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Background: Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS., Methods: We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to 5 consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level ≥10%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster-Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes., Results: No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% ± 0.7% [cohort 1]; 4.9% ± 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% ± 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R2 = 0.9205; P < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects., Conclusion: Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials., Trial Registration: ClinicalTrials.gov NCT02425579., Funding: NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695.

The injurious effects of alveolar overdistention are well accepted, and there is little debate regarding the importance of pressure and volume limitation during mechanical ventilation. The role of recruitment maneuvers is more controversial. Alveolar recruitment is desirable if it can be achieved, but the potential for recruitment is variable among patients with ARDS. A stepwise recruitment maneuver, similar to an incremental PEEP titration, is favored over sustained inflation recruitment maneuvers. Many approaches to PEEP titration have been proposed, and the best method to choose the most appropriate level for an individual patient is unclear. A PEEP level should be selected that balances alveolar recruitment against overdistention. The easiest approach to select PEEP might be according to the severity of the disease: 5-10 cm H2O PEEP in mild ARDS, 10-15 cm H2O PEEP in moderate ARDS, and 15-20 cm H2O PEEP in severe ARDS. Recruitment maneuvers and PEEP should be used within the context of lung protection and not just as a means of improving oxygenation., (Copyright © 2015 by Daedalus Enterprises.)

Respiratory mechanics refers to the expression of lung function through measures of pressure and flow. From these measurements, a variety of derived indices can be determined, such as volume, compliance, resistance, and work of breathing. Plateau pressure is a measure of end-inspiratory distending pressure. It has become increasingly appreciated that end-inspiratory transpulmonary pressure (stress) might be a better indicator of the potential for lung injury than plateau pressure alone. This has resulted in a resurgence of interest in the use of esophageal manometry in mechanically ventilated patients. End-expiratory transpulmonary pressure might also be useful to guide the setting of PEEP to counterbalance the collapsing effects of the chest wall. The shape of the pressure-time curve might also be useful to guide the setting of PEEP (stress index). This has focused interest in the roles of stress and strain to assess the potential for lung injury during mechanical ventilation. This paper covers both basic and advanced respiratory mechanics during mechanical ventilation., (Copyright © 2014 by Daedalus Enterprises.)

Lung-protective ventilator strategies are considered standard practice in the care of patients with the acute respiratory distress syndrome (ARDS). To minimize ventilator-induced lung injury, attention is directed at avoidance of alveolar overdistention and cyclical opening and closing. The lowest possible plateau pressure and tidal volume (V(T)) should be selected. A reasonable target V(T) in all mechanically ventilated patients is 6 mL/kg. A topic of much controversy is the optimal setting of positive end-expiratory pressure (PEEP). Results of a meta-analysis using individual patient data from three randomized controlled trials suggest that higher PEEP should be used for moderate and severe ARDS, whereas lower PEEP may be more appropriate in patients with mild ARDS. PEEP should be set to maximize alveolar recruitment while avoiding overdistention. Volume and pressure limitation during mechanical ventilation can be described in terms of stress and strain. Fraction of inspired oxygen (Fio(2)) and PEEP are typically titrated to maintain arterial oxygen saturation (Spo(2)) of 88 to 95% (Pao(2) 55-80 mm Hg). There is currently no clear proven benefit for advanced modes., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objectives: Acute respiratory distress syndrome develops commonly in critically ill patients in response to an injurious stimulus. The prevalence and risk factors for development of acute respiratory distress syndrome after spontaneous intracerebral hemorrhage have not been reported. We sought to determine the prevalence of acute respiratory distress syndrome after intracerebral hemorrhage, characterize risk factors for its development, and assess its impact on patient outcomes., Design: Retrospective cohort study at two academic centers., Patients: We included consecutive patients presenting from June 1, 2000, to November 1, 2010, with intracerebral hemorrhage requiring mechanical ventilation. We excluded patients with age less than 18 years, intracerebral hemorrhage secondary to trauma, tumor, ischemic stroke, or structural lesion; if they required intubation only during surgery; if they were admitted for comfort measures; or for a history of immunodeficiency., Interventions: None., Measurements and Main Results: Data were collected both prospectively as part of an ongoing cohort study and by retrospective chart review. Of 1,665 patients identified by database query, 697 met inclusion criteria. The prevalence of acute respiratory distress syndrome was 27%. In unadjusted analysis, high tidal volume ventilation was associated with an increased risk of acute respiratory distress syndrome (hazard ratio, 1.79 [95% CI, 1.13-2.83]), as were male sex, RBC and plasma transfusion, higher fluid balance, obesity, hypoxemia, acidosis, tobacco use, emergent hematoma evacuation, and vasopressor dependence. In multivariable modeling, high tidal volume ventilation was the strongest risk factor for acute respiratory distress syndrome development (hazard ratio, 1.74 [95% CI, 1.08-2.81]) and for inhospital mortality (hazard ratio, 2.52 [95% CI, 1.46-4.34])., Conclusions: Development of acute respiratory distress syndrome is common after intubation for intracerebral hemorrhage. Modifiable risk factors, including high tidal volume ventilation, are associated with its development and in-patient mortality.

To minimize ventilator-induced lung injury, attention should be directed toward avoidance of alveolar over-distention and cyclical opening and closure of alveoli. The most impressive study of mechanical ventilation to date is the Acute Respiratory Distress Syndrome (ARDS) Network study of higher versus lower tidal volume (V(T)), which reported a reduction in mortality from 39.8% to 31.0% with 6 mL/kg ideal body weight rather than 12 mL/kg ideal body weight (number-needed-to-treat of 12 patients). To achieve optimal lung protection, the lowest plateau pressure and V(T) possible should be selected. What is most important is limitation of V(T) and alveolar distending pressure, regardless of the mode set on the ventilator. Accumulating observational evidence suggests that V(T) should be limited in all mechanically ventilated patients-even those who do not have ALI/ARDS. Evidence does not support the use of pressure controlled inverse-ratio ventilation. Although zero PEEP is probably injurious, an area of considerable controversy is the optimal setting of PEEP. Available evidence does not support the use of higher PEEP, compared to lower PEEP, in unselected patients with acute lung injury (ALI)/ARDS. However, results of a meta-analysis using individual patients from 3 randomized controlled trials suggest that higher PEEP should be used for ARDS, whereas lower PEEP may be more appropriate in patients with ALI. PEEP should be set to maximize alveolar recruitment while avoiding over-distention. Many approaches for setting PEEP have been described, but evidence is lacking that any one approach is superior to any other. In most, if not all, cases of ALI/ARDS, conventional ventilation strategies can be used effectively to provide lung-protective ventilation strategies.

ARDS is characterized by hypoxemic respiratory failure, which can be refractory and life-threatening. Modifications to traditional mechanical ventilation and nontraditional modes of ventilation are discussed in Part 1 of this two-part series. In this second article, we examine nonventilatory strategies that can influence oxygenation, with particular emphasis on their role in rescue from severe hypoxemia. A literature search was conducted and a narrative review written to summarize the use of adjunctive, nonventilatory interventions intended to improve oxygenation in ARDS. Several adjunctive interventions have been demonstrated to rapidly ameliorate severe hypoxemia in many patients with severe ARDS and therefore may be suitable as rescue therapy for hypoxemia that is refractory to prior optimization of mechanical ventilation. These include neuromuscular blockade, inhaled vasoactive agents, prone positioning, and extracorporeal life support. Although these interventions have been linked to physiologic improvement, including relief from severe hypoxemia, and some are associated with outcome benefits, such as shorter duration of mechanical ventilation, demonstration of survival benefit has been rare in clinical trials. Furthermore, some of these nonventilatory interventions carry additional risks and/or high cost; thus, when used as rescue therapy for hypoxemia, it is important that they be demonstrated to yield clinically significant improvement in gas exchange, which should be periodically reassessed. Additionally, various management strategies can produce a more gradual improvement in oxygenation in ARDS, such as conservative fluid management, intravenous corticosteroids, and nutritional modification. Although improvement in oxygenation has been reported with such strategies, demonstration of additional beneficial outcomes, such as reduced duration of mechanical ventilation or ICU length of stay, or improved survival in randomized controlled trials, as well as consideration of potential adverse effects should guide decisions on their use. Various nonventilatory interventions can positively impact oxygenation as well as outcomes of ARDS. These interventions may be considered for use, particularly for cases of refractory severe hypoxemia, with proper appreciation of potential costs and adverse effects.

Approximately 16% of deaths in patients with ARDS results from refractory hypoxemia, which is the inability to achieve adequate arterial oxygenation despite high levels of inspired oxygen or the development of barotrauma. A number of ventilator-focused rescue therapies that can be used when conventional mechanical ventilation does not achieve a specific target level of oxygenation are discussed. A literature search was conducted and narrative review written to summarize the use of high levels of positive end-expiratory pressure, recruitment maneuvers, airway pressure-release ventilation, and high-frequency ventilation. Each therapy reviewed has been reported to improve oxygenation in patients with ARDS. However, none of them have been shown to improve survival when studied in heterogeneous populations of patients with ARDS. Moreover, none of the therapies has been reported to be superior to another for the goal of improving oxygenation. The goal of improving oxygenation must always be balanced against the risk of further lung injury. The optimal time to initiate rescue therapies, if needed, is within 96 h of the onset of ARDS, a time when alveolar recruitment potential is the greatest. A variety of ventilatory approaches are available to improve oxygenation in the setting of refractory hypoxemia and ARDS. Which, if any, of these approaches should be used is often determined by the availability of equipment and clinician bias.

In patients with acute respiratory distress syndrome (ARDS), inhaled vasodilator can result in important physiologic benefits (eg, improved hypoxemia, lower pulmonary arterial pressure, and improved right-ventricular function and cardiac output) without systemic hemodynamic effects. Inhaled nitric oxide (INO) and aerosolized prostacyclins are currently the most frequently used inhaled vasodilators. Inhaled prostacyclins are as effective physiologically as INO and cost less. Randomized controlled trials of INO in the treatment of ARDS have shown short-term physiologic benefits, but no benefit in long-term outcomes. No outcome studies have been reported on the use of prostacyclin in patients with ARDS. There is no role for the routine use of inhaled vasodilators in patients with ARDS. Inhaled vasodilator as a rescue therapy for severe refractory hypoxemia in patients with ARDS may be reasonable, but is controversial.

Objective: Previously published methods to assess the chest wall effect on total respiratory system pressure-volume (P-V) curves in acute respiratory distress syndrome have been performed on the lung and chest wall in isolation. We sought to quantify the effect of the chest wall by considering the chest wall and lung in series., Design: Prospective study., Setting: Academic health center medical and surgical intensive care units., Patients: Twenty-two patients with acute respiratory distress syndrome/acute lung injury., Interventions: Using a sigmoidal equation, we fit the pressure-volume data of the lung alone, and defined for each curve the pressure at the point of maximum compliance increase (Pmci), decrease (Pmcd), and the point of inflection (Pinf). We calculated the pressure to which the total respiratory system must be inflated to achieve a volume that would place the lung at each point of interest. We compared these "corrected" pressures (Pmci,c, Pmcd,c, and Pinf,c) to the measured values of the total respiratory system., Measurements and Main Results: The average difference between Pmci and Pmci,c was 0.12 cm H2O on inflation (2sd = 5.6 cm H2O) and -1.4 cm H2O on deflation (2sd = 5.0 cm H2O); between Pmcd and Pmcd,c was 1.73 cm H2O on inflation (2sd = 4.5 cm H2O) and -0.15 cm H2O on deflation (2sd = 4.9 cm H2O); and between Pinf and Pinf,c was 0.14 cm H2O on inflation (2sd = 6.7 cm H2O) and -0.35 cm H2O on deflation (2sd = 5.0 cm H2O)., Conclusions: This method of "correcting" the total respiratory system P-V curve for the chest wall allows for calculation of an airway pressure that would place the lung at a desired volume on its P-V curve. For most patients, the chest wall had little influence on the total respiratory system P-V curve. However, there were patients in whom the chest wall did potentially have clinical significance.

The current understanding of lung mechanics and ventilator-induced lung injury suggests that patients who have acute respiratory distress syndrome should be ventilated in such a way as to minimize alveolar over-distension and repeated alveolar collapse. Clinical trials have used such lung protective strategies and shown a reduction in mortality; however, there is data that these "one-size fits all" strategies do not work equally well in all patients. This article reviews other methods that may prove useful in monitoring for potential lung injury: exhaled breath condensate, pressure-volume curves, and esophageal manometry. The authors explore the concepts, benefits, difficulties, and relevant clinical trials of each.

Purpose of Review: There has recently been renewed interest in the chest wall during mechanical ventilation, related to lung-protective ventilation strategies, as well as in the role of abdominal pressure in many facets of critical illness. The purpose of this review is to address relevant issues related to the chest wall and mechanical ventilation, particularly in patients with acute lung injury/acute respiratory distress syndrome., Recent Findings: In mechanically ventilated patients with acute lung injury, intra-abdominal pressure is an important determinant of chest wall compliance. With elevated intra-abdominal pressure, the compliance of the chest wall and total respiratory system is decreased, with a relatively normal compliance of the lungs. The lung compression effects of increased intra-abdominal pressure may lead to a loss of lung volume with atelectasis. An appropriate level of positive end-expiratory pressure is necessary to counterbalance this collapsing effect on the lungs. Also, the stiff chest wall results in a lower transpulmonary pressure during positive-pressure ventilation., Summary: As chest wall compliance may have important clinical implications during positive-pressure ventilation, the physiology of this effect should be considered, particularly in patients with acute lung injury and increased abdominal pressure.

High-frequency ventilation is the application of mechanical ventilation with a respiratory rate > 100 breaths/min. High-frequency oscillatory ventilation (HFOV) is the form of high-frequency ventilation most widely used in adult critical care. The principles of lung-protective ventilation have matured in parallel with the technology for HFOV. The 2 basic principles of lung-protective ventilation are the use of small tidal volume and maintenance of adequate alveolar recruitment. Research in animal models and humans demonstrate that HFOV can support gas exchange with much smaller tidal volume than can be achieved with conventional ventilation. HFOV also provides more effective lung recruitment than conventional mechanical ventilation. However, at present, evidence is lacking that survival in adults with acute respiratory distress syndrome is improved by HFOV. Although HFOV may improve P(aO(2)) in some patients, this improvement is often transitory. Available evidence does not support that pulmonary inflammation is reduced with HFOV in adult acute respiratory distress syndrome. Heavy sedation and often paralysis are necessary. The promise of HFOV as a lung-protective ventilation strategy remains attractive, but additional clinical trials are needed to determine whether this approach is superior to lung-protective ventilation with conventional mechanical ventilation.

Acute lung injury and acute respiratory distress syndrome are inflammatory conditions involving a broad spectrum of lung injury from mild respiratory abnormality to severe respiratory derangement. Regardless of cause (direct or indirect lung injury), pulmonary physiology and mechanics are altered, leading to hypoxemic respiratory failure. the use of positive pressure ventilation itself may cause lung injury (ventilator-induced lung injury, or VILI). VILI may amplify preexisting injury, delay lung recovery, and result in adverse outcomes. This article examines the evidence supporting lung-protective ventilation strategies and addresses the methods, outcomes, and potential obstacles to implementation of such approaches.