Inhaled nitric oxide and the risk of renal dysfunction in patients with acute respiratory distress syndrome: a propensity-matched cohort study

Critical Care, Nov 2016

Background Inhaled nitric oxide (iNO) is a rescue therapy for severe hypoxemia in patients with acute respiratory distress syndrome (ARDS). Pooled data from clinical trials have signaled a renal safety warning for iNO therapy, but the significance of these findings in daily clinical practice is unclear. We used primary data to evaluate the risk of iNO-associated renal dysfunction in patients with ARDS. Methods We conducted a cohort study using data from a tertiary teaching hospital to evaluate the risk of incident renal replacement therapy (RRT) in iNO users compared with that of non-users. Propensity score matching and competing-risks regression were used for data analysis. Residual confounding was assessed by means of a rule-out approach. We also evaluated effect modification by pre-specified factors using stratified analysis. Results We identified 547 patients with ARDS, including 216 iNO users and 331 non-users. At study entry, 313 (57.2%) patients had moderate ARDS and 234 (42.8%) had severe ARDS. The mean patient age was 63 ± 17 years. The crude hazard ratio of the need for RRT in iNO users compared with non-users was 2.23 (95% CI, 1.61–3.09, p < 0.001). After propensity score matching, there were 151 iNO users matched to 151 non-users. The adjusted hazard ratio was 1.59 (95% CI, 1.08–2.34, p = 0.02). In the stratified analysis, we found that older aged patients (≥65 years) were more susceptible to iNO-associated kidney injury than younger patients (p = 0.05). Conclusions This study showed that iNO substantially increased the risk of renal dysfunction in patients with ARDS. Older aged patients were especially susceptible to this adverse event.

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Inhaled nitric oxide and the risk of renal dysfunction in patients with acute respiratory distress syndrome: a propensity-matched cohort study

Ruan et al. Critical Care Inhaled nitric oxide and the risk of renal dysfunction in patients with acute respiratory distress syndrome: a propensity-matched cohort study Sheng-Yuan Ruan 0 2 Hon-Yen Wu 0 1 3 Hsien-Ho Lin 0 Huey-Dong Wu 2 Chong-Jen Yu 2 Mei-Shu Lai 0 0 Institute of Epidemiology and Preventive Medicine, National Taiwan University , No.17 Xu-Zhou Road, Taipei 10020 , Taiwan 1 Division of Nephrology, Department of Internal Medicine, Far Eastern Memorial Hospital , New Taipei City , Taiwan 2 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital , Taipei , Taiwan 3 School of Medicine, National Yang-Ming University , Taipei , Taiwan Background: Inhaled nitric oxide (iNO) is a rescue therapy for severe hypoxemia in patients with acute respiratory distress syndrome (ARDS). Pooled data from clinical trials have signaled a renal safety warning for iNO therapy, but the significance of these findings in daily clinical practice is unclear. We used primary data to evaluate the risk of iNO-associated renal dysfunction in patients with ARDS. Methods: We conducted a cohort study using data from a tertiary teaching hospital to evaluate the risk of incident renal replacement therapy (RRT) in iNO users compared with that of non-users. Propensity score matching and competing-risks regression were used for data analysis. Residual confounding was assessed by means of a rule-out approach. We also evaluated effect modification by pre-specified factors using stratified analysis. Results: We identified 547 patients with ARDS, including 216 iNO users and 331 non-users. At study entry, 313 (57.2%) patients had moderate ARDS and 234 (42.8%) had severe ARDS. The mean patient age was 63 ± 17 years. The crude hazard ratio of the need for RRT in iNO users compared with non-users was 2.23 (95% CI, 1.61-3.09, p < 0.001). After propensity score matching, there were 151 iNO users matched to 151 non-users. The adjusted hazard ratio was 1.59 (95% CI, 1.08-2.34, p = 0.02). In the stratified analysis, we found that older aged patients (≥65 years) were more susceptible to iNO-associated kidney injury than younger patients (p = 0.05). Conclusions: This study showed that iNO substantially increased the risk of renal dysfunction in patients with ARDS. Older aged patients were especially susceptible to this adverse event. Acute respiratory distress syndrome; Adverse effect; Nitric oxide; Renal failure; Treatment - Background Inhaled nitric oxide (iNO) is a rescue therapy for severe hypoxemia in patients with acute respiratory distress syndrome (ARDS). Inhaled nitric oxide gas administered via a gas mixture with the patient’s inhaled breath reaches only normally ventilated lung units and causes selective dilatation of the vessels surrounding normal alveoli [1]. This improves the ventilation-perfusion mismatch in patients with hypoxaemic respiratory failure due to acute lung injury. Although the routine use of iNO in ARDS is not recommended based on current evidence [2, 3], iNO has a substantial effect in improving oxygenation and is still frequently used in many institutions [4, 5]. Previous studies suggest that iNO has a good safety profile [6, 7]. When iNO was first introduced, common safety concerns based on pharmacological knowledge included formation of methaemogloblin, production of reactive nitrogen species, hypotension and platelet inhibition [6, 8, 9], but nephrotoxicity was not a major concern. However, a clinical trial of ARDS published in 1999 reported that iNO potentially doubled the risk of the need for renal replacement therapy (RRT) compared © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. with controls [10]. We recently performed a systematic review and meta-analysis to evaluate the association between iNO exposure and renal dysfunction in randomized controlled trials (RCTs), and found that iNO increased the risk of acute kidney injury by 50% in patients with ARDS [11]. However, the risk estimated from our meta-analysis of RCTs may not accurately reflect the risk in daily clinical practice because RCTs often exclude patients with severe organ dysfunction and haemodynamic instability. Excluding unstable patients who are particularly vulnerable to drug-induced kidney injury in clinical trials may underestimate the risk of druginduced nephrotoxicity [12]. Another concern about the results of meta-analysis (...truncated)


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Sheng-Yuan Ruan, Hon-Yen Wu, Hsien-Ho Lin, Huey-Dong Wu, Chong-Jen Yu, Mei-Shu Lai. Inhaled nitric oxide and the risk of renal dysfunction in patients with acute respiratory distress syndrome: a propensity-matched cohort study, Critical Care, 2016, pp. 389, 20, DOI: 10.1186/s13054-016-1566-0