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 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 with 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.
Etiologies of lactic acidosis
Lactate is generated via lactate dehydrogenase from an oxidative-reduction coupled reaction with NADH from pyruvate (Fig. 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).
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 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 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.” Moreover, 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 in isolation, mortality rates were 6.8% to 17.9%, but in combination with hypotension and vasopressor mortality rates increased to 35% to 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 found improved mortality in patients with septic shock when lactate-guided resuscitation was used compared with 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: decreased sensitivity of myocardial myofilaments to calcium; decreased energy production; and 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 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 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 with 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 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 were associated with decreased cardiac output, lower intracellular pH levels, and an increased or unchanged lactate level (67–70). Rats with lactic acidosis that 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. (77) found that hypertonic solutions decrease coronary perfusion pressure. It has been theorized that hypertonicity changes intracellular ion concentrations in vascular smooth muscle cells resulting in hyperpolarization and overall vasodilation. Another theory 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. Intramyocardial 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 decreases an average of 10 mm Hg 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).
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, 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 (Fig. 2). Bicarbonate buffering results in a decrease in free protons, shifting the nonbicarbonate 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 intra-cellularly while bicarbonate remains extracellular. In other words, nonbicarbonate 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 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 et al. (81) compared sodium bicarbonate with sodium chloride administration in 14 critically ill patients in septic shock with lactic acidosis requiring vasopressor therapy. 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 et al. (89) enrolled 10 critically ill patients with lactic acidosis from acute circulatory problems but without severe renal dysfunction. They similarly compared sodium bicarbonate with 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 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. (90) 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. 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 h 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 nonseptic patients (defined as a decrease in plasma bicarbonate by >3 mM) compared with 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 (Tables 3 and 4).
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 al. (92), the administration of sodium bicarbonate did not improve hemodynamic status or raise serum pH. In 2011, Jung et al. (93) 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. (94) found that after controlling for disease severity and initial serum bicarbonate levels, the administration of sodium bicarbonate was associated with an increase in mortality. 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. (95) 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. 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 36 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). 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/h for at least 24 h, 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 versus 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 were no discussion and no data surrounding the effect of increasing ventilation. Indeed, the average arterial carbon dioxide level on enrollment was 37 and 38 mm Hg 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 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.
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 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.
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