UP TO DATE This topic last updated: Jun 06, 2012 Supportive care and oxygenation in acute respiratory distress

syndrome Author Mark D Siegel, MD Section Editor Polly E Parsons, MD Deputy Editor Helen Hollingsworth, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Dec 2012. | This topic last updated: Jun 06, 2012. INTRODUCTION The acute respiratory distress syndrome (ARDS) previously had a mortality rate greater than 50 percent [1]. Mortality has since declined [2-6], but the precise mortality rate is uncertain because estimates tend to be higher in observational studies than randomized trials (figure 1) [7-9]. No single change in the management of ARDS can explain the decrease in mortality, which is likely multifactorial (improved approaches to mechanical ventilation and supportive care) [10]. The Berlin Definition of ARDS (published in 2012) has replaced the AmericanEuropean Consensus Conferences definition of ARDS (published in 1994) [10,11]. However, it should be recognized that most evidence is based upon prior definitions. The current diagnostic criteria for ARDS are provided separately. (See "Acute respiratory distress syndrome: Clinical features and diagnosis", section on 'Diagnostic criteria'.) Supportive care and the treatment of severe hypoxemia in patients with ARDS are discussed here. Epidemiology, diagnosis, etiologies, pathophysiology, clinical manifestations, prognosis, mechanical ventilation, and novel therapies are discussed in detail elsewhere. (See "Acute respiratory distress syndrome: Clinical features and diagnosis" and "Acute respiratory distress syndrome: Epidemiology; pathophysiology; pathology; and etiology" and "Mechanical ventilation in acute respiratory distress syndrome" and "Novel therapies for the acute respiratory distress syndrome".) SUPPORTIVE CARE A minority of patients with ARDS die from respiratory failure alone [3,12-14]. More commonly, such patients succumb to their primary illness or to secondary complications such as sepsis or multiorgan system failure. (See "Management of severe sepsis and septic shock in adults".) Patients with ARDS require meticulous supportive care, including intelligent use of sedatives and neuromuscular blockade, hemodynamic management, nutritional support, control of blood glucose levels, expeditious evaluation and treatment of nosocomial pneumonia, and prophylaxis against deep venous thrombosis (DVT) and gastrointestinal (GI) bleeding. Sedation The use of sedative-analgesic medications in critically ill patients, including patients with ARDS, is discussed in detail separately. (See "Sedativeanalgesic medications in critically ill patients: Selection, initiation, maintenance, and withdrawal".)

sedation and analgesia are useful in patients with ARDS because they improve tolerance of mechanical ventilation and decrease oxygen consumption [15,16]. This was illustrated by a study of seven critically ill patients, which found that the use of morphine reduced resting and total energy expenditure by 6 and 8.6 percent, respectively [16]. Since many patients with ARDS require sedation for several days or longer, longacting relatively inexpensive agents such as lorazepam are a logical choice [17]. Because benzodiazepines provide no analgesia, opioids (such as fentanyl or morphine) may be needed to treat pain. Opioids also provide synergy and may decrease the amount of benzodiazepine required [18]. Intermittent injections of sedative-analgesic agents are preferred, with continuous infusions reserved for patients who require repeated doses to achieve adequate sedation [19]. Occasionally, agents such as haloperidol and propofol may be useful alternatives, although the latter can be expensive, especially when used for prolonged periods [20,21]. Several articles highlight significant morbidity associated with excessive sedation. Strategies such as routinely waking patients each day [22], using intermittent instead of continuous infusions of sedatives [23], and following a sedation and analgesia protocol [19] may lead to important benefits such as decreased time on the ventilator and fewer nosocomial infections. The avoidance of excessive sedation is discussed in detail elsewhere. (See "Sedative-analgesic medications in critically ill patients: Selection, initiation, maintenance, and withdrawal", section on 'Avoid excess sedation'.) Using sedation scales such as the Richmond Agitation-Sedation Scale (RASS) may help clinicians meet sedation goals more effectively, decreasing the likelihood of over or under-sedation [19,24]. Most patients should be manageable with light sedation (eg, RASS of 0 or negative 1) although some patients with more severe lung injury or poor tolerance of mechanical ventilation may need to be sedated more deeply. Two studies found no evidence that increased sedation is required when patients are managed with low tidal volume as opposed to more traditional higher tidal volume ventilation [25,26]. There is evidence that using no pharmacological sedation may be superior to using a continuous sedative infusion with daily interruption. In a single center study that enrolled patients requiring mechanical ventilation for more than 24 hours (including patients with ARDS), a protocol of no sedation was compared to the use of a continuous sedative infusion with daily interruption [27]. Patients managed without sedation received intensive non-pharmacological support, such as verbal comforting and reassurance. The no sedation group spent more time off the ventilator and less time in the ICU than those managed with continuous sedative infusions that were interrupted daily. Similar studies in patients with ARDS need to be performed to determine whether a strategy of no sedation is a viable approach in such patients.

Paralysis Although it is widely recognized that neuromuscular blockade can have desirable effects (improves oxygenation [28]) and undesirable effects (prolonged neuromuscular weakness [29]) in patients with ARDS, the impact of these competing effects on patient-important outcomes has remained unclear. This uncertainty was addressed by a multicenter trial that randomly assigned 340 patients with ARDS to receive cisatracurium besylate or placebo by continuous infusion for 48 hours [30]. At the time of enrollment, all of the patients had been mechanically ventilated using low tidal volume ventilation and had a PaO 2/FiO2 ratio of <150 mmHg on a PEEP of 5 cm H2O for less than 48 hours. Both groups were deeply sedated to a Ramsay sedation score of 6 (no response to glabellar tap). Patients treated with cisatracurium besylate had non-statistically significant lower crude 90-day, 28-day, hospital, and ICU mortality rates compared to the placebo group. Following a pre-specified statistical plan, the authors adjusted for baseline differences in the PaO2/FiO2, SAPS II severity score, and plateau airway pressure, and found a statistically significant decrease in 90-day mortality in patients treated with cisatracurium besylate (HR 0.68, 95% CI 0.48-0.98). The beneficial effects on 90-day mortality were limited to patients who presented with a PaO 2/FiO2 ratio of less than 120 mm Hg. Patients treated with cisatracurium besylate also had significantly more ventilator-free days during the first 28 and 90 days (defined as the number of days since successful weaning from mechanical ventilation) and were significantly less likely to experience barotrauma. There was no difference in the frequency of ICU-acquired neuromuscular weakness. We believe that these findings need to be replicated before neuromuscular blockade becomes part of the routine management of patients with early, severe ARDS. Until then, the body of evidence suggests that the administration of shortterm (up to 48 hours) neuromuscular blockade to patients with ARDS who have severe gas exchange abnormalities (eg, PaO2/FiO2 120 mmHg) is probably safe and potentially beneficial. The neuromuscular blocking agents are discussed in detail separately. (See "Use of neuromuscular blocking medications in critically ill patients".) Hemodynamic monitoring Hemodynamic management guided by a central venous catheter (CVC) has been compared to that guided by a pulmonary artery catheter (PAC) in patients with ARDS [7]. In the trial, 1000 patients with ARDS were randomly assigned to receive a CVC or a PAC. There was no difference in mortality, lung function, ventilator-free days, organ failure free days, or ICU-free days at day 28. Rates of hypotension, dialysis, and vasopressor use were also the same in both groups. But, the PAC group had an approximately two-fold increase of catheterrelated complications, predominantly arrhythmias. This suggests that the PAC should not be used routinely in patients with ARDS. Nutritional support Patients with ARDS are intensely catabolic and benefit from nutritional support [31]. If the gastrointestinal tract is available for nutritional

intake, enteral feedings are preferred. Possible advantages of the enteral route include fewer intravascular infections, less GI bleeding because of gastric buffering, and preservation of the intestinal mucosal barrier, which in turn may decrease bacterial translocation across the gut. Overfeeding offers no nutritional advantage and should be avoided to prevent excessive carbon dioxide production. When patients are fed, it is essential that they be kept semirecumbent with their heads in the upright position to decrease the risk of ventilator-associated pneumonia [32]. (See "Nutrition support in critically ill patients: An overview".)

Glucose control The approach to glucose control in patients with ARDS is extrapolated from trials that enrolled patients with critical illness, including ARDS. This is discussed in detail elsewhere. (See "Glycemic control and intensive insulin therapy in critical illness".) Nosocomial pneumonia Nosocomial (ie, ventilator-associated) pneumonia frequently complicates the course of ARDS. As an example, one prospective study of 30 patients with severe ARDS found that nosocomial pneumonia developed in 60 percent [33]. The first episode occurred at an average of 10 days after the onset of ARDS. Nosocomial pneumonia increases morbidity in ARDS, although the impact on mortality is less clear [34]. Given the baseline radiographic abnormalities and frequent colonization by potential pathogens, it is difficult to diagnose pneumonia in patients with ARDS on the basis of clinical factors alone [34,35]. The misdiagnosis of pneumonia in patients with ARDS may have unfortunate consequences. Inappropriate treatment of patients without pneumonia promotes the emergence of organisms with antibiotic resistance, while a missed diagnosis may be lethal. The diagnosis of ventilator-associated pneumonia is discussed in detail elsewhere. (See "Clinical presentation and diagnosis of ventilator-associated pneumonia".) Microbiology Delayed, inappropriate, or inadequate antibiotic use is associated with poor outcome; therefore, it is essential to choose an initial antibiotic regimen sufficiently broad to cover likely infecting organisms [36]. Antibiotic choices should consider local sensitivity profiles, which may vary significantly from hospital to hospital. (See "Treatment of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults".) Prevention Nosocomial pneumonia is difficult to prevent since patients with ARDS are frequently malnourished and immunosuppressed. In addition, normal airway defenses are bypassed by the endotracheal tube (ETT), and pulmonary edema is an excellent growth medium for bacteria. Despite widespread pulmonary infiltration by neutrophils, these cells offer poor protection against invading organisms [37]. (See "Endotracheal tube management and complications".) A variety of strategies have been proposed to decrease the likelihood of a patient developing nosocomial pneumonia [38]. Some studies have suggested that selective decontamination of the digestive tract can decrease the risk of pneumonia. Unfortunately, evidence supporting this practice, particularly in the

medical ICU population, is uncertain at best; in addition, the procedure raises the cost of ICU care and promotes the emergence of resistant organisms [39]. Continuous subglottic aspiration may decrease infection by organisms occupying the digestive tract, but not by Pseudomonas [40]. Avoiding the supine position in mechanically ventilated patients, particularly those receiving enteral feedings, has been associated with a significant decrease in the rate of ventilator-associated pneumonia [32]. Other important considerations include avoiding unnecessary antibiotics, careful attention to mouth care, weaning patients in a timely manner to decrease the duration of mechanical ventilation, avoiding excessive sedation, avoiding ventilator circuit changes, and routinely draining ventilator circuit condensate [38].

Preliminary evidence initially suggested that closed tracheal suctioning systems might lower the incidence of ventilator-associated pneumonia (VAP). However, a more recent meta-analysis demonstrated that closed systems do not decrease the rate of VAP, mortality, or ICU length of stay [41]. (See "Risk factors and prevention of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults" and "The ventilator circuit and ventilator-associated pneumonia".) DVT prophylaxis The frequency of DVT and pulmonary embolism (PE) in patients with ARDS is unknown, but the risk is certainly high. These patients often have multiple risk factors for venous thrombosis, including prolonged immobility, trauma, activation of the coagulation pathway, and predisposing illnesses, such as obesity and malignancy. Prevention of venous thromboembolic disease is discussed separately. (See "Prevention of venous thromboembolic disease in surgical patients".) GI prophylaxis Patients requiring prolonged mechanical ventilation are at increased risk for gastrointestinal bleeding [42]. Prophylaxis against stress ulcers is discussed in detail elsewhere. (See "Stress ulcer prophylaxis in the intensive care unit".) MANAGEMENT OF HYPOXEMIA By definition, patients with ARDS are severely hypoxemic. Options available for improving arterial oxygen saturation (SaO2) include: Use of high fractions of inspired oxygen (FiO2) Decrease oxygen consumption Improve oxygen delivery Manipulate mechanical ventilatory support These options are most frequently applied in combination. Unfortunately, each modality is associated with an element of unquantifiable risk. As a result, the clinician must ultimately choose a strategy that provides adequate oxygenation (PaO2 55 to 80 mmHg) while minimizing the inevitable risks. Supplemental oxygen Most patients require a high FiO2, especially early in ARDS when pulmonary edema is most severe [43]. Although high flow oxygen can be provided through a face mask, it is difficult to provide more than approximately 70

percent noninvasively because environmental air is entrained. By comparison, up to 100 percent oxygen is delivered easily when administered through an endotracheal tube. Almost all patients therefore require intubation and mechanical ventilation. During the peri-intubation period, 95 to 100 percent oxygen should be given to ensure an adequate SaO2. Because oxygen uptake may exceed replenishment in areas with low V/Q ratios, some clinicians use slightly less than 100 percent oxygen (eg, 95 percent) in an attempt to prevent absorptive atelectasis [44]. Once well established, absorptive atelectasis is not rapidly reversed by reduction of FiO 2 to maintenance levels, emphasizing the desirability of rapid downward titration of FiO 2 to the lowest fraction necessary to maintain an SaO2 >90 percent [45].

Although the risk of high FiO2 supplementation has not been studied specifically in patients with ARDS, it is probably significant. Studies in animals and normal humans reveal that high concentrations of oxygen damage the lung within hours, in part by forming toxic oxygen species [46-48]. The specific threshold for oxygen toxicity is unknown but appears to begin above 50 percent, and the risk rises as concentrations approach 100 percent [49]. As a result, the FiO2 should be decreased to the 50 to 60 percent range as soon as safely possible. (See "Oxygen toxicity".) Mechanical ventilation strategies in patients with ARDS, including those that may allow a decrease in the FiO2 are discussed in detail elsewhere. (See "Mechanical ventilation in acute respiratory distress syndrome".) Fluid management Although increased vascular permeability is the primary cause of pulmonary edema in early ARDS, the quantity of edema formed depends directly upon hydrostatic pressure, since oncotic forces are less capable of retaining fluid within the capillaries (figure 2A-D) [50-52]. As a result, pulmonary edema is more likely to develop in ARDS than in normals for any given pulmonary capillary hydrostatic pressure. (See "Noncardiogenic pulmonary edema".) Thus, even in patients who are not volume overloaded, a strategy of conservative fluid management may help patients by reducing edema formation. This was best illustrated by a trial in which 1000 patients with established ARDS were randomly assigned to either a conservative or a liberal strategy of fluid management for seven days [8]. Patients assigned to the conservative group were managed with a fluid strategy that targeted a CVP <4 mmHg or a pulmonary artery occlusion pressure (PAOP) <8 mmHg. Patients managed with the liberal strategy targeted a CVP of 10 to 14 mmHg or a PAOP of 14 to 18 mmHg. The mean cumulative fluid balance was -136 mL in the conservative strategy group and +6992 mL in the liberal strategy group. The conservative strategy improved the oxygenation index and lung injury score, while increasing ventilator-free days (15 versus 12 days) and

ICU-free days (13 versus 11 days). The 60 day mortality rate was unaltered by the fluid management strategy. Despite clearly identified CVP and PAOP goals, mean CVP and PAOP remained well above the target goals in the conservative management group, suggesting that a CVP <4 mmHg or a PAOP <8 mmHg is difficult to achieve safely with the strategies outlined in this population. Given the clinical benefits demonstrated in this trial, we believe that a conservative strategy of fluid management is warranted in patients with ARDS, as long as hypotension and organ hypoperfusion can be avoided. It is reasonable to target a central venous pressure of <4 mmHg or a pulmonary artery occlusion pressure <8 mmHg; however, it should be recognized that such goals may be difficult to achieve. Preliminary data suggests that combination therapy with albumin and furosemide may improve fluid balance, oxygenation, and hemodynamics [53]. Ancillary measures The need to avoid oxygen toxicity justifies the consideration of a variety of other techniques designed to improve SaO2, including diuresis, prone positioning, and strategies to decrease oxygen consumption.

Prone positioning Prone positioning improves oxygenation in the majority of patients with ARDS. Individual studies have not shown a survival advantage, but a meta-analysis suggested a possible survival advantage among patients with the most severe hypoxemia [27]. The physiologic effects, efficacy, and application of prone ventilation are discussed in detail elsewhere. (See "Prone ventilation".) Decrease oxygen consumption In diseases with severe pulmonary shunting, increasing the saturation of mixed venous blood (SvO 2) may increase the SaO2. Therapies that decrease oxygen consumption may improve SvO2 (and SaO2 subsequently) by decreasing the amount of oxygen extracted from the blood. Common causes of increased oxygen consumption include fever, anxiety and pain, and use of respiratory muscles; therefore, arterial saturation may improve after treatment with anti-pyretics, sedatives, analgesics, or paralytics [28,54]. Increase oxygen delivery Oxygen delivery is determined by the following formula: DO2 = 10 x CO x (1.34 x Hgb x SaO2 + 0.003 x PaO2) where DO2 is oxygen delivered, CO is cardiac output, Hgb is hemoglobin concentration, SaO2 is the arterial oxygen saturation, and PaO2 is the partial pressure of oxygen in arterial blood. As a result, in addition to low SaO 2, DO2 may be decreased by a low Hgb and a low CO. In turn, a low DO2 may decrease SvO2. In anemic patients, attempts to increase the hemoglobin concentration may be useful, but exceeding 9 g/dL is unlikely to increase benefit. One multicenter trial randomized 838 critically ill patients to a "restrictive" transfusion strategy to maintain the hemoglobin concentration between 7 and 9 g/dL, or to a "liberal"

transfusion strategy to maintain it between 10 and 12 g/dL [55]. The 30-day mortality rates of the two groups did not differ significantly, and patients randomized to the restrictive strategy had a lower mortality rate during the period of hospitalization (22 versus 28 percent; p = 0.05). More recent studies suggest that transfusion of packed red blood cells may increase a patient's risk of developing ARDS and dying once ARDS is established [56]. For this reason, we suggest restricting transfusion of packed red blood cells in most ARDS patients, unless the hemoglobin falls below 7 g/dL or if there are other compelling reasons to justify transfusions. Cardiac output may be augmented by raising filling pressures if they are low (if pulmonary edema is not exacerbated) or by using inotropic agents. However, raising oxygen delivery to supernormal levels is not clinically useful and may be harmful in some circumstances [10,57,58]. One prospective study, for example, randomized 100 patients with a variety of critical illnesses to either intravenous dobutamine or placebo if volume expansion alone failed to achieve a boost in oxygen delivery [58]. Patients in the control group received dobutamine only if their cardiac index was below 2.8 liters per minute per square meter. Despite achieving higher oxygen delivery and cardiac indices, active therapy resulted in a higher mortality (54 versus 34 percent for the control group).

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Adult respiratory distress syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Data from the mid to late 1990s show a decrease in mortality from the acute respiratory distress syndrome (ARDS). The decrease in mortality is probably due to several factors, including improved supportive care and a more thoughtful approach to mechanical ventilation. (See 'Introduction' above.) Key components of supportive care include intelligent use of sedatives and neuromuscular blockade, careful hemodynamic management, nutritional support,

control of blood glucose, expeditious evaluation and treatment of nosocomial pneumonia, and prophylaxis against deep vein thrombosis (DVT) and gastrointestinal (GI) bleeding. (See 'Supportive care' above.) Patients with hypoxic respiratory failure may benefit from strategies that decrease oxygen utilization, such as antipyretics to control fever and sedatives to control agitation. Occasionally, neuromuscular blockade is required, particularly when asynchrony with the ventilator persists despite adequate sedation. For patients with particularly severe gas exchange abnormalities (eg, PaO 2/FiO2 120 mmHg), up to 48 hours of neuromuscular blockade is probably safe and potentially beneficial, but requires additional investigation. (See 'Sedation' above and 'Paralysis' above.) Ventilator-associated pneumonia is a frequent complication of ARDS. When initiating therapy, empiric antibiotics coverage should be sufficiently broad to target all likely pathogens pending the results of sensitivity testing. Strategies that may lower the risk of ventilator-associated pneumonia include avoiding all of the following: the supine position, excess sedation, unnecessary antibiotics, and unnecessary ventilator circuit changes. Additional strategies include providing good mouth care, weaning patients from the ventilator in a timely manner, and perhaps use of continuous subglottic aspiration. (See 'Nosocomial pneumonia' above.) Data suggest that a conservative fluid management strategy that aims to minimize or eliminate positive fluid balance for example, by aiming for a CVP <4 mmHg or a PAOP <8 mmHg offers clinical advantages, including improved oxygenation, increased ventilator-free days, and ICU-free days. (See 'Fluid management' above.)

While blood transfusion and inotropes may augment oxygen delivery, most data caution against indiscriminate use of these strategies. For most patients, packed red blood cells can be withheld until the hemoglobin concentration drops below 7 g/dL, unless there are alternative reasons for transfusion. Similarly, there is no evidence that inotropes benefit ARDS patients with a normal cardiac function. (See 'Ancillary measures' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES

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