Inhaled nitric oxide and acute kidney injury risk: a meta-analysis of randomized controlled trials

Figures & data

Figure 1. Flow chart for identification of studies in the meta-analysis.

Table 1. Characteristics of included studies.

Trial	Location	n	Men (%)	Age	Intervention description	AKI definition	Number of AKI patients		RR with 95% CI	p-Value	Disease
							iNO	Control
Dellinger et al. 1998 [9]	USA	iNO: 120 Control: 57	iNO: 64 Control: 70	iNO: 49 ± 18 years Control: 47 ± 18 years	iNO at concentrations of 1.25, 5, 20, 40, or 80 ppm for up to 28 days or till FiO2 < 0.5	Creatinine above 2 mg/dL	20	7	1.36 (0.61–3.02)	0.448	ARDS
Lundin et al. 1999 [11]	11 European countries	iNO: 80 Control: 74	iNO: 75 Control: 62	iNO: 58 ± 15 years Control: 56 ± 17 years	1–40 ppm of NO at the lowest effective dose for up to 30 days or until an end point was reached	Creatinine above 300 mmol/L and/or institution of RRT	28	12	2.16 (1.19–3.92)	0.008	ARDS
Kinsella et al. 1999 [10]	USA	iNO: 48 Control: 32	iNO: 58 Control: 63	iNO: Gestational 27.1 weeks Control: Gestational 26.8 weeks	5 ppm of NO for up to 7 days	Acute renal failure	2	2	0.67 (0.10–4.49)	0.675	Severe hypoxaemic respiratory failure
Payen et al. 1999 [12]	European countries	iNO: 98 Control: 105	Unknown	Adults	10 ppm of NO for 5 days	Requiring RRT	33	26	1.36 (0.88–2.10)	0.162	ARDS
Taylor et al. 2004 [13]	USA	iNO: 192 Control: 193	iNO: 52 Control: 54	iNO: 50 ± 17 years Control: 50 ± 17 years	5 ppm of NO until 28 days	Creatinine above 265.2 µmol/L	12	8	1.51 (0.63–3.61)	0.352	ARDS
Perrin et al. 2006 [14]	France	iNO: 15 Control: 15	iNO: 60 Control: 53	iNO: 37 ± 12 years Control: 33 ± 11 years	20 ppm of NO during a 12-h period	Requiring RRT	1	1	1.00 (0.07–14.55)	1.000	Lung transplantation
Fernandes et al. 2011 [15]	Brazil	iNO: 14 Control: 15	iNO: 7 Control: 20	iNO: 48 ± 11 years Control: 44 ± 13 years	10 ppm of NO for 48 h	Acute renal failure	0	1	0.36 (0.02–8.07)	0.517	Cardiac surgery
Potapov et al. 2011 [16]	Germany and USA	iNO: 73 Control: 77	iNO: 88 Control: 84	iNO: 58 ± 10 years Control: 54 ± 12 years	40 ppm of NO for 48 h	Requiring RRT	10	8	1.32 (0.55–3.16)	0.533	Cardiac surgery
Lang et al. 2014 (A) [17]	USA	iNO: 20 Control: 20	iNO: 80 Control: 80	iNO: 54 (36–72) years Control: 55 (45–68) years	80 ppm of NO during the operative phase of liver transplantation	Renal dysfunction	2	5	0.40 (0.09–1.83)	0.212	Liver transplantation
Lang et al. 2014 (B) [17]	USA	iNO: 20 Control: 20	iNO: 75 Control: 85	iNO: 59 (30–67) years Control: 57 (24–70) years	80 ppm of NO during the operative phase of liver transplantation	Renal dysfunction	1	2	0.50 (0.05–5.08)	0.548	Liver transplantation
Trzeciak et al. 2014 [18]	USA	iNO: 26 Control: 23	iNO: 42 Control: 57	iNO: 59 ± 15 years Control: 58 ± 20 years	40 ppm of NO for 6 h	Requiring RRT	2	1	1.77 (0.17–18.26)	0.626	Severe sepsis or septic shock
Hawkes et al. 2015 [19]	Uganda	iNO: 88 Control: 92	iNO: 60 Control: 53	iNO: 2 (1–3) years Control: 2 (1–3) years	80 ppm of NO for up to 72 h	Serum creatinine >1.5 × ULN (children age 1–2) or >2.0 × ULN (age 2–10) AND an abrupt (within 48 h) reduction in kidney function	7	3	2.44 (0.65–9.14)	0.169	Severe malaria
Liu et al. 2016 [20]	China	iNO: 19 Control: 13	iNO: 68 Control: 62	iNO: Gestational 37.4 weeks Control: Gestational 36.1 weeks	15–20 ppm of NO for 96 h	Acute renal failure	1	0	2.10 (0.09–47.89)	0.642	Hypoxic respiratory failure
Lei et al. 2018 [21]	China	iNO: 117 Control: 127	iNO: 44 Control: 41	iNO: 49 ± 10 years Control: 48 ± 9 years	80 ppm of NO for 24 h or less if patients were ready to be extubated early.	An increase in serum creatinine by 50% within 7 days of surgery, or an increase in serum creatinine by 0.3 mg/dL within 2 days of surgery from preoperative baseline levels of serum creatinine	58	81	0.78 (0.62–0.97)	0.025	Cardiac surgery
Kamenshchikov et al. 2019 [22]	Russia	iNO: 30 Control: 30	iNO: 83 Control: 70	iNO: 62 years Control: 58 years	40 ppm of NO during CPB	Unknown	1	3	0.33 (0.04–3.03)	0.301	Cardiac surgery

AKI: acute kidney injury; ARDS: acute respiratory distress syndrome; CPB: cardiopulmonary bypass; NO: nitric oxide; RRT: renal replacement therapy; ULN: upper limit of normal.

Table 2. Assessment of risk of bias in individual studies.

Trial	Sequence generation	Allocation concealment	Blinding	Incomplete outcome data	Selective outcome reporting	Other sources of bias
Dellinger et al. [9]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Lundin et al. [11]	Low risk	Low risk	High risk	Low risk	Low risk	High risk
Kinsella et al. [10]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Payen et al. [12]	Low risk	Low risk	Low risk	Low risk	Low risk	High risk
Taylor et al. [13]	Low risk	Low risk	Low risk	Low risk	Low risk	Unclear risk
Perrin et al. [14]	High risk	Unclear risk	High risk	Low risk	Low risk	Unclear risk
Fernandes et al. [15]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Potapov et al. [16]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Lang et al. (A) [17]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Lang et al. (B) [17]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Trzeciak et al. [18]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Hawkes et al. [19]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Liu et al. [20]	High risk	Unclear risk	Low risk	Low risk	Low risk	Low risk
Lei et al. [21]	High risk	Low risk	Low risk	Low risk	Low risk	Unclear risk
Kamenshchikov et al. [22]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk

Figure 2. Meta-analysis of the effect of inhaled nitric oxide on acute kidney injury risk by pooling the 15 randomized controlled trials.

Figure 3. Begg’s funnel plot for evaluating publication bias.

Figure 4. Meta-analysis of the effect of inhaled nitric oxide on acute kidney injury risk. (A) Acute respiratory distress syndrome. (B) Cardiac surgery. (C) Organ transplantation.

Table 3. Meta-analysis evaluation of the relationship between inhaled nitric oxide and acute kidney injury risk.

Subgroup	Number of studies	RR (95% CI)	p	Heterogeneity
				I^2	Phet
All	15	1.00 (0.84–1.18)	0.977	31.6%	0.116
ARDS	4	1.55 (1.15–2.10)	0.004	0	0.649
Cardiac surgery	4	0.80 (0.64–0.99)	0.037	0	0.528
Organ transplantation	3	0.50 (0.16–1.56)	0.233	0	0.842
Others	4	1.67 (0.65–4.27)	0.286	0	0.747

ARDS: acute respiratory distress syndrome; CI: confidence interval; RR: relative risk.

Table 4. Trim and Fill test results.

Subgroup	Model	RR (95% CI)	p	Heterogeneity
				I^2	Phet
ARDS	Fixed-effect	1.55 (1.15–2.10)	0.005	0	0.651
	Random-effect	1.55 (1.15–2.10)	0.005	0	0.651
Cardiac surgery	Fixed-effect	0.80 (0.64–0.99)	0.037	0	0.528
	Random-effect	0.80 (0.64–0.99)	0.037	0	0.528
Organ transplantation	Fixed-effect	0.40 (0.15–1.05)	0.061	0	0.914
	Random-effect	0.40 (0.15–1.05)	0.061	0	0.914

ARDS: acute respiratory distress syndrome; CI: confidence interval; RR: relative risk.

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