Urinary alkalinization using sodium bicarbonate

ORIGINAL ARTICLE
Efficacy and Safety of Perioperative Sodium Bicarbonate
Therapy for Cardiac Surgery-associated Acute Kidney
Injury: A Meta-analysis
Mao-Lu Tian, MMed, Ying Hu, MMed, Jing Yuan, MMed, and Yan Zha, MD
Objective: Urinary alkalinization with sodium bicarbonate infusion
can theoretically protect against the mechanisms of acute kidney
injury (AKI). Controversy exists regarding whether sodium bicar-
bonate infusion can reduce the incidence of AKI from cardiac
surgery. A meta-analysis was conducted to show the efficacy and
safety of perioperative sodium bicarbonate use for preventing AKI in
patients undergoing cardiac surgery.
Data Sources: PubMed, CBM, EMBASE, CENTRAL, and Cochrane
renal group specialized register were searched for pertinent studies.
Study Selection: Randomized controlled trails and prospective
observational cohort studies that compared sodium bicarbonate with
sodium chloride or blank control in cardiac surgery with cardiopul-
monary bypass were included. Exclusion criteria were duplicate
publications, nonadult studies, oral administration of sodium bicar-
bonate, retrospective analyses, and studies with small sample size
(n , 50) or with no data on AKI.
Data Extraction: Study end points, study design, population,
operation information, and sodium bicarbonate doses were extracted.
Data Synthesis: Data from 1673 patients in 5 randomized trials
and 1 prospective observational cohort study were analyzed. The
analysis showed that sodium bicarbonate did not reduce the
incidence of postoperative AKI and the need for renal replacement
therapy. Postoperative ventilation time, hospital length of stay,
hospital death, and mortality within 90 days had no statistical
difference between 2 groups. Time in intensive care unit was even
slightly longer in the experimental group.
Conclusions: Urinary alkalinization using sodium bicarbonate
infusion failed to reduce the incidence rate of AKI or other outcomes
in patients undergoing cardiac surgery. This intervention might even
prolong intensive care unit stay.
Key Words: cardiac surgery, sodium bicarbonate, acute kidney
injury, renal replacement therapy, mortality
(J Cardiovasc PharmacolÔ 2015;65:130–136)
INTRODUCTION
Acute kidney injury (AKI) is a common and serious
postoperative complication of cardiac surgery using cardiopul-
monary bypass (CBP), with incidence rates up to 40% in high-
risk patients.1–3
Even a smaller elevation of serum creatinine
after cardiac surgery is an independent risk factor for increased
intensive care unit (ICU) stay, hospital stay, and mortality.4
Kinds of preoperative and intraoperative risk factors have been
found to associate with cardiac surgery-associated acute kidney
injury (CSA-AKI), including female sex, hypertension, cardiac
disease with left ventricular ejection fraction less than 35%,
chronic obstructive pulmonary disease, diabetes mellitus,
chronic kidney disease, the complexity of planned surgical pro-
cedures, and duration of cardiopulmonary bypass (CPB).5,6
Sev-
eral scoring systems for risk stratification also have been
designed.7–9
The pathophysiology of CSA-AKI is multifactorial
and not yet completely understood. No safe and effective inter-
vention has been found, so its incidence, morbidity, or mortality
has not improved significantly in the past few decades.
Sodium bicarbonate can alkalinize tubular fluid and has
been supposed to exert a renal protective effect mainly through
2 mechanisms, preventing the formation of injurious reactive
oxygen species and the conversion of hemoglobin to methemo-
globin.10
Red blood cell damage during CPB results in the
release of free hemoglobin into the circulation. Cardiac surgery
with CBP can decrease urine PH of these patients. In an acidic
renal environment, hemoglobin is converted into methemoglo-
bin, a substance that precipitates in the distal tubule, leading to
cast formation, obstruction, and tubular necrosis. Urinary acidity
may also promote the Haber–Weiss reaction, facilitate the gen-
eration and toxicity of reactive oxygen species, further contrib-
uting to tubular necrosis.11
Urinary alkalinization may protect
from renal injury induced by these reactions. Sodium bicarbon-
ate may also directly scavenge other reactive species from the
blood, such as peroxynitrite and hydroxyl radicals.12
CSA-AKI
shares some of the same pathophysiological mechanisms with
contrast-induced nephropathy (CIN), especially the generation
of oxygen-free radicals. Several meta-analyses concluded that
CIN was significantly attenuated, both in prevalence and sever-
ity, by the prophylactic infusion of sodium bicarbonate com-
pared with hydration with sodium chloride.13–15
Received for publication August 14, 2014; accepted September 11, 2014.
From the Department of Nephrology, Institute of Nephritic and Urinary Dis-
ease, Guizhou Provincial People’s Hospital, Guiyang, China.
The authors report no conflicts of interest.
M-L. Tian and Y. Zha designed the study. M-L. Tian and Y. Hu carried out
studies searching and the eligibility assessments. M-L. Tian and J. Yuan
evaluated the qualities of the included studies and carried out data
extracting. M-L. Tian, Y. Zha, J. Yuan, and Y. Hu participated in writing
the manuscript. All authors read and approved the final manuscript.
Reprints: Yan Zha, MD, Department of Nephrology, Institute of Nephritic and
Urinary Disease, Guizhou Provincial People’s Hospital, 83 Zhongshan
Road, Guiyang 550002, China (e-mail: Zhayan72@126.com).
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
130 | www.jcvp.org J Cardiovasc Pharmacolä Volume 65, Number 2, February 2015
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

The studies on the protective effect of sodium bicar-
bonate infusion against AKI in patients undergoing cardiac
surgery were limited, the sample size of single study was
insufficient, and the results were not identical with the
theories. Therefore, we conducted a meta-analysis of appro-
priate published studies to determine the efficacy and safety
of sodium bicarbonate in preventing CSA-AKI among the
adult surgical population.
METHODS
Search Strategy
A computerized search of the PubMed, CBM, EMBASE,
CENTRAL, and Cochrane renal group specialized register
was independently undertaken by 2 authors to identify
potentially eligible studies. The search was not limited to
English language or publication type, and the recent date for
the search was May 30, 2014. The MESH terms and
keywords used to search included the following: “cardiac
surgery or heart surgery or cardiac surgical procedures or
cardio-thoracic surgery or heart operation or CABG or valve
surgery” and “bicarbonate sodium” and “acute kidney injury
or acute kidney failure or renal insufficiency or renal failure
or AKI or ARF.” The reference lists from all studies, sys-
tematic reviews, and narrative reviews identified by elec-
tronic databases were handsearched to identify other
potentially relevant citations.
Study Selection
The prospective cohort studies and randomized control
trials that had reported the effects of perioperative sodium
bicarbonate infusion on the postoperative renal outcomes in
adult patients undergoing cardiac surgery with CBP were
identified and analyzed for inclusion. Comparison of sodium
bicarbonate with control had no restriction on either dose or
time of administration. Exclusion criteria were as follows: Age
,18 years, emergency cardiac surgery, end-stage renal disease,
planned off-pump cardiac surgery, pregnancy, animal studies,
oral administration of sodium bicarbonate, retrospective analy-
ses, and studies with small sample size (n , 50) or with no data
on AKI. Two investigators independently examined and as-
sessed the studies, and disagreement was resolved by discus-
sion. Titles and abstracts from the electronic search were
reviewed. After the initial review of the abstracts, the relevant
studies were identified, and a detailed evaluation of the full text
was done. In the case of multiple reports with the same or
overlapping data published by the same researchers, we
selected the most recent or most informative citation.
Data Extraction
Data extraction and collection were performed indepen-
dently by 2 authors using standard data-extraction forms, with
differences of opinion resolved by consensus. The data extraction
included authorship, sample size, study design, country of origin,
baseline patient characteristics (age, sex, hypertension, diabetes
mellitus, chronic obstructive pulmonary disease, left ventricular
ejection fraction, preoperative mean creatinine level, dyslipide-
mia), type and duration of operations, sodium bicarbonate
dosage, definitions of AKI and adjusted covariates (AKIN,
RIFLE, Scr .25% baseline within 2 days, Scr .25% baseline
within 5 days, Scr .50% baseline within 5 days), and other
outcomes (the need for renal replacement therapy [RRT], post-
operative ventilation time, time in ICU, hospital length of stay,
FIGURE 1. Flowchart of search.
TABLE 1. Characteristics of the Included Studies
Source
Sample
Size, n Country
Patient
Recruitment
Study
Type Blind
NaHCO3
Dose,
mmole/Kg Main Operation
CPB time
(NaHCO3/
Control, min)
Michael Haase 100 Australia 2006.06–2006.11 RCT Yes 4 Valve surgery
CABG
131.1/142.6
Matthias Heringlake 584 Germany 2009.07–2010.12 Cohort No 4 Valve surgery
CABG
115/115
Judith L. Kristeller 92 USA 2009.01–2011.03 RCT Yes 1.35 Valve surgery
CABG
UN
BIC-MC study 350 Germany, Canada,
Ireland
2008.05–2011.06 RCT Yes 5.1 Valve surgery
CABG
132/121
Shay P. McGuinness 427 Australia, New
Zealand
2009.03–2011.06 RCT Yes 5.1 Valve surgery
CABG
128/129
Katja R. Turner 120 USA 2006.08–2011.02 RCT NO 3 Valve surgery
CABG
UN
J Cardiovasc Pharmacolä Volume 65, Number 2, February 2015 Acute Kidney Injury
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved. www.jcvp.org | 131

hospital death, and mortality within 90 days). Six studies were
included in the meta-analysis.
Quality Assessment
The quality of each study was evaluated using the
checklist developed by Downs and Black,16
which included
27 questions based on the study’s reporting, external validity,
bias, confounding, and power. Twenty-five questions gave
a score of 0 or 1, one item in the reporting subscale scored
0 to 2, and the single item on power scored 0 to 5, so the total
maximum score was 31. Studies with scores $23 were con-
sidered to be high quality, 18 to 23 were moderate quality,
and scores ,18 were of low quality.
Data Analysis and Synthesis
According to guidelines in the Cochrane reviewers’
handbook, all analyses were performed with RevMan 5.0 soft-
ware (Cochrane Collaboration). Between-study heterogeneity
was assessed using the x2 test. Random-effects analysis was
used when I2 $ 50%, whereas fixed-effects analysis was used
when I2 , 50%. We used odds ratio with 95% confidence
interval (CI) to express dichotomous data. Continuous data
were expressed as mean, SD, and weighted mean difference.
The data from various studies were pooled and expressed as
pooled odds ratio or weighted mean difference with 95% CI.
Potential publication bias was evaluated using the funnel plot
method for the author-defined AKI risk. Statistical significance
was set at a 2-tailed level of 0.05 for hypothesis testing.
RESULTS
Study Characteristics
As outlined in Figure 1, the search strategy generated
198 studies. After applying inclusion and exclusion criteria, 6
studies of 1673 patients were included in the final analysis: 5
randomized trials and 1 prospective observational cohort
study.17–22
The characteristics and details of the included stud-
ies were summarized in Tables 1 and 2. We could easily found
that these patients were at relatively high risk of AKI after on-
pump cardiac surgery. According to the scoring system from
Downs and Black, 3 studies were of high Quality,17–19
2 of
intermediate quality,20,21
and 1 of poor quality.22
Funnel plot of
studies used in author-defined AKI risk analysis showed no
evidence of publication bias (Fig. 2). The dosages of sodium
bicarbonate varied between 1.35 and 5.1 mmole/kg with
a continuous infusion after the bolus. The investigated popu-
lations of each study were too small to turn out significant
results in clinical outcome variables, but when they were
assessed together in a meta-analysis, sufficient numbers of
patients were available for a more reliable analysis. Each of
the included studies used more than 1 AKI definition, so this
meta-analysis consisted of 5 criteria.
Quantitative Data Synthesis
Renal Outcomes
The studies that were included had different definitions for
AKI. Compared with control group, the incidence of author-
defined AKI in bicarbonate group did not decrease. According to
other common definitions, including AKIN, RIFLE, Scr .25%
baseline within 2 days, Scr .25% baseline within 5 days, and
Scr .50% baseline within 5 days, we extracted available data of
these studies to analyze the AKI incidence. Likewise, no differ-
ence was found by pooling effect. In the bicarbonate and control
groups, 44 of 781 and 45 of 797 patients respectively suffering
from CSA-AKI had requirement of RRT. Therefore, whichever
definition of renal injury was adopted, the results of our analysis
consistently showed that renal outcomes were not improved by
the use of sodium bicarbonate infusion. Forest plot and results
were shown in Figure 3.
Other Related Outcomes
Several continuous data were displayed as the mean
(95% CI) and in 3 included studies as the median
FIGURE 2. A funnel plot of author-defined AKI risk.
TABLE 2. Demographic Data of Included Studies (NaHCO3/Control Groups)
Study Age, yr Female, % Weight, kg HT, % DM, % COPD, % LVEF, %
Mean Baseline
Scr, mmole/L Dyslipidemia, %
Michael Haase 71.5/70.6 40/34 77.7/78.2 92/84 UN 12/16 UN 91.9/89.5 62/58
Matthias Heringlake 68.5/68.5 35.7/33.9 80.1/82.3 83.6/82.2 30.7/23.8 UN UN 82/81 68.9/71.4
Judith L. Kristeller 72/73 36/48 88/84.6 89/92 52/38 UN 48/49 UN 86/73
BIC-MC study 66.4/64.6 28/29 UN 70/66 20/30 8/11 51.1/51.4 89.2/84 62/59
Shay P. McGuinness 66.3/67.8 31/35 82/76 66/68 UN 10/13 52/54 86.6/84.8 59/60
Katja R. Turner 69.7/70.2 27/47 90.2/85.4 86/80 44/47 10/12 UN 106.1/88.4 UN
CABG, coronary artery bypass grafting; UN, unknown.
Tian et al J Cardiovasc Pharmacolä Volume 65, Number 2, February 2015
132 | www.jcvp.org Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.

FIGURE 3. Forest plots for renal outcomes.

(interquartile range).17–19
Given the relatively large sam-
ple size, these data were converted to mean (SD) accord-
ing to the formulas recommended by the Cochrane
Handbook for systematic reviews of interventions.23
The administration of sodium bicarbonate could poten-
tially cause a metabolic alkalosis with compensatory
respiratory acidosis leading to prolonged need for
mechanical ventilation, but no significant difference was
noted in the duration of mechanical ventilation between
the 2 groups. Hospital length of stay, hospital death,
and mortality within 90 days also had no statistical differ-
ence between the sodium bicarbonate group and control
group. Postoperative time of ICU stay was slightly longer
in the experimental group. Forest plot and results were
shown in Figure 4.
Sensitivity Analysis
Analyses involving computations using a fixed-effect
model and a random-effect model respectively remained in
the same direction for renal outcomes and all other outcomes.
DISCUSSION
This meta-analysis included 6 total studies with 1673
patients focusing on the efficacy and safety of perioperative
sodium bicarbonate infusion for CSA-AKI. The renal out-
comes involving the incidence of AKI with several definitions
and the need for RRT or other outcomes including post-
operative ventilation time, ICU/hospital stay, and mortality
showed no differences between sodium bicarbonate group
and control group.
FIGURE 4. Forest plots for other related
outcomes.

AKI is not only a common complication in heart
surgical patients24
but has also been approved to be indepen-
dently associated with morbidity and mortality.25,26
Unfortu-
nately, little progress has been done within the last years in
the development of measures to reduce the incidence and
improve the prognosis of this complication. It is speculated
that the use of hypertonic solutions may have had confound-
ing effects, but this is likely to be alleviated by the simulta-
neous large volumes of intravenous fluids managed as part of
routine care in the perioperative heart surgical setting.27
Kris-
teller et al22
only supplied their patients with sodium bicar-
bonate of 1.35 mmole/kg, so one may assume that the lack of
a renal protective effect of bicarbonate infusion may be asso-
ciated with the fact that no enough alkalization was gained.
Actually, a similar infusion of sodium bicarbonate resulted in
a urine pH of 6.5 in a study of CIN.28
Given the positive
effect of bicarbonate in the Michael Haase’s earlier trial and
the negative effect in next 5 included studies, a more severe
AKI end point definition, such as doubling of serum creati-
nine or commencement of postoperative RRT, may decrease
the chance of type I errors.
A serum creatinine rise after CBP might partly relate to
renal tubular injury induced by reactive oxygen species and free
hemoglobin release.29,30
Physiologically, intravenous sodium
bicarbonate causes blood and urine alkalization. During heart
surgery, operation per se and effects of the extracorporeal cir-
culation result in urine acidification.31
Therefore, investigators
have proposed that perioperative use of sodium bicarbonate
might be beneficial in terms of reducing postoperative renal
tubular injury. The pathophysiology of AKI in cardiac surgical
patients is unknown and may be diverse. It might be also
involved with activation of proinflammatory cytokines, reduc-
tion in renal perfusion pressure and direct nephrotoxicity.5
On-pump surgery leads to the occurrence of systemic inflam-
matory response syndrome due to contact of blood components
with artificial surface of the bypass circuit.32
The most likely
explanation for the lack of benefit of a perioperative sodium
bicarbonate infusion is the multifactorial etiology of CSA-AKI,
more complicated than contrast-induced nephropathy—a condi-
tion where free oxygen radical generation may be involved.33
Therefore, a modification of only 1 contributing factor is insuf-
ficient to impact the development of renal injury.
Strengths of our meta-analysis include main composing
of randomized control trials and selection of a group of trials of
direct relevance to perioperative medicine. The I2 statistic dis-
plays an acceptable risk of between-study heterogeneity, and
this combined with narrow CIs suggests that our findings are
valid. Our study also has some potential limitations. First, the
authors may not have identified unpublished reports despite
searching the literature extensively, which may limit the effec-
tive assessment of drug effects and safety. Second, serum bicar-
bonate and potassium levels after sodium bicarbonate infusion,
which could be hazardous for patients, were not analyzed due
to lack of effective data. Third, although our analysis did not
show publication bias, we cannot exclude outcomes reporting
bias. Finally, because of the lack of adequate information pro-
vided in the studies used for meta-analysis, we could not per-
form separate analyses to assess the impact of other variables
that can affect AKI, such as baseline kidney function, ejection
fraction, congestive heart failure, hemodilution technique, and
pulsatile perfusion.
CONCLUSIONS
Sodium bicarbonate infusion has no beneficial effect on
the postoperative occurrence of AKI, requirement for RRT,
ventilation time, hospital and ICU stays, or hospital and
within 90-day mortality in patients at relatively high risk of
AKI after open heart surgery with CBP. Given the absence of
demonstrable benefit, potential fluid overload, and potential
unknown risks, routine clinical use of sodium bicarbonate
solution in surgical patients is unable to be recommended.
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