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
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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
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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)