–75. [78] El-Solh AA, Pietrantoni C, Bhat A, Okada M, Zambon J, Aquilina A, et al. Colonization of dental plaques: A reservoir of respiratory pathogens for hospitalacquired pneumonia in institutionalized elders. Chest 2004;126:1575–82. [79] Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004;292:1955–60. [80] Herzig SJ, Howell MD, Ngo LH, Marcantonio ER. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA 2009;301:2120–8. [81] Yamasaki K, Kawanami T, Yatera K, Fukuda K, Noguchi S, Nagata S, et al. Significance of anaerobes and oral bacteria in community-acquired pneumonia. PLoS One 2013;8(e63103):1–9. [82] Bartlett JG. Anaerobic bacterial pneumonitis. Am Rev Respir Dis 1979;119:19–23. [83] Finegold SM. Aspiration pneumonia. Rev Infect Dis 1991;13(Suppl. 9):S737–42. [84] El-Solh AA, Vora H, Knight III PR, Porhomayon J. Diagnostic use of serum procalcitonin levels in pulmonary aspiration syndromes. Crit Care Med 2011; 39:1251–6. [85] Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993; 341:515–8. [86] Weiss CH, Moazed F, DiBardino D, Swaroop M, Wunderink RG. Bronchoalveolar lavage amylase is associated with risk factors for aspiration and predicts bacterial pneumonia. Crit Care Med 2013;41:765–73. [87] Filloux B, Bedel A, Nseir S, Mathiaux J, Amadeo B, Clouzeau B, et al. Tracheal amylase dosage as a marker for microaspiration: A pilot study. Minerva Anestesiol 2013;79:1003–10. [88] Tripathi A, Mirant-Borde MC, Lee A. Amylase in bronchoalveolar lavage as a potential marker of oropharyngeal-to-pulmonary aspiration. Abstract presented at American Thoracic Society, 21897. , ; 2011. p. 2011. [89] Curtis HW, Richard GW, Grant WW. Bronchoalveolar lavage amylase predicts ventilator-associated pneumonia. A25 the changing face of pneumonia and its management: American Thoracic Society; 2013. A1148-A1148. [90] Amir M, Kristi H, Curtis HW, Michael A, Nicole W, Richard GW. Microcuff endotracheal tubes and risk of microaspiration. A46 icu outcomes: American Thoracic Society; 2013. A1602-A1602. [91] Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med 1974;56:202–7. [92] Cesar L, Gonzalez C, Calia FM. Bacteriologic flora of aspiration-induced pulmonary infections. Arch Intern Med 1975;135:711–4. [93] Lorber B, Swenson RM. Bacteriology of aspiration pneumonia. A prospective study of community- and hospital-acquired cases. Ann Intern Med 1974; 81:329–31. [94] Brook I, Finegold SM. Bacteriology of aspiration pneumonia in children. Pediatrics 1980;65:1115–20. [95] Marina M, Strong CA, Civen R, Molitoris E, Finegold SM. Bacteriology of anaerobic pleuropulmonary infections: Preliminary report. Clin Infect Dis 1993;16 (Suppl 4):S256–62. [96] El-Solh AA, Pietrantoni C, Bhat A, Aquilina AT, Okada M, Grover V, et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med 2003;167:1650–4. [97] Tokuyasu H, Harada T, Watanabe E, Okazaki R, Touge H, Kawasaki Y, et al. Effectiveness of meropenem for the treatment of aspiration pneumonia in elderly patients. Intern Med 2009;48:129–35. [98] Takayanagi N, Kagiyama N, Ishiguro T, Tokunaga D, Sugita Y. Etiology and outcome of community-acquired lung abscess. Respiration 2010;80:98–105. [99] Wang JL, Chen KY, Fang CT, Hsueh PR, Yang PC, Chang SC. Changing bacteriology of adult community-acquired lung abscess in taiwan: Klebsiella pneumoniae versus anaerobes. Clin Infect Dis 2005;40:915–22. [100] Lobo LJ, Reed KD, Wunderink RG. Expanded clinical presentation of communityacquired methicillin-resistant staphylococcus aureus pneumonia. Chest 2010; 138:130–6. [101] Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44(Suppl. 2):S27–72. [102] Weiss W. Oral antibiotic therapy of acute primary lung abscess: Comparison of penicillin g and tetracycline. Curr Ther Res Clin Exp 1970;12:154–60. [103] Weiss W. Cavity behavior in acute, primary, nonspecific lung abscess. Am Rev Respir Dis 1973;108:1273–5. [104] Levison ME, Mangura CT, Lorber B, Abrutyn E, Pesanti EL, Levy RS, et al. Clindamycin compared with penicillin for the treatment of anaerobic lung abscess. Ann Intern Med 1983;98:466–71. [105] Gudiol F, Manresa F, Pallares R, Dorca J, Rufi G, Boada J, et al. Clindamycin vs penicillin for anaerobic lung infections. High rate of penicillin failures associated with penicillin-resistant bacteroides melaninogenicus. Arch Intern Med 1990; 150:2525–9. [106] Sanders CV, Hanna BJ, Lewis AC. Metronidazole in the treatment of anaerobic infections. Am Rev Respir Dis 1979;120:337–43. [107] Perlino CA. Metronidazole vs clindamycin treatment of anerobic pulmonary infection. Failure of metronidazole therapy. Arch Intern Med 1981; 141:1424–7. [108] Kadowaki M, Demura Y, Mizuno S, Uesaka D, Ameshima S, Miyamori I, et al. Reappraisal of clindamycin iv monotherapy for treatment of mild-to-moderate aspiration pneumonia in elderly patients. Chest 2005;127:1276–82.

48

D.M. DiBardino, R.G. Wunderink / Journal of Critical Care 30 (2015) 40–48

[109] Ott SR, Allewelt M, Lorenz J, Reimnitz P, Lode H. Moxifloxacin vs ampicillin/ sulbactam in aspiration pneumonia and primary lung abscess. Infection 2008; 36:23–30. [110] Groher M. Bolus management and aspiration pneumonia in patients with pseudobulbar dysphagia. Dysphagia 1987;1:215–6. [111] DePippo KL, Holas MA, Reding MJ, Mandel FS, Lesser ML. Dysphagia therapy following stroke: A controlled trial. Neurology 1994;44:1655–60. [112] Okaishi K, Morimoto S, Fukuo K, Niinobu T, Hata S, Onishi T, et al. Reduction of risk of pneumonia associated with use of angiotensin i converting enzyme inhibitors in elderly inpatients. Am J Hypertens 1999;12:778–83. [113] Takahashi T, Morimoto S, Okaishi K, Kanda T, Nakahashi T, Okuro M, et al. Reduction of pneumonia risk by an angiotensin i-converting enzyme inhibitor in elderly japanese inpatients according to insertion/deletion polymorphism of the angiotensin i-converting enzyme gene. Am J Hypertens 2005;18:1353–9. [114] Esparza J, Boivin MA, Hartshorne MF, Levy H. Equal aspiration rates in gastrically and transpylorically fed critically ill patients. Intensive Care Med 2001;27:660–4. [115] Strong RM, Condon SC, Solinger MR, Namihas BN, Ito-Wong LA, Leuty JE. Equal aspiration rates from postpylorus and intragastric-placed small-bore nasoenteric feeding tubes: A randomized, prospective study. JPEN J Parenter Enteral Nutr 1992;16:59–63. [116] Montecalvo MA, Steger KA, Farber HW, Smith BF, Dennis RC, Fitzpatrick GF, et al. Nutritional outcome and pneumonia in critical care patients randomized to gastric versus jejunal tube feedings. The critical care research team. Crit Care Med 1992;20:1377–87. [117] Adams GF, Guest DP, Ciraulo DL, Lewis PL, Hill RC, Barker DE. Maximizing tolerance of enteral nutrition in severely injured trauma patients: A comparison of enteral feedings by means of percutaneous endoscopic gastrostomy versus percutaneous endoscopic gastrojejunostomy. J Trauma 2000;48:459–64[discussion 464–455]. [118] Gomes Jr CA, Lustosa SA, Matos D, Andriolo RB, Waisberg DR, Waisberg J. Percutaneous endoscopic gastrostomy versus nasogastric tube feeding for adults with swallowing disturbances. Cochrane Database Syst Rev 2012;3:1–50 [CD008096].

[119] Nugent B, Lewis S, O'Sullivan JM. Enteral feeding methods for nutritional management in patients with head and neck cancers being treated with radiotherapy and/or chemotherapy. Cochrane Database Syst Rev 2013;1:1–18 [CD007904]. [120] Loser C, Aschl G, Hebuterne X, Mathus-Vliegen EM, Muscaritoli M, Niv Y, et al. Espen guidelines on artificial enteral nutrition–percutaneous endoscopic gastrostomy (peg). Clin Nutr 2005;24:848–61. [121] McClave SA, Lukan JK, Stefater JA, Lowen CC, Looney SW, Matheson PJ, et al. Poor validity of residual volumes as a marker for risk of aspiration in critically ill patients. Crit Care Med 2005;33:324–30. [122] Reignier J, Mercier E, Le Gouge A, Boulain T, Desachy A, Bellec F, et al. Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: A randomized controlled trial. JAMA 2013;309:249–56. [123] Sarin J, Balasubramaniam R, Corcoran AM, Laudenbach JM, Stoopler ET. Reducing the risk of aspiration pneumonia among elderly patients in long-term care facilities through oral health interventions. J Am Med Dir Assoc 2008;9:128–35. [124] Sirvent JM, Torres A, El-Ebiary M, Castro P, de Batlle J, Bonet A. Protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma. Am J Respir Crit Care Med 1997;155:1729–34. [125] Valles J, Peredo R, Burgueno MJ, Rodrigues de Freitas AP, Millan S, Espasa M, et al. Efficacy of single-dose antibiotic against early-onset pneumonia in comatose patients who are ventilated. Chest 2013;143:1219–25. [126] Torres A, Serra-Batlles J, Ros E, Piera C, Puig de la Bellacasa J, Cobos A, et al. Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: The effect of body position. Ann Intern Med 1992;116:540–3. [127] Drakulovic MB, Torres A, Bauer TT, Nicolas JM, Nogue S, Ferrer M. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: A randomised trial. Lancet 1999;354:1851–8. [128] van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, Joore HC, van Schijndel RJ, van der Tweel I, et al. Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: A randomized study. Crit Care Med 2006;34:396–402.