Targeting Transfusion-Related Acute Lung Injury: The Journey From Basic Science to Novel Therapies. (Colman)

Semple JW, et al. Targeting Transfusion-Related Acute Lung Injury: The Journey From Basic Science to Novel Therapies. Crit Care Med. 2018 May;46(5):e452-e458.

OBJECTIVES: Transfusion-related acute lung injury is characterized by the onset of respiratory distress and acute lung injury following blood transfusion, but its pathogenesis remains poorly understood. Generally, a two-hit model is presumed to underlie transfusion-related acute lung injury with the first hit being risk factors present in the transfused patient (such as inflammation), whereas the second hit is conveyed by factors in the transfused donor blood (such as antileukocyte antibodies). At least 80% of transfusion-related acute lung injury cases are related to the presence of donor antibodies such as antihuman leukocyte or antihuman neutrophil antibodies. The remaining cases may be related to nonantibody-mediated factors such as biolipids or components related to storage and ageing of the transfused blood cells. At present, transfusion-related acute lung injury is the leading cause of transfusion-related fatalities and no specific therapy is clinically available. In this article, we critically appraise and discuss recent preclinical (bench) insights related to transfusion-related acute lung injury pathogenesis and their therapeutic potential for future use at the patients’ bedside in order to combat this devastating and possibly fatal complication of transfusion.

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Effect of Inhaled Nitric Oxide on Outcomes in Children With Acute Lung Injury: Propensity Matched Analysis From a Linked Database. (Chaudhary)

Gupta P, Richardson T, Hall M, Bertoch D, Hebbar KB, Fortenberry JD, Wetzel
RC. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. Crit Care Med. 2016 Oct;44(10):1901-9.

OBJECTIVES: To evaluate the effect of inhaled nitric oxide on outcomes in children with acute lung injury.

DESIGN: Retrospective study with a secondary data analysis of linked data from two national databases. Propensity score matching was performed to adjust for potential confounding variables between patients who received at least 24 hours of inhaled nitric oxide (inhaled nitric oxide group) and those who did not receive inhaled nitric oxide (no inhaled nitric oxide group).

SETTING: Linked data from Virtual Pediatric Systems (LLC) database and Pediatric Health Information System.

PATIENTS: Patients less than 18 years old receiving mechanical ventilation for acute lung injury at nine participating hospitals were included (2009-2014).


MEASUREMENTS AND MAIN RESULTS: A total of 20,106 patients from nine hospitals were included. Of these, 859 patients (4.3%) received inhaled nitric oxide for at least 24 hours during their hospital stay. Prior to matching, patients in the inhaled nitric oxide group were younger, with more comorbidities, greater severity of illness scores, higher prevalence of cardiopulmonary resuscitation, and greater resource utilization. Before matching, unadjusted outcomes, including mortality, were worse in the inhaled nitric oxide group (inhaled nitric oxide vs no inhaled nitric oxide; 25.7% vs 7.9%; p < 0.001; standardized mortality ratio, 2.6 [2.3-3.1] vs 1.1 [1.0-1.2]; p < 0.001). Propensity score matching of 521 patient pairs revealed no difference in mortality in the two groups (22.3% vs 20.2%; p = 0.40; standardized mortality ratio, 2.5 [2.1-3.0] vs 2.3 [1.9-2.8]; p = 0.53). However, the other outcomes such as ventilation free days (10.1 vs 13.6 d; p < 0.001), duration of mechanical ventilation (13.8 vs 10.1 d; p < 0.001), duration of ICU and hospital stay (15.5 vs 12.2 d; p < 0.001 and 28.0 vs 24.1 d; p < 0.001), and hospital costs ($150,569 vs $102,823; p < 0.001) were significantly worse in the inhaled nitric oxide group.

CONCLUSIONS: This large observational study demonstrated that inhaled nitric oxide administration in children with acute lung injury was not associated with improved mortality. Rather, it was associated with increased hospital utilization and hospital costs.

Tidal volume and mortality in mechanically ventilated children: a systematic review and meta-analysis of observational studies. (Fortenberry)

de Jager P, Burgerhof JG, van Heerde M, et al. Tidal volume and mortality in mechanically ventilated children: a systematic review and meta-analysis of observational studies*. Crit Care Med. 2014 Dec;42(12):2461-72.

Full-text for Children’s and Emory users.

OBJECTIVE: To determine whether tidal volume is associated with mortality in critically ill, mechanically ventilated children.

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Pediatric calfactant in acute respiratory distress syndrome trial. (Dugan)

Willson DF, Thomas NJ, Tamburro R, Truemper E, Truwit J, Conaway M, Traul C, Egan EE; Pediatric Acute Lung and Sepsis Investigators Network. Pediatric Calfactant in Acute Respiratory Distress Syndrome Trial*. Pediatr Crit Care Med. 2013 Sep;14(7):657-665.

RATIONALE: Our previous studies in children with acute lung injury/acute respiratory distress syndrome demonstrated improved outcomes with exogenous surfactant (calfactant) administration. Sample sizes in those studies were small, however, and the subject populations heterogeneous, thus making recommendations tenuous.

OBJECTIVE: To investigate the efficacy of surfactant administration in a larger, more homogenous population of children with lung injury/acute respiratory distress syndrome due to direct lung injury.

DESIGN AND SETTING: Masked, randomized, placebo-controlled trial in 24 children’s hospitals in six different countries.

PATIENTS AND METHODS: Children 37 weeks postconception to 18 years old with lung injury/acute respiratory distress syndrome due to direct lung injury were randomized to receive up to three doses of 30 mg/cm height of surfactant (calfactant) versus placebo (air) within 48 hours of intubation and initiation of mechanical ventilation. The primary outcome was mortality at 90 days. Ventilator-free days, changes in oxygenation, and adverse events were also assessed.

RESULTS: The study was stopped at the sponsor’s request after the second interim analysis for presumed futility. A total of 110 subjects were enrolled, with consent withdrawn from one whose data are unavailable. There were no significant differences between groups except in hospital-free days (10.4 ± 7.8 placebo vs 6.4 ± 7.8 surfactant; p = 0.01). Overall 90-day mortality was 11% (seven surfactant, five placebo). No immediate improvement in oxygenation was associated with surfactant administration.

CONCLUSIONS: Surfactant did not improve outcomes relative to placebo in this trial of children with direct lung injury/acute respiratory distress syndrome. Differences in concentration of the surfactant, failure to recruit the lung during surfactant administration, or using two rather than four position changes during administration are possible explanations for the difference from previous studies. Exogenous surfactant cannot be recommended at this time for children with direct lung injury/acute respiratory distress syndrome.

Full-text for Children’s and Emory users.