Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6

Contents lists available at ScienceDirect

Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Uses and misuses of sodium bicarbonate in the neonatal intensive care

unit
lie Collins, Rakesh Sahni*
Ame
Columbia University College of Physicians and Surgeons, New York, NY, USA

a b s t r a c t
Keywords: Over the past several decades, bicarbonate therapy continues to be used routinely in the treatment of
Metabolic acidosis acute metabolic acidosis in critically ill neonates despite the lack of evidence for its effectiveness in the
Neonate
treatment of acidebase imbalance, and evidence indicating that it may be detrimental. Clinicians often
Acidebase homeostasis
Buffers
feel compelled to use bicarbonate since acidosis implies a need for such therapy and thus the justification
for its use is based on hearsay rather than science. This review summarizes the evidence and refutes the
clinical practice of administering sodium bicarbonate to treat metabolic acidosis associated with several
specific clinical syndromes in neonates.
© 2017 Elsevier Ltd. All rights reserved.

1. Introduction 2. Extracellular and intracellular buffer systems and

Sodium bicarbonate was first commercially available for use in
the late 1950s, and soon thereafter its use in neonatal intensive care
units (NICUs) became commonplace, not only for resuscitation of
depressed newborn infants, but also as a therapy for correcting
metabolic acidemia, and preventing azotemia, hypoglycemia, and
elevations in serum potassium concentrations (the so-called Usher
regimen) [1]. Despite limited data to recommend the practice, the
use of sodium bicarbonate infusions during neonatal resuscitation
and following cardiac arrest has continued. Moreover, sodium bi-
carbonate therapy may be detrimental. At the cellular level,
increasing the bicarbonate concentration may not normalize
intracellular pH but rather may paradoxically create a situation that
lowers intracellular pH [2,3]. On the other hand, long-term
administration of sodium bicarbonate has been efficacious in sit-
uations where metabolic acidosis is largely secondary to loss of
bicarbonate from the kidney or gastrointestinal tract [4]. After a
brief review of general acidebase physiology, several specific clin-
ical syndromes in neonates are discussed in terms of acidebase
physiology and physiological evidence with respect to bicarbonate
therapy.
* Corresponding author. Columbia University College of Physicians and Surgeons,
622W 168th Street Room PH17-201F, New York, NY 10032, USA.
E-mail address: rs62@columbia.edu (R. Sahni).
acidebase homeostasis in neonates
In general, acidebase homeostasis is tightly regulated by
extracellular and intracellular buffer systems and respiratory and
renal compensatory mechanisms of the organism. This involves
various chemical and physiologic processes that maintain the
acidity of body fluids at levels that allow optimal function of the
whole individual. Chemical processes (buffering Hþ and hydrating
CO2) represent the first line of defense to an acid or alkali load and
include the extracellular and intracellular buffers, whereas physi-
ologic processes (pulmonary ventilation and renal acidification)
modulate acidebase composition by changes in cellular meta-
bolism and by adaptive responses in the excretion of volatile acids
by the lungs and fixed acids by the kidneys. Clinicians track these
intrinsic regulatory systems by measuring the difference between
the normal range of buffer base in the body and the prevailing
levels of buffer base in the patient's blood, referred to as ‘base
excess’. Base excess may be positive (indicating a relative excess of
buffer base) or negative (indicating a reduction in the whole blood
buffer base pool); the units are expressed as milliequivalents per
liter (mEq/L). Blood buffering is accomplished by both bicarbonate
and non-bicarbonate (hemoglobin, oxyhemoglobin, phosphates,
and proteins) buffers. Total buffering capacity is divided approxi-
mately equally between the two buffer systems [5].
Bicarbonate acts as a buffer for Hþ by formation of carbonic acid
(H2CO3) and its subsequent dissociation to H2O and CO2:

http://dx.doi.org/10.1016/j.siny.2017.07.010
1744-165X/© 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Collins A, Sahni R, Uses and misuses of sodium bicarbonate in the neonatal intensive care unit, Seminars in
Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.07.010
2 A. Collins, R. Sahni / Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6
HCO þ
3 þ H 4H2 CO3 4H2 O þ CO2
Bicarbonate levels are computed using the Hender-
soneHasselbalch equation, which relates pH to the proportion of
bicarbonate and H2CO3 acid:

h i.  tion and decreased myocardial sensitivity to catecholamines during
pH ¼ pKa þ log10 HCO
3 ½H2 CO3 
As the concentration of H2CO3 is related to the partial pressure
of CO2, and with the acid dissociation constant of carbonic acid
being 6.1, the equation can be rewritten to relate pH to the ratio of
HCO3 and pCO2:

h i.  istration of exogenous sodium bicarbonate. The argument for doing
pH ¼ 6:1 þ log10 HCO
3 0:03  pCO2
From Equation (3) it can be seen that in order for blood pH to be
maintained close to 7.4, the ratio of HCO
3 to pCO2 needs to be close
to 20:1 (log10 of 20 being 1.3). Serum bicarbonate levels can be
calculated with reasonable accuracy using this formula despite the
variation in the dissociation constant of H2CO3 caused by the non-
aqueous physical and chemical properties of whole blood and the
methodologic limitations of the primary measurements. However,
changes in total blood buffer base cannot be estimated accurately
from bicarbonate levels alone without adjusting for non-
bicarbonate buffering. Additionally, without correction for the he-
moglobin concentration or, preferably, multipoint CO2 titration
data, the base deficit measurement and the bicarbonate measure-
ment contain the same information. Most estimates of acidebase
balance in the NICU do not take these covariates into account.
Finally, it must be remembered that, although all buffers will
equilibrate according to the isohydric principle, the time to equi-
librium within the body is variable, and transient differences will
necessarily exist among body compartments.
The intravascular fluid compartment communicates freely with
the interstitium, which is roughly three times the size of the
intravascular fluid and is buffered primarily by bicarbonate. The
intracellular fluid compartment houses the metabolic machinery
(mitochondria) and ultimately it is the mitochondrial pH that
therapeutic manipulations of the blood buffer base are used to
protect [6,7]. The intracellular fluid is buffered by a mixture of
phosphates, protein, and bicarbonate. Experimental evidence sug-
gests that 15e20% of an infusion of strong acid is buffered by the
blood, 30% by the interstitium, and 55% by intracellular buffers [8],
which implies that clinicians must monitor the quantitatively least
important body buffer system and infer indirectly what is
happening intracellularly.
Faced with a neonate with reduced stores of blood buffer base in
the vascular space, the clinician should not attempt immediate
replenishment. Once the limitations of the actual measurement are
considered, ensuring that the numbers in the acidebase profile are
consistent with the clinical condition of the neonate, one should
focus on ways to address immediately the primary cause of the
acidebase disturbance such as improving alveolar ventilation or
oxygen transport. The clinician then should articulate specific
therapeutic objectives with goals to reduce the acidosis in the
microenvironment surrounding essential energy-generating or-
ganelles and assist the cell in restoring normal bioenergetics. In
some clinical syndromes associated with metabolic acidosis in the
neonate, a bicarbonate infusion will not meet the desired objectives
of benefitting the neonate but may be associated with adverse
outcomes of intraventricular hemorrhage [9], fluctuations in cere-
bral blood flow [10], worsening intracellular acidosis [2], aggravated
myocardial injury [11], and deterioration of cardiac function [12],
making the bicarbonate therapy not only useless but detrimental.
Please cite this article in press as: Collins A, Sahni R, Uses and misuses of sodium bicarbonate in the neonatal intensive care unit, Seminars in
Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.07.010
3. Role of bicarbonate therapy during cardiac arrest
(1)
Severe bradycardia or cardiac arrest leads to decreased cardiac
output, poor perfusion, inadequate oxygen delivery to the tissues,
depletion of intracellular energy stores, and ultimately metabolic
acidosis. Early studies demonstrated decreased myocardial func-
(2) acidosis [13]. The initial rise in Hþ ions in the face of decreased
tissue oxygenation is mainly a consequence of hydrolysis of ATP
during anaerobic glycolysis, with accumulation of lactic acid rep-
resenting a late event. The liberated Hþ ions are buffered by both
the bicarbonate and non-bicarbonate systems, and many have been
tempted to replenish diminishing bicarbonate levels with admin-
(3) so is to maintain buffering ability against ongoing acid production,
to correct presumed intracellular acidosis to optimize enzymatic
function, and to correct acidemia in which endogenous and exog-
enous catecholamines are ineffective. Based on such rationales,
sodium bicarbonate was frequently employed in cardiopulmonary
resuscitation (CPR) long before any experimental evidence vali-
dated (or invalidated) these hypotheses.
Experimental models have established that administration of
sodium bicarbonate may, under certain circumstances, result in a
“paradoxical” intracellular acidification [3]. Addition of bicarbonate
to the intravascular (i.e. extracellular) space will buffer excess Hþ
ions by forming carbonic acid, which is further dissociated to water
and CO2. In situations where CO2 cannot be rapidly eliminated from
the local environment (i.e. in venous stasis or low perfusion states,
as occur during cardiac arrest and CPR, when cardiac output is
thought to be only 30% of normal), CO2 accumulates, leading to
local hypercarbia. Diffusion of CO2 across the cell membrane occurs
far more quickly than transport of HCO 3 , resulting in initial over-
production of intracellular Hþ from carbonic acid. This intracellular
acidification is the result of conversion of extracellular HCO 3 to CO2
by carbonic anhydrase. CO2 ultimately diffuses across the cell
membrane, resulting in intracellular acidosis. This reaction may be
prevented by the addition of acetazolamide, a reversible inhibitor
of carbonic anhydrase [3] (Fig. 1).
Levraut and colleagues further expanded on these observations
and showed that the degree of intracellular acidification depended
on the proportion of extracellular non-bicarbonate buffering ca-
pacity present, due to back-titration of the non-bicarbonate buffer
[14,15]. Extracellular alkalization will therefore come at the price of
intracellular acidification, which is often precisely the exact oppo-
site of what the clinician had intended, and has two deleterious
consequences. First, deepening of intracellular acidosis worsens
myocardial contractility as Hþ ions compete with Ca2þ ions for
binding to troponin. Second, extracellular alkalosis shifts the oxy-
genehemoglobin saturation curve to the left, which impedes oxy-
gen release to the tissues, exacerbating the situation.
These observations have been extended by animal models [16].
Fig. 1. The effect of abrupt rise in extracellular sodium bicarbonate concentration on
intracellular pH. CA, carbonic anhydrase.
 A. Collins, R. Sahni / Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6
Experiments in pig models of cardiac arrest demonstrated that
bicarbonate infusion immediately after ventricular fibrillation did
not improve intramyocardial acidosis [11]. Furthermore, the rapid
infusion of a hyperosmolar solution decreased arterial tone, which
lowered coronary perfusion pressure [12], a key determinant of
return of spontaneous circulation after arrest [17]. The majority of
human studies have been retrospective analyses or prospective
studies in which all patients received bicarbonate or were
compared to historical controls [13]. The only randomized
controlled trial of sodium bicarbonate (in a buffer mixture) was
conducted in adults being treated for ventricular fibrillation out of
the hospital, and it failed to show any benefit over 0.9% normal
saline [18] with respect to return of spontaneous circulation or
survival to hospital discharge. It was not powered to detect changes
in overall survival. No clinical trials have evaluated sodium bicar-
bonate for cardiac arrest in either pediatric or neonatal patients.
A rigorous review of the evidence for sodium bicarbonate in
both animal models of cardiac arrest and human trials concluded
that, by widely accepted levels of evidence, there was insufficient
evidence to support its use [13]. Although completed almost 20
years ago, recent literature does not do much to change that
conclusion. Therefore, based on the lack of clear evidence of benefit,
and the potential for significant harm, sodium bicarbonate infusion
during cardiac arrest is no longer recommended in adult, pediatric,
or neonatal patients [19e21].
4. Role of bicarbonate therapy for neonatal metabolic
acidosis secondary to hypoxia and ischemia
Metabolic acidosis in the absence of cardiac arrest is a frequently
encountered situation in the delivery room and the NICU, often in
the setting of perinatal asphyxia, prolonged hypoxia (as in persis-
tent pulmonary hypertension of the newborn), or ischemia (e.g.
necrotizing enterocolitis). Based on the observation that rapid
infusion of bicarbonate (or amine buffers) could reverse the pul-
monary vasoconstriction associated with hypoxia in newborn
calves [22], and growing evidence that infusion of bicarbonate-
containing fluid to neonates with respiratory distress syndrome
(RDS) improved their outcomes (see next section), administration
of sodium bicarbonate became a routine part of neonatal resusci-
tation and treatment of neonatal metabolic acidosis.
As in cardiopulmonary resuscitation, the use of sodium bicar-
bonate in neonatal metabolic acidosis has been widespread despite
poor evidence as to its utility. In a controlled prospective trial of low
birth weight neonates with hypoxia and acidemia, administration
of sodium bicarbonate had no effect on right-to-left shunts and did
not improve oxygenation [23]. The only randomized clinical trial of
sodium bicarbonate versus 5% dextrose for metabolic acidosis in
asphyxiated neonates continuing to need positive pressure venti-
lation at 5 min of life failed to show any differences in death or
abnormal neurological examination at discharge [24]; the sec-
ondary outcomes of encephalopathy, cerebral edema, and need for
inotropic support were more prevalent in the bicarbonate group,
although this was not statistically significant.
In multiple animal models of hemorrhagic ischemia, infusion of
solutions that match sodium bicarbonate in osmolality and/or so-
dium content are as effective in improving hemodynamics,
oxygenation, and pulmonary vascular resistance without
improving blood pH [25e32], calling into question the assumption
that it is correction of the acidosis that improves outcomes. In dogs
with phenformin-induced lactic acidosis who were administered
sodium bicarbonate, no improvement in blood pH or mortality was
seen. However, erythrocyte and hepatocyte intracellular pH
decreased, hepatic portal venous flow and cardiac output
decreased, and gut lactate production increased [33]. Similarly, in a
Please cite this article in press as: Collins A, Sahni R, Uses and misuses of sodium bicarbonate in the neonatal intensive care unit, Seminars in
Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.07.010
3
model of hypoxic lactic acidosis, dogs treated with sodium bicar-
bonate had significantly increased blood lactate levels, decreased
blood pressure, and decreased cardiac output compared with dogs
given sodium chloride or no treatment [34]. Sodium bicarbonate
therapy is thus not recommended to treat metabolic acidosis sec-
ondary to hypoxia and ischemia, not only for lack of benefit but also
evidence of harm [21,35].
5. Role of bicarbonate therapy for acidosis associated with
respiratory distress syndrome
Respiratory distress syndrome (RDS) of prematurity is a sur-
factant insufficiency state that results in alveolar collapse, hypo-
ventilation, ventilationeperfusion mismatch, hypoxemia, and
ultimately respiratory failure. This condition is deceptively com-
plex. Typically, a neonate is on substantial mechanical ventilatory
support but remains persistently hypercapnic, with a pH around
7.25 and a whole blood buffer base deficit of 8e15 mEq/L. The
primary disorder begins as a pure respiratory acidosis caused by
diminished alveolar ventilation. Metabolic CO2 that accumulates in
the blood is hydrated to H2CO3, and dissociates to Hþ and HCO 3.
Hydrogen ions are buffered by the non-bicarbonate buffers, and
HCO 3 is released into the solution. Were the intravascular
compartment a closed system, as is the case in vitro, total buffer
base would remain unchanged, and there would be no change in
total body buffering because the HCO 3 would replace the non-
bicarbonate buffer base (mostly hemoglobin) consumed in
neutralizing the free Hþ. However, in vivo, the HCO 3 liberated
when Hþ is buffered by hemoglobin is not contained in a closed
system but diffuses out into the interstitium [5]. This process re-
sults in a reduced concentration of bicarbonate in the total buffers
of the blood and, all other things being equal, an increase in the
base deficit. Thus, plasma HCO 3 concentration at any given eleva-
tion of plasma pCO2 rises higher in vitro than in vivo.
Since the interstitial space is larger in the neonate than in the
adult and larger still in the premature, sick neonate, the measured
base deficit is significant even though the CO2 has been adequately
buffered and no metabolic acid has been produced. One may as-
sume that reduction in whole blood buffer base during transient
changes in CO2 represents waxing and waning metabolic acidosis,
even though the limits of the decrease in HCO 3 have not been
defined in premature neonates. The diffusion of HCO 3 into the
enlarging extracellular fluid compartment of the premature, sick
neonate infant might be viewed as dilution of HCO 3 , suggestive of
expansion acidosis. Thus, a better way to think of RDS is as
incompletely compensated respiratory acidosis. Eventually, renal
mechanisms will compensate for this diluted buffering and
replenish HCO 3 in the extracellular fluid, but it is not clear how
quickly this process is accomplished.
In the 1950s, Robert Usher observed that neonates with severe
RDS who died, as compared to those who survived, had hyper-
kalemia, metabolic and respiratory acidosis, and hypoglycemia, and
he showed that infusion of intravenous fluids containing glucose
and sodium bicarbonate reduced mortality [1]. The early adminis-
tration of alkali therapy became a mainstay in the treatment of RDS
based on the assumption that prevention or correction of acidosis
was crucial in the prevention of pulmonary vasoconstriction, hyp-
oxemia, and ultimately death from the disease. A critical point from
this seminal study is that the control group of neonates received no
intravenous fluid at all, and thus the reduction in mortality could
not be ascribed to sodium bicarbonate per se. To address this,
Corbet et al. performed a randomized trial of sodium bicarbonate in
acidotic premature neonates with RDS, showing that the neonates
who received bicarbonate had no improvement in morbidity
(intraventricular hemorrhage) or mortality. Furthermore,
4 A. Collins, R. Sahni / Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6
bicarbonate did not correct their pH any faster than those neonates
who received 10% dextrose alone. In fact, there was a suggestion of
excess mortality in the neonates who received sodium bicarbonate
[36]. Usher himself showed that rapid infusion of sodium bicar-
bonate resulted in significantly higher mortality compared with
slow infusion, and several authors have similarly observed delete-
rious effects of sodium bicarbonate in premature neonates with
RDS [9,37e39].
Acidosis in premature neonates with RDS is also proposed to
result from metabolic perturbations with hypoxemia, leading to
inadequate oxygen delivery to the tissues. Although not all neo-
nates with RDS develop lactic acidosis [40,41] there is evidence to
suggest that neonates with RDS and elevated lactate do worse and
have elevated mortality compared to those neonates with RDS
without elevations in lactate [42]. A simple reminder of the
mechanism of bicarbonate buffering serves to illustrate why bi-
carbonate therapy cannot be effective therapy for respiratory
acidosis (Equations (1)e(3) above). Regardless of the source of
excess Hþ, in order for bicarbonate to effectively buffer it and move
Equation (1) to the right, CO2 must be eliminated from the lungs via
ventilation.
If CO2 cannot be eliminated from the lungs due to ineffective
ventilation, addition of bicarbonate to the system will not only be
ineffective, but may worsen acidosis by pushing Equation (1) to the
left. That bicarbonate cannot buffer an acid load in a “closed sys-
tem” was demonstrated by Ostrea and Odell [43], who showed that
addition of sodium bicarbonate to human blood in sealed flasks
resulted in minimal change in the pH of the blood but a marked
increase in pCO2, in contrast to the increasing pH in open flasks.
Their experiments further illustrated the effect of tonicity in a
closed system; addition of hypertonic solutions resulted in
decreased pH and increased pCO2 due to the shift of water from
erythrocytes to the surrounding plasma, increasing the ionic
strength of intracellular acids (primarily hemoglobin) and causing a
further release of CO2. They and others extrapolated from their
results that in those clinical situations in which a severe limitation
of CO2 excretion may exist, addition of hypertonic bicarbonate may
result in a fall in blood pH rather than the expected rise [43,44].
Evidence exists in experimental animals and premature neo-
nates that inadequate ventilation may mimic such a closed system
with respect to bicarbonate administration. Neonatal puppies with
fixed mechanical hypoventilation given rapid infusions of hyper-
tonic bicarbonate have only transient increases in pH, after which
their pH falls and pCO2 rises. Control groups of hypoventilated
puppies administered 5% dextrose alone or administered bicar-
bonate but hypoventilated with 100% oxygen have better outcomes
[45]. Similar results were found in acidotic premature neonates
with RDS who were treated with either Trisehydroxyethylamino-
methane (THAM) or sodium bicarbonate. All neonates experienced
an increase in pH at 10 min; the neonates treated with THAM had
decreased PaCO2 whereas in those treated with bicarbonate the
PaCO2 was increased [46].
6. Role of bicarbonate therapy for ongoing renal or
gastrointestinal losses
Neonates have lower serum bicarbonate compared to adults, as
their renal compensatory mechanisms are immature, resulting in a
developmentally regulated reduced ability to maintain acidebase
balance [47,48]. Both renal micro-hemodynamic and tubular
epithelial factors play a role in the limited renal compensatory
capacity of the neonate. The glomerular filtration rate is low in the
immediate postnatal period and increases as a function of both
gestational and postnatal age [49,50], making it one of the most
important factors limiting the ability of the preterm and term
Please cite this article in press as: Collins A, Sahni R, Uses and misuses of sodium bicarbonate in the neonatal intensive care unit, Seminars in
Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.07.010
neonate to handle acid loads adequately [47,48]. Net renal acid
excretion also depends on several gestational and postnatal age-
dependent tubular epithelial functions. Neonates have a lower bi-
carbonate threshold; above that threshold, bicarbonate enters the
urine because the capacity to reabsorb bicarbonate is exceeded
[51]. Most bicarbonate reabsorption in neonates occurs in the
proximal tubule and is approximately one-third that of the adult
proximal tubule [52]. Thus, lower serum bicarbonate levels result
from decreased rate of bicarbonate reabsorption rather than
leakage of transported bicarbonate into the tubular lumen [53]. All
of the transporters responsible for the reabsorption of bicarbonate
have a lower activity in the neonatal proximal tubule when
compared to the adult, limiting active transport [54,55]. The bi-
carbonate threshold for reabsorption has been reported to be ~18
mEq/L in the preterm neonate [56,57] and ~21 mEq/L in the term
neonate [56]. It reaches adult levels (24e26 mEq/L) only after one
year of age [58]. In extremely preterm neonates in the early post-
natal period the renal bicarbonate threshold may be as low as 14
mEq/L [55].
Another important aspect in the development of acidification is
genesis of ammonia. Since most of the produced acid is secreted in
the form of ammonia, without this crucial buffer it is very difficult
to excrete large amounts of acid in a relatively small volume of
urine. Like adults, the neonate must excrete acid generated from
metabolism in the form of ammonia and titratable acid. Whereas
adults need to excrete ~1 mEq/kg per day of acid, neonates need to
excrete two to three times this amount because of their protein
intake and the formation of new bone. Although the enzymes for
the genesis of ammonia are present in the neonate, ammonia
production rates are lower than in adults [59,60]. The primary
enzyme, glutaminase, has a lower activity in the neonatal kidney.
Additionally, whereas the adult kidney can increase ammonia
production by 10-fold during acidosis, the neonate cannot. Thus,
when neonates become acidotic (for instance with diarrhea) it
takes them much longer to recover from the acidosis.
The acidebase balance with the developmentally low rates of
acid excretion in neonates is maintained in part by the ingestion of
base equivalents. These base equivalents e also found in breast
milk e help in combating increased acid production from bone
mineralization and maintain acidebase balance at a time when the
renal excretion of acid is underdeveloped. Occasionally, very pre-
term neonates may have a generalized proximal tubule transport
disorder known as Fanconi syndrome comprising of glucosuria
with normal serum glucose levels, aminoaciduria, and lower serum
bicarbonate levels. Bicarbonate therapy is used in this situation but
it does little to improve growth in these very preterm neonates
[61].
Another issue in neonates is the loss of bicarbonate due to
gastrointestinal disturbances. The pancreas secretes bicarbonate
into the small intestine to neutralize the gastric acid. When neo-
nates develop diarrhea, much of this bicarbonate is lost and they
become acidotic. Growing neonates depend on base equivalents in
the mother's milk to help maintain acidebase balance; when they
have diarrhea, milk is often withheld, depriving them of this source
of base. Second, whereas the ammonia production of the kidney of
neonates may help maintain balance under normal conditions,
unlike adults, there is limited ability of the neonatal kidney to in-
crease ammonia production to replace the bicarbonate that was
lost in the gastrointestinal tract. Thus, it will take the neonate much
longer than an adult to recover from the loss of bicarbonate. The
same factors probably also limit the neonate's ability to recover
from acidosis generated by sepsis (i.e. lactic acidosis) or from the
administration of amino acids in the total parenteral nutrition.
Thus, the utility of bicarbonate replacement for ongoing renal or
gastrointestinal losses may seem reasonable as the loss of sodium
 A. Collins, R. Sahni / Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6
bicarbonate contributes to generation of the acidosis, but remains
unproven.
7. Conclusions
Whereas sodium bicarbonate has been used in neonatal clinical
practice for a long time, evidence of more favorable clinical out-
comes associated with its use in order to increase plasma pH in
most acute conditions featuring metabolic acidosis in neonates is
not definitive. Available evidence suggests that the severity of
metabolic acidosis in these conditions reflects the gravity of the
underlying illness rather than being itself a contributor to mortal-
ity. Therapy of such situations should be focused on the cause of the
acidosis. On the other hand, the utility of sodium bicarbonate
replacement for ongoing renal or gastrointestinal losses may seem
reasonable, as the loss of sodium bicarbonate contributes to gen-
eration of the acidosis but remains unproven. Clinicians should
resist the impulse to administer bicarbonate in neonates with
metabolic acidosis, instead concentrating their efforts on under-
standing and treating the underlying cause of the acidosis.
7.1. Practice points
 In treating metabolic acidosis in neonates, clinicians should
resist the impulse to administer bicarbonate, instead concen-
trating their efforts on understanding and treating the under-
lying cause of the acidosis.
 Despite more than fifty years of experience with sodium bicar-
bonate use in neonates with metabolic acidosis, the data do not
demonstrate any beneficial effects other than when given as
replacement for ongoing renal or gastrointestinal bicarbonate
losses.
 Administration of sodium bicarbonates has been associated
with intraventricular hemorrhage, fluctuations in cerebral blood
flow, diminished tissue oxygenation, worsening intracellular
acidosis, aggravated myocardial injury, and deterioration of
cardiac function.
Funding sources
None.
Conflict of interest statement
None declared.
Acknowledgements
The authors wish to thank Richard Polin, MD, for reviewing and
providing feedback during preparation of this manuscript.
References
[1] Usher R. Reduction in mortality from respiratory distress syndrome of pre-
maturity with early administration of intravenous glucose and sodium bi-
carbonate. Pediatrics 1963;32:966e75.
[2] Howell JH. Sodium bicarbonate in the perinatal setting: revisited. Clin Peri-
natol 1987;14:807e16.
[3] Ritter JM, Doktor HS, Benjamin N. Paradoxical effect of bicarbonate on cyto-
plasmic pH. Lancet 1990;335(8700):1243e6.
[4] Narins RG, Jones ER, Townsend R, Goodkin DA, Shay RJ. In: Arieff AI,
DeFronzo RA, editors. Fluid electrolyte and acidebase disorders. New York:
Churchill Livingstone; 1985. p. 281e335.
[5] Adrogue HE, Adrogue HJ. Acidebase physiology. Respir Care 2001;46:328e41.
[6] Siegel SR, Phelps DL, Leake RD, Oh W. The effects of rapid infusion of hyper-
tonic sodium bicarbonate in infants with respiratory distress. Pediatrics
1973;51:651e4.
[7] Bonventre JV, Cheung JY. Effects of metabolic acidosis on viability of cells
Please cite this article in press as: Collins A, Sahni R, Uses and misuses of sodium bicarbonate in the neonatal intensive care unit, Seminars in
Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.07.010
5
exposed to anoxia. Am J Physiol 1985;249:C149e59.
[8] Winters RW, Dell RB. Regulation of acidebase equilibrium. In: Yamamoto WS,
Brobeck JR, editors. Physiological controls and regulations. Philadelphia:
Saunders; 1965. p. 39e60.
[9] Papile LA, Burstein J, Burstein R. Relationship of intravenous sodium bicar-
bonate infusions and cerebral intraventricular hemorrhage. J Pediatr 1978;93:
834e6.
[10] Lou HC, Lassen NA, Fris-Hansen B. Decreased cerebral blood flow after
administration of sodium bicarbonate in the distressed newborn infant. Acta
Neurol Scand 1978;57:239e47.
[11] Kette F, Weil MH, von Planta M, Gazmuri RJ, Rackow EC. Buffer agents do not
reverse intramyocardial acidosis during cardiac resuscitation. Circulation
1990;81:1660e6.
[12] Kette F, Weil MH, Gazmuri RJ. Buffer solutions may compromise cardiac
resuscitation by reducing coronary perfusion pressure. JAMA 1991;266:
2121e6 [Published correction in JAMA 1991;266:3286.].
[13] Levy MM. An evidence-based evaluation of the use of sodium bicarbonate
during CPR. Crit Care Clin 1998;14:457e83.
[14] Levraut J, Labib Y, Chave S, Payan P, Raucoules-Aime M, Grimaud D. Effect of
sodium bicarbonate on intracellular pH under different buffering conditions.
Kidney Int 1996;49:1262e7.
[15] Levraut J, Giunti C, Ciebiera JP, et al. Initial effect of sodium bicarbonate on
intracellular pH depends on the extracellular nonbicarbonate buffering ca-
pacity. Crit Care Med 2001;29:1033e9.
[16] Von Planta M, Weil MH, Gazmuri RJ, Bisera J, Rackow EC. Myocardial acidosis
associated with CO2 production during cardiac arrest and resuscitation. Cir-
culation 1989;80:684e92.
[17] Maldonado FA, Weil MH, Tang W, et al. Myocardial hypercarbic acidosis re-
duces cardiac resuscitability. Anesthesiology 1993;78:343e52.
[18] Dybvik T, Strand T, Steen PA. Buffer therapy during out-of-hospital cardio-
pulmonary resuscitation. Resuscitation 1995;29:89e95.
[19] Niermeyer S, Kattwinkel J, Van Reempts P, et al. International guidelines for
neonatal resuscitation: an excerpt from the Guidelines 2000 for Cardiopul-
monary Resuscitation and Emergency Cardiovascular Care: international
consensus on science. Pediatrics 2000;106(3). http://www.pediatrics.org/cgi/
content/full/106/3/e2914.
[20] Emergency Cardiovascular Care Committee. Subcommittees and task forces of
the American Heart Association. 2005 American Heart Association guidelines
for cardiopulmonary resuscitation and emergency cardiovascular care. Cir-
culation 2005;112(24 suppl):IV1e203.
[21] Beveridge CJ, Wilkinson AR. Sodium bicarbonate infusion during resuscitation
of infants at birth. Cochrane Database Syst Rev 2006;(1):CD004864.
[22] Rudolph AM, Yuan D. Response of the pulmonary vasculature to hypoxia and
H ion concentration changes. J Clin Invest 1966;45:399e411.
[23] Sinclair JC, Engel K, Silverman W. Early correction of hypoxemia and acidemia
in infants of low birth weight: a controlled trial of oxygen breathing, rapid
alkali infusion and assisted ventilation. Pediatrics 1968;42:565e89.
[24] Lokesh L, Kumar P, Murki S, Narang A. A randomized controlled trial of so-
dium bicarbonate in neonatal resuscitation: effect on immediate outcome.
Resuscitation 2004;60:219e23.
[25] Rowe MI, Arango A. The cardiovascular response of the acidotic newborn to
sodium bicarbonate. Arch Surg 1973;106:327e32.
[26] Bergentz SE, Brief DF. The effect of pH and osmolality on the production of
canine hemorrhagic shock. Surgery 1965;58:412e23.
[27] Baue AE, Tragus ET, Parkins WM. Effects of increased osmolality and correc-
tion of acidosis on blood flow and oxygen consumption in hemorrhagic shock.
J Surg Res 1967;7:349e56.
[28] Baue AE, Tragus ET, Parkins WM. Metabolic and circulatory effects of hyper-
tonic solutions on acidosis in hemorrhagic shock. Fed Proc 1966;25:698.
[29] Baue AE, Tragus ET, Parkins WM. Effects of sodium chloride and bicarbonate in
shock with metabolic acidosis. Am J Physiol 1965;212:54e60.
[30] Assali NS, Morris JA, Beck R. Cardiovascular hemodynamics in the fetal lamb
before and after lung expansion. Am J Physiol 1965;208:122e9.
[31] Vaughn D, Kirschbaum TH, Bersentes T, Dilts Jr PV, Assali NS. Fetal and
neonatal response to acid loading in the sheep. J Appl Physiol 1968;24:
135e41.
[32] Assali NS, Johnson GH, Brinkman 3rd CR, Kirschbaum TH. Control of pulmo-
nary and systemic vasomotor tone in the fetus and neonate. Am J Obstet
Gynecol 1970;108:761e72.
[33] Arieff AI, Leach W, Park R, Lazarowitz VC. Systemic effects of NaHCO3 in
experimental lactic acidosis in dogs. Am J Physiol 1982;242:F586e91.
[34] Graf H, Leach W, Arieff AI. Evidence for a detrimental effect of bicarbonate
therapy in hypoxic lactic acidosis. Science 1985;227:754e6.
[35] Hein HA. The use of sodium bicarbonate in neonatal resuscitation: help or
harm? Pediatrics 1993;91:496e7.
[36] Corbet AJ, Adams JM, Kenny JD, Kennedy J, Rudolph AJ. Controlled trial of
bicarbonate therapy in high-risk premature newborn infants. J Pediatr
1977;91:771e6.
[37] Usher R. Correction of rapid versus gradual correction of acidosis in RDS of
prematurity: a sequential study. Pediatr Res 1967;1:221.
[38] Berg CS, Barnette AR, Myers BJ, Shimony MK, Barton AW, Inder TE. Sodium
bicarbonate administration and outcome in preterm infants. J Pediatr
2010;157:684e7.
[39] Simmons MA, Adcock EW, Bard H, Battaglia FC. Hypernatremia and intra-
cranial hemorrhage in neonates. N Engl J Med 1974;291:6e10.
6 A. Collins, R. Sahni / Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6
[40] Beca JP, Scopes JW. Serial determinations of blood lactate in respiratory
distress syndrome. Archs Dis Childh 1972;47:550e7.
[41] Graven SN, Criscuolo D, Holcomb TN. Blood lactate in the respiratory distress
syndrome. Am J Dis Child 1965;110:614e7.
[42] Deshpande SA, Platt MP. Association between blood lactate and acidebase
status and mortality in ventilated babies. Archs Dis Childh Fetal Neonatal Ed
1997;76:F15e20.
[43] Ostrea EM, Odell GB. The influence of bicarbonate administration on blood pH
in a “closed system”: clinical implications. J Pediatr 1972;80:671e80.
[44] Dell RB, Winters RW. Acidebase effects of hypertonic sodium bicarbonate
solutions: a commentary. J Pediatr 1972;80:681e2.
[45] Steichen JJ, Kleinman LI. Studies in acidebase balance, part I: effect of alkali
therapy in newborn dogs with mechanically fixed ventilation. J Pediatr
1977;91:287e91.
[46] Baum JD, Robertson NRC. Immediate effects of alkaline infusion in infants
with respiratory distress syndrome. J Pediatr 1975;87:255e61.
[47] Guignard JP, John EG. Renal function in the tiny, premature infant. Clin Peri-
natol 1986;13:377e401.
[48] Jones DP, Chesney RW. Development of tubular function. Clin Perinatol
1992;19:33e57.
[49] Guignard JP, Torrado A, Da Cunha O, Gautier E. Glomerular filtration rate in
the first three weeks of life. J Pediatr 1975;87:268e72.
[50] Arant Jr BS. Developmental patterns of renal functional maturation compared
in the human neonate. J Pediatr 1978;92:705e12.
[51] Baum M, Quigley R, Satlin LM. Postnatal renal development. In: Alpern BJ,
Please cite this article in press as: Collins A, Sahni R, Uses and misuses of sodium bicarbonate in the neonatal intensive care unit, Seminars in
Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.07.010
Caplan NJ, Mow OW, editors. Seldin and Giebisch's the kidney. fifth ed. Lon-
don: Academic Press; 2013. p. 911e31.
[52] Schwartz GJ, Evan AP. Development of solute transport in rabbit proximal
tubule. I. HCO3 and glucose absorption. Am J Physiol 1983;245:F382e90.
[53] Quigley R, Baum M. Developmental changes in rabbit juxtamedullary prox-
imal convoluted tubule bicarbonate permeability. Pediatr Res 1990;28:663e6.
[54] Baum M, Quigley R. Maturation of proximal tubular acidification. Pediatr
Nephrol 1993;7:785e91.
[55] Schwartz GJ, Evan AP. Development of solute transport in rabbit proximal
tubule. III. Na-K-ATPase activity. Am J Physiol 1984;246:F845e52.
[56] Svenningsen NW. Renal acidebase titration studies in infants with and
without metabolic acidosis in the postneonatal period. Pediatr Res 1974;8:
659e72.
[57] Schwartz GJ, George MD, Haycock B, Edelmann CM, Spitzer A. Late metabolic
acidosis: a reassessment of the definition. J Pediatr 1975;95:102e7.
[58] Edelmann CM, Soriano JR, Boichis H, Gruskin AB, Acosta MI. Renal bicarbonate
reabsorption and hydrogen ion excretion in normal infants. J Clin Invest
1967;46:1309e17.
[59] Goldstein L. Renal ammonia and acid excretion in infant rats. Am J Physiol
1970;218:1394e8.
[60] Goldstein l. Ammonia metabolism in kidneys of suckling rats. Am J Physiol
1971;220:213e7.
[61] Schwartz GJ, Haycock GB, Edelmann Jr CM, Spitzer A. Late metabolic acidosis:
a reassessment of the definition. J Pediatr 1979;95:102e7.