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The ef cacy of sodium bicarbonate inpreventing contrast-induced nephropathyin patients with pre-existing renal
insuf
ciency: a meta-analysisBin Zhang,1,2 Long Liang,1,2 Wenbo Chen,1 Changhong Liang,1 Shuixing Zhang1
To cite: Zhang B, Liang L,
Chen Wb, et al . The efficacy
of sodium bicarbonate in
preventing contrast-induced
nephropathy in patients with
pre-existing renal insufficiency:
a meta-analysis. BMJ Open 2015;5:e006989. doi:10.1136/
bmjopen-2014-006989
▸ Prepublication history for
this paper is available online.
To view these files please
visit the journal online
(http://dx.doi.org/10.1136/
bmjopen-2014-006989 ).
Received 23 October 2014
Revised 28 January 2015
Accepted 29 January 2015
1Department of Radiology,
Guangdong Academy of
Medical Sciences/Guangdong
General Hospital, Graduate
College, Guangzhou,
Guangdong Province, China2Southern Medical University,
Guangzhou, Guangdong
Province, China
Correspondence to
Dr Shuixing Zhang;
ABSTRACTObjective: The aim of this meta-analysis was toexplore the efficacy of sodium bicarbonate inpreventing contrast-induced nephropathy (CIN).
Methods: We searched PubMed, Medline and the
Cochrane Library from 1 January 2004 to 1 August2014. The effect estimate was expressed as a pooledOR with 95% CI, using the fixed-effects or random-effects model.
Results: 20 randomised controlled trials (n=4280)were identified. Hydration with sodium bicarbonatewas associated with a significant decrease in CINamong patients with pre-existing renal insufficiency
(OR 0.67, 95% CI 0.47 to 0.96; p=0.027). However,moderate heterogeneity was noted across trials(I2=48%; p=0.008). Subgroup analyses indicated a
better effect of sodium bicarbonate in studies usinglow-osmolar (OR 0.59, 95% CI 0.37 to 0.93;p=0.024) compared with iso-osmolar contrast agents
(OR 0.76, 95% CI 0.43 to 1.34; p=0.351). The oddsof CIN with sodium bicarbonate were lower instudies including only patients undergoing
emergency (OR 0.16, 95% CI 0.05 to 0.51; p=0.002)compared with elective procedures (OR 0.76, 95% CI0.54 to 1.06; p=0.105). Sodium bicarbonate was
more beneficial in patients given a bolus injectionbefore procedures (OR 0.15, 95% CI 0.04 to 0.54;p=0.004) compared with continuous infusion
(OR 0.75, 95% CI 0.53 to 1.05; p=0.091). Sodiumbicarbonate plus N-acetylcysteine (OR 0.17, 95% CI0.04 to 0.79; p=0.024) was better than sodium
bicarbonate alone (OR 0.71, 95% CI 0.48 to 1.03;
p=0.071). The effect of sodium bicarbonate wasconsidered greater in papers published before (OR
0.19, 95% CI 0.09 to 0.41; p=0.000) compared withafter 2008 (OR 0.85, 95% CI 0.62 to 1.16; p=0.302).
However, no significant differences were found inmortality (OR 0.69, 95% CI 0.36 to 1.32; p=0.263)or requirement for dialysis (OR 1.08, 95% CI 0.52 to
2.25; p=0.841).
Conclusions: Sodium bicarbonate is effective inpreventing CIN among patients with pre-existingrenal insufficiency. However, it fails to lower the risksof dialysis and mortality and therefore cannot
improve the clinical prognosis of patients with CIN.
INTRODUCTIONContrast-induced nephropathy (CIN) is the
third leading cause of in-hospital acutekidney injury,1–3 which is a serious complica-tion of angiographic procedures resulting from the administration of contrast media. Although the denition of CIN varies, it isusually dened as an increase in the serumcreatinine (Scr) level of 25% or an increaseof 0.5 mg/dL (or 44 μmol/L) from baseline within 48–72 h of contrast exposure. CINresults in increased morbidity, prolonged hos-pital stay and increased healthcare expend-iture, and is associated with higher mortality.4
The incidence of CIN in the general popu-lation is low, but increases exponentially inpatients with high-risk factors, such aspre-exist ing renal insuf ciency or diabetesmellitus.5 In a recent study, 21.7% of a group with pre-existing chronic renal insuf ciency and 6.3% of a group without pre-existing chronic renal insuf ciency developed CIN.6
Thus, baseline renal insuf ciency may be asignicant predisposing factor for CIN.
Sodium bicarbonate-based hydration hasbeen proposed to prevent CIN. Some recent studies suggested that sodium bicarbonate
Strengths and limitations of this study
▪ In this updated meta-analysis, we demonstratedthat pre-procedural hydration with sodium bicar-bonate was associated with a significant decrease
in the incidence of contrast-induced nephropathy(CIN) among patients with pre-existing renalinsufficiency.
▪ We found that sodium bicarbonate did not lowerthe risks of dialysis and mortality and so did notimprove the clinical prognosis of patients with CIN.
▪ The new Jadad scale was used to assess the
quality of reviewed articles.
▪ Publication bias and moderate heterogeneitywere found among the included trials.
Zhang B, et al . BMJ Open 2015;5:e006989. doi:10.1136/bmjopen-2014-006989 1
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had a more protective effect compared with sodiumchloride for the prevention of CIN, while others didnot.7–17 Although most previous meta-analyses supportedthe use of sodium bicarbonate, there may have beenpublication bias and none of the studies focused onpatients with pre-existing renal insuf ciency. Therefore, we performed this meta-analysis to determine the ef -cacy of sodium bicarbonate in preventing CIN among
patients with renal insuf ciency undergoing proceduresneeding contrast agents. In addition, differences in therequirement for dialysis and post-procedural deathbetween the two groups in various studies were com-pared in this analysis.
METHODSData sources and searches We searched PubMed, Medline and the CochraneLibrary from 1 January 2004 to 1 August 2014 without language limitations. Medical subject headings andkeyword searches included the terms ‘contrast induced
nephropathy ’, ‘sodium bicarbonate’, ‘sodium chloride’,‘saline’, ‘acute kidney injury ’ and ‘renal failure’. The ref-erence lists of selected articles were reviewed for otherpotentially relevant citations. In addition, the top 50 cita-tions for each identied relevant study were searched by using the ‘related articles’ function of PubMed.
Study selectionTwo investigators (BZ and LL) independently reviewedthe titles and abstracts of all studies to identify those of interest. The online publications identied from the pre-liminary selection were then reviewed in full text to
assess if the studies met the following inclusion criteria:1. Participants: adult patients (≥18 years) with pre-
existing renal insuf ciency, dened as an Scr concen-tration of >1.1 mg/dL or estimat ed glomerularltration rate (eGFR) of
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T a b l e 1
T h e b a s e l i n e c h a r a c t e r i s t i c s o f i n c l u d e d s t u d i e s
A g e ( y e a r s )
B a s e l i n e S c r ( m g / d L )
e G F R ( m L / m i n / 1 . 7
3 m ² )
S t u d y
C a s e s ( n )
B i c a r b o n a t e
S a l i n e
M a l e ( % )
D M ( % )
H T ( % )
B i c a r b o n a t e
S a l i n e
B i c a r b o n a t e
S a l i n e
M e r t e n e t a l 1 9
1 1 9
6 6
. 7 *
6 9
. 2 *
7 3 v s 7 6
5 0 v s 4 6
N A
1 . 8
9 *
1 . 7
1 *
4 1 . 0
*
4 5 . 0
*
O z c a n e t a l 5 0
1 7 6
6 8
. 0 *
7 0
. 0 *
7 6 v s 7 5
4 2 v s 4 8
7 5 v s 8 1
1 . 3
6 *
1 . 4
0 *
N A
N A
M a s u d a e t a l 3 3
5 9
7 5 . 0
± 8
. 0
7 6
. 0 ±
1 1
. 0
6 3 v s 5 9
2 7 v s 3 5
N A
1 . 3
1 ±
0 . 5
2
1 . 3
2 ±
0 . 6
5
4 0 . 2
± 1 5 . 4
3 8
. 7 ±
1 5 . 4
R E M E D I A L e t a l 2 0
2 1 9
7 0
. 0 ±
9 . 0
7 1
. 0 ±
9 . 0
8 8 v s 8 1
4 9 v s 5 5
9 2 v s 8 7
2 . 0
4 *
1 . 9
5 *
3 2 . 0
± 7 . 0
7 1
. 0 ±
9 . 0
A d o l p h e t a l 7
1 4 5
7 0
. 1 ±
8 . 4
7 2
. 7 ±
6 . 6
7 5 v s 8 1
3 7 v s 2 8
8 3 v s 9 1
1 . 5
4 ±
0 . 5
1
1 . 5
7 ±
0 . 3
6
N A
N A
B r a r e t a l 8
3 2 3
7 1
. 0 *
7 1
. 0 *
6 2 v s 6 5
4 3 v s 4 6
N A
1 . 4
9 †
1 . 4
9 †
4 7 . 7
†
4 8
. 3 †
M a i o l i e t a l 9
5 0 2
7 4
. 0 *
7 4
. 0 *
5 7 v s 6 1
2 5 v s 2 3
5 9 v s 5 7
1 . 2
1 ±
0 . 3
0
1 . 2
0 ±
0 . 3
0
N A
N A
T a m u r a e t a l 2 3
1 4 4
7 2
. 3 ±
9 . 9
7 3
. 3 ± 7 . 7
9 2 v s 8 3
6 0 v s 5 7
8 5 v s 8 3
1 . 3
6 ±
0 . 1
8
1 . 3
8 ±
0 . 1
9
4 0 . 0
± 7 . 5
3 8
. 2 ±
0 . 2
V a s h e g h a n i e t a l 1 0
2 6 5
6 2
. 9 ±
1 0
. 0
6 3
. 8 ±
9 . 0
8 4 v s 8 2
2 2 v s 2 1
3 0 v s 4 1
1 . 6
3 ±
0 . 3
2
1 . 6
6 ±
0 . 5
0
4 6 . 4
± 1 2
. 0
4 5 . 4
± 1 2
. 0
C a s t i n i e t a l 1 2
1 0 3
7 0
. 0 ±
8 . 3
7 2
. 7 ±
8 . 2
8 5 v s 8 4
3 5 v s 2 0
7 1 v s 7 8
1 . 5
9 ±
0 . 3
8
1 . 4
9 ±
0 . 3
0
4 6 . 9
± 1 2
. 8
4 9
. 9 ±
1 0
. 3
V a s h e g h a n i e t a l 1 1
7 2
6 1
. 4 †
6 2
. 7 †
7 8 v s 8 1
3 3 v s 3 8
6 6 v s 7 1
1 . 7
7 †
1 . 7
1 †
4 2 . 7
†
4 4
. 2 †
M o t o h i r o e t a l 2 4
1 5 5
7 1
. 0 ±
9 . 0
7 4
. 0 ± 7 . 0
7 6 v s 6 4
5 6 v s 6 3
8 6 v s 8 3
1 . 5
4 ±
0 . 4
3
1 . 5
5 ±
0 . 4
4
4 5 . 7
± 1 2
. 9
4 2
. 8 ±
1 3
. 8
P R E V E N T e t a l 1 3
3 8 2
6 5 . 8
*
6 7 . 5
*
7 1 v s 7 1
1 0 0 v s 1 0 0
7 7 v s 8 0
1 . 5
0 *
1 . 5
0 *
4 6 . 0
*
4 6
. 0 *
U e d a e t a l 1 8
5 9
7 7 . 0
± 9
. 0
7 5 . 0
± 1 0
. 0
7 7 v s 7 9
1 0 v s 1 0
N A
1 . 3
2 ±
0 . 4
6
1 . 5
1 ±
0 . 5
9
4 2 . 4
± 1 1
. 5
3 8
. 7 ±
1 2
. 6
K l i m a e t a l 2 1
1 7 6
7 8
. 0 *
7 5 . 0
*
6 6 v s 6 2
3 9 v s 3 4
9 0 v s 8 1
1 . 6
0 *
1 . 6
0 *
4 3 . 1
†
4 3
. 0 †
G o m e s e t a l 1 5
3 0 1
6 4
. 1 ±
1 2
. 0
6 4
. 5 ±
1 2
. 0
1 5 v s 7 5
2 9 v s 3 0
7 7 v s 7 4
1 . 5
0 ±
0 . 4
0
1 . 4
9 ±
0 . 5
0
5 0 . 5
± 1 3
. 0
5 1
. 9 ±
1 3
H a f i z e t a l 1 4
3 2 0
7 4
. 0 *
7 3
. 0 *
5 7 v s 5 7
4 9 v s 4 5
9 5 v s 9 4
1 . 6
5 *
1 . 6
0 *
4 1 . 5
*
4 0
. 5 *
K r i s t e l l e r e t a l 1 7
9 2
7 2
. 0 ±
1 1
. 0
7 3
. 0 ±
1 1
. 0
6 4 v s 5 2
5 2 v s 3 8
8 9 v s 9 2
N A
N A
4 8 . 9
†
4 9
. 4 †
B o u c e k e t a l 1 6
1 2 0
6 3
. 0 †
6 7 . 0
†
7 5 v s 7 5
N A
N A
1 . 9
2 †
1 . 8
1 †
4 3 . 6
†
4 4
. 6 †
K o o i m a n e t a l 2 2
5 4 8
7 1
. 6 †
7 2
. 5 †
6 0 v s 6 1
2 7 v s 2 7
N A
N A
N A
4 9 . 9
†
5 0
. 9 †
C o n t i n u e d
Zhang B, et al . BMJ Open 2015;5:e006989. doi:10.1136/bmjopen-2014-006989 3
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T a b l e 1
C o n t i n u e d
C o n t r a s t t y p e a n d
v o l u m e ( m L )
P r o c e d u r e
I n t e r v e
n t i o n s
B i c a r b o n a t e
S a l i n e
H y d r a t i o n r e g i m e n
D e f i n i t i o n o f C I N
E l e c t i v e d i a g n o s t i c /
i n t e r v e n t i o n a l p r o c e d u r e s
S B v s S C
N A
N A
3 m L / k g / h f o r 1 h b e f o r e a n d 1 m
L / k g / h f o r 6 h a f t e r t h e
p r o c e d u r e o f S B o r S C
S c r ↑ ≥ 2
5 %
w i t h i n 2 d a y s
I o p a m i d o l , n o n - i
o n i c
,
l o w - o
s m o l a r
E l e c t i v e C A G / P C I
S B v s S C
1 0 0 *
1 0 0 *
1 m L / k g / h f o r 6 h b e f o r e a n d a f t e
r t h e p r o c e d u r e o f S B o r
S C
S c r ↑ > 0
. 5 m g / d L o r 2 5 %
w i t h i n 2
d a y s
I o x a g l a t e ,
i o n i c
, l o w - o
s m o l a r
E m e r g e n c y C A G / P C I
S B v s S C
1 1 2 ±
8 9
1 2 0 ±
6 1
3 m L / k g / h f o r 1 h b e f o r e a n d 1 m
l / k g / h f o r 6 h a f t e r t h e
p r o c e d u r e o f S B o r S C B o l u s 0 . 5 m g / m L S B b e f o r e a n d S C
1 m L / k g / h f o r 6 h d u r i n g a n d a f t e r i n b o t h g r o u p s
S c r ↑ ≥ 0
. 5 m g / d L o r 2 5 %
w i t h i n 2
d a y s
I o p a m i d o l , n o n - i
o n i c
,
l o w - o
s m o l a r
E l e c t i v e C A G / P C I /
p e r i p h e r a l p r o c e d u r e
S B +
N A
C v s
N S +
N A
C
1 6 9 ±
9 2
1 7 9 ±
9
S B :
3 m L / k g / h f o r 1 h b e f o r e a n d
1 m L / k g / h f o r 6 h a f t e r ;
N S :
1 m L / k g / h f o r 1 2 h b e f o r e a n
d 1 2 h a f t e r
S c r ↑ ≥ 2
5 %
w i t h i n 2 d a y s
I o d i x a n o l , n o n - i
o n i c
, i s o -
o s m o l a r
E l e c t i v e C A G / P C I
S B v s S C
1 4 1 ± 5 0
1 3 8 ± 5 2
2 m L / k g / h f o r 2 h b e f o r e a n d 1 m
L / k g / h f o r 6 h a f t e r t h e
p r o c e d u r e o f S B o r S C
S c r ↑ > 0
. 5 m g / d L o r 2 5 %
w i t h i n 2
d a y s
I o d i x a n o l , n o n - i
o n i c
, i s o -
o s m o l a r
E l e c t i v e C A G
S B v s S C
1 2 6 *
1 3 7 *
3 m L / k g / h f o r 1 h b e f o r e a n d 1 . 5
m L / k g / h f o r 4 h a f t e r t h e
p r o c e d u r e o f S B o r S C
e G F R ↓
> 2 5 %
w i t h i n 4 d a y s
I o x i l a n ,
n o n - i
o n i c
, i s o -
o s m o l a r
E l e c t i v e C A G / P C I
S B v s I S
1 6 0 *
1 7 0 *
S B :
3 m L / k g / h f o r 1 h b e f o r e a n d
1 m L / k g / h f o r 6 h a f t e r ;
I S :
1 m L k g / h f o r 1 2 h a f t e r
S c r ↑ ≥ 0
. 5 m g / d L w i t h i n 5 d a y s
I o d i x a n o l , n o n - i
o n i c
, i s o -
o s m o l a r
E l e c t i v e C A G / P C I
B o l u s S
B +
S C
v s S C
8 2 ±
4 0
8 8 ±
4 5
S i n g l e - b
o l u s S B 2 0 m L f o r 5 m i n
b e f o r e a n d S C 1 m L / k g / h
f o r 1 2 h b e f o r e a n d a f t e r t h e p r o c e d u r e ;
1 m L / k g / h f o r 1 2 h
b e f o r e a n d a f t e r t h e p r o c e d u r e o
f S C
S c r ↑ > 0
. 5 m g / d L o r 2 5 %
w i t h i n 3
d a y s
I o h e x o l , n o n - i
o n i c
,
l o w - o
s m o l a r
E l e c t i v e C A G
S B +
I S
v s I S
1 1 5 ±
4 1
1 1 3
. 2 ±
3 6
3 m L / k g / h f o r 1 h b e f o r e a n d 1 m
L / k g / h f o r 6 h a f t e r i n b o t h
g r o u p s
S c r ↑ ≥ 0
. 5 m g / d L o r 2 5 %
w i t h i n 2
d a y s
I o h e x o l , n o n - i
o n i c
,
l o w - o
s m o l a r
E l e c t i v e C A G / P C I
S B v s S C
1 7 9 ±
1 2 5
1 9 6 ±
1 2 8
S B :
3 m L / k g / h f o r 1 h b e f o r e a n d
1 m L / k g / h f o r 6 h a f t e r ;
S C :
1 m L / k g / h f o r 1 2 h b e f o r e a n
d a f t e r
S c r ↑ ≥ 2
5 %
w i t h i n 5 d a y s
I o d i x a n o l , n o n - i
o n i c
,
l o w - o
s m o l a r
E l e c t i v e C A G
S B +
h a l f S C v s
h a l f S C
1 1 2 †
1 2 3 †
3 m L / k g / h f o r 1 h b e f o r e a n d 1 m
L / k g / h f o r 6 h a f t e r t h e
p r o c e d u r e o f 7 5 m L S B t o 1 L o f
0 . 4
5 %
S C ;
1 0 7 5 m L o f
0 . 4
5 %
S C
S c r ↑ ≥ 0
. 5 m g / d L o r 2 5 %
w i t h i n 2
d a y s
I o h e x o l , n o n - i
o n i c
,
l o w - o
s m o l a r
C o n t i n u e d
4 Zhang B, et al . BMJ Open 2015;5:e006989. doi:10.1136/bmjopen-2014-006989
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T a b l e 1
C o n t i n u e d
C o n t r a s t t y p e a n d
v o l u m e ( m L )
P r o c e d u r e
I n t e r v e
n t i o n s
B i c a r b o n a t e
S a l i n e
H y d r a t i o n r e g i m e n
D e f i n i t i o n o f C I N
E l e c t i v e C A G / P C I
S B +
S C
v s S C
1 4 0 ± 5 0
1 3 0 ±
4 0
1 m L / k g / h S C 1 2 h b e f o r e a n d 1
m L / k g / h S B f r o m
3 h b e f o r e
t o 6 h a f t e r t h e p r o c e d u r e ,
t h e n 1 m L / k g / h S C f o r 1 2 h ;
1 m L / k g / h S C 1 2 h b e f o r e a n d 1 2 h a f t e r t h e p r o c e d u r e
S c r ↑ ≥ 0
. 5 m g / d L o r >
2 5 %
w i t h i n 2
d a y s
I o p a m i d o l ,
n o n - i
o n i c
, l o w - o
s m o l a r
E l e c t i v e C A G / a n g i o p l a s t y /
e n d o v a s c u l a r i n t e r v e n t i o n
S B v s S C
1 1 3 *
1 2 0 *
S B :
3 m L / k g / h f o r 1 h b e f o r e a n d
1 m L k g h f o r 6 h a f t e r ;
S C :
1 m L / k g / h f o r 1 2 h
S c r ↑ ≥ 0
. 5 m g / d L o r >
2 5 %
w i t h i n 2
d a y s
I o d i x a n o l ,
n o n - i
o n i c
, l o w - o
s m o l a r
E m e r g e n c y C A G / P C I
S B v s S C
1 1 6 ±
6 3
1 0 4 ± 5 7
B o l u s 0
. 5 m g / m L S B b e f o r e a n d
S C 1 m L / k g / h f o r 6 h d u r i n g
a n d a f t e r i n b o t h g r o u p s
S c r ↑ ≥ 0
. 5 m g / d L o r >
2 5 %
w i t h i n 2
d a y s
I o p a m i d o l / i o h e x o l ,
l o w - o
s m o l a r
E l e c t i v e C A G / P C I / P T A /
C T / P A G
S B v s S C
1 0 0 *
1 0 0 *
S B :
3 m L / k g / h f o r 1 h b e f o r e a n d
1 m L / k g / h f o r 6 h a f t e r ;
S C :
1 m / k g / h f o r 2 4 h
S c r ↑ ≥ 0
. 5 m g / d L o r 2 5 %
w i t h i n 2
d a y s
I o p r o m i d e / i o h e x o l , e t c . ,
i s o / l o w - o
s m o l a r
E l e c t i v e C A G / P C I
S B v s N S
1 2 4 ±
6 5
1 2 5 ±
8 7
3 m L / k g / h f o r 1 h b e f o r e a n d 1 m
L / k g / h f o r 6 h a f t e r t h e
p r o c e d u r e o f S B o r N S
S c r ↑ ≥ 0
. 5 m g / d L w i t h i n 2 d a y s
H e x a b r i x /
l o x a g l a t e ,
l o w - o
s m o l a r
E l e c t i v e C A G / P A G /
i n t e r v e n t i o n
S B w / o
N A C
v s N S w / o N A C
1 1 0 *
1 0 0 *
S B :
3 m L / k g / h f o r 1 h b e f o r e a n d
1 m L / k g / h f o r 6 h a f t e r ;
N S :
1 m L / k g / h f o r 1 2 h b e f o r e a n
d 1 2 h a f t e r
S c r ↑ > 0
. 5 m g / d L o r 2 5 %
w i t h i n 2
d a y s
I o d i x a n o l / i o p a m i d o l / i o v e r s o
l ,
n o n - i
o n i c
, l o w - o
s m o l a r
E l e c t i v e C P B
S B v s I S
7 4 †
8 3 †
3 m L / k g / h f o r 1 h b e f o r e a n d 1 m
L / k g / h f o r 6 h a f t e r t h e
p r o c e d u r e o f S B o r I S
S c r ↑ ≥ 0
. 3 m g / d L o r 5 0 %
o r
u r i n e o u
t p u t <
0 . 5
m L / k g / h
( > 6 h ) w
i t h i n 5 d a y s
N A
N A
E l e c t i v e C A G / l o w e r l i m b
a n g i o g r a p h y a n d / o r
a n g i o p l a s t y
S B v s N S
1 1 5 †
1 0 4 †
3 m L / k g / h f o r 1 h b e f o r e a n d 1 m
L / k g / h f o r 6 h a f t e r t h e
p r o c e d u r e o f S B o r S C
S c r ↑ ≥ 0
. 5 m g / d L o r 2 5 %
w i t h i n 2
d a y s
I o d i n a t e d
,
n o n - i
o n i c
, l o w - o
s m o l a r
E l e c t i v e C E C T
S B v s I S
1 0 5 . 7
†
1 0 4
. 7 †
2 5 0 m L S B f o r 1 h b e f o r e ;
1 0 0 0
m L I S b e f o r e a n d 1 0 0 0 m L
I S a f t e r
S c r ↑ 0 . 5
m g / d L o r 2 5 %
w i t h i n
4 d a y s
I o m e p r o l / i o b i t r i d o l / i o d i x a n o
l ,
l o w - o
s m o l a r
* M e d i a n v a l u e
.
† M e a n v a l u e
.
D M
, d i a b e t e s m e l l i t u s ;
C A G
, c o r o n a r y a n g i o g r a p h y ;
C E C T
, c o n t r a s t - e n h a n c e d c o m
p u t e r i s e d t o m o g r a p h y ;
C I N
, c o n t r a s t - i n d u c e d n e p h r o p a t h y ;
C P B
, c a r d i o p u l m o n a r y b y p a s s ; e G F R
, e s t i m a t e d
g l o m e r u l a r f i l t r a t i o n r a t e ;
H T
, h y p e r t e n s i o n ;
I S ,
i s o t o n i c s a l i n e ;
N A
, n o t a p p l i c a b l e ; N A C
, N
- a c e t y l c y s t e i n e ;
N S
, n o r m a l s a l i n e ;
P A G
, p e r i p h e r a l a n g i o g r a p h y ;
P C I , p e r c u t a n e o u s c o r o n a r y
i n t e r v e n t i o n ;
P T A
, p e r c u t a n e o u s t r a n s l u m i n a l a n g i o p l a s t y ;
S B
, s o d i u m
b i c a r b o n a t e
; S C
, s o d i u m
c h l o r i d e ;
S c r , s e r u m
c r e a t i n i n
e ; w / o
, w i t h / w i t h o u t .
Zhang B, et al . BMJ Open 2015;5:e006989. doi:10.1136/bmjopen-2014-006989 5
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T a b l e 2
Q u a l i t y a s s e s s m e n t o f i n c l u d e
d s t u d i e s
I n c l u d e d t r i a l s
T r i a l d e s c r i b e d a
s
r a n d o m i s e d
( 1 = y e s ,
0 = n o )
R a n d o m i s e d m e t h o d
d e s c r i b e d a n d
a p p r o p r i a t e ( 1 = y e s ,
0 = n o )
A l l o c a t i o n
c o n c e a l m e n
t
d e s c r i b e d * ( 1 = y e s ,
0 = n o )
A l l o c a t i o n
c o n c e a l m e n t
d e s c r i b e d a n d
a p p r o p r i a t e
( 1 = y e s ,
0 = n o )
T r i a l d e s c r i b e d
a s d o u b
l e b l i n d
( 1 = y e s ,
0 = n o )
D o u b l e b l i n d m e t h o d
d e s c r i b e d a n d
a p p r o p r i a t e ( 1 = y e s ,
0 = n o )
W i t h d
r a w a l s a n d
d r o p o
u t s d e s c r i b e d
( 1 = y e
s ,
0 = n o )
J a d a d
s c o r e †
M e r t e n e t a l 1 9
1
1
0
0
0
0
1
4
O z c a n e t a l 5 0
1
0
0
0
0
0
1
2
M a s u d a e t a l 3 3
1
1
0
0
0
0
1
4
R E M E D I A L e t a l 2 0
1
1
0
0
1
0
1
5
A d o l p h e t a l 7
1
1
0
0
1
0
1
5
B r a r e t a l 8
1
1
1
1
0
0
1
5
M a i o l i e t a l 9
1
1
1
1
0
0
0
4
T a m u r a e t a l 2 3
1
1
0
0
0
0
1
4
V a s h e g h a n i e t a l 1 0
1
1
0
0
1
0
0
4
C a s t i n i e t a l 1 2
1
1
0
0
0
0
0
3
V a s h e g h a n i e t a l 1 1
1
1
0
0
1
0
0
4
M o t o h i r o e t a l 2 4
1
1
0
0
0
0
1
4
P R E V E N T e t a l 1 3
1
1
0
0
0
0
1
4
U e d a e t a l 1 8
1
1
0
0
0
0
0
3
K l i m a e t a l 2 1
1
0
1
1
0
0
0
3
G o m e s e t a l 1 5
1
0
1
1
0
0
0
3
H a f i z e t a l 1 4
1
1
0
0
0
0
1
4
K r i s t e l l e r e t a l 1 7
1
1
1
1
1
0
0
5
B o u c e k e t a l 1 6
1
1
1
1
1
0
1
6
K o o i m a n e t a l 2 2
1
1
0
0
0
0
1
4
* O n e p o i n t i s a l l o c a t e d a c c o r d i n g t o t h e
J a d a d s c o r e i f t h e r a n d o m i s a t i o n m e t h o d o f t h e t r i a l i s d e s c r i b e d a n d a p p r o p r i a t e
.
† A s s e s s m e n t o f i n c l u d e d t r i a l s :
l o w q u a l i t y
, 1 –
3 ;
h i g h q u a l i t y
, 4 –
7 .
6 Zhang B, et al . BMJ Open 2015;5:e006989. doi:10.1136/bmjopen-2014-006989
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A detailed description of the baseline characteristicsof the included studies is given in table 1. Patients inmost studies underwent coronary angiography or inter- ventional procedures. There were also seven studies which examined peripheral procedures, angioplasty, car-diopulmonary bypass and CT.8 18 1 9 2 1–24 The sodiumbicarbonate hydration regimen in 13 studies was asdescribed by Merten et al and consisted of sodium bicar-bonate infusion at a rate of 3 mL/kg/h for 1 h beforeand 1 mL/kg/h for 6 h after the procedure.
Primary outcomeCIN occurred in 158 of 2130 patients who received
sodium bicarbonate compared with 217 of 2150 patients
who received saline, demonstrating a lower overall inci-dence of CIN in the sodium bicarbonate group (gure 2).The pooled OR was 0.67 (95% CI 0.47 to 0.96; p=0.027),also in favour of sodium bicarbonate (gure 2).
However, moderate heterogeneity (I2=48%; p=0.008)across studies was found (gure 2). Therefore, subgroupanalyses were conducted using a random-effects modeland showed a more pronounced effect of sodium bicar-bonate in studies using low-osmolar contrast media (OR 0.59, 95% CI 0.37 to 0.93; p=0.024) (table 3). Similarly,subgroup analysis by setting suggested a lower incidenceof CIN with sodium bicarbonate in studies of patientsundergoing emergency procedures (OR 0.16, 95% CI
0.05 to 0.51; p=0.002) (table 3). The effect of sodium
Table 3 Subgroup analyses used to assess the effect of sodium bicarbonate in various conditions
Subgroups Trials/patients OR (95% CI) Test for overall effect Heterogeneity
Type of contrast
Low-osmolar 14/2823 0.59 (0.37 to 0.93) Z=2.26 ( p=0.024) χ²=26.61, df=13 (p=0.014), I²=51%
Iso-osmolar 4/1189 0.76 (0.43 to 1.34) Z=0.93 ( p=0.351) χ²=4.67, df=3 ( p=0.198), I²=36%
Setting
Elective 18/4162 0.76 (0.54 to 1.06) Z=1.62 ( p=0.105) χ²=29.54, df=17 (p=0.030), I²=43%
Emergency 2/118 0.16 (0.05 to 0.51) Z=3.11 ( p=0.002) χ²=0.07, df=1 ( p=0.784), I²=0%
Using NAC or not
Use 1/219 0.17 (0.04 to 0.79) Z=2.26 (p=0.024) Not applicable
Non-use 18/3741 0.71 (0.48 to 1.03) Z=1.80 ( p=0.071) χ²=33.13, df=17 (p=0.011), I²=49%
Publication year
Before 2008 4/573 0.19 (0.09 to 0.41) Z=4.26 ( p=0.000) χ²=1.06, df=10 ( p=0.788), I²=0%
After 2008 16/3707 0.85 (0.62 to 1.16) Z=1.03 ( p=0.302) χ²=22.13, df=15 (p=0.105), I²=32%
Manner of administration
Continuous 18/4077 0.75 (0.53 to 1.05) Z=1.69 ( p=0.091) χ²=30.21, df=17 (p=0.025), I²=44%
Bolus 2/203 0.15 (0.04 to 0.54) Z=2.90 (p=0.004) χ²=0.23, df=1 ( p=0.632), I²=0%
NAC, N-acetylcysteine.
Figure 1 Flow diagram of
included studies. NAC,
N-acetylcysteine.
Zhang B, et al . BMJ Open 2015;5:e006989. doi:10.1136/bmjopen-2014-006989 7
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Various mechanisms have been proposed to explainhow sodium bicarbonate administration prevents CIN.31 32
One suggestion is that sodium bicarbonate makes tubularurine more alkaline, thus attenuating free radical forma-tion and peroxide injury.28 Oxygen free radicals and per-oxide are usually generated in acidic conditions, and sosodium bicarbonate infusion could increase the pH of local renal tissue to neutral or slightly alkaline, thereby reducing the production of free radicals and peroxide.
Merten et al 19 rst introduced the administration of sodium bicarbonate at a concentration of 154 mmol/L toprev ent CIN. In our study, the hydration regimens of 13trials9–17 19–21 33 were similar to the Merten protocol. Although most previous systematic reviews and relevant meta-analyses demonstrated that sodium bicarbonate infu-sion could decrease the incidence of CIN,25 26 34–42 sec-ondary clinical endpoints as diverse as renal replacement therapy and mortality were not improved. Furthermore, a
Figure 3 (A) The forest plot of the requirement for dialysis. (B) The forest plot of mortality ORs.
Zhang B, et al . BMJ Open 2015;5:e006989. doi:10.1136/bmjopen-2014-006989 9
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retrospective cohort study of 7977 patients at Mayo Clinicdrew a surprising conclusion: sodium bicarbonate was asso-ciated with an increased incidence of CIN.43 In contrast tomost RCTs which used creatinine elevation within 48–72 hafter contrast exposure to dene CIN, From et al extendedthe denition time of CIN to a week as creatinine may peak 3–7 days after exposure to contrast. However, thisissue remains to be discussed. Since all patients in ourstudy had a history of renal insuf ciency, Scr levels may have peaked earlier.
The underlying sources of moderate heterogeneity should be taken into account in this meta-analysis,because the study subjects, study settings and types of
contrast media varied. In this case, subgroup analyses were conducted and the results revealed signicant dif-ferences between emergency and elective procedures, with sodium bicarbonate providing more prot ection inthe former than the latter. In a meta-analysis42 of theeffect of sodium bicarbonate on preventing CIN, sub-group analyses also showed a more pronounced ef cacy of sodium bicarbonate in three trials18 3 3 4 4 including
patients undergoing emergency procedures compared with those undergoing elective procedures. However, theexact mechanism by which sodium bicarbonate resultsin a decrease incidence of CIN remains unknown;perhaps it is related to the method of administrationand dosage. Similarly, sodium bicarbonate was morebenecial in patients who received low-osmolar contrast agents.45 46 However, since a signicantly fewer numberof patients received iso-osmolar contrast media (n=1189)compared with those receiving low-osmolar contrast media (n=2823), the main reason for the better effect of sodium bicarbonate was dif cult to determine.
Although the use of NAC has been reported to
reduce the incidence of CIN in many studies, thedenitive effect of NAC has not yet been established. A number of trials and meta-analyses indicated that the combination of sodium bicarbonate and NAC issuperior to eit her regimen alone in preventing CIN.Three studies20 4 4 4 7 included patients who receivedNAC in both groups after infusion of sodium bicar-bonate or saline and the results f avoured sodiumbicarbonate. The BINARIO study 48 indicated that hydration with sodium bicarbonate in addition tohigh-dose NAC in the setting of urgent percutaneouscoronary intervention for ST-elevation myocardial
infarction was associated with a net clinical bene
t.However, Yang et al 27 and Thayssen et al 49 concludedthat the use of NAC did not result in a signicant reduction in the incidence of CIN. In our study, only one trial20 using NAC was included in the sub-analysis,the effect of which may be overestimated (OR 0.17,95% CI 0.04 to 0.79; p=0.024). Accordingly, morelarge-scale and well designed RCTs are warranted todetermine whether sodium bicarbonate plus NAC ismore useful in preventing CIN than either alone.
Many studies have shown that patients with CIN are at greater risk of
