Shock, Publish Ahead of Print

DOI : 10.1097/SHK.0000000000001415

Title Page

Complete Title: Lactic Acidosis and the Role of Sodium Bicarbonate: A Narrative Opinion

Running Head: Lactic Acidosis and Sodium Bicarbonate

Authors:
Mona R Rudnicka, Gregory J Blaira, Ware G Kuschnerb,d,, and Juliana Barra,d

a
Stanford University School of Medicine, Department of Anesthesiology, Perioperative, and
Pain Medicine
b
Stanford University School of Medicine, Department of Internal Medicine
c
Veteran Affairs Palo Alto Health Care System, Anesthesiology and Perioperative Care
Service
d
Veteran Affairs Palo Alto Health Care System, Pulmonary Section, Medical Service

Corresponding Author:
Mona R Rudnick
234 Los Gatos Blvd.
Los Gatos, CA 95030
[email protected]

Conflicts of Interest: The authors have no relevant conflicts of interest to report.

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 ABSTRACT

Lactic acidosis occurs commonly and can be a marker of significant physiologic

derangements. However what an elevated lactate level and acidemia connotes and what

should be done about it is subject to inconsistent interpretations. This review examines the

varied etiologies of lactic acidosis, the physiologic consequences, and the known effects of its

treatment with sodium bicarbonate. Lactic acidosis is often assumed to be a marker of

hypoperfusion, but it can also result from medications, organ dysfunction, and sepsis even in

the absence of malperfusion. Acidemia causes deleterious effects in almost every organ

system but it can also have positive effects, increasing localized blood flow and oxygen

delivery, as well as providing protection against hypoxic cellular injury. The use of sodium

bicarbonate to correct severe acidemia may be tempting to clinicians, but previous studies

have failed to show improved patient outcomes following bicarbonate administration.

Bicarbonate use is known to decrease vasomotor tone, decrease myocardial contractility, and

induce intracellular acidosis. This suggests that mild to moderate acidemia does not require

correction. Most recently, a randomized control trial found a survival benefit in a subgroup of

critically ill patients with serum pH levels < 7.2 with concomitant acute kidney injury. There

is no known benefit of correcting serum pH levels ≥ 7.2, and sparse evidence supports

bicarbonate use < 7.2. If administered, bicarbonate is best given as a slow IV infusion in the

setting of adequate ventilation and calcium replacement to mitigate its untoward effects.

Keywords: Intensive care; acidosis; acidemia; sodium bicarbonate; sepsis; hyperlactatemia;

lactic acid

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 INTRODUCTION

Lactic acidosis is the most common form of metabolic acidemia encountered clinically. High

serum levels of lactate are associated with a worse clinical prognosis in patients, but it is

unclear if lactate is merely a marker of disease severity or if it directly contributes to

mortality.1,2 Those that ascribe to the latter theory often advocate for the use of exogenous

buffers to raise pH with the hope that recreating a more physiologic milieu that will support

cardiovascular function. But this practice is controversial as highlighted by a 2005 survey of

nephrologists and critical care physicians, where only 67% of intensivists favored

administration of a base to treat lactic acidosis, as compared to 86% of nephrologists.3

Furthermore, intensivists had a lower pH threshold to initiate bicarbonate therapy than

nephrologists. Although a good deal is known about the pathophysiology of lactic acidosis

and the effects of acidemia on the body, to date, few human studies have been conducted on

the treatment of lactic acidosis with sodium bicarbonate and its effects on clinical outcomes.

This review will examine what is currently known about these topics to provide clinicians

with the background information needed to make critical therapeutic decisions about the use

of sodium bicarbonate in the treatment of lactic acidosis.

DISCUSSION

ETIOLOGIES OF LACTIC ACIDOSIS

Lactate is generated via lactate dehydrogenase from an oxidative-reduction coupled reaction

with NADH from pyruvate (Figure 1). Hyperlactatemia results most commonly from an

increase in its substrate, pyruvate, or an increase in the ratio of reduced and oxidized

nicotinamide adenine dinucleotide (NADH/NAD+) (Table 1).

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Pyruvate substrate is increased from increased glycolysis and/or inhibition of its entry into

the Cori, Cahill, or tricarboxylic acid (TCA) cycles.4 Under oxygen poor conditions, pyruvate

is unable to enter the TCA cycle leading to its buildup and hyperlactatemia. Hypoxia

additionally leads to an increase in the NADH/NAD+ ratio as NAD+ is regenerated in the

TCA cycle. Other causes of increased pyruvate concentrations include thiamine deficiency, a

necessary cofactor of pyruvate dehydrogenase.5 Additionally, even in the absence of

hypoperfusion, an isolated systemic inflammatory response increases lactate by two

mechanisms; first, by increasing cellular glucose uptake leading to increased glycolysis and,

second, by direct inhibition of skeletal and hepatic pyruvate dehydrogenase.6-8

Glycolysis, and thereby pyruvate production, is also favored when there is a decrease in the

intracellular ATP/ADP ratio, which in turn, stimulates glycolysis through the enzyme

phosphofructokinase. Exercise, physiologic stress, cocaine, vasopressors such as epinephrine

and norepinephrine, and isolated liver, intestinal or pulmonary dysfunction all decrease the

ATP/ADP ratio via stimulation of the Na+/K+ ATPase pump.9-11 In an animal model of

hemorrhagic shock, lactate production during stress is attenuated with the addition of β-

adrenergic antagonists or ouabain, a direct inhibitor of the Na+/K+ ATPase pump suggesting

that beta stimulation directly increases lactate production.12

Factors that increase the NADH/NAD+ ratio include inhibition of aerobic metabolism (i.e.,

due to inadequate oxygen delivery, mitochondrial dysfunction from medications such as

propofol or cyanide, and inhibitors of pyruvate dehydrogenase such as methanol and

metformin).13,14 Fulminant liver failure also increases the NADH/NAD+ ratio due to the lack

of hepatic lactate dehydrogenase and a breakdown of the Cori Cycle, which serves to

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regenerate glucose from peripherally generated lactate. This results in the breakdown of the

Cori Cycle which is responsible for the regeneration of glucose from lactate.

It is overly simplistic to consider elevated lactate as a marker of inadequate oxygen delivery.

Multiple causes may be driving increased lactate production and these may not be reversed

by simply increasing systemic perfusion and improving tissue oxygen delivery.

Physiologic Effects and the Significance of Hyperlactatemia

An elevated lactate level does not necessarily imply acidemia. Indeed, prior to the Cohen and

Woods classification of Type A and B lactic acidosis, Huckabee in 1961 categorized

hyperlactatemia into whether there was an associated acidemia. Hyperlactatemia without

acidemia occurs most often when hypoxia is not present and buffering systems have not yet

been overwhelmed. Common causes of isolated hyperlactatemia include increased aerobic

glycolysis such as during strenuous exercise, with seizures, or from hypermetabolic

malignancies.15 Hyperlactatemia under these conditions typically has a normal

lactate/pyruvate ratio of less than 20 mM/L.16 Likely for this reason, lactate levels alone were

found to be less predictive of mortality than the degree of associated acidemia.17 When

acidemia does occur the degree is only explained partially by lactate levels as unmeasured

anions also contribute significantly to reductions in serum pH.18

Studies have shown both positive and negative effects of isolated hyperlactatemia. In-vitro,

myocardial muscle bathed in a lactate perfusate buffered to a neutral pH results in decreased

inotropy.19 However, lactate may reflect a protective mechanism during increased anaerobic

energy production.20 It improves myocardial function after hemorrhagic shock and attenuates

cerebral dysfunction from hypoglycemia or ischemic insult.21-24 In one study of postoperative

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coronary artery bypass patients, an infusion of hypertonic sodium lactate led to an increase in

cardiac index, oxygen delivery, and serum pH. However, these results may be secondary to

the sodium load and the hypertonicity of the fluid, both known to increase intravascular

volume and improve hemodynamics, rather than a direct effect of lactate.25

Many practitioners have adopted lactate clearance as a surrogate marker of adequate

resuscitation from early sepsis and a reflection of whole body energy consumption.

Opponents argue that due to the complexity of lactate homeostasis, serum lactate has poor

sensitivity in detecting septic shock, with up to 45% of septic patients having normal serum

lactate levels.26 Additionally, serum lactate is a late indicator of tissue hypoperfusion, while

central venous oxygenation more closely reflects real time tissue perfusion. A recent

prospective observational study of patients in septic shock found no association with lactate

clearance and improved microcirculatory blood flow, suggesting that lactate levels do not

directly correlate with tissue perfusion.27

In the latest International Consensus Definitions of Sepsis and Septic shock (Sepsis -3), the

majority of task force members believe that “lactate level is reflective of cellular dysfunction

in sepsis, albeit recognizing that multiple factors, such as insufficient tissue oxygen delivery,

impaired aerobic respiration, accelerated aerobic glycolysis and reduced hepatic clearance,

also contribute.” Moreveover, the authors go on to emphasize the need to use lactate in

conjunction with other clinical markers. When lactate levels are greater than 2 mmol/L is

isolation mortality rates were 6.8-17.9%, but in combination with hypotension and

vasopressor mortality rates increased to 35-54%.28 The 2016 Surviving Sepsis Guidelines

provide a weak recommendation based on low quality evidence that resuscitation efforts be

guided to normalize lactate levels.29 This is based on five randomized control trials which

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found improved mortality in patients with septic shock when lactate-guided resuscitation was

used compared to no lactate monitoring. 30-34

In summary, an isolated elevated lactate level has complex physiologic effects. It is best

viewed as an alert which may represent malperfusion, but when the overall clinical picture

suggests sepsis as the underlying driver of hyperlactatemia, directing resuscitation methods to

normalize lactate likely has a mortality benefit.

Physiologic Effects of Acidemia

There are both positive and negative physiologic effects of academia (Table 2). In the

cardiovascular system, there is abundant evidence in both animal and human models that

acidemia decreases myocardial contractility.35-41 This effect is thought to be a result of: 1)

decreased sensitivity of myocardial myofilaments to calcium; 2) decreased energy

production; and 3) impaired actin-myosin cross-bridging. Additionally, acidemia decreases

myocardial responsiveness to catecholamines by downregulation of cell receptors and

decreasing calcium influx into myocardial.41-45 It also increases the risk of cardiac

arrhythmias and decreases the likelihood of successful resuscitation after cardiac arrest,

although studies examining the effects of acidemia on clinical outcomes in these patients

have had conflicting results.46-50 Systemically, a low serum pH causes vasodilation by

inducing hyperpolarization of endothelial cells, releasing nitric oxide, inhibiting calcium

influx into cells, and sequestering intracellular calcium stores.42,51

In vivo, the cumulative effect of acidemia is less clear due to the interplay of cardiac

function, increased sympathetic tone and decreased vascular resistance. In two studies

examining acute acidemia associated with permissive hypercapnia, a decrease in systemic

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vascular resistance was observed, but there was an overall increase in cardiac output and

oxygen delivery while oxygen consumption remained the same.52,53

In diabetic ketoacidosis with pH levels as low as 6.75, no significant cardiac effects were

observed.54 Increased inotropy sometimes observed in acidemia can be reversed with beta-

blockade, suggesting that increased sympathetic tone may compensate for the myocardial

depressant effects of acidemia. This effect, however, appears to be overwhelmed whenever

the pH drops below 7.2, with cardiac contractility precipitously dropping below this pH

threshold.55 This suggests that in catecholamine depleted states, the negative effects of

acidemia on cardiac function may be more pronounced.

Acidemia has various detrimental influences on other organ systems. Metabolic effects of

acidemia include increased insulin resistance, decreased anaerobic glycolysis, increased

protein degradation and reduction in ATP synthesis.56 In the central nervous system, acidemia

disrupts volume regulation and inhibits cerebral metabolism leading to obtundation, coma,

and seizures. Acidemia may induce an inflammatory response, impair immune cell function,

and induce a coagulopathic state.57-59

However, not all physiologic effects of acidemia are disadvantageous. By the Bohr effect,

acidemia causes a rightward shift in the hemoglobin dissociation curve favoring the delivery

of oxygen to ischemic tissues. Similarly, although systemic vasodilation may result in the

hypoperfusion of critical organs, when acidemia occurs in a localized region, vasodilation

increases blood flow to ischemic tissue beds. Less intuitive is the finding that acidosis can

provide protection against hypoxic cell injury and death. In a canine study, when the left

anterior descending coronary artery is occluded, reperfusion with acidotic blood decreases the

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subsequent infarction size suggesting that prolonged extracellular acidosis is protective.60

Similarly, in other nonprimate animal models, metabolic acidosis conferred protection against

anoxic cell injury in the liver, kidney, and brain.61,62 Notably, acidosis itself appears to limit

lactic acid production by limiting glycolysis in part by inhibition of phosphofructokinase.63

To further complicate the picture, the measured pH of a blood sample often does not reflect

the interstitial (pHE) or the intracellular pH (pHi). These are the primary fluid compartments

responsible for cellular dysfunction. An abnormally low pH in these compartments can

disrupt membrane channel function, alter intracellular electrolyte concentrations, and change

membrane electrical potential.64 Additionally, during conditions of severe global

hypoperfusion, the measured pH and PaCO2 from peripheral arterial blood may significantly

underestimate the degree of acidosis when compared to central venous measurements.56

In summary, in vitro studies have found various and opposing physiologic effects of acidemia

(Table 2). The type, degree, location and presence of buffers significantly influence the

clinical effect. The net effect on an individual, therefore, is a result of the interplay between

positive and negative effects with the latter likely predominating as the acidemia increasing

in severity. It is an oversimplification to state that acidemia, especially when pH levels are

greater than 7.2, is deleterious and ought always be corrected.

SODIUM BICARBONATE TREATMENT

Proponents of correcting a lactic acidosis with a buffer such as sodium bicarbonate argue that

acidemia produces detrimental physiologic consequences and that normalizing the serum pH

will mitigate these adverse effects. Bicarbonate replacement in the setting of systemic

bicarbonate losses (i.e., due to chronic diarrhea or renal tubular losses) is less

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controversial.65,66 Conversely, when lactate is buffered from endogenous bicarbonate, this

bicarbonate has not been lost and can be regenerated after the lactate has been metabolized.

The purpose of exogenous bicarbonate administration in this setting is to temporarily

decrease the physiologic effects of the acidemia while also attempting to correct the

underlying pathophysiology. Whether this temporary correction in serum pH results in

improved clinical outcomes is the subject of the following discussion.

Physiologic Effects of Sodium Bicarbonate

Animal studies exploring sodium bicarbonate administration during lactic acidosis have

demonstrated no significant hemodynamic benefits. Several canine studies investigating

sodium bicarbonate in lactic acidosis not only failed to show a benefit but was associated

with decreased cardiac output, lower intracellular pH levels, and an increased or unchanged

lactate level.67-70 Rats with lactic acidosis who were given sodium bicarbonate similarly

showed increased levels of lactate and decreased or unchanged cardiac output and mean

arterial pressure.71-74 Porcine models have confirmed these findings as well.35,75

There are several potentially detrimental effects of sodium bicarbonate. Sodium bicarbonate

is a hypertonic solution which may decrease vasomotor tone. A study comparing sodium

bicarbonate to hypertonic saline and normal saline administration found that the hypertonic

bicarbonate and saline solutions caused a significant decrease in the mean arterial pressure.76

Similarly, Kette et al. found that hypertonic solutions decrease coronary perfusion pressure.77

It has been theorized that hypertonicity changes intracellular ion concentrations in vascular

smooth muscle cells resulting in hyperpolarization and overall vasodilation. Another theory

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suggests that peripheral vasodilation may be mediated through the vagal reflex originating

from pulmonary receptors exposed to hypertonic solutions.78

Sodium bicarbonate may also decrease cardiac output due to increased carbon dioxide

production. Intra-myocardial carbon dioxide, rather than lactate, is primarily responsible for

the myocardial acidosis and dysfunction seen both during and after a cardiac arrest.79

Additionally, in one study, sodium bicarbonate after myocardial arrest increased systemic pH

levels but failed to improve intramyocardial pH.80 These findings suggest that exogenous

buffers not only fail to diffuse into myocardial cells, but they may, in fact, worsen

intracellular acidosis and myocardial function by the addition of intramyocardial CO2.

Myocardial contractility itself decreases following bicarbonate administration likely as a

result of decreased serum ionized calcium levels.81 Bicarbonate directly binds to calcium and

by raising serum pH it also increases the binding of calcium to albumin.82 This decrease in

ionized calcium is especially relevant as hyperlactatemia itself is associated with

hypocalcemia.83 The mechanism for this association is not completely understood but may be

a result of lactate directly chelating free ionized calcium.84 Sodium bicarbonate also

decreases myocardial oxygen extraction resulting in myocardial ischemia thereby decreasing

myocardial contractility. Systemic oxygen tension (pO2) decreases an average of 10 mmHg

after sodium bicarbonate administration.85 The mechanism behind this is unknown but

theoretically can result from a left shift of the hemoglobin-oxygen disassociation curve from

the Bohr effect, decreased 2,3-diphosphoglycerate (2,3-DPG) levels, intrapulmonary shunting

from vasodilation, or from direct dysfunction of cellular oxygen consumption.85,86

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Worsening of intracellular acidosis, independent of its effects in the plasma, is a common

explanation for the deleterious effects of sodium bicarbonate. As the theory goes, sodium

bicarbonate produces CO2 after buffering plasma protons. This CO2 is then free to diffuse

across cell membranes resulting in an intracellular hypercarbic acidemia, while bicarbonate is

unable to cross cell membranes to buffer this effect. But the evidence for intracellular

acidification with bicarbonate administration is mixed. Sodium bicarbonate has been shown

to either decrease or increase intramyocardial pH; decrease hepatic, erythrocyte, and

leukocyte pH, or had no significant effect on intracellular pH. 67,69,70,72,73,80,87

Higher amounts of extracellular nonbicarbonate buffers (NBB), such as albumin and

hemoglobin, are responsible for inducing intracellular acidemia.88 The authors theorize that

this may be understood by examining the respective chemical equations (Figure 2).

Bicarbonate buffering results in a decrease in free protons, shifting the non-bicarbonate

buffer equation to the left, resulting in a replenishment of free protons. These protons are

again buffered by bicarbonate producing more CO2. The CO2 is then able to diffuse

intracellularly while bicarbonate remains extracellular. In other words, non-bicarbonate

buffers serve as a pool of protons producing substantial amounts of CO2 which can diffuse

into cells, decreasing intracellular pH in the setting of bicarbonate replacement. Whether

intracellular acidification occurs depends on the presence of reduced CO2 clearance from

limited ventilation or low-flow states and the presence of intact intracellular buffering

systems.64 Rapid administration of bicarbonate infusions have also been associated with

lowering of pHi.87

Although there are several potential adverse consequences of sodium bicarbonate

administration, many of these may be mitigated. Decreased ionized calcium can be

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anticipated and replaced. Similarly, to avoid the harmful consequences of a rapid infusion of

hypertonic solution, sodium bicarbonate can be diluted or administered at a lower infusion

rate. When ventilation is fixed such as during permissive hypercapnia, sodium bicarbonate

would likely result in significant intracellular acidemia. But increasing minute ventilation

(when feasible) in anticipation of the higher production of CO2 following bicarbonate

administration may allow pH to rise.

Human Trials Investigating the Use of Sodium Bicarbonate

The most recent 2016 Surviving Sepsis Guidelines give a “weak recommendation” based on

a “moderate quality of evidence” against the use of sodium bicarbonate therapy to improve

hemodynamics or reduce vasopressor requirements when the serum pH is > 7.15.29 This

recommendation is unchanged from the 2012 Sepsis Guidelines and is based on two small

randomized control trials conducted in humans. Cooper and colleagues compared sodium

bicarbonate to sodium chloride administration in 14 critically ill patients in septic shock with

lactic acidosis requiring vasopressor therapy.81 Although sodium bicarbonate increased

arterial pH significantly, there was no difference in cardiac output, blood pressure, or

pulmonary capillary wedge pressure in these patients. A decrease in ionized calcium and an

increase in end tidal CO2 was also observed which is consistent with the known physiologic

effects of sodium bicarbonate. There was also no difference in cardiovascular response to

vasopressor therapy. Subgroup analysis of seven patients with an arterial pH <7.2 yielded

similar results. The second trial by Mathieu and colleagues enrolled 10 critically ill patients

with lactic acidosis from acute circulatory problems but without severe renal dysfunction.89

They similarly compared sodium bicarbonate to sodium chloride administration, but found no

significant differences in cardiac output, blood pressure, or pulmonary capillary wedge

pressure in these patients. As discussed previously, bicarbonate may theoretically decease

oxygen delivery by causing a left-shift in the hemoglobin-oxygen dissociation curve by the

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Bohr effect and by decreasing 2,3-DPG. This study, however, found no such effect and

transcutaneous oxygen levels did not decrease, suggesting that bicarbonate, at least, did not

worsen tissue oxygenation.

Since the Cooper and Mathieu trials were published, a few additional prospective randomized

controlled trial in septic patients have been conducted. Fang et al. randomized 94 patients

with severe sepsis or septic shock with or without lactic acidosis to receive normal saline,

3.5% sodium chloride, or 5% sodium bicarbonate.90 Although there was an earlier

improvement in blood pressure and cardiac output in the sodium bicarbonate group, there was

no overall difference in cardiac output, mean arterial pressure, heart rate, or respiratory rate

either at 2 or 8 hours after treatment. Additionally, there was no difference in 28-day

mortality between the three groups.

Another prospective randomized control trial investigated the intraoperative use of sodium

bicarbonate in the setting of mild metabolic acidosis in non-septic patients (defined as a

decrease in plasma bicarbonate by >3mM) compared to sodium chloride.91 Although arterial

pH was increased significantly after sodium bicarbonate, no difference was found in cardiac

output or in systemic or pulmonary arterial pressures in these patients. Of note, this study also

found no significant change in ionized calcium levels, but since these patients had only mild

acidemia, the change in pH may not have been sufficient to cause significant changes in

calcium binding.

Other studies in humans have replicated some of these findings. In a subgroup analysis of the

placebo arm investigating the use of sodium diachloracetate in lactic acidosis by Stacpoole et

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al., the administration of sodium bicarbonate did not improve hemodynamic status or raise

serum pH.92 In 2011, Jung et al conducted a prospective observational multicenter study of

bicarbonate administration in patients with a plasma pH <7.2 Although the use of sodium

bicarbonate was heterogeneous between centers, it was not associated with a decrease in ICU

length of stay, duration of vasopressor requirements, duration of mechanical ventilation, or

ICU mortality.93

A separate retrospective study of critically ill patients with lactic acidosis by Kim et al. found

that after controlling for disease severity and initial serum bicarbonate levels, the

administration of sodium bicarbonate was associated with an increase in mortality.94 The

authors theorized that stimulation of phosphofructokinase by alkali resulted in increased

glycolysis leading to persistently high levels of lactate. This finding is in contrast to the

conclusions drawn by Halperin et al. in their study of lactic acidosis in rats who believed the

net effect of increased glycolysis during hypoxia is beneficial due to increased ATP

production.95 It should be noted that, as of this writing, the results by Kim et al. have not been

replicated and the study design was retrospective.

Some possible benefits of sodium bicarbonate therapy have also been found. A retrospective

analysis of thirty-six patients with septic shock found no difference in mortality after sodium

bicarbonate administration, but did find that patients would wean from the ventilator earlier

and had a shorter ICU length of stay.96

The recently published 2018 BICAR-ICU trial is the largest trial to date examining the effects

of bicarbonate treatment. It was a multicenter open-label study which randomized critically

ill patients with severe acidemia (defined at pH ≤ 7.2, PaCO2 ≤45, and sodium bicarbonate

≤20 mmol/L) to either placebo or 4.2% sodium bicarbonate to achieve an arterial pH of 7.3.97

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Hypocalcemia, hypernatremia and metabolic alkalosis were unsurprisingly significantly more

frequent with bicarbonate administration. A significant 28-day survival benefit (63% vs. 46%

p = 0.0283) was found in the a priori defined group of patients with acute kidney injury.

These patients also had less days of renal-replacement therapy and more vasopressor-free

days. The authors theorized some benefit may be a result of avoiding or delaying the

initiation of renal-replacement therapy. However, as they also pointed out, previous studies

do not support the theory that late renal-replacement therapy confers a survival benefit to

critically ill patients.98 A significant limitation in the trial was that renal-replacement therapy

was standardized to initiate if the patient met two of three criteria: urine output less than 0.3

ml/kg/hr for at least 24 hours, arterial pH < 7.2, or hyperkalemia >6.5 mmol/L. In other

words, one of the criteria for initiating renal-replacement therapy was the same criteria for

enrollment in the bicarbonate group. It is then not surprising this group of patient received

more days of renal-replacement therapy. So although there is no survival advantage to late vs.

early renal replacement therapy, there may be harm in initiating renal-replacement therapy

based on criteria listed in the study. Another limitation of this study was there was no

discussion and no data surrounding the effect of increasing ventilation. Indeed, the average

arterial carbon dioxide level on enrollment was 37 and 38mmHg in the control and

bicarbonate groups respectively. Over 80% of the randomized patients were mechanically

ventilated suggesting there may have been room to provide some respiratory compensation

for the severe acidosis.

A significant difference in these studies from previous studies was that smaller sodium

bicarbonate doses were given and were administered at a slower rate which could have

attenuated some harmful effects. This suggests that there may be a role for sodium

bicarbonate specifically during septic shock, and perhaps specifically in patients with renal

insufficiency, if efforts are made to minimize the harmful side-effects. Further prospective

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trials are needed to delineate if there is a role for sodium bicarbonate in other subgroups of

patients and elucidate the timing and methods of administration.

CONCLUSIONS

Much of critical care medicine is devoted to supporting hemodynamics and ensuring

adequate tissue oxygen delivery in critically ill patients. Although serum lactate levels may

be prognostic early on in sepsis, lactate levels serve as poor markers of perfusion status.

Serum lactate elevation can be the result of a myriad of sources, especially in the critically ill

patient and its presence may actually protect against hypoxic cell injury. Lactate, therefore, is

best viewed as a marker of overall clinical status and is not likely to drive the underlying

pathophysiology in patients with a lactic acidosis.

Peripheral arterial blood gas analysis is an easy and simple measurement tool but often is not

indicative of the acid-base status where it matters most: the intracellular and interstitial fluid

compartments. Even if a diagnostic device could measure the pH of these compartments in

real time, a serum pH above 7.2, in vivo, appears to be well tolerated.

Assuming that an acidemia is harmful, the attempt to raise the pH with sodium bicarbonate is

fraught with possible negative consequences including decreases in cardiac function,

systemic vascular resistance, ionized calcium, oxygen tension, and intracellular pH. Sodium

bicarbonate administration in the setting of lactic acidosis has consistently failed to

significantly improve hemodynamic status in humans. But aside from a single retrospective

analysis, the administration of sodium bicarbonate does not appear to produce harm. If the

decision is made to administer sodium bicarbonate, it appears prudent to administer it as a

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slow infusion with the goal of raising the pH above 7.2 rather than completely correcting the

metabolic acidemia. Adequate ventilation and calcium replacement as indicated may also

help to avoid some of the negative consequences of sodium bicarbonate administration.

Presently, there are more questions than answers when it comes to the effective treatment of

lactic acidosis, which explains the wide variation in clinical practice. The recent BICAR-ICU

trial suggests there may be subgroups of patients that benefit from thoughtful bicarbonate

supplementation but further studies are still required to delineate its role.

Acknowledgements

This research did not receive any specific grant from funding agencies in the public,

commercial, or not-for-profit sectors.

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Figure 1: Glycolysis pathways. Hyperlactatemia results from factors which favor production
of pyruvate and/or inhibition of pyruvate’s entry into the TCA cycle.

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Figure 2: Nonbicarbonate Buffers. Bicarbonate buffering results in carbon dioxide production
and a lowering of free proton concentration. Lower free protons favors disassociation of non-
bicarbonate buffers which, in turn, are buffered again by bicarbonate resulting in increasing
carbon dioxide production resulting in a cycle of increasing intracellular carbon dioxide so
long as exogenous bicarbonate is administered.

NBB = non-bicarbonate buffer, CO2 = carbon dioxide, HCO3- = bicarbonate, H+ = free

proton, H2O = water

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Table 1: Causes of Hyperlactatemia

Increased NADH/NAD

• Inadequate oxygen delivery

• Liver dysfunction (Cori cycle) – lactate is taken up by hepatic cells, converted to
pyruvate which is a necessary substrate for gluconeogenesis. Note the responsible
enzyme for the “metabolism” of lactate is still lactate dehydrogenase.
• Mitochondrial dysfunction
o Inborn errors
o Medications: propofol, cyanide
Increased Pyruvate

• Inhibition of pyruvate dehydrogenase

o Thiamine deficiency
o Sepsis
• Decreased ATP/ADP ratio – stimulates phosphofructokinase
o Exercise, stress
o Liver, intestinal, pulmonary dysfunction
o Beta-adrenergic medications – epinephrine, norepinephrine, or cocaine via
stimulation of Na/K ATPase

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Table 2: Physiologic Effects of Acidosis

Physiologic Effects of Acidosis

Negative Positive

Decrease myocardial contractility Decreased hemoglobin-oxygen affinity

Decreased responsiveness to Increased localized blood flow

catecholamines

Increase susceptibility to cardiac Protection against hypoxic cell injury

arrhythmias

Vasodilation Increased sympathetic tone

Insulin resistance Limits lactic acid generation

Decreased glycolysis

Increased protein degradation

Disrupted CNS volume regulation

Inhibits CNS metabolism

Induces inflammatory mediators

Impairs immune function

Creates coagulopathy

Hyperkalemia

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Table 3: Negative Effects of Sodium Bicarbonate

Effect Possible mechanisms

Vasodilation Hyperpolarization of vascular smooth muscle
Decreased cardiac output Decreased intramyocardial pH, decreased serum ionized
calcium
Decreased pO2 Left shift of Hbg-O2 disassociation curve, decreased 2,3-
DPG levels, intrapulmonary shunting, dysfunctional O2
consumption.
Intracellular acidosis High concentration of non-bicarbonate buffers, limited
ventilation, low perfusion

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Table 4 Summary of human trials investigating bicarbonate use

Trial Year Design Patient population Intervent Results

ion
Cooper 1990 RCT 14 pts in septic Sodium No difference in CO,
et al75 shock with lactic bicarbon BP, PCWP, vasopressor
acidosis requiring ate vs. requirement. Decreased
vasopressors sodium iCa and increased ETT
chloride CO2
Mathieu 1991 RCT 10 pts with lactic Sodium No difference in CO,
et al.84 acidosis requiring bicarbon BP, PCWP or tissue
vasopressors ate vs. oxygen levels.
without severe sodium
renal dysfunction chloride
Mark et 1993 RCT 40 pts with Sodium No difference in total
al. 86 coronary artery bicarbon body O2 consumption or
disease with ate vs. lactate production.
intraoperative sodium Trend toward lower
decrease in plasma chloride cardiac output and O2
HCO3- of >3mM consumption with
bicarbonate but was not
statistically significant.
Stacpool 1994 RCT 126 pts with lactic Dichloro In pts receiving
e et al.87 acidosis acetate bicarbonate, no
vs. improvement in acid-
placebo base nor hemodynamic
status.
Fang et 2008 RCT 94 pts with severe Normal No difference in CO,
al.85 sepsis or septic saline vs. MAP, HR, respiratory
shock with or 3.5% rate 2 or 8 hours after
without lactic sodium treatment. No difference
acidosis. chloride in 28 day mortality.
vs. 5%
sodium
bicarbon
ate
El Solh 2010 Retrospecti 36 pts with septic Decreased time of
et al 91 ve shock who received mechanical ventilation
continuous and decreased ICU
bicarbonate length of stay. No
infusion difference in 28 day
survival.
Jung et 2011 Observation 155 pts with pH No decrease in ICU
al.94 al <7.2 without length of stay, duration
diabetic of vasopressors usage,
ketoacidosis or duration of mechanical
severe respiratory ventilation or ICU
acidemia mortality.
Kim et 2013 Retrospecti 103 pts with lactic Increased mortality with
al.89 ve acidosis sodium bicarbonate

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 even when accounting
for disease severity
BICAR- 2018 RCT 389 pts with pH 4.2% No difference in
ICU92 <7.2, PaCO2 <45 sodium composite outcome of
mmHg and HCO3- bicarbon death from any cause or
<20 mmol/L with ate presence of at least one
SOFA ≥4 or infusion organ failure, except in
arterial lactate ≥ 2 vs. usual apriori defined group of
mmol/L care patients with acute
kidney injury.

RCT = randomized control trial, pts = patients, CO = cardiac output, BP = blood pressure,
PCWP = pulmonary wedge pressure, iCa = ionized calcium, ETT CO2 = end tidal carbon
dioxide, O2 = oxygen, HR = heart rate, ICU = intensive care unit.

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