ECMO is an intensive treatment that is currently used to support patients with respiratory or cardiac failure who are unresponsive to conventional therapeutic interventions. However, ECMO treatments for adult ARDS patients were controversial until a recent date even though the use of ECMO is occurring more commonly^2,3. In 2009, a randomized controlled study (known as Central European Society for Anticancer Research [CESAR] study) indicated that more patients with severe ARDS survived significantly if they were treated in an ECMO center compared with patients who were managed conventionally⁴. CESAR study was the first randomized controlled trial (RCT) report to show positive result of ECMO for ARDS.

This study by Noah et al.¹ present evidence in support of ECMO as a treatment strategy early in the course of ARDS related to H1N1 infection. However, this study has some limitations. Some ARDS patients were required transfer to specialized ECMO centers. The design of this study makes it unclear whether the mortality benefit associated with ECMO was attributable to management of severe respiratory failure in a specialized center or to the use of ECMO. To consider ECMO as a potential treatment modality for severe ARDS from all causes, large RCTs are needed.

Another study with very similar design of this study was reported in the same issue of the journal consicutively⁶. Both studies represent corticosteroids were harmful in critically ill patients with influenza A H1N1 infection. Many clinicians used corticosteroids to patients with acute lung injury (ALI)/ARDS to reduce lung inflammation and hope improving clinical outcomes. However, no randomized clinical trials have been performed to confirm the effects of steroids in ALI/ARDS by acute viral pneumonia. Given the acute nature of the H1N1 influenza pandemic, a prospective randomized trial was not possible. To overcome this problem, the authors used several analytic techniques to adjust for differences in the steroid-treated and non-treated groups to compare clinical outcomes. These two studies showed very similar results in spite of different ethnic groups. So, my view is that steroids should not be used in severe viral pneumonia, unless new study provides evidence that steroids are beneficial.

Early goal-directed quantitative resuscitation refers to the use of a specific protocol that targets predefined physiological or laboratory goals to be achieved within the first several hours. Results of a recent meta-analysis indicated a survival benefit associated with the use of this strategy applied to heterogeneous populations of patients with sepsis⁸.

The optimal method for determining tissue oxygen delivery remains uncertain. Published practice surveys have shown that the expertise technique and specialized equipment required to measure ScvO₂ make a major barrier to the completion of this protocol⁹. In contrast, lactate clearance, derived from calculating the change in lactate concentration from 2 blood specimens drawn at different times, potentially represents a more accessible method to assess tissue oxygen delivery. The authors of this study observed that management to normalize lactate clearance in initial sepsis treatment has suspicious benefit. However, only a small fraction (10%) of enrolled patients received therapies (dobutamine or transfusions) that influenced by the resuscitation targets being compared. So interpretation of the results is somewhat complicated. Nevertheless, the data support the noninferiority of the lactate guidance strategy.

Despite many studies have emphasized the importance of lactate targeted treatment in prognosis of sepsis, little evidence exists on what interventions would benefit patients with increased lactate levels or a failure to reduce lactate¹¹. In this study, patients with increased lactate level on ICU admission, lactate lowering treatment significantly reduced ICU length of stay, ICU and hospital. This study suggests that initial treatment aimed at reducing lactate levels has clinical benefit.

Beta-2 agonists activate Beta-2 receptors on alveolar type-1 and type-2 cells, which increases intracellular cAMP, leading to increased sodium transport and acceleration of alveolar fluid reabsorption. Findings from the β-agonist lung injury trial (BALTI) showed that an infusion of salbutamol caused significant reductions in extravascular lung¹³. However, the results of the truncated BALTI-2 trial are very disappointed and sufficient to change practice. Beta-2 agonist treatment in patients with ARDS should be limited to the treatment of clinically important reversible airway obstruction and should not be part of routine care.

The potential value of aerosolized beta 2-agonist therapy for treatment of acute lung injury has not been tested previously in a phase III, randomized clinical trial. The results of this randomized double-blind clinical trial demonstrate that aerosolized b2-agonist therapy with albuterol did not improve clinical outcomes in patients with acute lung injury. However, the majority of animal studies of ALI demonstrating a benefit used beta2-agonists as a pre-injury treatment. Though treatment role of beta-agonists for ALI has not been proved, the potential role in the prophylactic setting is expected. Several studies are ongoing to investigate this possibility.

Because artificial nutrition showed potential effects on clinical outcomes in critically ill patients during the last decade, nutrition is now considered therapy not supportive care^16,17. Therefore, it was unexpected and disappointing that enrollment was suspended early in the OMEGA trial because of perceived futility. There are several possible explanations for these negative results. For example, although all patients in the OMEGA trial received a similar number of calories (but by design a different composition of lipids), the control group received up to 20 g of additional protein per day from the control solution. Delivery of a different amount of protein perhaps favorably influenced outcomes in that group. An alternative explanation is that because continuous administration of these supplements appeared beneficial in prior trials, perhaps the bolus delivery method used in this trial blunted the inflammation modulation effect.

Abundant evidence exists in sepsis for the appearance of high plasma levels of proinflammatory cytokines and chemokines characterized by clinical signs of fever, tachycardia, and tachypnea and followed rapidly by development of shock, multiorgan failure, and death. Additional evidence indicates that sepsis can be associated with a state of immunosuppression, broadly defined as lymphopenia and loss of immune function, though the timing, incidence, and nature of the immunosuppression remain poorly characterized, especially in humans. Numerous investigative agents have been directed at down modulating this initial hyperimmune phase. After numerous unsuccessful trials of anti-inflammatory agents in patients with sepsis, a major shift has occurred in the way investigators view the problem of sepsis¹⁹. Those who survive early sepsis often develop nosocomial infections with organisms not typically pathogenic in immunocompetent hosts and have reactivation of latent viruses. Sepsis may not be attributable solely to a "cytokine storm" but may indicate an immune system that is severely compromised and unable to eradicate pathogens. Although animal studies demonstrate progression to an immunosuppressive phase, epidemiologic studies in clinical sepsis are lacking²⁰. In this study, the authors have presented an informative report documenting immunosuppression in humans with septic shock. A next step might be to determine why during sepsis immune cells switch to anti-immune cells. Another question is whether such derangements in sepsis can be reversed by treatment with immune restoring agents.

Irrespective of the underlying cause, the treatment of shock includes initial resuscitation with vasopressor and volume. A critical question is which vasopressor should be used initially. Dopamine and norepinephrine may have different effects on the kidney, the splanchnic region, and the pituitary axis, but the 9 clinical implications of these differences are still uncertain. Guidelines recommend that either agent may be used as a first-choice vasopressor in patients with shock. However, observational studies have shown that the administration of dopamine may be associated with higher rates of death than those associated with the administration of norepinephrine. In this study, the authors conclude that their study raises serious concerns about the safety of dopamine. However, a few important limitations of this study are noted. First, the authors defined the adequate administration of fluids as at least 1 L of crystalloids or 500 mL of colloids. This seems to be not sufficient for septic or hypovolemic shock. Second, the authors suggest that they used "equipotent" doses of vasopressors, equating 20µg per kilogram of body weight per minute of dopamine with 0.19µg per kilogram per minute of norepinephrine. However, the evidence of this equipotent does not exist. A remaining question is the role of vasopressin as a therapeutic agent for shock. In this study, the authors used vasopressin as rescue therapy, and only two patients in each group received vasopressin. Vasopressin is another direct-acting agent. Previous studies have compared that norepinephrine and vasopressin among patients with septic shock²². Vasopressin may be as effective as norepinephrine.