|
July 1997
Pretreatment with inhaled nitric oxide inhibits neutrophil migration and oxidative activity resulting in attenuated sepsis-induced acute lung injury.
Bloomfield GL; Halloway, S; Ridings PC; Fisher BJ; Blocher CR; Sholley M; Bunch T; Sugerman HJ; Fouler AA.
Critical Care Medicine 1997;25:584-593.
[ see abstract below ]
In this paper by Bloomfield, et al., the authors emphasize that gram negative sepsis in adult respiratory distress syndrome are majors causes of morbidity and mortality in hospitalized patients--up to 500,000 patients per year are affected with a mortality rate of about 50%. Adult respiratory distress syndrome (ARDS) affects about 43% of patients with sepsis and is associated with mortality rates approaching 80%-90% when associated with other organ failure. Although a variety of promising strategies have been deployed in the treatment of ARDS, none have proven to be singularly affective.
Inhaled nitric oxide gas is a therapy which has promise in the treatment of acute lung injury, although the mechanisms by which this is achieved are not defined. These authors used a porcine model of distress syndrome induced by gram-negative sepsis to examine these various mechanisms of therapeutic action produced by nitric-oxide.
The underlying hypothesis was that inhaled nitric oxide may reduce neutrophil-dependent acute lung injury by interfering with adhesive interactions between pulmonary endothelium and activated neutrophils. The lung injury model that is used for this study is known to be highly dependent on the adhesion and sequestration of activated neutrophils within the lung.
In this study, the authors report that nitric oxide attenuates sepsis-induced acute lung injury. They also show that markers of alveolar-capillary membrane injury, including bronchoaveolar lavage protein content, neutrophil count, and PaO2 are improved by nitric oxide treatment. Additionally, they found that nitric oxide attenuated neutrophil priming for oxidant bursts, and, finally, that the transendothelial migration of activated neutrophils was inhibited by nitric oxide, even though neutrophil sequestration in the lung was about the same in treated and untreated septic animals.
The authors concluded that inhaled nitric oxide attenuates alveolar-capillary membrane injury in the porcine model of gram-negative sepsis, but does not adversely effect systemic hemodynamics. The observed preservation of alveolar-capillary membrane integrity associated with nitric oxide in this model may be a result of; a) inhibiting transendothelial migration of activated, tightly adherent neutrophils; and b) possible attenuation of the neutrophil oxidant bursts.
As indicated in his editorial (Eichacher, Peter Q., Critical Medicine, 1997, Vol. 25, No. 4: "Inhaled Nitric-Oxide in Adult Respiratory Distress Syndrome: Do We Know the Risks vs. Benefits,") Eichacher acknowledges the potentially important clinical implications of the present study. Appropriately, some caution should be exercised before concluding that nitric oxide is of uniform benefit in treatment of acute lung injury.
Dr. Eichacher and others represent the perspective that if acute exposure to inhaled nitric oxide limits leukocyte migration in oxidant function, it is also reasonable to consider that, in longer-term exposures it may interfere with normal host defense mechanisms, a potentially harmful characteristic of the drug. In the present article by Dr. Bloomfield, et al., animals were observed for a relatively brief period of time after challenge with bacteria, following which the reductions in leukocytic migration and oxidant function with inhaled nitric oxide were viewed as beneficial.
In the clinical environment in which ARDS patients are treated with nitric oxide, exposures to the drug have continued over periods extending from several days to weeks. The continued benefits of nitric oxide need to be considered under these different conditions, particularly in those patients with pulmonary infection.
The introduction of nitric oxide in the treatment of ARDS was initiated on the basis of a limited pre-clinical experience, and then subsequent controlled case studies served as the basis for treatment with ARDS in Europe. More controlled and targeted systematic studies of the effects of nitric oxide in patients with ARDS have been conducted over the last several years.
Prospective, controlled studies evaluating the benefits and specific effects of inhaled nitric oxide in ARDS have been very slow in coming. Some of the recent reviews of the outcomes related to nitric oxide therapy in ARDS have been disappointing in terms of clinical benefit. Given the multi-factorial nature of ARDS, it should be of no surprise to anyone that no single drug is likely to provide uniform benefits.
Finally, Eichacher raises the caution that prolonged exposure to inhaled nitric oxide appears to alter pulmonary arterial reactivity, which may lead to life threatening alterations in hemodynamics and oxygen exchange when nitric oxide treatment is discontinued.
Although the article by Bloomfield, et al., is in itself very well done and of significant value and promise from a mechanistic perspective, it is also serves to exemplify the need to view the results of individual controlled laboratory studies in the larger context of the clinical environment in which such information would be applied before generalizing the principles learned from a specific study.
The authors of this paper have done a fine job and their work helps to underscore the need for further, more clearly defined clinical trials of the risk and benefits associate with inhaled nitric oxide in ARDS.
Return to the Current Literature Review Front Page, or read the abstract:
ABSTRACT
Objective: To determine if, and by what mechanisms, inhaled nitric oxide attenuates acute lung injury in a porcine model of adult respiratory distress syndrome induced by Gram-negative sepsis.
Design: Non-randomized, controlled study.
Setting: Thirty pathogen-free Yorkshire swine (15-20 kg).
Interventions: Four groups of swine-were anesthetized, mechanically ventilated, and studied for 5 hrs. Both control-nitric oxide and septic-nitric oxide animals received inhaled nitric oxide at 20 parts per million throughout the study. Control (n=10) and control-nitric oxide (n=5) animals received a 1-hr infusion of sterile saline. Sepsis was induced in septic (n=10) and septic-nitric oxide (n=5) animals with a 1-hr intravenous infusion of live Pseudomonas aeruginosa.
Measurements and Main Results: Untreated septic animals developed a progressive decrease in PaO2 that was prevented in septic-nitric oxide animals (73+4 vs. 23 torr [9.7+0.5 vs. 28.5+3.1 kPa], respectively, at 5 hrs, p < .05). Untreated septic animals showed a significant increase in bronchoalveolar lavage protein and neutrophil count at 5 hrs, compared with the baseline value, indicating acute lung injury.
Septic-nitric oxide animals showed no significant increase in these parameters. Peripheral blood neutrophils from untreated septic animals and septic-nitric oxide animals exhibited significant (p <.05) up-regulation of CD18 receptor expression and oxidant activity (10.5+0.9 and 5.0 +0.9 nmol of superoxide anion/106 neutrophils/10mins, respectively) compared with both control and control-nitric oxide animals (3.0+0.6 and 2.6+0.2 nmol of superoxide anion/106 neutrophils/10 mins, respectively).
Also, priming for the oxidant burst at 5 hrs was decreased by 50% in septic-nitric oxide animals compared with untreated septic animals. Both untreated septic and septic-nitric oxide animals showed a significant increase in pulmonary arterial pressure at 30 mins (47.5+2.4 and 51.0+3.0 mm Hg, respectively), followed by a progressive decrease (32.8+2.6 and 31.3+5.4 mm Hg, respectively, at 5 hrs).
Both of these changes were significant (p <.05) compared with baseline values and compared with the control groups. There was no significant difference in pulmonary arterial pressure or systemic arterial pressure at any time between untreated septic and septic-nitric oxide animals.
Conclusions: These results demonstrate that inhaled nitric oxide attenuates alveolar-capillary membrane injury in this porcine model of Gram-negative sepsis but does not adversely affect systemic hemodynamics. The data suggest that inhaled nitric oxide preserves alveolar-capillary membrane integrity by the following means: a) inhibiting transendothelial migration of activated, tightly adherent neutrophils; and b) possibly by attenuating the neutrophil oxidant burst.
|
