Inhaled nitric oxide therapy and risk of renal dysfunction: a systematic review and meta-analysis of randomized trials

Literature search and study characteristics

Through the electronic searches and from references, 252 citations were identified.
According to our predefined inclusion and exclusion criteria, 10 RCTs involving a
total of 1,363 patients were included in the final analysis 12],20]-28]. To calculate the risk for incident AKI, 26 patients were excluded from the analysis
because they had received hemodialysis before the enrollment of trials. The number
of studies evaluated at each stage of the literature review is shown in Figure 1. Quality assessment (see Additional file 2) of the included studies suggested a low risk of bias, except for one study which
was published with an abstract 21].

Figure 1. Study flow through this systematic review. RCT, randomized controlled trial.

The characteristics of the included studies are summarized in Table 1. The publication year ranged from 1998 to 2014, and included four studies on patients
with ARDS, four studies on patients undergoing surgery, one study on neonates with
hypoxemic respiratory failure, and one study on patients with sepsis. The administered
dose and duration of iNO varied largely among these studies. In the ARDS trials, the
dose of iNO shifted from a titrated dose of 1 to 40 ppm in the 1990s to a fixed dose
of 5 ppm in the latest trial 12],23]. The treatment duration was longer in the ARDS studies (7 days) than in the non-ARDS
studies (?7 days).

Table 1. Details of the included randomized controlled trials

Reporting of renal dysfunction

Renal dysfunction in these trials was usually defined as an excess of creatinine level
to a predefined level or the need for renal replacement therapy (Table 1). Among these trials, three reported the data of two different definitions of renal
dysfunction. Notably, many clinical trials of iNO were excluded from this systematic
review due to a lack of data on renal adverse effects, especially in the pediatric
studies. Bleeding and neurological complications were the main concerns for the pediatric
patients, and data on renal dysfunction were rarely reported in the safety outcomes.

Quantitative data synthesis

For the primary outcome of AKI with any severity (Figure 2), the pooled effect from 10 studies showed that iNO therapy significantly increased
the risk of AKI with an RR of 1.40 (95% CI, 1.06 to 1.83, P?=?0.02, I²?=?0%). The study by Payen 21] accounted for 39% of meta-analysis weight but was only published with an abstract.
After omitting this influential study, the effect estimate remained similar (RR, 1.42,
95% CI, 1.003 to 2.01, P?=?0.048, I²?=?0%). The statistical heterogeneity was low among the analyses.

Figure 2. Forest plot for the risk of acute kidney injury. iNO, inhaled nitric oxide.

For the endpoint of AKI requiring renal replacement therapy (Figure 3), iNO also increased the risk with a RR of 1.51 (95% CI, 1.09 to 2.11, P?=?0.01, I²?=?0%). The effect estimate became larger after we omitted the influential study by
Payen (RR, 1.76, 95% CI, 1.05 to 2.93, P?=?0.03, I²?=?0%).

Figure 3. Forest plot for the risk of initiating renal replacement therapy. iNO, inhaled nitric oxide.

Due to the presence of sparse data and imbalance of trial size, sensitivity analysis
was performed to evaluate the influence of data synthesis methods on the estimate
of summary effect. The effect estimate by the Peto method was similar to that obtained
by the primary analysis with a random-effects model (Table 2).

Table 2. Sensitivity analysis by different data synthesis methods

Figure 4 shows a funnel plot based on the primary outcome. The asymmetry of the funnel plot
on visual inspection implied a lack of studies in which iNO increased the risk of
AKI. This suggests that the pooled effect from the current data may underestimate
the effect size of the risk. However, the statistical test for publication bias, Egger’s
test (P?=?0.33), did not reach statistical significance.

Figure 4. Funnel plot based on the primary outcome.

The risk of AKI associated with iNO therapy varied among the different populations
(Table 3). The risk was significantly increased in the patients with ARDS (RR, 1.55, 95% CI,
1.15 to 2.09, P?=?0.005), but not in patients without ARDS (RR, 0.9, 95%CI, 0.49 to 1.67, P?=?0.75). Among the patients with ARDS, the risk difference for AKI between iNO and
control groups was 0.067 (95% CI, 0.000 to 0.135, P?=?0.05, I²?=?50%), and the number needed-to-harm to cause one additional AKI was 15.

Table 3. Subgroup analysis by study population

To test the dose-response relationship between iNO and the risk of AKI, we performed
stratified analysis by duration and dosage of iNO therapy. Prolonged use of iNO (7 days)
significantly increased the risk of AKI (RR, 1.55, 95% CI, 1.15 to 2.09, P?=?0.005, four studies), whereas short-term use did not (RR, 0.90, 95% CI, 0.49 to
1.67, P?=?0.75, six studies). Notably, the four studies involving the prolonged use of iNO
are all ARDS studies. Table 4 summarizes the risk of renal dysfunction for different iNO exposure levels. We classified
the included studies into three groups according to the cumulative dose in the stratified
analysis. High cumulative dose of iNO significantly increased the risk of renal dysfunction
but medium and low cumulative doses did not (Table 4). Figure 5 depicts the relationship between the risk of renal dysfunction and cumulative dose
of iNO. Visual inspection suggested a possible association between the cumulative
dose and risk of renal dysfunction but statistical test by meta-regression analysis
was not significant due to small sample size (P?=?0.10).

Table 4. Dose-response relationship between inhaled nitric oxide and the risk of acute kidney
injury

Figure 5. Bubble plot with fitted meta-regression line depicting the relationship between the
risk of renal dysfunction and cumulative dose of inhaled nitric oxide (Ino).