Journal of Critical Care 29 (2014) 1124–1125
Contents lists available at ScienceDirect
Journal of Critical Care journal homepage: www.jccjournal.org
Noninvasive mechanical ventilation and neutrophil elastase inhibitor: A new potential approaching to acute hypoxemic failure To the Editor:
We thank Dr Esquinas  for his interesting and constructive questions on our article. In this study , all enrolled acute respiratory distress syndrome (ARDS) patients showed increased numbers of white blood cells with severe neutropenia. There are currently no therapeutic agents that have been conﬁrmed to be effective for ARDS based on multicenter randomized clinical trials. However, Yokoyama  reported that the early induction of noninvasive ventilation (NIV) was useful for patients with rapidly progressive interstitial pneumonia because of end-positive expiratory pressure. The pathologic ﬁndings of diffuse alveolar damages of ARDS resemble the new inﬁltration lesions of rapidly progressive interstitial pneumonia. Yokoyama et al suggested that early intervention with NIV, mainly continuous positive pressure ventilation, is beneﬁcial for the management of patients with rapidly progressive interstitial pneumonia. In his report, NIV was initiated earlier in the survivors than in the nonsurvivors. Twenty-one patients were treated by NIV on the ﬁrst hospital day. Of these 21 patients, 20 were still alive on the 30th hospital day. The initiation of NIV within the ﬁrst hospital day was deﬁned as early intervention with NIV. Table 3 in this study  indicates that there were no statistically signiﬁcant differences in the time after onset until the initiation of NIV and the administration of the neutrophil elastase inhibitor between survivors and nonsurvivors. The surviving mild ARDS patients started to receive the neutrophil elastase inhibitor signiﬁcantly earlier than did the nonsurvivors. Therefore, we supposed that the time until the induction of NIV after the occurrence of ARDS may have been inﬂuenced by the results of the baseline PaO2/fraction of inspired oxygen (FIO2) because of respiratory deterioration. In the pathogenesis of ARDS, suppression of the production of neutrophil elastase has potential as an important therapeutic approach. Neutrophil elastase inhibitors are thought to exhibit maximal efﬁcacy when administered early, before the development of severe inﬂammation in the injured lungs. Two human clinical trials have shown contradictory results [4,5]. This may have been due to the differences in the severity of ARDS between the patients in each of the trials. In a Japanese double-blind phase III clinical trial of neutrophil elastase inhibitor therapy , the lung injury score of the ARDS patients ranged from 1.5 to 2.5. In the STRIVE study, however, the lung injury score ranged from 2.5 to 3.5, indicating that ARDS was more severe in the latter study [4,6]. In a retrospective subgroup analysis of the STRIVE study of 100 patients who met the inclusion criteria for the Japanese clinical trials  and whose lung injury scores were similar to those of patients in the
DOI of original article: http://dx.doi.org/10.1016/j.jcrc.2014.07.018. 0883-9441/© 2014 Elsevier Inc. All rights reserved.
Japanese double-blind clinical trial, the ventilation-free time of the placebo and treated groups was 15.9 and 12.0 days, respectively, whereas the 28-day mortality was 34.0% (18/53 patients) and 12.8% (6/47 patients), respectively . Aggarwal et al  described that 65% of the cases of NIV failure occurred within 1 to 48 hours during NIV. In Japan, as patients and their families of ARDS patients tend to avoid intratracheal intubation, there were few ARDS patients with NIV failure within 48 hours after the initiation of NIV. Therefore, we could investigate combined therapy using noninvasive ventilation and a neutrophil elastase inhibitor at the early phase of ARDS. We set 5 cm H2O as the minimum expiratory positive airway pressure (EPAP) under a full face mask or total face mask with bi-level positive airway pressure ventilation (BiPAP). Air leakage has to keep at less than 50 L/min. After setting the NIV, enrolled ARDS patients were measured the PaO2 while taking into consideration the conditions at the same alveolar recruitment and calculated the PaO2/FIO2. After measuring the PaO2, the inspiratory positive airway pressure (IPAP), EPAP, and FIO2 were adjusted to maintain the SpO2 greater than 90% or the PaO2 greater than 60 Torr, with a respiratory rate less than 35 breaths per minute and pH greater than 7.3. The EPAP has the strongest inﬂuence on the PaO2 to open the alveoli, and the EPAP was adjusted to keep a low FIO2 (b 60% oxygen concentration). The pharmacokinetics of the neutrophil elastase inhibitor indicate that it only inﬂuences the inactivation of the neutrophil elastase produced by active neutrophils in the blood ﬂow, not the neutrophils that have inﬁltrated into the alveoli, because of the short half-life outside of the blood ﬂow. Moreover, the neutrophil elastase inhibitor may not be able to be recruited into the inﬂammatory lesions because the inﬂammation in the severe ARDS stage may lead to the development of microemboli in the injured lungs. Therefore, we recommend using the neutrophil elastase inhibitor immediately after the induction of NIV to avoid the deterioration of the respiratory condition, such as the development of severe ARDS. In this study, the surviving mild ARDS patients started to receive the neutrophil elastase inhibitor signiﬁcantly earlier than did the nonsurvivors. We suppose that the timing and the severity of ARDS are important factors to consider for the treatment of ARDS patients with NIV combined with a neutrophil elastase inhibitor. Unfortunately, our study cannot assess the morphometric differences and pharmacokinetics of the neutrophil elastase inhibitor in pulmonary lesions in cases with direct and indirect ARDS. We need to approach these morphological lung neutrophil inﬁltrations. Further prospective randomized clinical trials are needed to compare the effectiveness of NIV and neutrophil elastase inhibitors at each ARDS stage.
Letter / Journal of Critical Care 29 (2014) 1124–1125
Kenji Tsushima MD, PhD⁎ Koichiro Tatsumi MD, PhD Department of Respirology, Graduate School of Medicine, Chiba University Chiba 260-8670 Japan ⁎Corresponding author. Department of Respirology Graduate School of Medicine, Chiba University 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan. E-mail address: [email protected]
References  Esquinas AM. Noninvasive mechanical ventilation and neutrophil elastase inhibitor: Is it a new potential approach to acute hypoxemic failure? J Crit Care 2014;29:1123.
 Tsushima K, Yokoyama T, Matsumura T, Koizumi T, Kubo K, Tatsumi K, et al. Acute Lung Injury Group in Nagano. The potential efﬁcacy of noninvasive ventilation with administration of a neutrophil elastase inhibitor for acute respiratory distress syndrome. J Crit Care 2014;29(3):420–5.  Yokoyama T, Tsushima K, Yamamoto H, Koizumi T, Kubo K, et al. Potential beneﬁts of early continuous positive pressure ventilation in patients with rapidly progressive interstitial pneumonia. Respirology 2012;17:315–21. http://dx.doi.org/10.1111/j.14401843.2011.02051.x.  Zeiher BG, Artigas A, Vincent JL, et al, STRIVE Study Group. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med 2004;32: 1695–702.  Tamakuma S, Ogawa M, Aikawa N, et al. Relationship between neutrophil elastase and acute lung injury in humans. Pulm Pharmacol Ther 2004;17: 271–9.  Neutrophil elastase inhibitor ELASPOL 100 for injection. Internal data of Ono Pharmaceutical Co., Ltd.: Summary of the Phase-II Clinical Trial conducted in foreign country, 9; 2009 1.  Agarwal R, Handa A, Aggarwal AN, et al. Outcomes of noninvasive ventilation in acute hypoxemic respiratory failure in a respiratory intensive care unit in north India. Respir Care 2009;54:1679–87.