Novel Therapies in Adults

Official reprint from UpToDate
www.uptodate.com 2014 UpToDate

Author
Mark D Siegel, MD
Section Editor
Polly E Parsons, MD
Deputy Editor
Geraldine Finlay, MD
Acute respiratory distress syndrome: Novel therapies in adults
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2014. | This topic last updated: May 27, 2014.
INTRODUCTION Most current therapies for acute respiratory distress syndrome (ARDS) are supportive, aimed at improving gas exchange and
preventing complications while the underlying condition that precipitated the ARDS is addressed. Potential therapies for ARDS are being evaluated in
an attempt to improve clinical outcomes; however, none are currently recommended as routine therapy because patient-important effects are
uncertain. Potential explanations for this uncertainty include inconsistent evidence, imprecise estimates of effect, and the enrollment of heterogeneous
populations in clinical trials.
The Berlin Definition of ARDS (published in 2012) [1] has replaced the American-European Consensus Conferences definition of ARDS (published in
1994) [2,3]. The Berlin Definition may assist future trials of novel treatments by improving diagnostic reliability and allowing more precise stratification
of patients according to severity. However, it should be recognized that most existing evidence is based upon prior definitions. The current diagnostic
criteria for ARDS are provided separately. (See "Acute respiratory distress syndrome: Clinical features and diagnosis in adults", section on
'Diagnostic criteria'.)
Potential therapies for ARDS that are currently being investigated are reviewed here. The supportive care, mechanical ventilation, clinical features,
diagnosis, prognosis, etiology, and pathophysiology of ARDS are discussed separately. (See "Acute respiratory distress syndrome: Supportive care
and oxygenation in adults" and "Mechanical ventilation of adults in acute respiratory distress syndrome" and "Acute respiratory distress syndrome:
Clinical features and diagnosis in adults" and "Acute respiratory distress syndrome: Prognosis and outcomes in adults" and "Acute respiratory distress
syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults".)
SURFACTANT Surfactant therapy is not used to treat adults with ARDS because the evidence regarding its effect on patient-important outcomes
is inconsistent. However, it is generally thought that exogenous surfactant therapy is unlikely to prove helpful for the treatment of ARDS.
Examples of the conflicting data include the following:
It has been suggested that the inconsistent results may reflect differences in the formulation (ie, types and amounts of protein and phospholipid) of
surfactant, population studied (ie, severity of illness, adults or children), method of drug delivery, dose, concurrent ventilation strategy, or inactivation
of the delivered agent [12-14]. However, when differences in the formulation were evaluated by a meta-analysis, there were no differences in
mortality when surfactant with surface protein was compared to surfactant without surface protein [9]. When differences in the severity of illness were
investigated by a meta-analysis, it was found that recombinant surfactant protein C improved oxygenation and decreased mortality (26.3 versus 39.3
percent, adjusted odds ratio 0.30, 95% CI 0.11-0.82) in the subgroup of patients who had severe ARDS due to pneumonia or aspiration, but not in the
overall ARDS population [15]. A subsequent trial designed to evaluate surfactant therapy in this subgroup was inconclusive because of a
methodological flaw (the resuspension process partially inactivated the surfactant) [16]. Therefore, the reasons for the inconsistent results remain
unknown.
The idea of using exogenous surfactant therapy to treat patients with ARDS is based upon several observations. First, the major purpose of
endogenous surfactant is to prevent atelectasis. Second, multiple surfactant abnormalities (composition and function) have been described in patients
with ARDS [17-19] and may be exacerbated by mechanical ventilation [14]. And, finally, atelectasis is a major contributor to hypoxemia and the
propagation of lung injury in ARDS [20]. The aim of exogenous surfactant therapy is to mitigate or eliminate atelectasis caused by insufficient or
abnormal surfactant by administering functional surfactant. (See "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and
etiology in adults" and "Ventilator-associated lung injury".)
ANTIOXIDANTS There is no evidence to support the routine use of antioxidant therapy in patients with ARDS. Antioxidant therapy with dietary oil
supplementation has not become routine therapy for adults with ARDS due to inconsistent evidence. The basis of the hypothesis that antioxidant
therapy might be beneficial in patients with ARDS are the observations that reactive oxygen species and partial depletion of antioxidant defense
appear to be important in the establishment and propagation of ARDS, as well as evidence that indices of oxidative stress are higher among
non-survivors than survivors of ARDS [21].
Examples of the conflicting data regarding dietary oil supplementation include the following:
Numerous randomized trials found no clinical benefit from recombinant surfactant protein C, synthetic surfactant, or freeze dried natural animal
surfactant in patients with ARDS [4-8]. When these trials were pooled in a meta-analysis, there was again no improvement in mortality (odds
ratio 0.97, 95% CI 0.73-1.30) despite a trend toward improved oxygenation (mean difference +13.18 mmHg, 95% CI, -2.95 - +29.32 mmHg)
among patients treated exogenous surfactant [9].
In contrast, a trial that randomly assigned 153 infants, children, and adolescents to intratracheal calfactant (a type of exogenous surfactant) or
placebo demonstrated decreased mortality (19 versus 33 percent for placebo) and more rapid improvement of oxygenation among patients who
received calfactant [10]. A similar trial of intratracheal calfactant in adults was terminated with results as yet unavailable [11].
Favoring dietary oil supplementation, a trial that randomly assigned 98 patients with ARDS to receive standard tube feeds or a combination of
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Further research is needed to better understand whether the conflicting results are due to the study designs (ie, different controls), different
combinations of dietary supplements, or different doses of dietary supplements.
In addition to dietary oil supplementation, two other antioxidant therapies have been studied. Lisophylline (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) is
an agent that decreases circulating fatty acids, which have been shown to increase several-fold in patients with ARDS and act as proinflammatory
mediators [26,27]. Despite promising animal data, a randomized trial comparing lisophylline to placebo in adults with ARDS was stopped after the
enrollment of 235 patients because an interim analysis showed no difference in survival or other clinical end points [27]. N-acetylcysteine and
L-2-oxothiazolidine-4-carboxylate (Procysteine) are agents that restore glutathione, an important antioxidant. While a trial confirmed that these
therapies restored glutathione stores [28], they did not decrease the production of reactive oxygen species and they had little effect on physiological
or patient-important outcomes [29,30]. (See 'Ineffective or harmful therapies' below.) Further research is needed before antioxidant therapy can be
used routinely in patients with ARDS.
GRANULOCYTE-MONOCYTE COLONY STIMULATING FACTOR The hypothesis that granulocyte-monocyte colony stimulating factor
(GM-CSF) may be beneficial to patients with ARDS is based upon the observation that increased GM-CSF in the bronchoalveolar lavage fluid of
humans with ARDS is associated with better survival [31]. In addition, animal studies have found that GM-CSF limits epithelial cell injury and maintains
alveolar macrophage function [32,33]. Granulocyte-monocyte colony stimulating factor (GM-CSF) has not become routine therapy for adults with
ARDS because the evidence is still inconclusive. As an example, in a trial that randomly assigned 131 patients with ARDS to receive either
intravenous GM-CSF or placebo for 14 days, patients who received GM-CSF had lower mortality (17 versus 23 percent) and more organ failure-free
days (15.7 versus 12.8 days) than patients who received placebo, but these differences were not statistically significant [34]. There was no difference
in the number of ventilator-free days. These findings indicate that larger trials with more events are necessary to confirm or exclude these effects. A
provocative report investigating the use of inhaled GM-CSF in a small group of patients with pneumonia-associated ARDS demonstrated significant
improvement in oxygenation, lung compliance, and severity of illness scores compared to untreated patients [35]. Treatment with GM-CSF appeared
to improve macrophage host defense capacity, which may provide a mechanism of action. Additional investigation of GM-CSF as a potential
treatment for ARDS appears warranted.
INHALED VASODILATORS Inhaled vasodilators (eg, nitric oxide, prostacyclin, prostaglandin E1) selectively dilate the vessels that perfuse
well-ventilated lung zones, resulting in improved oxygenation due to better ventilation/perfusion (V/Q) matching and the amelioration of pulmonary
hypertension (figure 1) [36]. Inhaled vasodilators have few systemic effects and rarely cause systemic hypotension since they act locally and have
short half-lives.
Nitric oxide Routine inhaled nitric oxide (NO) has not become routine therapy for adults with ARDS because, although it improves oxygenation, it
has not been shown to reduce morbidity or mortality [37-41]. Instead, inhaled NO may be considered for patients with intractable, life-threatening
hypoxemia despite conventional management [42].
The evidence is best illustrated by two meta-analyses (each with over 1200 patients) that compared inhaled NO to either placebo or conventional
management [39,40]. Both studies found that inhaled NO induced a modest, transient improvement in oxygenation, without any improvement in
mortality, duration of mechanical ventilation, or ventilator-free days.
While the major effect of inhaled NO appears to be improved oxygenation, oxygenation does not improve in all patients who receive inhaled NO
[36,43]. The factors that determine responsiveness are uncertain, but several have been suggested in retrospective cohort studies. Patients without
sepsis or septic shock may respond to inhaled NO more frequently than patients with septic shock [44]. In addition, high baseline pulmonary vascular
resistance and responsiveness to positive end-expiratory pressure (PEEP) may predict a response in inhaled NO [45].
Although published guidelines endorse monitoring methemoglobin concentrations when inhaled nitric oxide is given, the risk of methemoglobinemia is
rare when typical doses are used and appears to be limited to patients with methemoglobin reductase deficiency [46,47]. A meta-analysis found that
inhaled NO increased the risk of renal impairment (relative risk 1.59, 95% CI 1.17 to 2.16), but did not increase the risk of bleeding, methemoglobin
formation, or nitrogen dioxide formation [48]. The lack of proven outcome benefits and risk of renal impairment argue against the use of inhaled nitric
oxide in settings other than refractory hypoxemia.
Prostacyclin Routine inhaled prostacyclin has not become routine therapy for adults with ARDS because it has not been shown to improve
patient-important outcomes, despite the consistent finding that it is associated with an improvement in oxygenation and a decrease in pulmonary
arterial pressure [49-55]. These effects are comparable to those associated with inhaled NO (figure 2A-B). Inhaled prostacyclin may be considered in
patients with intractable, life-threatening hypoxemia despite conventional management.
The major advantage of inhaled prostacyclin compared with inhaled NO is that inhaled prostacyclin does not require sophisticated equipment for
administration. Clinical experience with inhaled prostacyclin for patients with ARDS suggests that adverse effects are infrequent, although published
data are limited [55]. Preliminary studies of inhaled iloprost, a prostacyclin analog, in patients with ARDS and pulmonary hypertension reported
improved oxygenation without adverse effects on lung mechanics or systemic hemodynamics [56]. Further studies are required to fully evaluate the
safety and efficacy of inhaled prostacyclin as a therapy for patients with ARDS or any subgroup that might benefit.
eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) found that the patients who received EPA and GLA required fewer days of
ventilatory support and fewer days in the ICU [22]. Moreover, another trial that randomly assigned 100 patients with ARDS to receive standard
tube feeds or a combination of EPA and GLA found that patients who received EPA and GLA had better oxygenation and required a shorter
duration of mechanical ventilation [23].
Arguing against dietary oil supplementation, more recent trials have found no effect from supplementation with dietary oils. One trial comparing a
combination of omega-3 fatty acids, GLA, and antioxidants to placebo was terminated due to futility [24], while another trial comparing EPA plus
docosahexanoic acid to saline placebo found no difference in clinical outcomes [25].

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ANTI-INFLAMMATORY THERAPIES Most patients who succumb to ARDS do not die from respiratory failure, but rather from complications of a
prolonged stay in the intensive care unit (ICU) such as nosocomial infection or multiple organ dysfunction syndrome (MODS) [51]. Persistent
inflammation may contribute to these complications and is associated with poor outcomes from ARDS; as an example, mortality is higher among
patients who have large quantities of neutrophils and proinflammatory cytokines [57,58] and/or low levels of anti-inflammatory cytokines [59]. Based
upon these observations, it has been hypothesized that anti-inflammatory medications might improve the outcome of ARDS.
Glucocorticoids The role of glucocorticoids in the management of ARDS is a source of ongoing controversy. Systemic glucocorticoids clearly
have a role in situations when ARDS has been precipitated by a steroid-responsive process (eg, acute eosinophilic pneumonia) [60]. However,
systemic glucocorticoid therapy has not become routine therapy for adults with other types of ARDS because its effect on mortality is uncertain and it
tends to cause important side effects.
The uncertain effect of glucocorticoids on mortality is exemplified by four meta-analyses that compared systemic glucocorticoid therapy to placebo in
patients with ARDS. One meta-analysis found that glucocorticoid therapy reduced mortality [61]. However, the other three meta-analyses reported a
reduction of mortality that did not reach statistical significance, indicating that larger trials with more events are necessary to either confirm or exclude
an effect on mortality [62-64]. Regarding other patient-important outcomes, the meta-analyses found that glucocorticoid therapy improved gas
exchange, decreased the duration of mechanical ventilation, and decreased the length of stay in the ICU [61,62,64].
It has been suggested that the effects of systemic glucocorticoids vary according to when they are initiated:
Taken together, these data indicate that systemic glucocorticoid therapy should NOT be initiated 14 days or longer after the onset of ARDS and the
impact of earlier therapy on mortality is uncertain. Larger trials are indicated to resolve the uncertainty regarding the effect of early systemic
glucocorticoid therapy in ARDS.
The major adverse effects of systemic glucocorticoids are described separately. (See "Major side effects of systemic glucocorticoids".)
Macrolide antibiotics Macrolide antibiotics have both antimicrobial and anti-inflammatory effects, and animal models suggest that these agents
may have a beneficial effect in ARDS [67,68]. To evaluate the effects of macrolide antibiotics in humans with ARDS, an observational study was
conducted using data from the Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) randomized trial [27]. In the observational
study, 47 patients with ARDS who received a macrolide antibiotic within the initial 24 hours were compared with 188 patients who did not [69]. There
was a trend toward lower 180-day mortality among patients who received a macrolide antibiotic (23 versus 36 percent); after adjusting for potential
confounders (eg, patients who received a macrolide antibiotic were less likely to have received low tidal volume ventilation), the lower 180-day
mortality became statistically significant (hazard ratio 0.46, 95% CI 0.23-0.92). This preliminary evidence warrants further evaluation with a controlled
clinical trial.
BETA AGONISTS Several studies have shown that beta agonists improve physiological outcomes in patients with ARDS [70-74]. As an example,
a trial that randomly assigned 40 patients with ARDS to receive intravenous albuterol (15 mcg/kg per hour) or placebo for seven days found that
intravenous albuterol was associated with less lung water (9 versus 13 mL/kg) and a lower plateau airway pressure (24 versus 30 cm H O) [74].
Inhaled albuterol was not studied in the trial.
Such promising physiological evidence prompted several clinical trials to measure patient-important outcomes, none of which demonstrated efficacy
[75-77]. One trial randomly assigned 282 patients with ARDS to receive aerosolized albuterol (5 mg) or placebo every four hours for up to ten days
[75]. No differences in the mean number of ventilator-free days or hospital mortality were detected. Heart rates were higher in the albuterol group, but
there was no difference in the frequency of dysrhythmias. Another trial randomly assigned 326 patients to receive intravenous salbutamol or placebo
[76]. The trial was terminated due to increased mortality among patients receiving salbutamol.
While these studies indicate that beta agonists do not have a direct beneficial effect on ARDS per se, they are effective agents for treating
bronchospasm in patients who have ARDS.
MESENCHYMAL STEM CELLS Preclinical studies suggest that treatment with exogenously administered mesenchymal stem cells (MSCs) may
help to attenuate lung injury and promote repair [78]. In animal models, MSCs appear to secrete growth factors and cytokines capable of modulating
local inflammation and promoting tissue repair via a paracrine mechanism. MSCs may also improve bacterial clearance and potentially differentiate
Late: Several studies have evaluated the impact of systemic glucocorticoids during persistent ARDS, also known as the fibroproliferative phase
of ARDS or late ARDS. The most notable was a double-blind trial by the ARDS Network that randomly assigned 180 patients with persistent
ARDS (defined as ongoing disease 7 to 28 days after its onset) to receive methylprednisolone or placebo for 21 days [65]. Overall, there was
no difference in 60-day mortality or 180-day mortality. However, there were important differences when the patients were divided according to
when they received glucocorticoid therapy. In the subgroup of patients randomized 7 to 13 days after the onset of ARDS, methylprednisolone
caused a non-statistically significant reduction in 60-day mortality (27 versus 36 percent) and 180-day mortality (27 versus 39 percent). In
contrast, among patients randomized more than 14 days after the onset of ARDS, methylprednisolone increased 60-day mortality (35 versus 8
percent) and 180-day mortality (44 versus 12 percent). Methylprednisolone increased ventilator-free days, shock-free days, oxygenation, lung
compliance, and blood pressure, but also increased neuromuscular weakness.
Early: Other clinical trials addressed the possibility that systemic glucocorticoids might be effective when given early in ARDS. In a double-blind
trial, patients with early ARDS (defined as 72 hours) were randomly assigned in a 2:1 ratio to receive glucocorticoid therapy (n = 63) or
placebo (n = 28) [66]. Patients in the glucocorticoid group were given methylprednisolone at 1 mg/kg per day for up to 28 days. Important
features of this trial included vigilant surveillance for infection and avoidance of neuromuscular blockade. Glucocorticoid therapy reduced the
duration of mechanical ventilation, length of ICU stay, and ICU mortality (21 versus 43 percent). The results of this trial are provocative, but not
definitive, given the trial's small size and imbalances in the treatment arms (including a larger number of patients with catecholamine-dependent
shock in the placebo group).
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into mature cells to replace those that have been injured. A Phase I clinical trial enrolled 12 patients with ARDS in a randomized placebo controlled
study designed to evaluate the safety and feasibility of using systemically administered allogeneic adipose-derived MSCs [79]. Infusion of MSCs was
well tolerated. Patients treated with MSCs had lower levels of surfactant protein-D on day 5, suggesting amelioration of epithelial cell injury. No
significant differences were demonstrated in levels of inflammatory cytokines. The study was not sufficiently powered to assess the impact of
treatment on clinically important outcomes such as survival or duration of mechanical ventilation. A Phase 1, open label, dose escalation, multi-center
trial of allogeneic bone marrow-derived human MSCs to treat ARDS is recruiting patients [80].
INEFFECTIVE OR HARMFUL THERAPIES A number of potential therapies for ARDS were once regarded as promising, but have since proven to
be either ineffective or harmful. They include the following:
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REFERENCES
Anonymous. Acute respiratory distress syndrome: The Berlin definition. JAMA 2012; 307:2526. 1.
N-acetylcysteine [29,30]
Procysteine (L-2-oxothiazolidine-4-carboxylate) [29]
Glutamine [81,82]
Antioxidant preparations (selenium, beta carotene, zinc, vitamin E and C) [81,83]
Lisophylline [27]
Intravenous prostaglandin E1 [84,85]
Neutrophil elastase inhibitors [86]
Ibuprofen [87]
Activated protein C [88]
Ketoconazole [89-93]
Statins [74,94,95]
th th
th th
Basics topics (see "Patient information: Adult respiratory distress syndrome (The Basics)")
Most current therapies for acute respiratory distress syndrome (ARDS) are supportive, aimed at improving gas exchange and preventing
complications while the underlying condition that precipitated the ARDS is addressed. (See 'Introduction' above.)
Potential therapies for ARDS are being evaluated in an attempt to improve clinical outcomes in ARDS; however, these therapies have not
become routine in adults with ARDS because either there are physiological benefits without definitive patient-important benefits or the patient-
important effects are uncertain (due to inconsistent evidence or imprecise estimates of effect) (see 'Introduction' above):
Exogenous surfactant therapy and antioxidant therapy via dietary oil supplementation do not have sufficient evidence to support their
routine use in patients with ARDS. (See 'Surfactant' above and 'Antioxidants' above.)
Inhaled nitric oxide, inhaled prostacyclin, and inhaled prostaglandin E1 improve physiologic parameters (eg, oxygenation) in patients with
ARDS, but do not appear to improve patient-important outcomes. (See 'Inhaled vasodilators' above.)
While the effects of systemic glucocorticoids administered within the first two weeks of ARDS are uncertain and require further study,
systemic glucocorticoids administered two weeks or later appear to be harmful. We suggest NOT administering systemic glucocorticoids
to patients 14 days or longer after the onset of ARDS (Grade 2C). (See 'Glucocorticoids' above.)
A number of potential therapies were once regarded as promising in patients with ARDS, but have since proven to be either ineffective or
harmful. These include beta agonists, N-acetylcysteine, procysteine, lisophylline, intravenous prostaglandin E1, neutrophil elastase inhibitors,
ketoconazole, ibuprofen, and statins. (See 'Ineffective or harmful therapies' above.)
Preclinical data and preliminary data in humans suggest that human mesenchymal stem cells may prove promising as a means to ameliorate
lung injury and promote tissue repair in patients with ARDS.

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Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant
outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818.
2.
Artigas A, Bernard GR, Carlet J, et al. The American-European Consensus Conference on ARDS, part 2: Ventilatory, pharmacologic,
supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome. Am J Respir
Crit Care Med 1998; 157:1332.
3.
Weg JG, Balk RA, Tharratt RS, et al. Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory
distress syndrome. JAMA 1994; 272:1433.
4.
Spragg RG, Lewis JF, Wurst W, et al. Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant. Am J
Respir Crit Care Med 2003; 167:1562.
5.
Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome.
Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. N Engl J Med 1996; 334:1417.
6.
Spragg RG, Lewis JF, Walmrath HD, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress
syndrome. N Engl J Med 2004; 351:884.
7.
Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit
Care Med 1997; 155:1309.
8.
Davidson WJ, Dorscheid D, Spragg R, et al. Exogenous pulmonary surfactant for the treatment of adult patients with acute respiratory distress
syndrome: results of a meta-analysis. Crit Care 2006; 10:R41.
9.
Willson DF, Thomas NJ, Markovitz BP, et al. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled
trial. JAMA 2005; 293:470.
10.
Calfactant for Direct Acute Respiratory Distress Syndrome (CARDS) http://clinicaltrials.gov/show/NCT00682500 (Accessed on May 16, 2014). 11.
Kerr CL, Ito Y, Manwell SE, et al. Effects of surfactant distribution and ventilation strategies on efficacy of exogenous surfactant. J Appl Physiol
(1985) 1998; 85:676.
12.
Ito Y, Manwell SE, Kerr CL, et al. Effects of ventilation strategies on the efficacy of exogenous surfactant therapy in a rabbit model of acute
lung injury. Am J Respir Crit Care Med 1998; 157:149.
13.
Albert RK. The role of ventilation-induced surfactant dysfunction and atelectasis in causing acute respiratory distress syndrome. Am J Respir
Crit Care Med 2012; 185:702.
14.
Taut FJ, Rippin G, Schenk P, et al. A Search for subgroups of patients with ARDS who may benefit from surfactant replacement therapy: a
pooled analysis of five studies with recombinant surfactant protein-C surfactant (Venticute). Chest 2008; 134:724.
15.
Spragg RG, Taut FJ, Lewis JF, et al. Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury. Am J Respir
Crit Care Med 2011; 183:1055.
16.
Zimmerman JJ. Surfactant is a target during acute lung injury inflammation. Crit Care Med 1996; 24:916. 17.
Hallman M, Spragg R, Harrell JH, et al. Evidence of lung surfactant abnormality in respiratory failure. Study of bronchoalveolar lavage
phospholipids, surface activity, phospholipase activity, and plasma myoinositol. J Clin Invest 1982; 70:673.
18.
Gregory, TJ, Longmore, WJ, Moxley, MA, et al. Surfactant chemical composition and biophysical activity in acute respiratory distress
syndrome. J Clin Invest 1991; 88:1976.
19.
Gattinoni L, Presenti A, Torresin A, et al. Adult respiratory distress syndrome profiles by computed tomography. J Thorac Imaging 1986; 1:25. 20.
Quinlan GJ, Lamb NJ, Tilley R, et al. Plasma hypoxanthine levels in ARDS: implications for oxidative stress, morbidity, and mortality. Am J
21.
Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in
patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group. Crit Care Med 1999; 27:1409.
22.
Singer P, Theilla M, Fisher H, et al. Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients
with acute lung injury. Crit Care Med 2006; 34:1033.
23.
Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung
injury. JAMA 2011; 306:1574.
24.
Stapleton RD, Martin TR, Weiss NS, et al. A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung
injury. Crit Care Med 2011; 39:1655.
25.
Bursten SL, Federighi DA, Parsons P, et al. An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute
respiratory distress syndrome. Crit Care Med 1996; 24:1129.
26.
Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care
Med 2002; 30:1.
27.
Laurent T, Markert M, Feihl F, et al. Oxidant-antioxidant balance in granulocytes during ARDS. Effect of N-acetylcysteine. Chest 1996; 109:163. 28.
Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study
Group. Chest 1997; 112:164.
29.
Jepsen S, Herlevsen P, Knudsen P, et al. Antioxidant treatment with N-acetylcysteine during adult respiratory distress syndrome: a prospective,
randomized, placebo-controlled study. Crit Care Med 1992; 20:918.
30.
Matute-Bello G, Liles WC, Radella F 2nd, et al. Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and
granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit Care Med 2000; 28:1.
31.
Paine R 3rd, Wilcoxen SE, Morris SB, et al. Transgenic overexpression of granulocyte macrophage-colony stimulating factor in the lung
prevents hyperoxic lung injury. Am J Pathol 2003; 163:2397.
32.
Baleeiro CE, Christensen PJ, Morris SB, et al. GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress. Am J
Physiol Lung Cell Mol Physiol 2006; 291:L1246.
33.
Paine R 3rd, Standiford TJ, Dechert RE, et al. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for 34.
5 of 11 8/3/2014 10:23 PM
patients with acute lung injury. Crit Care Med 2012; 40:90.
Herold S, Hoegner K, Vadsz I, et al. Inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute
respiratory distress syndrome. Am J Respir Crit Care Med 2014; 189:609.
35.
Rossaint R, Falke KJ, Lpez F, et al. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993; 328:399. 36.
Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial.
JAMA 2004; 291:1603.
37.
Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a
randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med 1998; 26:15.
38.
Adhikari NK, Burns KE, Friedrich JO, et al. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and
meta-analysis. BMJ 2007; 334:779.
39.
Afshari A, Brok J, Mller AM, Wetterslev J. Inhaled nitric oxide for acute respiratory distress syndrome and acute lung injury in adults and
children: a systematic review with meta-analysis and trial sequential analysis. Anesth Analg 2011; 112:1411.
40.
Adhikari NK, Dellinger RP, Lundin S, et al. Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome
regardless of severity: systematic review and meta-analysis. Crit Care Med 2014; 42:404.
41.
Pipeling MR, Fan E. Therapies for refractory hypoxemia in acute respiratory distress syndrome. JAMA 2010; 304:2521. 42.
Rossaint R, Gerlach H, Schmidt-Ruhnke H, et al. Efficacy of inhaled nitric oxide in patients with severe ARDS. Chest 1995; 107:1107. 43.
Manktelow C, Bigatello LM, Hess D, Hurford WE. Physiologic determinants of the response to inhaled nitric oxide in patients with acute
respiratory distress syndrome. Anesthesiology 1997; 87:297.
44.
Puybasset L, Rouby JJ, Mourgeon E, et al. Factors influencing cardiopulmonary effects of inhaled nitric oxide in acute respiratory failure. Am J
45.
Puri N, Dellinger RP. Inhaled nitric oxide and inhaled prostacyclin in acute respiratory distress syndrome: what is the evidence? Crit Care Clin
2011; 27:561.
46.
Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med 2005; 353:2683. 47.
Afshari A, Brok J, Mller AM, Wetterslev J. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children
and adults. Cochrane Database Syst Rev 2010; :CD002787.
48.
Zwissler B, Kemming G, Habler O, et al. Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respiratory distress syndrome. Am J
49.
Walmrath D, Schneider T, Schermuly R, et al. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress
syndrome. Am J Respir Crit Care Med 1996; 153:991.
50.
Ferring M, Vincent JL. Is outcome from ARDS related to the severity of respiratory failure? Eur Respir J 1997; 10:1297. 51.
Royston D. Inhalational agents for pulmonary hypertension. Lancet 1993; 342:941. 52.
van Heerden PV, Barden A, Michalopoulos N, et al. Dose-response to inhaled aerosolized prostacyclin for hypoxemia due to ARDS. Chest
2000; 117:819.
53.
Domenighetti G, Stricker H, Waldispuehl B. Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary
injury) and secondary (extrapulmonary injury) disease on gas exchange response. Crit Care Med 2001; 29:57.
54.
Afshari A, Brok J, Mller AM, Wetterslev J. Aerosolized prostacyclin for acute lung injury (ALI) and acute respiratory distress syndrome
(ARDS). Cochrane Database Syst Rev 2010; :CD007733.
55.
Sawheny E, Ellis AL, Kinasewitz GT. Iloprost improves gas exchange in patients with pulmonary hypertension and ARDS. Chest 2013; 144:55. 56.
Headley AS, Tolley E, Meduri GU. Infections and the inflammatory response in acute respiratory distress syndrome. Chest 1997; 111:1306. 57.
Steinberg KP, Milberg JA, Martin TR, et al. Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome. Am J Respir
Crit Care Med 1994; 150:113.
58.
Donnelly SC, Strieter RM, Reid PT, et al. The association between mortality rates and decreased concentrations of interleukin-10 and
interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome. Ann Intern Med 1996; 125:191.
59.
Davis WB, Wilson HE, Wall RL. Eosinophilic alveolitis in acute respiratory failure. A clinical marker for a non-infectious etiology. Chest 1986;
90:7.
60.
Tang BM, Craig JC, Eslick GD, et al. Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review
and meta-analysis. Crit Care Med 2009; 37:1594.
61.
Meduri GU, Marik PE, Chrousos GP, et al. Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature.
Intensive Care Med 2008; 34:61.
62.
Agarwal R, Nath A, Aggarwal AN, Gupta D. Do glucocorticoids decrease mortality in acute respiratory distress syndrome? A meta-analysis.
Respirology 2007; 12:585.
63.
Peter JV, John P, Graham PL, et al. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults:
meta-analysis. BMJ 2008; 336:1006.
64.
Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl
J Med 2006; 354:1671.
65.
Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 2007;
131:954.
66.
Kawashima M, yatsunami J, Fukuno Y, et al. Inhibitory effects of 14-membered ring macrolide antibiotics on bleomycin-induced acute lung
injury. Lung 2002; 180:73.
67.
Leiva M, Ruiz-Bravo A, Jimenez-Valera M. Effects of telithromycin in in vitro and in vivo models of lipopolysaccharide-induced airway
inflammation. Chest 2008; 134:20.
68.
6 of 11 8/3/2014 10:23 PM
Walkey AJ, Wiener RS. Macrolide antibiotics and survival in patients with acute lung injury. Chest 2012; 141:1153. 69.
Sakuma T, Okaniwa G, Nakada T, et al. Alveolar fluid clearance in the resected human lung. Am J Respir Crit Care Med 1994; 150:305. 70.
Sakuma T, Suzuki S, Usuda K, et al. Preservation of alveolar epithelial fluid transport mechanisms in rewarmed human lung after severe
hypothermia. J Appl Physiol (1985) 1996; 80:1681.
71.
Sartori C, Allemann Y, Duplain H, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 2002; 346:1631. 72.
Perkins GD, Gao F, Thickett DR. In vivo and in vitro effects of salbutamol on alveolar epithelial repair in acute lung injury. Thorax 2008; 63:215. 73.
Perkins GD, McAuley DF, Thickett DR, Gao F. The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am J
74.
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Matthay MA, Brower RG, et al.
Randomized, placebo-controlled clinical trial of an aerosolized -agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011;
184:561.
75.
Gao Smith F, Perkins GD, Gates S, et al. Effect of intravenous -2 agonist treatment on clinical outcomes in acute respiratory distress
syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 2012; 379:229.
76.
Perkins GD, Gates S, Park D, et al. The beta agonist lung injury trial prevention. A randomized controlled trial. Am J Respir Crit Care Med
2014; 189:674.
77.
Mac Sweeney R, McAuley DF. Mesenchymal stem cell therapy in acute lung injury: is it time for a clinical trial? Thorax 2012; 67:475. 78.
Zheng G, Huang L, Tong H, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a
randomized, placebo-controlled pilot study. Respir Res 2014; 15:39.
79.
http://clinicaltrials.gov/ct2/show/NCT01775774 (Accessed on May 16, 2014). 80.
Andrews PJ, Avenell A, Noble DW, et al. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill
patients. BMJ 2011; 342:d1542.
81.
Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med 2013;
368:1489.
82.
Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med 2013;
368:1489.
83.
Bone RC, Slotman G, Maunder R, et al. Randomized double-blind, multicenter study of prostaglandin E1 in patients with the adult respiratory
distress syndrome. Prostaglandin E1 Study Group. Chest 1989; 96:114.
84.
Abraham E, Baughman R, Fletcher E, et al. Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled,
randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group. Crit Care Med 1999; 27:1478.
85.
Zeiher BG, Artigas A, Vincent JL, et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med 2004;
32:1695.
86.
Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in
Sepsis Study Group. N Engl J Med 1997; 336:912.
87.
Liu KD, Levitt J, Zhuo H, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med
2008; 178:618.
88.
Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS
Network. JAMA 2000; 283:1995.
89.
Slotman GJ, Burchard KW, D'Arezzo A, Gann DS. Ketoconazole prevents acute respiratory failure in critically ill surgical patients. J Trauma
1988; 28:648.
90.
Yu M, Tomasa G. A double-blind, prospective, randomized trial of ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of the
adult respiratory distress syndrome. Crit Care Med 1993; 21:1635.
91.
Sinuff T, Cook DJ, Peterson JC, Fuller HD. Development, implementation, and evaluation of a ketoconazole practice guideline for ARDS
prophylaxis. J Crit Care 1999; 14:1.
92.
Williams JG, Maier RV. Ketoconazole inhibits alveolar macrophage production of inflammatory mediators involved in acute lung injury (adult
respiratory distress syndrome). Surgery 1992; 112:270.
93.
Simvastatin Effect on the Incidence of Acute Lung Injury/Adult Respiratory Distress Syndrome (ALI/ARDS) http://www.clinicaltrials.gov/ct2/show
/NCT01195428 (Accessed on February 08, 2012).
94.
National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, Truwit JD, Bernard GR, et al. Rosuvastatin for sepsis-associated acute
respiratory distress syndrome. N Engl J Med 2014; 370:2191.
95.
Topic 1618 Version 18.0
7 of 11 8/3/2014 10:23 PM
GRAPHICS
Effect of inhaled vasodilators on blood flow
Inhaled vasodilators (green circles) preferentially dilate the pulmonary
vessels (red lines) that perfuse functioning alveoli (white circles),
recruiting blood flow away from poorly ventilated units (black circles).
The net effect is improved ventilation/perfusion matching.
Graphic 56760 Version 3.0
8 of 11 8/3/2014 10:23 PM
Effects of inhaled prostacyclin and inhaled nitric
oxide on oxygenation and shunt fraction
Both inhaled prostacyclin (PGI2) and inhaled nitric oxide (NO) improved
arterial oxygenation and shunt fraction (QsQt) in patients with severe
ARDS who were treated sequentially with both agents.
Redrawn from Zwissler, B, Kemming, G, Habler, O, et al, Am J Respir Crit
Care Med 1996; 154:1671.
9 of 11 8/3/2014 10:23 PM
Effects of inhaled prostacyclin and inhaled nitric
oxide on pulmonary hemodynamics
The approximately equivalent efficacy of inhaled prostacyclin (PGI2) and
inhaled nitric oxide (NO) was demonstrated in eight patients with severe
ARDS who were treated sequentially with both agents.
Redrawn from Zwissler, B, Kemming, G, Habler, O, et al, Am J Respir Crit
Care Med 1996; 154:1671.
10 of 11 8/3/2014 10:23 PM
Disclosures: Mark D Siegel, MD Nothing to disclose. Polly E Parsons, MD Nothing to disclose. Geraldine Finlay, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through
requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
Disclosures
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