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Home , Anaerobic infection, Aspiration pneumonia, Chemical pneumonitis, Lobar pneumonia, Lung abscess, Pneumonia (non-human)

The new england journal of medicine

Review Article

Dan L. Longo, M.D., Editor Aspiration

Lionel A. Mandell, M.D., and Michael S. Niederman, M.D.​​

spiration pneumonia is best considered not as a distinct entity From McMaster University, Hamilton, but as part of a continuum that also includes community- and hospital- ON, Canada (L.A.M.); and Weill Cornell Medical College, New York (M.S.N.). Ad- acquired . It is estimated that accounts dress reprint requests to Dr. Mandell at A ­lmandell@​­mcmaster​.­ca. for 5 to 15% of cases of community-acquired pneumonia, but figures for hospital- 1 acquired pneumonia are unavailable. Robust diagnostic criteria for aspiration N Engl J Med 2019;380:651-63. pneumonia are lacking, and as a result, studies of this disorder include heteroge- DOI: 10.1056/NEJMra1714562 neous patient populations. Copyright © 2019 Massachusetts Medical Society. Aspiration of small amounts of oropharyngeal secretions is normal in healthy persons during sleep, yet microaspiration is also the major pathogenetic mecha- nism of most pneumonias.2 Large-volume aspiration (macroaspiration) of colo- nized oropharyngeal or upper gastrointestinal contents is the sine qua non of aspiration pneumonia. Variables affecting patient presentation and disease man- agement include bacterial virulence, the risk of repeated events, and the site of acquisition (nursing home, hospital, or community). According to this spectrum, patients labeled as having aspiration pneumonia usually represent a clinical phe- notype with risk factors for macroaspiration and involvement of characteristic anatomical pulmonary locations. Aspiration syndromes may involve the airways or pulmonary parenchyma, resulting in a variety of clinical presentations.3 This review focuses on aspiration involving the parenchyma, primarily aspiration pneumonia and chemical . Aspiration of noninfectious material such as blood or a foreign body is also important. Aspiration pneumonia is an caused by specific , whereas is an inflammatory reaction to irritative gastric contents. Our understanding of the interaction between and the lung has improved. We examine this improvement, along with changing concepts of the microbiology and pathogenesis of aspiration pneumonia. We also examine the clinical features, diagnosis, treat- ment, and prevention of both aspiration pneumonia and chemical pneumonitis, as well as the risk factors.

Changing Microbiologic and Pathogenetic Concepts of Aspiration Pneumonia

Our understanding of normal lower-airway microbiota in humans has evolved with the use of targeted polymerase-chain-reaction studies, sequencing of bacterial 16S ribosomal RNA genes, and metagenomics. A recent study of oral microbiota in patients with acute identified 103 different bacterial phylotypes, 29 of which had not been reported previously.4 Whether these new microbes are pathogens is uncertain. The Human Microbiome Project has helped define the role that intestinal micro- organisms play in the development of mucosal immunity and in the interplay between health and disease. Studies of the lung microbiome have challenged our

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assumptions of lung sterility and of bacterial ac- such as glucocorticoids, have been shown in vi- cess to the through aspiration (microaspi- tro to promote the growth of S. pneumoniae and ration or macro­aspiration) and inhalation. Spe- certain gram-negative rods.13-16 cifically, genomic methods have defined a One hypothesis linking the airway microbiome complex taxonomic landscape of bacteria in the with aspiration pneumonia is that illness may lung and revealed the presence of diverse com- result in a change in the lung microbiota (dys- munities of microbiota. We are still learning biosis), which may, in turn, interfere with or about the role of the microbiome in health and impair pulmonary defenses. A macroaspiration disease, as well as in the pathogenesis of pneu- event, particularly in a patient with risk factors monia.5,6 In the healthy state, the immune tone for impaired bacterial elimination, such as re- of the airways and alveoli appears to be calibrated duced consciousness or an impaired reflex, by the bacteria constituting the lung microbiota, could then overwhelm the elimination side of the an observation recently reported in both healthy immigration–elimination balance, further dis- humans and experimental animal models.7,8 Con- rupting bacterial homeostasis and triggering an cepts of virulence have also changed; virulence increase in a positive feedback loop leading to is defined as “the relative capacity of a microor- acute infection. ganism to cause damage to a host.”9 Infection is Bacteria may colonize various sites in the hu- not simply the result of bacterial replication or of man oral cavity, such as the gingiva, dental plaque, bacterial gene products; it is also a consequence and tongue.17,18 , including of the host response, resultant inflammation, gram-negative species that are not seen in the and tissue damage.9,10 normal host, may emerge in the elderly, as well Models proposed to explain the possible role as in patients in nursing homes or hospitals and of the lung microbiome in pneumonia include those with nasogastric tubes.19-21 Cleavage of cell- the adapted island model of lung biogeography, surface fibronectin exposes receptors for gram- effects of environmental gradients on lung micro- negative rods on underlying airway epithelial cells biota (e.g., regional differences in oxygen ten- and is more closely correlated with host factors sion and nutrient availability in the lungs), and such as acute illness than with the site of care.22 finally, pneumonia as an emerging phenomenon In the 1970s, anaerobes with or without aerobes in the complex adaptive system of the lung micro- were the predominant pathogens in aspiration bial ecosystem.11,12 The stability of the lung mi- pneumonia.23-26 More recently, there has been a crobiome is probably maintained by a balance of shift to bacteria usually associated with commu- immigration and elimination of bacteria and by nity- and hospital-acquired pneumonias, and feedback loops. Immigration involves bacterial anaerobes are recovered less frequently.26 One movement from the oropharynx to the lung pri- study of aspiration pneumonia in patients in the marily by means of microaspiration, and elimi- intensive care unit showed that in community- nation mainly occurs through ciliary clearance acquired cases, the main isolates were S. pneu- and coughing. Negative and positive feedback moniae, , , loops can suppress or magnify signals, respec- and Enterobacteriaceae, whereas gram-negative tively, such as those for bacterial growth. An bacilli, including P. aeruginosa, were found with- inflammatory event may lead to epithelial and out anaerobes in hospital-acquired cases.27 An- endothelial injury, creating a positive feedback other study assessed the incidence of anaerobic loop that can promote inflammation, disrupt bacteria in patients with ventilator-associated bacterial homeostasis, and increase susceptibil- pneumonia and in those with aspiration pneu- ity to infection. The complex adaptive system monia.28 was diagnosed in model suggests that acute bacterial pneumonia 63 patients with ventilator-associated pneumonia results from enhancement of a growth-promoting and in 12 patients with aspiration pneumonia. signal by a positive feedback loop. This may re- Among patients with aspiration pneumonia, en- sult in a rapid shift from a diverse microbial teric gram-negative organisms were isolated in the mixture to dominance by a single species (e.g., patients with gastrointestinal disorders, whereas pneumoniae or ).12 S. pneumoniae and H. inf luenzae predominated in Various signaling molecules in humans, includ- those with community-acquired aspiration events. ing neurotransmitters, cytokines, and hormones Only one was found, and

652 n engl j med 380;7 nejm.org February 14, 2019 The New England Journal of Medicine Downloaded from nejm.org by GIUSEPPE GIOCOLI on February 18, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. Aspiration Pneumonia the authors questioned the need for anaerobic tion at the time of extubation continue to have coverage in both ventilator-associated pneumo- this problem at the time of discharge.33 nia and aspiration pneumonia.28 Additional risks include degenerative neuro- Studies of the elderly continue to show the logic diseases (, parkinsonism, trend away from anaerobes. A study involving 95 and ) and impaired consciousness, par- institutionalized elderly patients with severe ticularly as a result of stroke and intracerebral aspiration pneumonia reported 67 pathogens.29 hemorrhage, which can also impair cough clear- Gram-negative enteric bacteria accounted for ance. The frequency of stroke-associated pneu- 49% of the pathogens, anaerobes for 16%, and monia is related to the severity of neurologic S. aureus for 12%. Aerobic gram-negative bacteria illness and its associated immune impairment, were found in conjunction with 55% of anaero- with higher rates among patients requiring inten- bic isolates. Another study, involving 62 elderly sive care than among those admitted to a stroke hospitalized patients with aspiration pneumonia, unit.34 Impaired consciousness can also result showed that of 111 bacteria identified, gram- from drug overdose and , including negative bacilli and anaerobes each accounted narcotic agents, general anesthetic agents, certain for 19.8% of the bacteria, and anaerobes and antidepressant agents, and alcohol (Fig. 2A). aerobes together were found in 66.7% of pa- After adjustment for other risk factors, antipsy- tients who died.30 It is unclear why the patho- chotic medications increased the risk of aspira- gens have changed, but it may be due to a shift tion pneumonia by a factor of 1.5 in a study in- in the demographic characteristics of patients volving 146,552 hospitalized patients.35 Enteral and earlier sampling today than in the past. feeding can lead to high-volume aspiration, espe- Prior studies often collected cultures later in the cially when associated with gastric dysmotility, illness, often after the development of poor cough, and altered mental status. In three or lung .1 This discussion does not apply studies of enteral feeding after a stroke in a total to chemical pneumonitis, which unlike aspiration of more than 5000 patients, early tube feeding pneumonia, is a noninfectious, inflammatory improved survival, as compared with no feeding, response of the airways and pulmonary paren- and in the first 2 to 3 weeks after the stroke, chyma to acidic gastric contents or bile acids.1,31 nasogastric tube feeding was associated with improved survival and functional outcomes, as Risk Factors compared with percutaneous enteral tube feed- ing.36 Enteral feeding tubes are not currently Aspiration is often the result of impaired swal- recommended for patients with dementia.37 lowing, which allows oral or gastric contents, Patients with multiple risks have increased or both, to enter the lung, especially in patients rates of aspiration pneumonia, death, and other who also have an ineffective cough reflex (Fig. 1). adverse outcomes. A meta-analysis of studies Large-volume aspiration occurs with ; involving frail elderly patients showed that dys- head, , and ; esophageal phagia increased the odds ratio for aspiration stricture and motility disorders; chronic obstruc- pneumonia by a factor of 9.4, but when cerebro- tive pulmonary disease; and .1,3,32-41 In a vascular disease was also present, the odds ratio case–control study involving elderly patients with rose to 12.9.38 In a study involving 1348 patients pneumonia and healthy elderly controls, oropha- with community-acquired pneumonia, 13.8% of ryngeal dysphagia increased the risk of pneumo- the patients were considered to be at risk for nia (odds ratio, 11.9) and was present in nearly aspiration, and this subgroup of patients had a 92% of the patients who had pneumonia. Results higher 1-year mortality (hazard ratio, 1.73) and of videofluoroscopic evaluation showed that increased risks of recurrent pneumonia (hazard 16.7% of the patients with pneumonia were able ratio, 3.13) and rehospitalization (hazard ratio, to swallow safely, as compared with 80% of the 1.52) as compared with the rest of the study controls.32 In extubated survivors of respiratory population.39 Similarly, a study involving 322 failure, dysphagia and aspiration are identified patients with community-acquired pneumonia in at least 20% of patients. The frequency of identified the important risk factors for aspira- dysfunction declines over time, but tion pneumonia as dementia (odds ratio, 5.20), up to 35% of patients with swallowing dysfunc- poor performance status (odds ratio, 3.31), and

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Pathogenesis and risk factors for the development of pneumonia after macroaspiration

Risk Factors

Impaired swallowing Esophageal disease: dysphagia, cancer, stricture Chronic obstructive pulmonary disease Brain–swallowing axis Neurologic diseases: seizures, multiple sclerosis, parkinsonism, stroke, dementia Oropharyngeal contents Mechanical ventilation extubation Gastric contents Impaired consciousness Neurologic disease: stroke Cardiac arrest Medications General Alcohol consumption Increased chance of gastric contents reaching the lung Reflux Tube feeding Impaired cough reflex Medications Alcohol Stroke Dementia Degenerative neurologic disease Impaired consciousness

Figure 1. Pathogenesis of and Risk Factors for Pneumonia after Macroaspiration. Macroaspiration can occur as a result of abnormalities in the swallowing mechanism or altered swallowing due to dysfunction of the central nervous system. In patients with these disorders, oropharyngeal or gastric contents can enter the lung. An impaired cough reflex increases the likelihood that aspirated material will reach the lung. Shown are the disease processes that serve as risk factors for macroaspiration by impairing consciousness, swallowing, and cough and by increasing the chance that gastric contents will reach the lung.

use of sleeping pills (odds ratio, 2.08).40 Those pneumonia is cardiac arrest. In a study involving with two or more risk factors had an increased 641 patients with cardiac arrest, pneumonia de- incidence of recurrent pneumonia and increased veloped within 3 days after the event in 65% of 30-day and 6-month mortality, with rates rising the patients.41 The presumed mechanism is aspi- in parallel with the number of risk factors. The ration of gastric contents during resuscitation relationship between distinct risk factors for (promoted by ventilation and the resus- macroaspiration and the frequency and outcome citation procedure) and inhalation of oral secre- of aspiration pneumonia underscores the differ- tions during bag–valve–mask ventilation and in- ence between aspiration pneumonia and tradi- tubation. When therapeutic hypothermia to 33°C tional community-acquired pneumonia: patients was used after cardiac arrest, the odds ratio for with traditional community-acquired pneumo- early-onset pneumonia rose by a factor of 1.9.41 nia have no associated increase in the risk of However, a target temperature of 36°C may be aspiration. associated with a lower risk of pneumonia.42 An important clinical context for aspiration Some studies showed that the incidence of early-

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A B

C D

Figure 2. Characteristic Imaging Findings in Patients with Aspiration Pneumonia. The in Panel A shows the findings in a 68-year-old man who presented with a several-week history of cough, blood in the , and a 6.8-kg weight loss but who was otherwise in generally good health. He had extensive and gingival inflammation. He did not drink alcohol or use illicit drugs but did take an anti- depressant known to cause somnolence. The radiograph shows a cavitary infiltrate in the left lower lobe and an in- filtrate in the left upper lobe. The radiograph in Panel B is from an 84-year-old man with small-bowel obstruction. He had repeated episodes of , with the development of bilateral lung infiltrates, , and the acute respiratory distress syndrome. Initial cultures were sterile, but 1 week later, he continued to have lung infil- trates and showed methicillin-resistant Staphylococcus aureus. The computed tomographic (CT) scan in Panel C shows a cavitary infiltrate in the right upper lobe posteriorly in a 56-year-old man with cough after tooth extraction performed with local anesthesia. He drank four beers per day. Bronchoscopic cultures revealed . The CT scan in Panel D shows new bilateral infiltrates in posterior, gravity-dependent lung segments in a 79-year-old man with dyspnea after upper endoscopy complicated by vomiting.

onset pneumonia decreased among patients re- Clinical features range from no symptoms to ceiving systemic at the time of car- severe distress with respiratory failure, and the diac arrest.43 Two intervention studies involving clinical consequences may develop acutely, sub- comatose patients showed a benefit of adminis- acutely, or slowly and progressively. Aspiration tering prophylactic antibiotics for up to 24 hours into the lung can affect either the airway (caus- after emergency intubation.44,45 ing bronchospasm, , and chronic cough) or the lung parenchyma. This discussion focuses Clinical Features on aspiration into the lung parenchyma, which can take the form of aspiration resulting in Although macroaspiration is an essential feature chemical pneumonitis, aspiration of bland mate- of aspiration pneumonia and chemical pneumo- rial (blood or the contents of tube feeding), or nitis, many episodes are unwitnessed; therefore, aspiration resulting in bacterial pneumonia. the magnitude of the exposure is often unknown. Aspiration pneumonia is usually acute, with

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symptoms developing within hours to a few days and a pattern that is characteristic of acute respi- after a sentinel event, although anaerobic aspira- ratory distress syndrome develops in up to 16.5% tion may be subacute because of the less virulent of patients with witnessed aspiration, although bacteria, and clinical features are difficult to the frequency rises if other risk factors (shock, distinguish from those of other bacterial pneu- trauma, or pancreatitis) are also present51 monias. In a study involving patients with pneu- (Fig. 2B). Low-pH aspirates are usually sterile, and monia who were more than 80 years of age, bacterial infection is unusual initially, although those with aspiration had a higher mortality, superinfection may develop subsequently. higher serum sodium levels, and worse renal In most cases, neither chemical pneumonitis function than patients without aspiration.46 In a nor aspiration pneumonia occurs with tube feed- group of 53 patients with pneumonia and fluoro- ings or aspirated blood, since the aspirate pH is scopically documented dysphagia, more patients usually high and uncontaminated by bacteria. had than Although acid-suppressing therapy is associated (68% vs. 15%), and 92% had posterior infiltrates.47 with an increased risk of community- or hospital- Most patients with poor performance status had acquired pneumonia, which is related to gastric diffuse and not focal infiltrates. Aspiration pneu- overgrowth by gram-negative bacteria, neutral- monia is associated with higher mortality than ization of gastric pH may reduce the risk of other forms of pneumonia acquired in the com- chemical pneumonitis.52 In a prospective cohort munity (29.4% vs. 11.6%), a finding that may study involving 255 patients undergoing gastro- have implications for hospitals that do not prop- intestinal endoscopy, the use of proton-pump 48 erly code its presence. In a survey of more than inhibitors or histamine H2 blockers was associ- 1 million patients in more than 4200 hospitals, ated with a significant reduction in the risk of aspiration was documented in 4 to 26% of epi- gastric contents with a pH of <2.5 (odds ratio, sodes of pneumonia. The expected mortality 0.24).53 Asphyxia may result if the aspirated vol- among patients with aspiration pneumonia is ume of the bland material is large, but there may higher than that for other forms of pneumonia, be few clinical findings if the volume is small. and the risk-adjusted mortality (now used as a The chest radiograph may initially be abnormal, quality metric) is lower for hospitals reporting until the aspirated material is cleared by suction a high frequency of aspiration than for hospitals or coughing. In cases of unwitnessed aspiration, reporting a low frequency of aspiration.48 it may be difficult to distinguish among chemi- Macroaspiration of gastric contents can lead cal pneumonitis, aspiration pneumonia, and as- to chemical pneumonitis but only with large- piration of bland material. An aspirated solid volume, low-pH (usually <2.5) aspiration. In ani- foreign body can obstruct the airway and lead to mal models, chemical pneumonitis develops only postobstructive pneumonia, further complicating after exposure to at least 120 ml of gastric con- the distinction from bacterial pneumonia. In a tents with a pH of 1. Described by Mendelson in series of patients with foreign-body aspiration 1946 as a consequence of obstetrical anesthesia, who were more than 65 years of age, the event chemical pneumonitis is uncommon with mod- was recognized in only 29% of the patients, ern anesthesia methods (1 case per 3216 proce- leading to a diagnostic delay of 1 to 3 months.54 dures), with a higher risk during emergency Chest radiographic findings were in the right and a lower risk with elective proce- lung in 65% of the patients, and food material dures.49 In up to 64% of patients with aspiration accounted for more than 80% of the episodes. during anesthesia, clinical or radiographic abnor- malities do not develop. Lung injury from acid Diagnosis aspiration is due to the release of inflammatory mediators, including chemokines (e.g., interleu- The diagnosis of aspiration pneumonia depends kin-8), proinflammatory cytokines (e.g., tumor on a characteristic clinical history (witnessed factor), and recruitment.50 macroaspiration), risk factors, and compatible Chemical pneumonitis is characterized by a findings on chest radiography. These radiograph- sudden onset of dyspnea, hypoxemia, tachycar- ic findings include infiltrates in gravity-dependent dia, and diffuse wheezes or crackles on exami- lung segments (superior lower-lobe or posterior nation. A chest radiograph is usually abnormal, upper-lobe segments, if the patient is in a supine

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n engl j med 380;7 nejm.org February 14, 2019 657 The New England Journal of Medicine Downloaded from nejm.org by GIUSEPPE GIOCOLI on February 18, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. The new england journal of medicine - - - - - shock), treat and MDR consider bron- If severe illness to guide decision (patients who are according to risks choscopy and BAL based on dentition reassess in 4 8– 72 hr; intubated or in septic Clear chest radiograph observe antibiotics and illness, withhold If mild-to-moderate care–acquired Hospital-acquired or long-term cefepime, or colistin plus either imipenem) piperacillin– tazobactam, levofloxacin, carbapenem (meropenem, If there is a risk aminoglycoside of MDR, treat with radiograph Abnormal chest sulbactam, ceftriaxone clavulanate, – carbapenem (ertapenem), (levofloxacin, moxifloxacin), fluoroquinolone If no risk of MDR, treat with ampicillin– , the addition of vancomycin or linezolid can be considered. BAL denotes bronchoalveolar lavage. Aspiration events including aspiration pneumonia and chemical pneumonitis shock), treat and MDR consider bron- If severe illness to guide decision (patients who are according to risks choscopy and BAL based on dentition reassess in 4 8– 72 hr; intubated or in septic Clear chest radiograph biotics and observe If mild-to-moderate illness, withhold anti- Community-acquired ceftriaxone sulbactam, ampicillin– clavulanate, amoxicillin– carbapenem (ertapenem), (levofloxacin, moxifloxacin), If normal dental fluoroquinolone health, treat with radiograph Abnormal chest sulbactam, clavulanate, amoxicillin– carbapenem (ertapenem) (moxifloxacin), fluoroquinolone If poor dental health, treat with ampicillin– Figure 3. An Algorithmic Approach to Antibiotic Therapy for Aspiration Pneumonia. For patients with suspected aspiration pneumonia, the decision about antibiotic therapy dictated is by the site of acquisition: community, hospital, or long-term care facility. Antibi otics are given to patients who have an aspiration event and an abnormal chest radiograph, although even with an initially normal radiograph, antibiotics are given to those with se vere illness (i.e., illness characterized by shock or requiring intubation). If chemical pneumonitis suspected, is antibiotics are not initially recommended, even with an abnormal ra diograph, unless the patient severely is ill; in patients with mild-to-moderate illness and an abnormal radiograph, the recommendation to withhold is antibiotics and reassess the patient in 48 hours. Therapy directed is at the pathogens likely to be present in the patient at the time of aspiration, determined on the basis of the site of acquisition, with risk fac tors for resistant pathogens taken into consideration. Patients with severe illness are treated on the basis of risks associated with their dental health and multidrug resistance Routine(MDR). treatment for anaerobic pathogens not is needed in patients withnormal dental health but should be considered in those with poor dental health (e.g., clindamycin in patients with poor dental health and necrotizing pneumonia If the or lung site abscess). of acquisition the is community, outpatient treatment with amoxicillin–clavulanate, moxi floxacin, levofloxacin, or clindamycin can be administered orally. the In hospital, treatment usually is administered intravenously, but oral options are available for select patients; if there nasal is or respiratory colonization with methicillin-resistant S. aureus

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68 samples. The investigators suggested that rou- Table 1. Antibiotic Treatment of Aspiration Pneumonia.* tine antibiotic treatment should be started only if bacterial infection is suspected but may be dis- Drug Dose, Schedule, and Route of Administration continued if bronchoscopic cultures are negative. Ampicillin–sulbactam 1.5–3 g every 6 hr, intravenous On the basis of data from studies of commu- Amoxicillin–clavulanate 875 mg twice daily, oral nity-acquired pneumonia and hospital-acquired Piperacillin–tazobactam 4.5 g every 8 hr or 3.375 g every 6 hr, intravenous or ventilator-associated pneumonia, we suggest 5 to 7 days of treatment for patients with a good Ceftriaxone 1–2 g once daily, intravenous clinical response and no evidence of extrapulmo- Cefepime 2 g every 8–12 hr, intravenous nary infection, and longer treatment for those Ertapenem 1 g once daily, intravenous with necrotizing pneumonia, lung abscess, or em- Imipenem 500 mg every 6 hr or 1 g every 8 hr, intravenous pyema. In the case of lung abscess or empyema, Meropenem 1 g every 8 hr, intravenous drainage for diagnostic and treatment purposes Levofloxacin 750 mg once daily, intravenous or oral may be needed. The choice of therapy should Moxifloxacin 400 mg once daily, intravenous or oral take into account potential drug-related adverse events, including difficile colitis and Clindamycin 450 mg three or four times daily, oral; or 600 mg every 8 hr, intravenous selection of antibiotic resistance. More data are Gentamicin or tobra­ 5–7 mg/kg once daily, intravenous needed to identify the best antibiotic regimens mycin† for aspiration pneumonia and to determine the Amikacin† 15 mg/kg once daily, intravenous duration of treatment. No randomized, controlled trials have shown a role for glucocorticoids in Colistin‡ 9 million IU per day in two or three divided doses, intravenous the routine treatment of aspiration pneumonia, Vancomycin† 15 mg/kg every 12 hr, intravenous and we do not recommend their use. Linezolid 600 mg every 12 hr, intravenous or oral Chemical Pneumonitis * Doses are for patients with normal renal function. Initial treatment of gastric aspiration requires air- † The dose should be adjusted to a trough level of less than 1 mg per liter for way maintenance, management of airway edema gentamicin and tobramycin, a trough level of less than 4 mg per liter for ami- kacin, and a trough level of 10 to 15 μg per milliliter for vancomycin, with renal or bronchospasm, and minimization of tissue function taken into consideration in all cases. damage. Depending on the severity of the pneu- ‡ A loading dose of 6 million to 9 million IU can be administered. monitis and the extent of care required, treatment may include suctioning, , intuba- tion, mechanical ventilation, and intensive care. formed (Table 2). Medications known to pro- Routine adjunctive treatment with glucocorticoids mote aspiration and interfere with swallowing is not recommended, and antibiotics are not should be avoided, including sedatives, antipsy- needed routinely unless the patient is taking acid- chotic agents, and for some at-risk patients, anti- suppressing or has small-bowel ob- histamines.35 Aspiration-prevention efforts focus- struction. In mild-to-moderate cases, we recom- ing on ventilator-associated pneumonia are not mend withholding antibiotics even if there is discussed here. radiographic evidence of an infiltrate, monitoring For patients with swallowing disorders, par- clinical and radiographic findings, and reassess- ticularly after stroke, a full speech and swallow- ing after 48 hours. In more serious cases, how- ing evaluation is necessary. Efforts should be ever, antibiotics should be started empirically, and made to promote oral rather than enteral tube the decision to continue antibiotic therapy for feeding, with the use of a mechanical soft diet more than 2 to 3 days should be guided by the with thickened liquids rather than pureed food clinical course. and thin liquids. In addition, “nutritional reha- bilitation” with swallowing exercises and early Prevention mobilization may help patients with dysphagia and may prevent recurrence of aspiration pneu- Postoperative chemical pneumonitis can be min- monia.69 Patients should receive enteral feeding imized by ensuring that the patient has fasted in a semirecumbent rather than supine position for at least 8 hours and has abstained from clear to minimize the risk of gastric aspiration. For liquids for at least 2 hours before surgery is per- patients with , an effort

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Table 2. Prevention of Aspiration Pneumonia. A meta-analysis of five randomized, controlled trials involving nonventilated patients at risk for Recommended in the appropriate clinical setting aspiration pneumonia showed that oral care with Antibiotic therapy for 24 hr in comatose patients after emergency intubation chlorhexidine or mechanical oral cleaning was No food for at least 8 hr and no clear liquids for at least 2 hr before elective effective in preventing pneumonia (odds ratio, surgery with general anesthesia 0.4 to 0.6).76 However, chlorhexidine use is con- To be considered in the appropriate clinical setting troversial and may be associated with increased Swallowing evaluation after stroke and after extubation from mechanical mortality among ventilated patients, possibly as ventilation a result of toxic effects if chlorhexidine is aspi- 77 Preference for angiotensin-converting–enzyme inhibitors for blood-pressure rated into the lung. In a randomized study in- control after stroke volving 252 patients, supplemental nutrition plus Oral care with brushing and removal of poorly maintained teeth daily oral cleaning reduced the frequency of Feeding in a semirecumbent position for patients with stroke pneumonia (7.8%, vs. 17.7% with usual care; 78 Not yet recommended; more data needed P = 0.06). In a case–control study involving 539 patients undergoing surgery for esophageal can- Swallowing exercises for patients with dysphagia after stroke cer, postoperative pneumonia developed in 19.1% Oral chlorhexidine in patients at risk for aspiration of the patients. Lack of preoperative oral care, including tooth scaling, mechanical cleaning, should be made to keep the patient’s chin down and tooth extraction if necessary, was an impor- and head turned to one side during feeding and tant risk factor.79 Despite these promising find- to encourage swallowing of small volumes, mul- ings, a cluster-randomized study involving 834 tiple swallows, and coughing after each swallow.33 nursing home patients, with a mean observation In a study involving comatose patients, the risk time of slightly more than 1 year, showed no of aspiration pneumonia was reduced by keep- benefit of a comprehensive oral care program, ing patients in either the prone or semirecum- which included manual tooth and gum brushing, bent position.70 chlorhexidine mouth washes, and upright posi- The role of nasogastric tubes in preventing tioning during feeding, with radiographic evi- aspiration pneumonia is uncertain. In a study dence of the development of pneumonia in 25% involving 1260 patients, the 630 patients with a of the patients.80 nasogastric tube in place did not have more as- Antibiotic administration for up to 24 hours piration events during endoscopic observation of in comatose patients who have been intubated swallowing than the 630 patients without a naso- on an emergency basis has shown a benefit in gastric tube.71 Postpyloric feeding is not superior two trials. An open, randomized, controlled study to gastric feeding, and monitoring of postfeed- involving 100 intubated, comatose patients with ing residual volume may not minimize the risk stroke or head injury showed that 1.5 g of cefu- of aspiration.3,72 For patients with stroke, particu- roxime given every 12 hours for two doses re- larly Asian patients, the use of angiotensin-con- duced the occurrence of pneumonia, particularly verting–enzyme (ACE) inhibitors to control blood early-onset pneumonia.44 Control patients receiv- pressure can reduce the risk of aspiration pneu- ing antibiotics at the time of intubation had lower monia, possibly by elevating substance P levels, pneumonia rates than those not receiving anti- which promotes cough and improves the swal- biotics. A subsequent cohort study showed that a lowing reflex.73,74 In a meta-analysis of data from single dose of antibiotic (ceftriaxone or ertapenem) 8693 patients with stroke, patients who received administered within 4 hours after intubation was ACE inhibitors had a reduced risk of aspiration, effective in preventing early-onset but not late- as compared with patients who did not receive onset pneumonia in comatose patients,45 includ- ACE inhibitors (odds ratio, 0.6).74 Cilostazol, an ing the 25% of patients who were intubated on antiplatelet agent that may have a similar effect an emergency basis after cardiac arrest. on substance P, has also been shown to prevent 34 pneumonia after stroke. Conclusions In the prevention of aspiration pneumonia, a focus on oral hygiene has yielded an inconsistent Aspiration pneumonia is an important illness benefit, possibly because of study design issues.75 that is difficult to accurately diagnose and to

660 n engl j med 380;7 nejm.org February 14, 2019 The New England Journal of Medicine Downloaded from nejm.org by GIUSEPPE GIOCOLI on February 18, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. Aspiration Pneumonia distinguish from other aspiration syndromes Dr. Mandell reports receiving fees for serving on a data moni- and community- and hospital-acquired pneumo- toring committee from Bayer and Polyphor, fees for serving on a data and safety monitoring board from Cubist Pharmaceuticals nias. The diagnosis should be considered in the and Shionogi, and lecture fees from Daiichi Sankyo; and Dr. Nieder- appropriate clinical settings in patients with man, receiving consulting fees from Thermo Fisher, Paratek, known risk factors for aspiration and character- Nabriva, Melinta, and Shionogi, advisory fees from Pfizer, and grant support and consulting fees from Merck and Bayer. No other istic clinical and radiographic findings. Aspira- potential conflict of interest relevant to this article was reported. tion pneumonia is treated with antibiotics as Disclosure forms provided by the authors are available with required but not with glucocorticoids. Preventive the full text of this article at NEJM.org. We thank Dr. Robert P. Dickson, Division of Pulmonary and measures should be used for patients at risk for Critical Care Medicine, University of Michigan, for his assistance aspiration. and thoughtful comments on an earlier version of the manuscript.

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