Introduction
Materials and methods
Search strategy
Study selection and data extraction
Assessment of risk of bias
Outcome measures
Stratified analysis
Data synthesis
Results
Literature search and study characteristics
Study (year)
|
Country
|
Study population
|
Protocol of iNO therapy
|
Mean iNO dosage
|
Age, years
|
Definition of acute kidney injury (AKI)
|
Number of AKI/number of cases
| |
---|---|---|---|---|---|---|---|---|
iNO
|
Control
| |||||||
Dellinger (1998) [12] | USA | ARDS | 1.25, 5.0, 20.0, 40.0, or 80.0 ppm iNO for 28 days or till FiO2 < 0.5 | 21 ppm | 48 | Creatinine >2 mg/dL | 20/120 | 7/57 |
Creatinine ≥3.5 mg/dL | 13/120 | 5/57 | ||||||
Lundin (1999) [20] | 11 European countries | ARDS | 1 to 40 ppm iNO at the lowest effective dose for up to 30 days or until an end point was reached | 9 ppm | 57 | Creatinine >3.4 mg/dL or RRT | 28/80 | 12/74 |
Incident RRT | 23/84 | 10/79 | ||||||
Kinsella (1999) [22] | USA | Neonate hypoxemic respiratory failure | 5 ppm for 7 days | 5 ppm | 27 weeks | Renal failure | 2/48 | 2/32 |
Payen (1999) [21] | Europe | ARDS | 10 ppm till PF >250, median 5 days | 10 ppm | Not reported | RRT | 33/98 | 26/105 |
Taylor (2004) [23] | USA | ARDS | 5 ppm until 28 days, discontinuation of assisted breathing, or death | 5 ppm | 50 | Creatinine ≥3 mg/dL | 12/192 | 8/193 |
Creatinine ≥3.5 mg/dL | 10/192 | 6/193 | ||||||
Perrin (2006) [24] | France | Lung transplantation | 20 ppm for 12 h | 20 ppm | 35 | RRT | 1/15 | 1/15 |
Potapov (2011) [26] | USA and Germany | Cardiac surgery | 40 ppm for 48 h | 40 ppm | 56 | RRT | 10/73 | 8/77 |
Fernandes (2011) [25] | Brazil | Cardiac surgery | 10 ppm for 48 h | 10 ppm | 46 | Urine output <0.3 ml/kg/h | 0/14 | 1/15 |
Lang (2014) [28] | USA | Liver transplantation | 80 ppm during the operative phase | 80 ppm | 56 | Renal dysfunction | 3/40 | 7/40 |
Trzeciak (2014) [27] | USA | Sepsis | 40 ppm for 6 h | 40 ppm | 59 | RRT | 2/26 | 1/23 |
Reporting of renal dysfunction
Quantitative data synthesis
Outcome measures
|
Number of studies (number of patients)
|
Statistical model
|
Effect size (95% CI)
|
P
-value (test for effect)
|
Heterogeneity
|
---|---|---|---|---|---|
Acute kidney injury | 10 (1337) | RR, random-effects | 1.40 (1.06 to 1.83) | 0.02 |
I
2 = 0% |
OR, random-effects | 1.50 (1.07 to 2.09) | 0.02 |
I
2 = 0% | ||
OR, Peto | 1.48 (1.07 to 2.05) | 0.02 |
I
2 = 0% | ||
Initiation of renal replacement therapy | 5 (595) | RR, random-effects | 1.51 (1.09 to 2.11) | 0.01 |
I
2 = 0% |
OR, random-effects | 1.73 (1.13 to 2.65) | 0.01 |
I
2 = 0% | ||
OR, Peto | 1.73 (1.14 to 2.41) | 0.01 |
I
2 = 0% |
Subgroups
|
Number of studies (number of patients)
|
Risk ratio of AKI (95% CI)
|
P
-value (test for effect)
|
Heterogeneity
|
---|---|---|---|---|
ARDS | 4 (919) | 1.55 (1.15 to 2.09) | 0.005 |
I
2 = 0% |
Non-ARDS | 6 (418) | 0.90 (0.49 to 1.67) | 0.75 |
I
2 = 0% |
Surgery | 4 (289) | 0.89 (0.45 to 1.75) | 0.73 |
I
2 = 0% |
Sepsis | 1 (49) | 1.77 (0.17 to 18.26) | 0.63 | Not applicable |
Pediatric hypoxemic respiratory failure | 1 (80) | 0.67 (0.10 to 4.49) | 0.68 | Not applicable |
Cumulative dose of inhaled nitric oxide
|
Numer of studies (number of patients)
|
Risk ratio of AKI (95% CI)
|
P
-value (test for effect)
|
Heterogeneity
|
References
|
---|---|---|---|---|---|
Low | 2 (109) | 0.56 (0.11 to 2.86) | 0.49 |
I
2 = 0% | |
Medium | 3 (159) | 0.64 (0.23 to 1.81) | 0.40 |
I
2 = 0% | |
High | 5 (1069) | 1.52 (1.14 to 2.02) | 0.004 |
I
2 = 0% |
Discussion
Study (year)
|
Species
|
Protocols of iNO
|
Main findings
|
---|---|---|---|
Valvini (1995) [38] | Human | 40 ppm for 3 days followed by 90 ppm for 2 days | 1. Inhaling 40 ppm nitric oxide would result in a daily nitrogen oxide load of about 25 mmol. |
2. Impairment of renal function would cause an increase in serum nitrogen oxides. | |||
Troncy (1997) [9] | Swine | 40 ppm iNO | Inhaled nitric oxide increased renal blood flow, glomerular filtration rate and urinary flow. |
Preiser (1998) [37] | Human | 1 to 20 ppm | 1. Renal excretion of NO2
− and NO3
− was unaltered by nitric oxide inhalation. |
2. Long-term nitric oxide inhalation was associated with a consistent increase in the NO3
− plasma concentration. | |||
Wraight (2001) [36] | Human | 40 ppm for 2 h | Inhaled nitric oxide may alter tubular salt and water resorbtion. |
Kielbasa (2001) [35] | Rat | 49 or 107 ppm iNO for 4 h | High dose of iNO increased nitric oxide synthase III protein expression, and nitrotyrosine and phosphotyrosine immunoreactivity. |
Da (2007) [34] | Swine | 30 ppm iNO for 3.5 h | Decreased swelling and necrosis of glomeruli. |
Gozdzik (2009) [33] | Swine | 40 ppm iNO for 30 h | 1. Transient natriuretic effect. |
2. Renal tubular apoptosis promotion after 30 h of iNO treatment. | |||
Göranson (2014) [44] | Swine | 30 ppm iNO for 30 h | Combined therapy with iNO and intravenous steroid is associated with partial protection of kidney function. |
Limitations
Conclusion
Key messages
-
Previous studies have shown that iNO has a good safety profile and favorable effects on renal and splanchnic perfusion; however, iNO therapy has been reported to be associated with renal dysfunction.
-
This meta-analysis updated the evidence regarding renal safety of iNO therapy. The study suggested that the risk of iNO-associated renal dysfunction differed between ARDS and non-ARDS populations. Nitric oxide inhalation may increase the risk of renal dysfunction, especially with prolonged use and in patients with ARDS.
-
The safety outcome of renal dysfunction was not universally reported across iNO trials, especially in non-ARDS studies. We suggest monitoring renal function during iNO therapy, and that future trials of iNO should evaluate renal safety.