1. Villgran, Vipin Das MD
  2. Lyons, Caitlan RN
  3. Nasrullah, Adeel MD
  4. Clarisse Abalos, Charmaine MD
  5. Bihler, Eric DO
  6. Alhajhusain, Ahmad MD


Respiratory failure is one of the most common reasons for hospitalization and intensive care unit (ICU) admissions, and a diverse range of etiologies can precipitate it. Respiratory failure can result from various mechanisms such as hypoventilation, diffusion impairment, shunting, ventilation-perfusion mismatch, or a combination of those mentioned earlier. Hence, an accurate understanding of different pathophysiologic mechanisms is required for appropriate patient care. Prompt identification and treatment of various respiratory emergencies such as tension pneumothorax, massive hemoptysis, and high-risk pulmonary embolism lead to fewer complications, shorter ICU and hospital stay, and improved survival. This review article entails common respiratory failure pathologies encountered in the ICU and addresses their epidemiology, pathophysiology, clinical presentation, and management.


Article Content

RESPIRATORY FAILURE is the failure of the lungs in its gas exchange functions of oxygenation and carbon dioxide elimination. Acute respiratory failure is characterized by hypoxia with or without hypercapnia resulting in life-threatening derangements in acid-base status due to the inability of the respiratory system to attain the patient's oxygenation, ventilation, or metabolic demands.


Respiratory failure can be categorized into 2 groups: type I or hypoxemic respiratory failure due to failure of oxygenation characterized by an arterial oxygen tension (PaO2) less than 60 mm Hg and type II or hypercapnic respiratory failure due to the failure of carbon dioxide elimination characterized by a PaCO2 greater than 50 mm Hg.



There are 4 main mechanisms of hypoxemic respiratory failure (Table 1):

Table 1 - Click to enlarge in new windowTable 1. Mechanisms of Hypoxia

1. Ventilation perfusion mismatch


2. Hypoventilation


3. Shunt


4. Diffusion impairment


Ventilation-perfusion mismatch (V/Q mismatch)

Ventilation-perfusion occurs because of the mismatch between alveolar ventilation and pulmonary blood flow. The V/Q mismatch is the most common cause of hypoxemic respiratory failure.1,2


In normal lungs, ventilation and perfusion are higher at the base of the lungs than in the apical portions of the lungs. This is due to the regional variations in intrapleural pressures and gravity. The value of the average V/Q level is between 0.8 and 1.2, and this value is higher at the apex than the lungs' bases. This gradient is due to the more significant increase in perfusion than ventilation in the bases of the lungs.3


Hypoxia due to low V/Q ratio can happen because of alveolar hypoxia secondary to airway disease in normal perfusion or increased perfusion in normal ventilation as in pulmonary embolism (PE). Alveolar hypoxia and subsequent arterial hypoxemia can result in subsequent compensatory pulmonary vasoconstriction reducing perfusion to areas of the lungs, thereby normalizing the V/Q ratio.4 Hypoxemia due to V/Q mismatch will have an elevated Alveolar-arterial gradient (A-a gradient) and respond to oxygen supplementation.



Hypoventilation results in low alveolar oxygen content (PAO2), leading to low arterial oxygen content (PO2). The primary manifestation of hypoventilation is a high arterial CO2 content (PaCO2) level.


Hypoventilation can be caused by central nervous system depression from various causes, obesity hypoventilation, and neuromuscular and chest wall abnormalities.


Hypoxemia due to hypoventilation will have a normal Alveolar-arterial gradient (A-a gradient) and respond to oxygen supplementation.



Shunt occurs when blood circulation from the right side of the heart bypasses oxygenation and gas exchange before entering the left side of the circulation. A shunt is essentially a severe form of ventilation-perfusion mismatch, which can be seen in acute respiratory distress syndrome (ARDS), pneumonia, pulmonary edema, intracardiac shunts, pulmonary arteriovenous communication, and hepatopulmonary syndrome.


Hypoxemia due to shunt will have an elevated Alveolar-arterial gradient (A-a gradient) and respond inadequately to oxygen supplementation.


Diffusion limitation

Diffusion limitation is the defective oxygen transport and gas exchange across the alveolar-capillary barrier from loss of surface area and decreased capillary transit time secondary to inflammation and fibrosis of the alveolocapillary membrane from interstitial lung diseases. This leads to hypoxia; however, hypercapnia is rare as carbon dioxide is much more water-soluble than oxygen.


Hypoxemia due to diffusion limitation will have a high Alveolar-arterial gradient (A-a gradient) and respond to oxygen supplementation.5


Type II or hypercapnic respiratory failure is characterized by a PaCO2 higher than 50 mm Hg. Common etiologies include drug overdose, neuromuscular disease, chest wall abnormalities, and severe airway disorders such as asthma and chronic obstructive pulmonary disease.6


Hypercapnia should always be suspected in those at risk for hypoventilation, such as those receiving sedatives or increased physiologic dead space and limited pulmonary reserve (eg, chronic obstructive pulmonary disease exacerbation) who present with shortness of breath, a change in mental status, new hypoxemia, and hypersomnolence.


A low clinical suspicion is all that is necessary to prompt ABG analysis for the diagnosis of acute hypercapnic respiratory failure. The identification of an elevated PaCO2 greater than 45 mm Hg is diagnostic of hypercapnia. Hypercapnia should then be classified as acute accompanying appropriate respiratory acidosis, chronic with a low-normal or near-normal pH, or acute-on-chronic.7


Management involves noninvasive ventilation for patients with mild to moderate acute acidosis with pH greater than 7.25 who are in moderate to severe respiratory distress, with tachypnea, usually with respiratory rate greater than 25 and an increased work of breathing.


The development of acute hypercapnia with significant refractory acidemia (eg, pH <7.2) accompanied by a marked depression in the level of consciousness is usually an indication for intubation and mechanical ventilation.8



Acute PE is due to sudden occlusion of a pulmonary artery or one of its branches by thrombus though occasionally this can be a tumor, air, or fat. The pathogenesis of PE and deep venous thrombosis can be explained by Virchow's triad of hypercoagulability, venous stasis, and endothelial injury. Risk factors include genetic like thrombophilia and acquired like immobilization, surgery, malignancy, cigarette smoking, or oral contraceptive pill use.


Diagnostic evaluation includes clinical probability scores such as Wells score (see Tables 2 and 3) and d-dimer testing. A low clinical probability score with a normal d-dimer has a high negative predictive value excluding PE. When the clinical probability score or d-dimer is high, computed tomographic pulmonary angiography (CTPA) is the preferred diagnostic imaging study with a sensitivity of 83% and a specificity of 96% in PE diagnosis. When CTPA is contraindicated, ventilation/perfusion scanning (V/Q scanning) is the favored diagnostic testing along with Doppler ultrasonography of lower extremities to look for deep venous thrombosis. Additional studies with echocardiography and cardiac enzymes troponin and prohormone BNP (proBNP) help in risk stratification along with Pulmonary Embolism Severity Index score (Table 4).9

Table 2 - Click to enlarge in new windowTable 2. Wells Criteria
Table 3 - Click to enlarge in new windowTable 3. Wells Criteria Probability Score
Table 4 - Click to enlarge in new windowTable 4. Pulmonary Embolism Severity Index (PESI)-Full


Management of acute PE depends on risk stratification based on Pulmonary Embolism Severity Index score and European Society of Cardiology 2014 guidelines (see Table 5). Systemic thrombolysis is indicated in hemodynamically unstable PE with obstructive shock (high risk) (Figure 1). They are defined as having a systolic blood pressure of less than 90 mm Hg or a drop in systolic blood pressure of 40 mm Hg or greater from baseline for more than 15 minutes. Embolectomy is indicated in patients with hemodynamically unstable PE in whom thrombolytic therapy is contraindicated. Intermediate high-risk patients with evidence of both right ventricle (RV) dysfunction as evidenced by RV dilation or hypokinesis (based on CTPA or echocardiogram) and elevated cardiac biomarkers have a worse prognosis than patients with no RV dysfunction, and they need close monitoring in addition to anticoagulation. They may benefit from catheter-directed thrombolysis or mechanical thrombectomy. Studies are ongoing to determine the benefits of thrombolysis or thrombectomy treatments. Intermediate low-risk patients with either evidence of RV dysfunction or elevated cardiac biomarkers or neither require hospitalization and anticoagulation. Low-risk patients can be treated with anticoagulation and considered for early discharge or home treatment. Inferior vena cava filter placement is indicated in patients in whom anticoagulation is contraindicated once the diagnosis of PE is confirmed.10,11

Figure 1 - Click to enlarge in new windowFigure 1. Massive pulmonary embolism. Case courtesy of Dr Mohamed Saber,
Table 5 - Click to enlarge in new windowTable 5. Risk Stratification ESC and PESI: 2014 ESC Guidelines


Pneumothorax refers to the entry of air in the pleural cavity due to a breach in the visceral or parietal pleura of the lung, impairing oxygenation and ventilation. The clinical implications depend on the acuity and degree of collapse of the lung on the affected side. They can range from asymptomatic in small pneumothorax to chest pain, shortness of breath, and significant hemodynamic instability and cardiac arrest as in tension pneumothorax (Figure 2). Early diagnosis and management are therefore imperative.12

Figure 2 - Click to enlarge in new windowFigure 2. Tension pneumothorax. Case courtesy of Dr Balint Botz,, rID: 73040.

Types of pneumothorax

Pneumothorax can be divided into spontaneous primary or secondary to lung diseases or traumatic from iatrogenic or spontaneous trauma (Table 6).

Table 6 - Click to enlarge in new windowTable 6. Types of Pneumothorax

Spontaneous pneumothorax

Primary spontaneous pneumothorax (PSP) occurs in individuals without underlying lung disorders. Risk factors include being thin, male, and smoker, and are thought to happen from bleb ruptures.


Secondary spontaneous pneumothorax develops because of a primary lung disorder with already compromised lung function as in chronic obstructive pulmonary disease, cystic fibrosis, and cystic lung diseases such as cystic fibrosis, diffuse Langerhans cell histiocytosis, lymphangioleiomyomatosis, lymphocytic interstitial pneumonitis, and Birt-Hogg-Dube syndrome. Catamenial pneumothorax occurs in women of reproductive age as right-sided pneumothorax with symptom onset within 48 hours of menstruation secondary to thoracic endometriosis.


Traumatic pneumothorax

Iatrogenic pneumothorax often occurs secondary to thoracic procedures such as thoracentesis, central lines, and mispositioned feeding tubes.


Spontaneous traumatic pneumothorax can occur secondary to external chest trauma or barotrauma from mechanical ventilation.12,13



Management depends on the type of pneumothorax. In clinically stable patients with small PSP as defined by 3 cm and less from the chest wall at the apex or 2 cm and less from the chest wall at the hilum, supplemental oxygenation and observation usually suffice. If they demonstrate worsening on follow-up imaging, they need pigtail catheter insertion and hospital admission.


In clinically stable patients with large PSP as defined by more than 3 cm from the chest wall at the apex or more than 2 cm from the chest wall at the hilum, they need hospital admission with supplemental oxygenation and needle aspiration or pigtail catheter insertion. For recurrent or unstable PSP, they need pigtail catheter insertion.


Following the first presentation of PSP, patients generally do not need a definitive procedure unless there is a recurrence or persistent air leak following the first episode. In secondary spontaneous pneumothorax or traumatic pneumothorax because of the underlying lung disease often with compromised lung function, they need hospital admission with supplemental oxygenation and evacuation of pleural air with pigtail catheter or chest tube insertion. Management also involves treatment of the underlying lung disease and definitive management with video-assisted thoracoscopy or pleurodesis in nonsurgical candidates.14,15



Hemoptysis is the coughing up of blood originating from the lower respiratory tract. Most cases of hemoptysis are mild that can be managed conservatively. However, around 5% of cases are massive hemoptysis defined by expectoration of 100 mL for more than 1 hour to up to 600 mL in 24 hours, resulting in respiratory failure, hemodynamic instability, and transfusion requirements. This constitutes a medical emergency with a 50% to 75% mortality rate.16,17



Although hemoptysis is common in lung cancer, only around 3% of patients experience massive hemoptysis. The most common causes of massive hemoptysis are bronchiectasis, mycetoma, active pulmonary tuberculosis, and malignancy. Tuberculosis is the most common cause of massive hemoptysis worldwide. Iatrogenic massive hemoptysis from procedures is rare (Table 7).

Table 7 - Click to enlarge in new windowTable 7. Etiology of Massive Hemoptysis


Radiographic studies such as chest radiography and computed tomography can potentially identify the diagnosis and likely etiology and localize the site. Bronchoscopy is superior with both diagnosis and localization, can be performed at the bedside, and has the advantage of adding therapeutic options until definitive management.18



Acute management of massive hemoptysis first involves basic life support to ensure hemodynamic stability, secure the airway, and provide adequate ventilation. Selective non-bleeding-site intubation and endobronchial blockers can be utilized to stabilize the patient. If the bleeding site is known, the patient should be turned to the bleeding side down to protect the nonbleeding airway. Endotracheal intubation may be needed if there is a concern for airway and ventilator compromise. Bronchoscopy can localize the bleeding and clear blood to improve oxygenation and ventilation.


Once the patient has been stabilized, definitive management involves arteriography to identify the potential bleeding site, followed by bronchial artery embolization. Bronchial artery embolization has been shown to have a significant success rate and low recurrence rates.


Surgical interventions such as lobectomy may rarely be needed in refractory hemoptysis and those secondary to arteriovenous malformations, leaking aortic aneurysms, iatrogenic pulmonary vascular ruptures, or chest trauma. Definitive management also involves the treatment of the underlying etiology, be it infection or malignancy.16



Despite the world's medical advances, pneumonia remains the deadliest communicable disease. It is ranked the ninth leading cause of death in the United States and the fourth leading cause of death globally.4 While defined as an infection of the lungs, its varied clinical presentation and possible etiology, diagnosis, and treatment are complex.19-21


Typical presentations are cough, sputum production, pleuritic chest pain, fever, fatigue, dyspnea, tachycardia, and tachypnea. These are typically associated with new lung infiltrates and leukocytosis.22 At the same time, some could also present with diarrhea and even confusion, especially in the elderly population. However, not all patients can present clinically, as different host factors such as age and underlying comorbidities interplay on their presentation. Moreover, different infectious and noninfectious syndromes can mimic pneumonia. As such, clinicians carry the burden of differentiating the true etiology and balancing to start patients on antibiotics empirically while practicing antimicrobial stewardship in an era where the rise of microbial resistance has been apparent.


There are about 100 microbes that can cause pneumonia, as such presents the difficulty of the etiologic diagnosis of the causative agent and the difficulty of managing these patients as no single antimicrobial agent can empirically cover all these microbes.


Identifying pneumonia syndromes based on a patient's epidemiologic, clinical, radiographic, and laboratory parameters allow clinicians to narrow down their etiologic agents based on clinical data of common pathogens associated with the particular syndromes. As such, it could give some guidance on the diagnosis and management of these patients. Syndromes that will be discussed in this chapter include community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). Health care associated pneumonia, which was previously used, is now eliminated on the basis of the latest Infectious Diseases Society of America (IDSA) guidelines.


Community-acquired pneumonia

Community-acquired pneumonia is aptly defined as pneumonia that has been acquired outside of the hospital. This syndrome does not include immunocompromised patients such as transplant patients, neutropenic patients, and HIV/AIDS patients with low CD4 counts.


In the intensive care unit setting, the most commonly encountered is the severe CAP, based on the IDSA guidelines, which is defined as containing 1 major criterion or 3 or more minor criteria (Table 8). All signs and symptoms should be due to infection alone.23,24

Table 8 - Click to enlarge in new windowTable 8. Community Acquired Pneumonia Criteria


Bacteria, viruses, and fungi can cause CAP. Bacterial-associated pathogens include Streptococcus pneumonia, Haemophilus influenzae, Mycoplasma pneumoniae, Staphylococcus aureus, Legionella species, Chlamydia pneumonia, and Moraxella catarrhalis. Streptococcus pneumoniae is the most common bacterial pathogen associated with CAP; it was noted to cause 95% of cases but has now decreased to about 10% to 15% in the advent of pneumococcal conjugate vaccinations. Other bacterial pathogens that cause CAP include gram-negative enteric bacilli and Pseudomonas aeruginosa, particularly in patients with structural lung disease, while Klebsiella pneumoniae has been linked mainly with patients with alcohol use disorder.22,23


In a study conducted by Jain et al23 in 2015, among patients diagnosed with CAP requiring hospitalizations, among the 2320 cases enrolled in the study, it has demonstrated that respiratory viruses are more common pathogens than bacterial pathogens. Common viral pathogens identified were human rhinovirus, influenza A or B, human metapneumovirus, parainfluenza virus, coronavirus, and adenovirus. This has been recognized in the latest IDSA guidelines with the rise of endemics and pandemics, the most recent being the COVID-19 virus pandemic. On the other hand, some fungal pathogens have also been implicated as the cause of CAP, albeit rare, and are most in the immunocompromised host. Endemic mycoses can cause in an immunocompetent host, and at times, geographic locations can help clinicians diagnose the treatment. This includes Coccidioides immitis in the southwest, Histoplasma capsulatum in regions near the Ohio and Mississippi River Valleys, and Blastomyces dermatitis in the south, central, and midwestern states.22,23,25



In a study conducted by Jain et al23 in 2015, among 2320 cases diagnosed with CAP, no identifiable pathogen could be identified even in the advancement of diagnostic studies, 65% of the cases.8 As such, this has been posted as one of the significant difficulties in managing pneumonia, pushing clinicians to treat patients empirically. However, finding the etiological agent is still essential to promote antimicrobial stewardship, limiting the adverse events and reducing cost, antimicrobial resistance, and Clostridioides difficile events.23


Based on the 2019 IDSA/ATS guideline for CAP, collection of sputum Gram stain and culture prior to the initiation of treatment are recommended to patients diagnosed to have severe CAP, empirically treated for methicillin-resistant S aureus (MRSA) and pseudomonas, patients with a previous history of MRSA or pseudomonas infection, and patients who have been hospitalized or received antibiotics in the last 90 days. The earlier a sputum sample has been collected prior to initiation of antibiotics and the higher the quality of the sample (>10 inflammatory cells per epithelial cells), the better the yield. Patients who had severe CAP who required intubation should also have lower respiratory tract samples such as from endotracheal tube aspirates sent for Gram stain and culture as this has been found to have better yield.22,23


Other tests recommended including enzyme-linked immunosorbent assay for detecting urine antigens are also used as etiologic agents for CAP. Both pneumococcal and legionella antigen testing are recommended to be tested only for patients with severe CAP. Pneumococcal urinary antigen has a 50% to 80% sensitivity and a specificity of more than 90%. Legionella urinary antigen is also recommended in legionella outbreaks or patients with recent travel. It is important to note that the Legionella urinary antigen can detect only L pneumophila serogroup 1, which is about 80% to 95% of all community-acquired cases. Legionella culture would be needed to detect the other serogroup if high clinical suspicion. Blood cultures have also been recommended to collect for all patients with severe CAP. On the other hand, respiratory viral testing has been used to detect many viral pathogens commonly implicated with CAP.22,23,26


Procalcitonin is a precursor peptide of mature hormone calcitonin released in multiple tissues in response to bacterial infections; as such, it is implicated as a serologic marker for detecting the bacterial pathogen as the cause of CAP. Procalcitonin has also shown a positive correlation to the extent and severity of bacterial infections. False positives associated with elevated procalcitonin include renal insufficiency, major surgery/shock, and certain malignancies.


However, there is a need for further studies to analyze its clinical use. In the 2019 IDSA/ATS guidelines, the committee has recommended using patients' clinical presentation rather than procalcitonin to determine the need to initiate empiric antibiotic treatment for patients.23



The distinction between non-severe CAP and severe CAP is warranted as the risks are higher if patients diagnosed with severe CAP are inadequately treated empirically. Clinicians are also encouraged to note patients' risk factors for MRSA and pseudomonas to guide their choice of antimicrobials. Prior history of identifying MRSA or pseudomonas on a patient's previous respiratory cultures within a year also increases the likelihood of growing the same pathogen; hence, empiric coverage is recommended. De-escalation of empiric antibiotics in patients with MRSA and P aeruginosa to standard CAP therapy is recommended if respiration cultures have remained negative for 48 hours.


Treatment recommendations for empiric treatment based on 2019 IDSA/ATS guidelines for CAP are as follows:


* Inpatient:


* Combination therapy: B-lactam + macrolide; beta-lactam (ampicillin-sulbactam 1.5-3 g every 6 hours, cefotaxime 1-2 g every 8 hours, ceftriaxone 1-2 g daily, or ceftaroline 600 mg every 12 hours); macrolide (azithromycin 500 mg daily or clarithromycin 500 mg twice daily)


* Monotherapy with a respiratory fluoroquinolone (levofloxacin 750 mg daily, moxifloxacin 400 mg daily)


* Alternative treatment: B-lactam + doxycycline


* Inpatient with severe CAP without risk factors for MRSA or P aeruginosa


* B-lactam + macrolide


* B-lactam + Respiratory FLQ


* Inpatient with severe CAP with risk factors for MRSA


* Vancomycin 15 mg/kg q12


* Linezolid 600 mg q12


* Inpatient with severe CAP with risk factors for P aeruginosa


* Piperacillin-tazobactam 4.5 g q6


* Cefepime 2 g q8


* Ceftazidime 2 g q8


* Aztreonam 2 g q8


* Meropenem 1 g q8


* Imipenem 500 mg q6


* Based on the surviving sepsis campaign, corticosteroids are recommended to patients with severe CAP associated with refractory septic shock.


* Clinicians are also encouraged to use their hospital's local antibiogram to guide them in their choice of antimicrobials further.


The most common pathogen associated with the influenza virus is S aureus, followed by S pneumoniae, H influenzae, and group A Streptococcus. Current recommendations for patients who tested positive for influenza include initiating oseltamivir to all patients diagnosed in the inpatient setting regardless of the onset of illness, as this has decreased the risk of death. Clinicians are also encouraged to assess the need for antibacterial treatment in patients diagnosed with influenza.


In patients suspected of aspirations pneumonia, studies have shown that anaerobic is less evident than previously suspected as such routine anaerobic coverage is not recommended unless there is the presence of empyema or lung abscess. Patients with aspirated gastric contents are more likely to have aspiration pneumonitis than pneumonia and are known to resolve in 24 to 48 hours without antibiotics.



Hospital-acquired pneumonia is defined as pneumonia that occurs after 48 hours or more after hospital admission in patients who do not require a mechanical ventilator. Ventilator-associated pneumonia is pneumonia that has occurred after 48 hours of endotracheal intubation. About 10% of patients requiring mechanical ventilation develop VAP, which has been noted to prolong ventilator days and hospitalization days. It is associated with a mortality rate of 20% to as high as 50%.26,27



Most pathogens associated with VAP/HAP are S aureus, P aeruginosa, enteric gram-negative bacilli, and Acinetobacter. Patient risk factors that increase the likelihood of multi drug resistance pathogens causing VAP include intravenous (IV) antibiotics used in the past 90 days, 5 or more days of hospitalization prior to intubation, and also noted septic shock at the time of VAP diagnosis. On the other hand, risk factors for MRSA causing VAP include prior use of IV antibiotics and MRSA colonization. Risk factors for multi drug resistance P aeruginosa include prior use of antibiotics, explicitly receiving carbapenems, broad-spectrum cephalosporins, and fluoroquinolones. History of cystic fibrosis and bronchiectasis also increases the likelihood of Pseudomonas pathogen than any other pulmonary condition.



Same diagnostic testing as previously mentioned for severe CAP is recommended for VAP. Respiratory cultures are recommended to be obtained on all patients suspected of VAP/HAP. Noninvasive sampling is preferred, as studies have failed to show improved clinical outcomes in favor of invasive respiratory sampling. Diagnostic thresholds to exclude VAP are a protected specimen brush of less than 103 colony forming unit (CFU)/mL, a BronchoAlveolar Lavage of less than 104 CFU/mL, and an Endo tracheal aspirate of less than 105 CFU/mL. Blood cultures are also recommended and could increase the likelihood of revealing the etiologic agent from a nonpulmonary source. On the latest IDSA/ATS guidelines, recommendations state the use of clinical criteria to determine the need for empiric therapy than using procalcitonin in conjunction with clinical criteria.11



Current studies favor short-term therapy for the management of VAP/HAP, with studies showing that a 7-day course of treatment will be sufficient for the management of these patients. Treatment principles in the management of HAP/VAP translate to ensure adequate coverage of pathogens to decrease mortality and prevent overtreatment that could lead to adverse drug effects.


Empiric treatment based on the latest 2016 IDSA/ATS guidelines for HAP/VAP recommends coverage for S aureus, P aeruginosa, and gram-negative bacilli. However, it is also recommended to start empiric antimicrobials based upon local hospital antibiogram.


* Not at high-risk mortality, no risk factors for MRSA


* Piperacillin-tazobactam 4.5 g IV q6


* Cefepime 2 g IV q8


* Levofloxacin 750 mg IV daily


* Imipenem 500 mg q6h


* Meropenem 1 g q8


* Not at high-risk mortality, with factors for MRSA


* Piperacillin-tazobactam 4.5 g IV q6


* Cefepime or ceftazidime 2 g IV q8


* Levofloxacin 750 mg IV daily or ciprofloxacin 400 mg IV q8


* Plus: (1 of these)


* Vancomycin 15 mg/kg IV q8-q12


* Linezolid 600 mg IV q12


* High risk of mortality or receipt of IV antibiotics during the last 90 days


* Two antibiotics avoiding two beta-lactams


* Piperacillin-tazobactam 4.5 g IV q6


* Cefepime or ceftazidime 2 g IV q8


* Levofloxacin 750 mg IV daily or ciprofloxacin 400 mg IV q8


* Imipenem 500 mg IV q6 or meropenem 1 g IV q8


* Amikacin 15-20 mg/kg IV daily or gentamicin 5-7 g/kg IV daily or tobramycin 5-7 mg/kg IV daily


* Plus: (1 of these)


* Vancomycin 15 mg/kg IV q8-q12


* Linezolid 600 mg IV q12Pathogen-specific therapy




* Vancomycin 15 mg/kg IV q8-q12


* Linezolid 600 mg IV q12


* HAP/VAP P aeruginosa should be based upon the results of antimicrobial susceptibility


* Monotherapy in patients who are not in septic shock or at high risk of death


* Recommend against aminoglycoside monotherapy


* Beta-lactams with antipseudomonal activity


* Piperacillin-tazobactam 4.5 g IV q6


* Cefepime or ceftazidime 2 g IV q8


* Imipenem 500 mg IV q6 or meropenem 1 g IV q8


* Aztreonam 2 g IV q8


* Non-beta-lactams with antipseudomonal activity


* Levofloxacin 750 mg IV daily or ciprofloxacin 400 mg IV q8


* Amikacin 15-20 mg/kg IV daily or gentamicin 5-7 g/kg IV daily or tobramycin 5-7 mg/kg IV daily


* Colistin 5 mg/kg IV x 1 (loading dose), followed by 2.5 mg x (1.5 x CrCl + 30) IV q12 h (maintenance dose) [135] polymyxin B 2.5-3.0 mg/kg/d divided in 2 daily IV doses


HAP/VAP due to acinetobacter species


* Carbapenem or ampicillin/sulbactam


* If only sensitive to polymyxin, IV colistin, or polymyxin B



Aspiration pneumonia is a prevalent cause of respiratory failure and results from oropharyngeal or gastric contents into the lower airways. In ordinary people, the aspiration of small amounts of oropharyngeal secretions is natural and usually resolves spontaneously. However, this can be consequential when the aspirated amount is significant, especially in patients with compromised cardiopulmonary reserve.


Respiratory failure from aspiration occurs from chemical pneumonitis caused by inflammation induced by the gastric contents, pneumonia from secondary infection, and mechanical obstruction caused by particulate matter.


Predisposing factors for aspiration include conditions that cause reduced consciousness, interfere with normal swallowing, impair airway clearance, or lead to frequent or large-volume aspiration (Table 9).1,28

Table 9 - Click to enlarge in new windowTable 9. Risk Factors for Aspiration


Management primarily involves supportive care securing the airway, oxygenation, and ventilation. Tracheal suctioning or bronchoscopy with lavage may be needed to clear particulate matter.


In most cases, antibiotics are not needed and can be considered a persistent or progressive respiratory impairment.


In critically ill patients, the elevation of head of bed to at least 30[degrees] and enteric feeding has been shown to reduce the incidence of aspiration.1,29



The discussion about pneumonia will not be complete without mentioning severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 pneumonia, which is now the world's leading cause of acute respiratory failure respiratory distress syndrome. The clinical spectrum of COVID-19 infection ranges from asymptomatic infection to ARDS. Prevention of infection is vital with social distancing, masking, and vaccination. For mild disease in individuals with a high risk for disease progression, monoclonal antibodies and antiviral medications are available. In severe disease with hypoxia requiring hospitalization, patients are treated with dexamethasone and remdesivir, and in select cases, anti-inflammatory agents such as tocilizumab and baricitinib can be helpful.30,31 As discussed later, individuals with severe disease are otherwise managed as ARDS patients with high-flow oxygen and noninvasive or invasive ventilation strategies. A detailed discussion of this topic is beyond the scope of this topic's review.


Acute respiratory distress syndrome

Acute respiratory distress syndrome is characterized by the acute onset of noncardiogenic pulmonary edema resulting in acute onset of bilateral alveolar infiltrates and acute hypoxic respiratory failure, often requiring ventilator support. Acute respiratory distress syndrome pathophysiology typically involves the initial exudative stage, followed by a proliferative stage culminating in a fibrotic stage. Pathology review of ARDS cases often shows diffuse alveolar damage.


Diagnostic criteria and classification of ARDS are based on the 2012 Berlin criteria, which require that all of the following criteria be present (Table 10).

Table 10 - Click to enlarge in new windowTable 10. Acute Respiratory Distress Syndrome Berlin Criteria

Acute respiratory distress syndrome can occur in the setting of pulmonary pathologies such as pneumonia, aspiration, or nonpulmonary etiologies such as sepsis, pancreatitis, and trauma.


Patients with ARDS should have basic diagnostic workup with routine hematology panel, chemistry, chest imaging, blood gas analysis, appropriate cultures, and infectious disease workup.


Management of ARDS regardless of the etiology depends on airway support, primarily with mechanical ventilation, oxygenation, and ventilation. The hallmarks of supportive care with lung-protective ventilation involve low tidal volume strategy (~6 mL/kg ideal body weight, pressure plateau <30 cm H2O, driving pressure <15 cm H2O) and conservative fluid ARDS management. The primary goal is to minimize lung injury, permit the lungs to heal and recover from the original insult, and allow etiology-specific management to become therapeutic.


Other therapeutic options, especially with the advent of COVID pneumonia, include high-flow oxygen delivery systems, noninvasive ventilator strategies with continuous positive airway pressure, and Bilevel positive airway pressure, and in patients with refractory hypoxia despite mechanical ventilation, prone ventilation, neuromuscular blockade, and extracorporeal membrane oxygenation. Despite improvements in ARDS care, mortality, unfortunately, remains high, around 30% to 40%.32-35




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acute respiratory distress syndrome; aspiration; hypercapnia; hypoxemia; pneumonia; pulmonary embolism; respiratory failure