Pauline K. Park
Krishnan Raghavendran
Lena M. Napolitano
Presentation
A 65-year-old female, with a history of chronic renal failure requiring hemodialysis, underwent an urgent left hemicolectomy for a partially obstructing colon cancer. On postoperative day 5, she develops fever, abdominal pain, and leukocytosis. Abdominal radiographs confirm extensive pneumoperitoneum. Emergent laparotomy confirms anastomotic disruption. Resection of the anastomosis with end-colostomy and Hartman’s procedure is performed. The patient develops worsening severe hypoxemia in the operating room, with a PaO2 of 85 mm Hg on FiO2 1.0. She is maintained intubated and mechanically ventilated and is admitted to the surgical intensive care unit (ICU) postoperatively.
Differential Diagnosis
This patient has severe hypoxemia and acute respiratory failure. It is important to establish a definitive diagnosis in patients with severe hypoxemia, as definitive treatment strategies must be aligned with the diagnosis. The differential diagnosis of severe hypoxemia in this patient includes the following:
· Bacterial pneumonia
· Aspiration pneumonia or pneumonitis
· Pulmonary embolus
· Heart failure
· Pulmonary edema
· Transfusion-associated acute lung injury (TRALI)
· Acute respiratory distress syndrome (ARDS)
Any patient with the acute onset of bilateral pulmonary infiltrates and severe hypoxemia in the absence of evidence of cardiogenic pulmonary edema should be evaluated for ARDS. ARDS is a syndrome defined by (1) the presence of bilateral pulmonary infiltrates of acute onset, (2) PaO2:FiO2 (P/F) ratio of ≤200, and (3) no evidence of left atrial hypertension.
Workup
The workup for ARDS includes diagnostic imaging and laboratory tests to exclude the other potential diagnoses of the acute hypoxemic respiratory failure. ARDS is ultimately a clinical diagnosis, excluding other etiologies of the severe hypoxemia. ARDS-associated mortality rates remain high, at approximately 40%, and therefore an early diagnosis is critical to initiation of optimal management.
Chest Radiograph
This patient had a normal chest radiograph preoperatively and developed bilateral infiltrates with the development of abdominal sepsis (Figure 1). Pneumonia generally demonstrates a lobar infiltrate rather than bilateral infiltrates.
FIGURE 1 • Preoperative chest radiograph (A) and on ICU admission (B).
Transthoracic Echocardiography
This diagnostic test is used to evaluate for cardiogenic pulmonary edema. This patient’s echocardiogram demonstrated a hyperdynamic state with an estimated ejection fraction of 70% and no evidence of left ventricular dysfunction, left atrial hypertension, or valvular disease. This is consistent with her diagnosis of abdominal sepsis and does not confirm a diagnosis of heart failure. There is no evidence of right heart strain or right ventricular dysfunction that may be present in patients with pulmonary embolus.
Laboratory Tests
Arterial blood gas confirms hypoxemia, PaO2 of 85 mm Hg on FiO2 1.0, which confirms a PaO2/FiO2 ratio ≤200 mm Hg. No other specific laboratory tests confirm a diagnosis of ARDS. Brain (B-type) natriuretic peptide (BNP) levels are elevated in acutely decompensated heart failure, so low levels may be indicative of a diagnosis of ARDS.
Sputum
Respiratory cultures should be obtained to evaluate for possible bacterial or aspiration pneumonia as the etiology of the patient’s acute respiratory failure.
Electrocardiogram
Electrocardiogram (EKG) reveals sinus tachycardia with no conduction abnormalities. In patients with pulmonary embolus or acute cor pulmonale, a right heart strain pattern may be present. EKG is also helpful to evaluate for possible acute myocardial infarction.
Chest Computed Tomography Scan
Computed tomographic (CT) pulmonary angiography is used to diagnose pulmonary embolism and may also be useful in identification of effusion, pneumothorax, or posterior dependent atelectasis that can help to guide treatment strategies. Some patients with severe hypoxemia will not be stable for transport for CT imaging. Four (4)-extremity venous duplex scan may be considered to evaluate for extremity venous thrombosis, which would warrant initiation of systemic anticoagulation, but this does not provide a definitive diagnosis of pulmonary embolism as the etiology of the severe hypoxemia.
Diagnosis
This patient has ARDS, meeting all of the criteria for the ARDS definition including bilateral infiltrates on chest radiograph, hypoxemia (PaO2/FiO2 ≤200 mm Hg), and no evidence of cardiogenic pulmonary edema (Table 1). The ARDS is likely secondary to the abdominal sepsis from anastomotic leak.
TABLE 1. The American-European Consensus Conference (AECC) Definition of Acute Lung Injury (ALI) and ARDS Developed in 1994
Pathophysiology
ARDS is characterized by diffuse alveolar damage and hyaline membranes representing epithelial injury and increased permeability of the endothelium and epithelium. This results in the accumulation of protein-and neutrophil-rich pulmonary edema in the lung interstitium and in the distal airways. Additional mechanisms impair the removal of pulmonary edema fluid and inflammatory cells from the lung (Figure 2).
FIGURE 2 • (A) The normal alveolus and (B) the injured alveolus in the acute phase of acute lung injury and the acute respiratory distress syndrome. In the acute phase of the syndrome (B), there is sloughing of both the bronchial and alveolar epithelial cells; protein-rich hyaline membranes form on the denuded basement membrane. Neutrophils adhere to the injured capillary endothelium and marginate through the interstitium into the air space, which is filled with protein-rich edema fluid. In the air space, alveolar macrophages secrete cytokines; interleukin (IL)-1, -6, -8, and -10; and tumor necrosis factor α(TNF-α), which act locally to stimulate chemotaxis and activate neutrophils. IL-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules such as platelet-activating factor (PAF). A number of anti-inflammatory mediators are also present in the alveolar milieu including IL-1 receptor antagonist, soluble TNF receptor, autoantibodies against IL-8, and cytokines such as IL-10 and -11 (not shown). The influx of protein-rich edema fluid into the alveolus leads to the inactivation of surfactant. MIF, macrophage-inhibitory factor. (Adapted from the Massachusetts Medical Society, with permission.)
Treatment
Treatment of the Cause
The first priority in management of ARDS is treatment of the underlying cause or precipitating event. In this patient, treatment of the abdominal sepsis is required, including broad-spectrum empiric antibiotics, surgical source control, resuscitation, and cardiorespiratory support.
Respiratory Support with Mechanical Ventilation
The goal of mechanical ventilation is to increase oxygenation while minimizing the risk of further lung injury, known as ventilator-induced lung injury. Low tidal volume (6 mL/kg) ventilation is associated with a significant reduction in mortality (Table 2) and is the standard ventilator management of ARDS. This strategy allows for permissive hypercapnia. With the development of the National Institutes of Health (NIH)-sponsored ARDS Clinical Trials Network, large well-controlled trials of ARDS therapies have been completed. Thus far, the only treatment found to improve survival rates in such a study is a mechanical ventilation strategy using low tidal volumes. If the ARDS patient has persistent hypoxemia, additional strategies including recruitment maneuvers (RM), “open lung” ventilation with higher end-expiratory pressure (PEEP), and mechanical ventilation with higher mean airway pressures (airway pressure release ventilation or high-frequency oscillatory ventilation) are considered.
TABLE 2. Low Tidal Volume Ventilation Strategy from ARDS Network (www.ardsnet.org)
Therapies Targeted at the Lung Injury
The use of a fluid-conservative strategy after patients with ARDS are no longer in shock was associated with improved oxygenation and a significant reduction in the duration of mechanical ventilation, and no difference in 60-day mortality or nonpulmonary organ failures. Therefore, conservative volume management and titrated diuretic administration (furosemide [Lasix], bumetamide [Bumex]) with either intermittent administration or continuous infusion can be considered. In patients with nonuniform infiltrates, positioning the patient with the good lung down can improve oxygenation by improving perfusion to the more aerated portion of the lung.
Supportive Therapies
Patients with ARDS require adequate sedation and analgesia, usually administered by IV continuous infusion titrated to effect. In critically ill patients with severe ARDS (defined as P/F ratio <150), early administration of a neuromuscular blocking agent (cisatracurium) for 48 hours improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. Neuromuscular blockade may be required in these severe cases, but prolonged neuromuscular blockade has been associated with myopathy and neuropathy in critically ill patients. Measures to reduce ventilator-associated pneumonia (VAP) are instituted, as ARDS patients can require prolonged mechanical ventilation and are at high risk for VAP. Early mobilization and physical therapy to reduce ICU-acquired weakness is an important component of care. All ARDS patients require nutritional support, and enteral nutrition is preferred as it is associated with decreased infectious complications in ICU patients. In some, but not all studies, administration of a specialized enteral nutrition formula (with omega-3 fatty acids [eicosapentaenoic acid, gamma-linolenic acid] and antioxidants) was associated with improved outcomes (reduced mortality, increased ventilator-free and ICU-free days, reduced organ failure and improved oxygenation).
Critical Care Approach to ARDS Rescue Strategies
The ARDS rescue strategies (Table 3) described below are implemented in ARDS patients with severe life-threatening hypoxemia (PaO2/FiO2 ≤100 mm Hg) that are not responsive to the standard ARDS management strategies reviewed above.
TABLE 3. Rescue Strategies for Severe Hypoxemia and ARDS)
Recruitment Maneuvers
Recruitment maneuvers (RM) attempt to increase the amount of aerated lung to improve gas exchange. RM are performed by sustained inflation with continuous positive airway pressure (i.e., 30 cm H2O PEEP for 30 seconds) or controlled ventilation at increased airway pressure. RM can improve oxygenation, but may also result in transient adverse events (hypotension, hypoxemia) or pneumothorax, and have not been shown to improve survival.
Prone Positioning
The prone position improves oxygenation in 70% to 80% of patients with ARDS, and maximal improvements are seen in the most hypoxemic patients. Both alveolar recruitment and end-expiratory lung volume increase with prone position, with improved ventilation/perfusion matching. A review of all published meta-analyses on the efficacy of prone position in ARDS concluded that prone ventilation was associated with reduced mortality only in the cohort of patients with severe hypoxemia, defined as PaO2/FiO2 ≤100 mm Hg.
Inhaled Nitric Oxide
Inhaled nitric oxide (INO) is a selective pulmonary vasodilator that improves oxygenation by increasing blood flow in ventilated areas to improve ventilation/perfusion matching. A meta-analysis of 12 trials and 1,237 patients confirmed that INO significantly increased oxygenation that persisted through day 4 of treatment, but no significant effect of INO on hospital mortality was identified.
Inhaled Prostacyclin and Other Vasodilatory Prostaglandins
Prostacyclin is a selective pulmonary vasodilator and inhibitor of platelet aggregation. When aerosolized, its vasodilatory action improves ventilation/perfusion matching in the lung, resulting in improved oxygenation and no effect on systemic arterial blood pressure. Inhaled iloprost is a more stable analog of prostacyclin and is approved by the FDA for pulmonary hypertension, and can be used instead of INO in ARDS patients with severe hypoxemia to improve oxygenation.
Extracorporeal Membrane Oxygenation
Extracorporeal membrane oxygenation (ECMO) is considered in patients with severe refractory hypoxemia unresponsive to all ARDS management strategies. Veno-venous ECMO is the most common strategy employed, with a 50% survival rate reported in 1,473 adults with ARDS treated with ECMO from the Extracorporeal Life Support Organization (ELSO). The CESAR trial was a multicenter trial performed in the United Kingdom that randomized 180 patients to conventional mechanical ventilation versus ECMO and demonstrated that ARDS management with a standardized algorithm including ECMO in an expert center resulted in improved 6-month outcome (death or severe disability at 6 months, 63% vs. 47%; RR, 0.69; 95% CI, 0.05–0.97; p = 0.03). But compliance with a low tidal volume ventilation strategy was not mandated in the control cohort. The precise role of ECMO in ARDS as a salvage therapy remains unclear.
Special Considerations
Complications in ARDS patients are common. Clinicians must pay careful attention to early recognition of potential complications, particularly pneumothorax and VAP. VAP is a common risk factor for development of ARDS and almost 60% of patients with ARDS from other risk factors can develop VAP. Evaluation for other common infectious complications (central line–associated bloodstream infection, catheter-associated urinary tract infection) in ICU patients should be considered if fever and/or leukocytosis develop during the ICU stay.
Follow-up
It has been documented that ARDS patients who survive have significant functional impairments during initial recovery, but most achieve near-normal lung function at 1 year, which persists without deterioration at 5 years. The major disability in these patients is a combination of exercise limitation, physical and psychological sequelae, and decreased physical quality of life. ARDS patients should have follow-up to assess the recovery of their pulmonary function. Chest radiograph, pulmonary function tests, and chest CT imaging are all considered dependent on the patient’s clinical condition at follow-up.
Case Conclusion
This patient with sepsis-associated ARDS was treated with low tidal volume ventilation, conservative fluid administration, prone positioning, and sepsis management. She required 12 days of mechanical ventilation and was successfully weaned and extubated. Quantitative lower respiratory tract cultures obtained by bronchoalveolar lavage were negative for bacterial pathogens. She completed a course of systemic antibiotics for treatment of abdominal sepsis due to secondary peritonitis. She did not require supplemental oxygen on discharge home. Arterial blood gas confirmed adequate oxygenation on room air.
TAKE HOME POINTS
· ARDS definition includes the acute onset of bilateral infiltrates, PaO2/FiO2 ≤200 mm Hg (regardless of PEEP level) and no clinical evidence of left atrial hypertension.
· ARDS can be caused by both direct (pulmonary) and indirect (nonpulmonary) etiologies.
· Any patient with the acute onset of bilateral pulmonary infiltrates and severe hypoxemia in the absence of cardiogenic pulmonary edema should be evaluated for ARDS.
· ARDS-associated mortality rates remain high, at approximately 40%, and therefore an early diagnosis is critical to initiation of optimal management.
· Low tidal volume (6 mL/kg) ventilation is associated with decreased mortality in ARDS.
· A fluid-conservative management strategy, supplemented with targeted diuretic administration, is associated with improved ICU outcomes in ARDS.
· ARDS rescue strategies should be considered in patients with severe life-threatening hypoxemia (PaO2/FiO2 ≤100 mm Hg) that are not responsive to the standard ARDS management strategies.
SUGGESTED READINGS
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Herridge MS, Tansey CM, Matte A, et al. Canadian critical care trials group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364:1293–1304.
Napolitano LM, Park PK, Raghavendran K, et al. Nonventilatory strategies for patients with life-threatening 2009 H1N1 influenza and severe respiratory failure. Crit Care Med. 2010; 38(4 suppl):e74–e90.
Papazian L, Forel JM, Gacouin A, et al. ACURASYS study investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107–1116.
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Raghavendran K, Napolitano LM. ALI and ARDS: advances and challenges. Crit Care Clin. 2011;27:xiii–xiv.
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Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354:2564–2575.