Preemptive application of airway pressure release ventilation prevents development of acute respiratory distress syndrome in a rat traumatic hemorrhagic shock model.

BACKGROUND: Once established, the acute respiratory distress syndrome (ARDS) is highly resistant to treatment and retains a high mortality. We hypothesized that preemptive application of airway pressure release ventilation (APRV) in a rat model of trauma/hemorrhagic shock (T/HS) would prevent ARDS. METHODS: Rats were anesthetized, instrumented for hemodynamic monitoring, subjected to T/HS, and randomized into two groups: (a) volume cycled ventilation (VC) (n = 5, tidal volume 10 mL/kg; positive end-expiratory pressure 0.5 cmH(2)O) or (b) APRV (n = 4, P(high) = 15-20 cmH(2)O; T(high) = 1.3-1.5 s to achieve 90% of the total cycle time; T(low) = 0.11-0.14 s, which was set to 75% of the peak expiratory flow rate; P(low) = 0 cmH(2)O). Study duration was 6 h. RESULTS: Airway pressure release ventilation prevented lung injury as measured by PaO(2)/FIO(2) (VC 143.3 ± 42.4 vs. APRV 426.8 ± 26.9, P < 0.05), which correlated with a significant decrease in histopathology as compared with the VC group. In addition, APRV resulted in a significant decrease in bronchoalveolar lavage fluid total protein, increased surfactant protein B concentration, and an increase in epithelial cadherin tissue expression. In vivo microscopy demonstrated that APRV significantly improved alveolar patency and stability as compared with the VC group. CONCLUSIONS: Our findings demonstrate that preemptive mechanical ventilation with APRV attenuates the clinical and histologic lung injury associated with T/HS. The mechanism of injury prevention is related to preservation of alveolar epithelial and endothelial integrity. These data support our hypothesis that preemptive APRV, applied using published guidelines, can prevent the development of ARDS.

Jack of all trades: pleiotropy and the application of chemically modified tetracycline-3 in sepsis and the acute respiratory distress syndrome (ARDS).

Sepsis is a disease process that has humbled the medical profession for centuries with its resistance to therapy, relentless mortality, and pathophysiologic complexity. Despite 30 years of aggressive, concerted, well-resourced efforts the biomedical community has been unable to reduce the mortality of sepsis from 30%, nor the mortality of septic shock from greater than 50%. In the last decade only one new drug for sepsis has been brought to the market, drotrecogin alfa-activated (Xigris™), and the success of this drug has been limited by patient safety issues. Clearly a new agent is desperately needed. The advent of recombinant human immune modulators held promise but the outcomes of clinical trials using biologics that target single immune mediators have been disappointing. The complex pathophysiology of the systemic inflammatory response syndrome (SIRS) is self-amplifying and redundant at multiple levels. In this review we argue that perhaps pharmacologic therapy for sepsis will only be successful if it addresses this pathophysiologic complexity; the drug would have to be pleiotropic, working on many components of the inflammatory cascade at once. In this context, therapy that targets any single inflammatory mediator will not adequately address the complexity of SIRS. We propose that chemically modified tetracycline-3, CMT-3 (or COL-3), a non-antimicrobial modified tetracycline with pleiotropic anti-inflammatory properties, is an excellent agent for the management of sepsis and its associated complication of the acute respiratory distress syndrome (ARDS). The purpose of this review is threefold: (1) to examine the shortcomings of current approaches to treatment of sepsis and ARDS in light of their pathophysiology, (2) to explore the application of COL-3 in ARDS and sepsis, and finally (3) to elucidate the mechanisms of COL-3 that may have potential therapeutic benefit in ARDS and sepsis.