Review ArticleSodium Bicarbonate Therapy in Patients withMetabolic Acidosis

Mara M. Adeva-Andany, Carlos Fernndez-Fernndez, David Mourio-Bayolo,Elvira Castro-Quintela, and Alberto Domnguez-Montero

Nephrology Division, Hospital General Juan Cardona, Avenida Pardo Bazan, s/n, Ferrol, 15406 A Coruna, Spain

Correspondence should be addressed to Mara M. Adeva-Andany; madevaa@yahoo.com

Received 30 July 2014; Revised 5 September 2014; Accepted 19 September 2014; Published 21 October 2014

Academic Editor: Biagio R. Di Iorio

Copyright 2014 Mara M. Adeva-Andany et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Metabolic acidosis occurs when a relative accumulation of plasma anions in excess of cations reduces plasma pH. Replacementof sodium bicarbonate to patients with sodium bicarbonate loss due to diarrhea or renal proximal tubular acidosis is useful,but there is no definite evidence that sodium bicarbonate administration to patients with acute metabolic acidosis, includingdiabetic ketoacidosis, lactic acidosis, septic shock, intraoperativemetabolic acidosis, or cardiac arrest, is beneficial regarding clinicaloutcomes or mortality rate. Patients with advanced chronic kidney disease usually show metabolic acidosis due to increasedunmeasured anions and hyperchloremia. It has been suggested thatmetabolic acidosis might have a negative impact on progressionof kidney dysfunction and that sodium bicarbonate administration might attenuate this effect, but further evaluation is requiredto validate such a renoprotective strategy. Sodium bicarbonate is the predominant buffer used in dialysis fluids and patients onmaintenance dialysis are subjected to a load of sodium bicarbonate during the sessions, suffering a transient metabolic alkalosis ofvariable severity. Side effects associatedwith sodiumbicarbonate therapy include hypercapnia, hypokalemia, ionized hypocalcemia,and QTc interval prolongation. The potential impact of regular sodium bicarbonate therapy on worsening vascular calcificationsin patients with chronic kidney disease has been insufficiently investigated.

1. Measurement of Plasma Bicarbonate

The analysis of blood gases includes three parameters relatedto the carbon dioxide (CO

2) content of blood: total concen-

tration of carbon dioxide in blood (tCO2), plasma partial

pressure of carbon dioxide (pCO2), and plasma bicarbonate

(HCO3

) concentration [1, 2].The plasma pCO

2is measured by blood gases analyzers

and indicates the pressure exerted by the small portion(approximately 5%) of total carbon dioxide dissolved inthe aqueous phase of plasma. The concentration of plasmabicarbonate is usually estimated from measured pH andpCO2values when blood gas analyzers are utilized. The

tCO2is chemically measured by laboratory analyzers and

reflects the total amount of carbon dioxide present in blood,which primarily corresponds to the sum of bicarbonate anddissolved carbon dioxide or pCO

2[1, 3].

The relationship between pH and pCO2used to calcu-

late plasma bicarbonate concentration is described by the

Henderson-Hasselbalch equation derived from the appli-cation of the law of mass action to the hydration anddissociation reactions of carbonic acid (H

2CO3) in plasma:

CO2+H2O H

2CO3

H2CO3 H+ +HCO

3

(1)

The equilibrium constant for the first reaction (1) is

1=

[H2CO3]

[CO2] [H2O]. (2)

The equilibrium constant for the second reaction (2) is

2=

[H+] [HCO3

]

[H2CO3]

. (3)

Hindawi Publishing Corporatione Scientic World JournalVolume 2014, Article ID 627673, 13 pageshttp://dx.doi.org/10.1155/2014/627673

2 The Scientific World Journal

Hemoglobin

Red blood cell at tissue capillary

CO2 + H2O

H+ + HCO3

Cl

O2

(a)

Hemoglobin

Red blood cell at lung capillary

CO2 + H2O

H+ + HCO3

Cl

O2

(b)

Figure 1: Carbonic anhydrase reaction.

The Henderson-Hasselbalch equation used for the calcula-tion of plasma bicarbonate is

pH = p+ log[HCO

3

]

pCO2

. (4)

The pvalue for this equation is obtained from a combined

equilibrium constant including the values of 1and

2.

The pof this new combined constant (6.1) is used in the

calculation of plasma bicarbonate concentration. is thesolubility coefficient for carbon dioxide gas (equal to 0.0306for plasma at 37C).

Substituting these values,

pH = 6.1 + log[HCO

3

]

0.03 pCO2

. (5)

Blood gases analyzers use this formula to estimate plasmabicarbonate concentration from known pH and pCO

2values.

However, the application of this equation to the calculationof the bicarbonate concentration in human plasma maybe misleading, as the hydration of carbon dioxide in vivorequires the action of isoenzymes of carbonic anhydrasewhich either are anchored to the plasma membrane ofred blood cells or lie inside the erythrocytes. Activity ofcarbonic anhydrase isoenzymes has not been reported inhuman plasma in sufficient amount to drive significantly thehydration of carbon dioxide on this location. In addition,isoforms of carbonic anhydrase catalyze the reversible hydra-tion of carbon dioxide into bicarbonate with no intermediateformation of carbonic acid (Figure 1) [4]. Therefore, theuse of a combined p

may not be appropriate, as there

is no carbonic acid formation in vivo. For these reasons,the application of the Henderson-Hasselbalch equation tothe calculation of the plasma bicarbonate concentration isnot straightforward and the physiological meaning of theplasma bicarbonate value estimated from the application ofthis equation to human plasma remains uncertain.

The tCO2in blood determined by laboratory analyzers

and the calculated plasma bicarbonate concentration frompoint-of-care blood gases analyzers are usually consideredequivalent and the tCO

2is generally measured as a surrogate

for plasma bicarbonate level, although some studies havefound poor agreement between the two parameters [3, 5].

Table 1: Acute conditions in which sodium bicarbonate therapy hasnot improved outcomes.

Acute conditions in which sodium bicarbonatetherapy does not improve outcomesDiabetic ketoacidosisLactic acidosisSeptic shockCardiac arrestIntraoperative metabolic acidosis

2. Sodium Bicarbonate Therapy inMetabolic Acidosis

Metabolic acidosis is usually associated with a reduction inplasma pH, although serum concentration of hydrogen ionsmay be near normal when a mixed acid-base disorder ispresent. For instance, the coexistence of vomiting-inducedmetabolic alkalosis may contribute to the rise in plasmapH in patients with metabolic acidosis. Common causesof metabolic acidosis include diabetic ketoacidosis (DKA),lactic acidosis, and hyperchloremic acidosis due to diarrheaor renal tubular acidosis. Excess net dietary acid load in thepresence of chronic kidney dysfunction induces metabolicacidosis with elevation of chloride and unmeasured anions.In acute conditions, such as DKA, lactic acidosis, and septicshock, the magnitude of the fall in plasma pH usually reflectsthe severity of the causative illness. Evidence that signifi-cant harmful effects are derived from metabolic acidosis byitself has not been provided in human beings [610] andtherefore the successful management of metabolic acidosisrequires the therapy of the underlying causative disorder [11].Replacement of sodium bicarbonate is beneficial in disordersassociated with loss of sodium bicarbonate, such as diarrheaand renal tubular acidosis, but symptomatic therapy withsodium bicarbonate to correct metabolic acidosis per sein other settings has not been demonstrated to ameliorateclinical outcomes ormortality (Table 1) [8, 10, 1214]. Further,sodium bicarbonate supplementation fails to raise plasma pHor increases it only slightly in some patients affected withmalignancy-associated lactic acidosis, while control of theunderlying malignancy brings plasma pH to normal [1522].

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2.1. Sodium Bicarbonate Therapy in Patients with DiabeticKetoacidosis. Both retrospective and prospective studieshave consistently documented that sodium bicarbonate ther-apy does not improve metabolic responses, biochemicalparameters, acid-base balance normalization, or clinical out-comes among patients with DKA, either children or adults.The rate of decline of blood glucose, the mean time toachieve an arterial pH 7.30, and the recovery rates ofplasma bicarbonate level and pH are similar among DKApatients with or without sodium bicarbonate infusion [2332]. The lack of benefit from sodium bicarbonate therapy inthe management of DKA has been also confirmed in patientswith severe DKA, with plasma pH values between 6.9 and 7.1and less than 6.9 [24, 27, 30, 33, 34].

2.2. Sodium Bicarbonate Therapy in Patients with LacticAcidosis. No benefit from sodium bicarbonate therapy hasbeen found in the management of lactic acidosis regardingclinical outcomes or mortality [35]. High doses of sodiumbicarbonate have failed to improve lactic acidosis induced bymalignancy while the acidosis subsides after chemotherapy[1619]. Other causes of lactic acidosis including sepsis andphenphormin-induced lactic acidosis are also resistant tobicarbonate therapy [20, 36]. Two prospective randomizedcrossover trials enrolling critically ill patients with metabolicacidosis and elevated blood lactate concentration have notfound benefit from the use of sodium bicarbonate comparedto sodium chloride on hemodynamic responses, even in veryacidemic participants [21, 22]. A recent retrospective single-center trial has evaluated the effect of sodium bicarbonate onmortality rate among patients with lactic acidosis, concludingthat sodium bicarbonate administration is independentlyassociated with higher mortality [37].

2.3. SodiumBicarbonateTherapy in Patients with Septic Shock.In patients diagnosed with septic shock, sodium bicarbon-ate therapy has not been associated with improvement ofhemodynamic variables ormortality rate in retrospective [38]and prospective [39] studies. Accordingly, the 2008 updateof the Surviving Sepsis Campaign guidelines recommendsagainst the use of sodium bicarbonate in patients withhypoperfusion-induced lactic acidosis and pH 7.15 [40].

2.4. Sodium Bicarbonate Therapy in Patients with Intraopera-tive Metabolic Acidosis. A negative impact on mortality hasbeen reported following the use of sodium bicarbonate in aretrospective cohort study of severely acidotic (arterial pH 7.10) trauma patients who underwent emergency surgery[14]. No benefit from bicarbonate therapy has been foundeither in a small prospective randomized trial of patientswho developed intraoperative mild metabolic acidosis in theabsence of hypoxemia [41].

2.5. Sodium Bicarbonate Therapy in Patients with CardiacArrest. Sodium bicarbonate therapy has long been removedfrom guidelines for advanced cardiac life support, as a reviewof the medical literature shows no beneficial effect of sodiumbicarbonate on survival rates in this setting [13].

2.6. Sodium Bicarbonate Therapy in Patients with AcuteKidney Disease. No randomized controlled trials have inves-tigated the effect of sodium bicarbonate therapy in acutekidney injury, excluding studies that evaluated the use ofsodium bicarbonate for acute kidney injury prevention [42].

2.7. Sodium BicarbonateTherapy in Patients with Chronic Kid-ney Disease. Long-lasting therapy with sodium bicarbonateis extensively used for management of metabolic acidosisassociated with chronic kidney disease (CKD), as currentguidelines suggest sodium bicarbonate supplementation tomaintain serum bicarbonate 22mmol/L (mM) (level ofevidence 2B) [43]. In addition, administration of sodiumbicarbonate to patients with CKD has been suggested inrecent years as a renoprotective approach to delay the dete-rioration of kidney function. However, in Cochrane [44] orsystematic [45] reviews of the medical literature, there is noconclusive evidence to support alkali therapy with sodiumbicarbonate in patients with CKD.

2.7.1. Prevalence of Metabolic Acidosis Associated with CKD.A significant reduction in serum bicarbonate concentrationoccurs in advanced CKD, when the glomerular filtrationrate (GFR) is approximately 20mL/min [4650]. Amongparticipants of the Third National Health and NutritionExamination Survey (NHANES), 19% of subjects with GFR1529mL/min/1.73m2 show a serum bicarbonate level 29mM [64].

2.7.4. Relationship between Metabolic Acidosis and KidneyDisease Progression. Results from recent clinical trials mightsuggest thatmetabolic acidosismay contribute to progressionof kidney dysfunction in patients with CKD, but evidenceis inconclusive and additional investigations are needed(Table 2) [65, 66].

A retrospective observational study enrolling 5,422 adultshas found an association between low serum bicarbonateconcentration and progression of kidney disease. Patientswith baseline serum bicarbonate level< 22mMbear a slightlyhigher risk of a composite renal outcome defined as eithera decrease in the eGFR by 50% or reaching an eGFR