Jean‐Sebastien Rachoin, MD

Hospitalists play a crucial role in improving hospital throughput and length of stay (LOS). The clinical decision unit (CDU) or observation unit (OU) is a strategy that was developed to facilitate both aims. CDUs and OUs are units where patients can be managed in the hospital for up to 24 hours prior to a decision being made to admit or discharge. Observation care is provided to patients who require further treatment or monitoring beyond what is accomplished in the emergency department (ED), but who do not require inpatient admission. CDUs arose in the 1990s in response to a desire to decrease inpatient costs as well as changing Medicare guidelines, which recognized observation status. Initially, CDUs and OUs were located within the ED and run by emergency medicine physicians. However, at the turn of the 21st century, hospitalists became involved in observation medicine, and the Society of Hospital Medicine issued a white paper on the OU in 2007. [1] Today, up to 50% of CDUs and OUs nationally are managed by hospitalists and located physically outside of the ED.[2, 3]

Despite the fact that nearly half of all CDUs and OUs nationally are run by hospitalists, there has been little published regarding the impact of hospitalist‐driven units. This study demonstrates the effect of observation care delivered in a hospitalist‐run geographic CDU. The primary objective was to determine the impact on LOS for patients in observation status managed in a hospitalist‐run CDU compared with LOS for observation patients with the same diagnoses cared for on medicalsurgical units prior to the existence of the CDU. The secondary objective was to determine the effect on the 30‐day ED or hospital revisit rate, as well as ED LOS. This work will guide health systems, hospitalist groups, and physicians in their decision making regarding the future structure and process of CDUs.

METHODS

RESULTS

DISCUSSION

In our study of a hospitalist‐run CDU for observation patients, we observed that the care in the CDU was associated with a lower median LOS, but no increase in ED or hospital revisits within 30 days.

Previous studies have reported the impact of clinical observation or clinical diagnosis units, particularly chest‐pain units.[5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15] Studies of hospitalist‐run units suggest shorter LOS in the entire hospital,[16] or in the target unit.[17] Although one study suggested a lower 30‐day readmission rate,[18] most others did not describe this effect.[16, 17] Our study differs from previous research in that our program employed a pull‐culture aimed at accepting the majority of observation status patients without focusing on a particular diagnosis. We also implemented a structured multidisciplinary team focused on expediting care and utilized BOOST‐framed transitions, including targeted medication reconciliation and tools such as teach‐back.

The CDU in our hospital produced shorter LOS even compared to our non‐CDU units, but the revisit rate did not improve despite activities to reduce revisits. During the study period, efforts to decrease readmissions were implemented in various areas of our hospital, but not a comprehensive institution‐wide readmissions strategy. Lack of impact on revisits could be viewed as a positive finding, in that shorter LOS did not result in patients being discharged home before clinically stable. Alternatively, lack of impact could be due to the uncertain effectiveness of BOOST specifically[19, 20, 21] or inpatient‐targeted transitions interventions more generally.[22]

Our study has certain limitations. Findings in our single‐center study in an urban academic medical center may not apply to CDUs in other settings. As a prepost design, our study is subject to external trends for which our analyses may be unable to account. For example, during CDU implementation, there were hospital‐wide initiatives aimed at improving inpatient LOS, including complex case rounds, increased use of active bed management, and improved case management efforts to decrease LOS. These may have been a factor in the small decrease in observation LOS seen in the medicalsurgical patients during the post period. Additionally, though we have attempted to control for possible confounders, there could have been differences in the study groups for which we were unable to account, including code status or social variables such as homelessness, which played a role in our revisit outcomes. The decrease in LOS by 35%, or 9.5 hours, in CDU patients is clinically important, as it allows low‐risk patients to spend less time in the hospital where they may have been at risk of hospital‐acquired conditions; however, this study did not include patient satisfaction data. It would be important to measure the effect on patient experience of potentially spending 1 fewer night in the hospital. Finally, our CDU was designed with specific clinical criteria for inclusion and exclusion. Patients who were higher risk or expected to need more than 24 hours of care were not placed in the CDU. We were not able to adjust our analyses for factors that were not in our data, such as severe vital sign or laboratory abnormalities or a physician's clinical impression of a patient. It is possible, therefore, that referral bias may have occurred and influenced our results. The fact that non‐CDU chest‐pain patients in the post‐CDU period did not experience any decrease in LOS, whereas other medicalsurgical observation patients did, may be an example of this bias. Patients were excluded from the CDU by virtue of being deemed higher risk as described in Methods section. We were unable to adjust for these differences.

Implementation of CDUs may be useful for health systems seeking to improve hospital throughput and improve utilization among common but low‐acuity patient groups. Although our initial results are promising, the concept of a CDU may require enhancements. For example, at our hospital we are addressing transitions of care by looking at models that address patient risk through a systematic process, and then target individuals for specific interventions to prevent revisits. Moreover, the study of CDUs should report impact on patient and referring physician satisfaction, and whether CDUs can reduce per‐case costs.

CONCLUSION

Caring for patients in a hospitalist‐run geographic CDU was associated with a 35% decrease in observation LOS for CDU patients compared with a 3.7% decrease for observation patients cared for elsewhere in the hospital. CDU patients' LOS was significantly decreased without increasing ED or hospital revisit rates.

Hospitalists play a crucial role in improving hospital throughput and length of stay (LOS). The clinical decision unit (CDU) or observation unit (OU) is a strategy that was developed to facilitate both aims. CDUs and OUs are units where patients can be managed in the hospital for up to 24 hours prior to a decision being made to admit or discharge. Observation care is provided to patients who require further treatment or monitoring beyond what is accomplished in the emergency department (ED), but who do not require inpatient admission. CDUs arose in the 1990s in response to a desire to decrease inpatient costs as well as changing Medicare guidelines, which recognized observation status. Initially, CDUs and OUs were located within the ED and run by emergency medicine physicians. However, at the turn of the 21st century, hospitalists became involved in observation medicine, and the Society of Hospital Medicine issued a white paper on the OU in 2007. [1] Today, up to 50% of CDUs and OUs nationally are managed by hospitalists and located physically outside of the ED.[2, 3]

Despite the fact that nearly half of all CDUs and OUs nationally are run by hospitalists, there has been little published regarding the impact of hospitalist‐driven units. This study demonstrates the effect of observation care delivered in a hospitalist‐run geographic CDU. The primary objective was to determine the impact on LOS for patients in observation status managed in a hospitalist‐run CDU compared with LOS for observation patients with the same diagnoses cared for on medicalsurgical units prior to the existence of the CDU. The secondary objective was to determine the effect on the 30‐day ED or hospital revisit rate, as well as ED LOS. This work will guide health systems, hospitalist groups, and physicians in their decision making regarding the future structure and process of CDUs.

METHODS

RESULTS

DISCUSSION

In our study of a hospitalist‐run CDU for observation patients, we observed that the care in the CDU was associated with a lower median LOS, but no increase in ED or hospital revisits within 30 days.

Previous studies have reported the impact of clinical observation or clinical diagnosis units, particularly chest‐pain units.[5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15] Studies of hospitalist‐run units suggest shorter LOS in the entire hospital,[16] or in the target unit.[17] Although one study suggested a lower 30‐day readmission rate,[18] most others did not describe this effect.[16, 17] Our study differs from previous research in that our program employed a pull‐culture aimed at accepting the majority of observation status patients without focusing on a particular diagnosis. We also implemented a structured multidisciplinary team focused on expediting care and utilized BOOST‐framed transitions, including targeted medication reconciliation and tools such as teach‐back.

The CDU in our hospital produced shorter LOS even compared to our non‐CDU units, but the revisit rate did not improve despite activities to reduce revisits. During the study period, efforts to decrease readmissions were implemented in various areas of our hospital, but not a comprehensive institution‐wide readmissions strategy. Lack of impact on revisits could be viewed as a positive finding, in that shorter LOS did not result in patients being discharged home before clinically stable. Alternatively, lack of impact could be due to the uncertain effectiveness of BOOST specifically[19, 20, 21] or inpatient‐targeted transitions interventions more generally.[22]

Our study has certain limitations. Findings in our single‐center study in an urban academic medical center may not apply to CDUs in other settings. As a prepost design, our study is subject to external trends for which our analyses may be unable to account. For example, during CDU implementation, there were hospital‐wide initiatives aimed at improving inpatient LOS, including complex case rounds, increased use of active bed management, and improved case management efforts to decrease LOS. These may have been a factor in the small decrease in observation LOS seen in the medicalsurgical patients during the post period. Additionally, though we have attempted to control for possible confounders, there could have been differences in the study groups for which we were unable to account, including code status or social variables such as homelessness, which played a role in our revisit outcomes. The decrease in LOS by 35%, or 9.5 hours, in CDU patients is clinically important, as it allows low‐risk patients to spend less time in the hospital where they may have been at risk of hospital‐acquired conditions; however, this study did not include patient satisfaction data. It would be important to measure the effect on patient experience of potentially spending 1 fewer night in the hospital. Finally, our CDU was designed with specific clinical criteria for inclusion and exclusion. Patients who were higher risk or expected to need more than 24 hours of care were not placed in the CDU. We were not able to adjust our analyses for factors that were not in our data, such as severe vital sign or laboratory abnormalities or a physician's clinical impression of a patient. It is possible, therefore, that referral bias may have occurred and influenced our results. The fact that non‐CDU chest‐pain patients in the post‐CDU period did not experience any decrease in LOS, whereas other medicalsurgical observation patients did, may be an example of this bias. Patients were excluded from the CDU by virtue of being deemed higher risk as described in Methods section. We were unable to adjust for these differences.

Implementation of CDUs may be useful for health systems seeking to improve hospital throughput and improve utilization among common but low‐acuity patient groups. Although our initial results are promising, the concept of a CDU may require enhancements. For example, at our hospital we are addressing transitions of care by looking at models that address patient risk through a systematic process, and then target individuals for specific interventions to prevent revisits. Moreover, the study of CDUs should report impact on patient and referring physician satisfaction, and whether CDUs can reduce per‐case costs.

CONCLUSION

Caring for patients in a hospitalist‐run geographic CDU was associated with a 35% decrease in observation LOS for CDU patients compared with a 3.7% decrease for observation patients cared for elsewhere in the hospital. CDU patients' LOS was significantly decreased without increasing ED or hospital revisit rates.

Hospitalists play a crucial role in improving hospital throughput and length of stay (LOS). The clinical decision unit (CDU) or observation unit (OU) is a strategy that was developed to facilitate both aims. CDUs and OUs are units where patients can be managed in the hospital for up to 24 hours prior to a decision being made to admit or discharge. Observation care is provided to patients who require further treatment or monitoring beyond what is accomplished in the emergency department (ED), but who do not require inpatient admission. CDUs arose in the 1990s in response to a desire to decrease inpatient costs as well as changing Medicare guidelines, which recognized observation status. Initially, CDUs and OUs were located within the ED and run by emergency medicine physicians. However, at the turn of the 21st century, hospitalists became involved in observation medicine, and the Society of Hospital Medicine issued a white paper on the OU in 2007. [1] Today, up to 50% of CDUs and OUs nationally are managed by hospitalists and located physically outside of the ED.[2, 3]

Despite the fact that nearly half of all CDUs and OUs nationally are run by hospitalists, there has been little published regarding the impact of hospitalist‐driven units. This study demonstrates the effect of observation care delivered in a hospitalist‐run geographic CDU. The primary objective was to determine the impact on LOS for patients in observation status managed in a hospitalist‐run CDU compared with LOS for observation patients with the same diagnoses cared for on medicalsurgical units prior to the existence of the CDU. The secondary objective was to determine the effect on the 30‐day ED or hospital revisit rate, as well as ED LOS. This work will guide health systems, hospitalist groups, and physicians in their decision making regarding the future structure and process of CDUs.

METHODS

RESULTS

DISCUSSION

In our study of a hospitalist‐run CDU for observation patients, we observed that the care in the CDU was associated with a lower median LOS, but no increase in ED or hospital revisits within 30 days.

Previous studies have reported the impact of clinical observation or clinical diagnosis units, particularly chest‐pain units.[5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15] Studies of hospitalist‐run units suggest shorter LOS in the entire hospital,[16] or in the target unit.[17] Although one study suggested a lower 30‐day readmission rate,[18] most others did not describe this effect.[16, 17] Our study differs from previous research in that our program employed a pull‐culture aimed at accepting the majority of observation status patients without focusing on a particular diagnosis. We also implemented a structured multidisciplinary team focused on expediting care and utilized BOOST‐framed transitions, including targeted medication reconciliation and tools such as teach‐back.

The CDU in our hospital produced shorter LOS even compared to our non‐CDU units, but the revisit rate did not improve despite activities to reduce revisits. During the study period, efforts to decrease readmissions were implemented in various areas of our hospital, but not a comprehensive institution‐wide readmissions strategy. Lack of impact on revisits could be viewed as a positive finding, in that shorter LOS did not result in patients being discharged home before clinically stable. Alternatively, lack of impact could be due to the uncertain effectiveness of BOOST specifically[19, 20, 21] or inpatient‐targeted transitions interventions more generally.[22]

Our study has certain limitations. Findings in our single‐center study in an urban academic medical center may not apply to CDUs in other settings. As a prepost design, our study is subject to external trends for which our analyses may be unable to account. For example, during CDU implementation, there were hospital‐wide initiatives aimed at improving inpatient LOS, including complex case rounds, increased use of active bed management, and improved case management efforts to decrease LOS. These may have been a factor in the small decrease in observation LOS seen in the medicalsurgical patients during the post period. Additionally, though we have attempted to control for possible confounders, there could have been differences in the study groups for which we were unable to account, including code status or social variables such as homelessness, which played a role in our revisit outcomes. The decrease in LOS by 35%, or 9.5 hours, in CDU patients is clinically important, as it allows low‐risk patients to spend less time in the hospital where they may have been at risk of hospital‐acquired conditions; however, this study did not include patient satisfaction data. It would be important to measure the effect on patient experience of potentially spending 1 fewer night in the hospital. Finally, our CDU was designed with specific clinical criteria for inclusion and exclusion. Patients who were higher risk or expected to need more than 24 hours of care were not placed in the CDU. We were not able to adjust our analyses for factors that were not in our data, such as severe vital sign or laboratory abnormalities or a physician's clinical impression of a patient. It is possible, therefore, that referral bias may have occurred and influenced our results. The fact that non‐CDU chest‐pain patients in the post‐CDU period did not experience any decrease in LOS, whereas other medicalsurgical observation patients did, may be an example of this bias. Patients were excluded from the CDU by virtue of being deemed higher risk as described in Methods section. We were unable to adjust for these differences.

Implementation of CDUs may be useful for health systems seeking to improve hospital throughput and improve utilization among common but low‐acuity patient groups. Although our initial results are promising, the concept of a CDU may require enhancements. For example, at our hospital we are addressing transitions of care by looking at models that address patient risk through a systematic process, and then target individuals for specific interventions to prevent revisits. Moreover, the study of CDUs should report impact on patient and referring physician satisfaction, and whether CDUs can reduce per‐case costs.

CONCLUSION

Caring for patients in a hospitalist‐run geographic CDU was associated with a 35% decrease in observation LOS for CDU patients compared with a 3.7% decrease for observation patients cared for elsewhere in the hospital. CDU patients' LOS was significantly decreased without increasing ED or hospital revisit rates.

There are many controversial topics relating to renal disease in hospitalized patients. The aim of this review is to shed light on some important and often debated issues. We will first discuss topics related to electrolytes disorder commonly seen in hospitalized patients (hyponatremia, hyperkalemia, metabolic acidosis) then the use of diuretics in patients with allergy to sulfa containing antibiotics.

Hypothyroidism and Hyponatremia

Hyponatremia is common in hospitalized patients and is associated with worse outcomes.1 It can be seen with a variety of conditions ranging from congestive heart failure to volume depletion. Careful history and physical examination are paramount and the initial work‐up usually includes serum and urine osmolality and urine sodium concentration.

For euvolemic hyponatremia, the differential diagnosis includes the syndrome of inappropriate adenine dinucleotide (ADH) secretion (SIADH), hypoadrenalism, and beer potomania. Additionally, many authorities also include hypothyroidism.

Although the simultaneous finding of hypothyroidism and hyponatremia can occur in patients as both diseases are widely prevalent in the general population, causation has yet to be convincingly demonstrated.

ADH is released in response to effective volume depletion; consequently when hypothyroidism is encountered in the setting of complete pituitary failure there is often hyponatremia.2, 3 Alternatively, with myxedema, the ability of the kidney to handle a water load and concentrate urine can be impaired.4

However, the observation that thyroid hormone administration did not raise sodium values in newborns with congenital hypothyroidism or in adults supports the absence of causal effect.5, 6And in addition, large studies done in the hospital and outpatient setting showed no differences between the serum sodium values of hypothyroid patients and that of controls.7, 8 In the study of outpatients, among those with hypothyroidism, for every increase of 10 mU/L of thyroid‐stimulating hormone (TSH), there was a drop of only 0.14 mmol/L of Na concentration.8 Thus, the elevation of TSH required for a clinically meaningful drop in sodium to occur was considerable.

Hence in patients with hyponatremia, the hospitalist should look for etiologies other than hypothyroidism and should only consider thyroid hypofunction as a culprit in cases of myxedema, or panhypopituitarism.

Sodium Bicarbonate for Hyperkalemia

Hyperkalemia is one of the most feared electrolyte disorders encountered in hospitalized patients and can lead to dire outcomes.9, 10

Potassium (K+) homeostasis is maintained in the body by 2 complimentary systems: a short‐term system that regulates K+ variation by modifying translocation across the cellular membrane and a long‐term system that adjusts overall K+ balance. The translocation system is regulated primarily by insulin and ‐2 stimulation. Overall K+ balance is mainly controlled by the kidney (90‐95%) although the gastrointestinal (GI) tract can have a more preponderant role in anephric patients.

Hyperkalemia can ensue by either a dysregulation of the translocation system (as in diabetic Ketoacidosis secondary to insulin deficiency) or impairment of K+ elimination.

Acid‐base status was previously thought to have a prominent influence on K+ concentration, based on studies that demonstrated that. However, studies looking at metabolic acidosis revealed that contrary to the effect of mineral acidosis (excess of nonmetabolizable anions)11 where there is an inverse correlation between potassium concentration and pH; organic acidosis (excess of metabolizable anions)11 was not associated with hyperkalemia.1214 However, organic acidosis can be seen simultaneously and induced by a same underlying disease (such as organ ischemia with lactic acidosis or insulin deficiency complicated by ketoacidosis). Also, when changes in pH are induced by respiratory variations or with alkalosis, the impact on serum K+ concentration is less remarkable.15 Hence, it seems that it is the nature of the acid‐base disturbance that impacts K+ concentration more than the change in pH itself.

In the kidney, the main site for regulation of K+ balance is the collecting duct. Factors that affect elimination include urinary sodium delivery, urine flow, and aldosterone.16 In order to adequately eliminate K+ these factors must be optimized in conjunction.

Treatment of hyperkalemia includes the sequential administration of agents that stabilize the cardiac membrane (calcium gluconate), shift the potassium intracellularly (insulin, ‐2 agonists), and remove the potassium (diuretics, sodium polystyrene, or dialysis).

The use of sodium bicarbonate for treatment of hyperkalemia has been long advocated.17 It was thought to act by translocation of potassium hence could be used to quickly lower K+ concentration. However, this dogma has been challenged recently.

To assess the true impact of sodium bicarbonate on potassium translocation, studies have been conducted on anephric patients with hyperkalemia. Bicarbonate infusion failed to elicit a significant rapid change in serum K+ concentration despite increase in bicarbonate concentration, arguing against a translocation mechanism.1821 After 60 minutes of treatment, neither isotonic nor hypertonic bicarbonate infusion affected Serum K+ levels in end‐stage renal disease (ESRD) patients.19, 20 On the contrary, hypertonic sodium bicarbonate increased the K+ concentration after 180 minutes of treatment,20 and it took a prolonged infusion of 4 hours to see a significant decrease in K+ concentration (0.6 mmol/L); half of which could be accounted for solely by volume administration. Moreover, this reduction was highly variable.

Rather, sodium bicarbonate seems to enhance potassium elimination by increasing sodium delivery to the distal tubule, increasing urinary pH and negative luminal charge and potentiating the action of diuretics.23 In an elegant study on normovolemic patients, the induction of bicarbonaturia practically doubled potassium excretion.23 However, such an effect is heterogeneous and usually takes place over 4 hours to 6 hours.17

At the cellular level, 2 ion exchange pumps cooperate to handle Na/K/H movement across the cellular membrane: an Na⁺/H⁺ exchanger (NHE) and the Na⁺/K⁺ ATP‐ase pump (Figure 1). The NHE is normally inactive and is only upregulated in cases of severe intracellular acidosis.24 The infusion of sodium bicarbonate to patients with severe metabolic acidosis could possibly decrease the serum potassium concentration by translocation if the NHE was significantly upregulated. However, this treatment can be associated with a drop in the ionized calcium level, a worsening of the intracellular acidosis, and a decreased peripheral oxygen delivery.25 Thus, the benefits should be balanced with the potential adverse effects and, even in cases of severe metabolic acidosis with hyperkalemia, we would advise the clinician to restrictively administer sodium bicarbonate.

Figure 1

In addition, in ESRD patients, the administration of sodium bicarbonate can be problematic owing to the osmotic and volume burden it carries. It should also be avoided in patients who are volume overload or in those with decreased ability to eliminate potassium.

When treating hyperkalemic patients, hospitalists should use sodium bicarbonate to potentiate urinary elimination of potassium and should consider administering it either with acetazolamide or a loop diuretic, anticipating a lowering effect after a few hours.26 It should be avoided in patients with volume overload and anuria. Immediate translocation of potassium into cells is best achieved by insulin and ‐2 agonists.

5‐Oxoprolinuria: A Newly Recognized Cause of High Anion Gap Metabolic Acidosis

There are several causes of metabolic high anion gap acidosis in hospitalized patients. However, despite careful investigations, the cause of that disorder is not always apparent.27 Recently, 5‐oxoprolinuria (also called pyroglutamic acidosis) has become increasingly recognized as a potential etiology.2832

The metabolism of glutamate (though the ‐Glutamyl cycle) generates glutathione which provides negative feedback to the ‐Glutamyl‐cysteine synthetase enzyme. The depletion of glutathione increases 5‐oxoproline production owing to the loss of that inhibition (Figures 2 and 3). Low glutathione levels can be seen with liver disease,33 chronic alcohol intake,34 acetaminophen use,35 malnutrition,36 renal dysfunction,29 use of vigabatrim (an antiepileptic that received Food and Drug Administration [FDA] approval for use in April 2009)37 and sepsis.38 Most of the reported cases were female and had more than one risk factor.39

Figure 2

Figure 3

Typically, patients present with high anion gap acidosis (often more than 20)28 with normal acetaminophen levels and all usual tests being negative. A history of chronic acetaminophen use with or without other risk factors can frequently be found. The true independent impact of this type of acidosis on outcomes is difficult to determine as all of the reported cases had many confounding factors.

A urinary organic acid level is diagnostic and will reveal increased levels of pyroglutamic acid. Alternatively, the finding of a positive urinary anion gap (U_Na +U_K U_Cl) with a positive urinary osmolar gap (Uosm_measured‐Uosm_calculated) in the appropriate clinical setting (unexplained high anion gap acidosis with negative workup and presence of risk factors for 5‐oxoproliniuria) can point towards the diagnosis.40

A study of patients with unexplained metabolic acidosis did not find any cases of 5‐oxoprolinuria.41 Although this might suggest that the incidence of this disease is low, very few of those patients were actually taking acetaminophen (therefore had a reduced propensity for developing pyroglutamic acidosis).41 Thus, the actual incidence of 5‐oxoprolinuria is hard to determine.

Once recognized, acetaminophen should be withheld and N‐acetylcysteine (NAC) can be used to replete glutathione levels although there is no convincing evidence for this use.42 It is important for hospitalists to be aware of this disorder as it can pose a diagnostic challenge (negative usual work‐up), is easy to treat by stopping acetaminophen, and can (possibly) negatively affect outcomes.

Furosemide and Patients With Sulfa Allergy

Allergic reactions are a common occurrence with sulfa‐containing antibiotics (SCA) and reports estimates the incidence to be approximately 3% to 5%.43, 44

One misbelief is that patients who are allergic to SCAs should not receive sulfa containing diuretics or other sulfa‐containing medications.45 This leads some physicians to substitute commonly used diuretics (such as furosemide or thiazides) for ethacrynic acid. The use of ethacrynic acid has several challenges: the limited supply of the intravenous form, the discontinuation of the oral form, the increased cost, and the risk of permanent ototoxicity.

The evidence for potential allergic cross‐reactivity among medications containing the sulfa moiety has been primarily derived from Case Reports.4649

The molecular structures of sulfamethoxazole and furosemide are shown below. The allergic antigen is most often the N1 component,45 and sometimes N4 but not the sulfa moiety. Both of the incriminated antigens are not present in the furosemide structure (as well as all other sulfa containing diuretics) (Figures 4 and 5).

Figure 4

Figure 5

Experimental data showed that serum from patients allergic to SCAs did not bind to diuretics.50 In addition, clinical reports failed to demonstrate cross‐reactivity.5153 In a large clinical trial, Strom et al.53 showed that although there was a higher risk for allergic reaction to sulfa containing medications (SCM) in patients allergic to SCA (compared to those who were not), it was lower among patients with an allergy to sulfa antibiotic than among patients with a history of hypersensitivity to penicillins, suggesting this was due to a predisposition to allergic reactions in general rather than true cross‐reactivity. In another report, patients who were receiving ethacrynic acid for many years were successfully and uneventfully switched to furosemide.54

Taken together, these findings suggest that there is no evidence for withholding sulfa nonantibiotics in patients allergic to sulfa containing antibiotics.

Conclusion

Hypothyroidism, unlike myxedema, is not a cause of hyponatremia (although it can be sometimes seen in conjunction with the latter) and additional investigations should be done to determine its etiology. Sodium bicarbonate is effective for treatment of hyperkalemia by enhancing renal potassium elimination, rather than from shifting potassium into cells. The 5‐oxoprolinuria is a newly recognized cause of high anion‐gap metabolic acidosis and should be considered in patients who have taken acetaminophen. Furosemide (and sulfa containing diuretics) can be used safely in patients with an allergy to SCA.

There are many controversial topics relating to renal disease in hospitalized patients. The aim of this review is to shed light on some important and often debated issues. We will first discuss topics related to electrolytes disorder commonly seen in hospitalized patients (hyponatremia, hyperkalemia, metabolic acidosis) then the use of diuretics in patients with allergy to sulfa containing antibiotics.

Hypothyroidism and Hyponatremia

Hyponatremia is common in hospitalized patients and is associated with worse outcomes.1 It can be seen with a variety of conditions ranging from congestive heart failure to volume depletion. Careful history and physical examination are paramount and the initial work‐up usually includes serum and urine osmolality and urine sodium concentration.

For euvolemic hyponatremia, the differential diagnosis includes the syndrome of inappropriate adenine dinucleotide (ADH) secretion (SIADH), hypoadrenalism, and beer potomania. Additionally, many authorities also include hypothyroidism.

Although the simultaneous finding of hypothyroidism and hyponatremia can occur in patients as both diseases are widely prevalent in the general population, causation has yet to be convincingly demonstrated.

ADH is released in response to effective volume depletion; consequently when hypothyroidism is encountered in the setting of complete pituitary failure there is often hyponatremia.2, 3 Alternatively, with myxedema, the ability of the kidney to handle a water load and concentrate urine can be impaired.4

However, the observation that thyroid hormone administration did not raise sodium values in newborns with congenital hypothyroidism or in adults supports the absence of causal effect.5, 6And in addition, large studies done in the hospital and outpatient setting showed no differences between the serum sodium values of hypothyroid patients and that of controls.7, 8 In the study of outpatients, among those with hypothyroidism, for every increase of 10 mU/L of thyroid‐stimulating hormone (TSH), there was a drop of only 0.14 mmol/L of Na concentration.8 Thus, the elevation of TSH required for a clinically meaningful drop in sodium to occur was considerable.

Hence in patients with hyponatremia, the hospitalist should look for etiologies other than hypothyroidism and should only consider thyroid hypofunction as a culprit in cases of myxedema, or panhypopituitarism.

Sodium Bicarbonate for Hyperkalemia

Hyperkalemia is one of the most feared electrolyte disorders encountered in hospitalized patients and can lead to dire outcomes.9, 10

Potassium (K+) homeostasis is maintained in the body by 2 complimentary systems: a short‐term system that regulates K+ variation by modifying translocation across the cellular membrane and a long‐term system that adjusts overall K+ balance. The translocation system is regulated primarily by insulin and ‐2 stimulation. Overall K+ balance is mainly controlled by the kidney (90‐95%) although the gastrointestinal (GI) tract can have a more preponderant role in anephric patients.

Hyperkalemia can ensue by either a dysregulation of the translocation system (as in diabetic Ketoacidosis secondary to insulin deficiency) or impairment of K+ elimination.

Acid‐base status was previously thought to have a prominent influence on K+ concentration, based on studies that demonstrated that. However, studies looking at metabolic acidosis revealed that contrary to the effect of mineral acidosis (excess of nonmetabolizable anions)11 where there is an inverse correlation between potassium concentration and pH; organic acidosis (excess of metabolizable anions)11 was not associated with hyperkalemia.1214 However, organic acidosis can be seen simultaneously and induced by a same underlying disease (such as organ ischemia with lactic acidosis or insulin deficiency complicated by ketoacidosis). Also, when changes in pH are induced by respiratory variations or with alkalosis, the impact on serum K+ concentration is less remarkable.15 Hence, it seems that it is the nature of the acid‐base disturbance that impacts K+ concentration more than the change in pH itself.

In the kidney, the main site for regulation of K+ balance is the collecting duct. Factors that affect elimination include urinary sodium delivery, urine flow, and aldosterone.16 In order to adequately eliminate K+ these factors must be optimized in conjunction.

Treatment of hyperkalemia includes the sequential administration of agents that stabilize the cardiac membrane (calcium gluconate), shift the potassium intracellularly (insulin, ‐2 agonists), and remove the potassium (diuretics, sodium polystyrene, or dialysis).

The use of sodium bicarbonate for treatment of hyperkalemia has been long advocated.17 It was thought to act by translocation of potassium hence could be used to quickly lower K+ concentration. However, this dogma has been challenged recently.

To assess the true impact of sodium bicarbonate on potassium translocation, studies have been conducted on anephric patients with hyperkalemia. Bicarbonate infusion failed to elicit a significant rapid change in serum K+ concentration despite increase in bicarbonate concentration, arguing against a translocation mechanism.1821 After 60 minutes of treatment, neither isotonic nor hypertonic bicarbonate infusion affected Serum K+ levels in end‐stage renal disease (ESRD) patients.19, 20 On the contrary, hypertonic sodium bicarbonate increased the K+ concentration after 180 minutes of treatment,20 and it took a prolonged infusion of 4 hours to see a significant decrease in K+ concentration (0.6 mmol/L); half of which could be accounted for solely by volume administration. Moreover, this reduction was highly variable.

Rather, sodium bicarbonate seems to enhance potassium elimination by increasing sodium delivery to the distal tubule, increasing urinary pH and negative luminal charge and potentiating the action of diuretics.23 In an elegant study on normovolemic patients, the induction of bicarbonaturia practically doubled potassium excretion.23 However, such an effect is heterogeneous and usually takes place over 4 hours to 6 hours.17

At the cellular level, 2 ion exchange pumps cooperate to handle Na/K/H movement across the cellular membrane: an Na⁺/H⁺ exchanger (NHE) and the Na⁺/K⁺ ATP‐ase pump (Figure 1). The NHE is normally inactive and is only upregulated in cases of severe intracellular acidosis.24 The infusion of sodium bicarbonate to patients with severe metabolic acidosis could possibly decrease the serum potassium concentration by translocation if the NHE was significantly upregulated. However, this treatment can be associated with a drop in the ionized calcium level, a worsening of the intracellular acidosis, and a decreased peripheral oxygen delivery.25 Thus, the benefits should be balanced with the potential adverse effects and, even in cases of severe metabolic acidosis with hyperkalemia, we would advise the clinician to restrictively administer sodium bicarbonate.

Figure 1

In addition, in ESRD patients, the administration of sodium bicarbonate can be problematic owing to the osmotic and volume burden it carries. It should also be avoided in patients who are volume overload or in those with decreased ability to eliminate potassium.

When treating hyperkalemic patients, hospitalists should use sodium bicarbonate to potentiate urinary elimination of potassium and should consider administering it either with acetazolamide or a loop diuretic, anticipating a lowering effect after a few hours.26 It should be avoided in patients with volume overload and anuria. Immediate translocation of potassium into cells is best achieved by insulin and ‐2 agonists.

5‐Oxoprolinuria: A Newly Recognized Cause of High Anion Gap Metabolic Acidosis

There are several causes of metabolic high anion gap acidosis in hospitalized patients. However, despite careful investigations, the cause of that disorder is not always apparent.27 Recently, 5‐oxoprolinuria (also called pyroglutamic acidosis) has become increasingly recognized as a potential etiology.2832

The metabolism of glutamate (though the ‐Glutamyl cycle) generates glutathione which provides negative feedback to the ‐Glutamyl‐cysteine synthetase enzyme. The depletion of glutathione increases 5‐oxoproline production owing to the loss of that inhibition (Figures 2 and 3). Low glutathione levels can be seen with liver disease,33 chronic alcohol intake,34 acetaminophen use,35 malnutrition,36 renal dysfunction,29 use of vigabatrim (an antiepileptic that received Food and Drug Administration [FDA] approval for use in April 2009)37 and sepsis.38 Most of the reported cases were female and had more than one risk factor.39

Figure 2

Figure 3

Typically, patients present with high anion gap acidosis (often more than 20)28 with normal acetaminophen levels and all usual tests being negative. A history of chronic acetaminophen use with or without other risk factors can frequently be found. The true independent impact of this type of acidosis on outcomes is difficult to determine as all of the reported cases had many confounding factors.

A urinary organic acid level is diagnostic and will reveal increased levels of pyroglutamic acid. Alternatively, the finding of a positive urinary anion gap (U_Na +U_K U_Cl) with a positive urinary osmolar gap (Uosm_measured‐Uosm_calculated) in the appropriate clinical setting (unexplained high anion gap acidosis with negative workup and presence of risk factors for 5‐oxoproliniuria) can point towards the diagnosis.40

A study of patients with unexplained metabolic acidosis did not find any cases of 5‐oxoprolinuria.41 Although this might suggest that the incidence of this disease is low, very few of those patients were actually taking acetaminophen (therefore had a reduced propensity for developing pyroglutamic acidosis).41 Thus, the actual incidence of 5‐oxoprolinuria is hard to determine.

Once recognized, acetaminophen should be withheld and N‐acetylcysteine (NAC) can be used to replete glutathione levels although there is no convincing evidence for this use.42 It is important for hospitalists to be aware of this disorder as it can pose a diagnostic challenge (negative usual work‐up), is easy to treat by stopping acetaminophen, and can (possibly) negatively affect outcomes.

Furosemide and Patients With Sulfa Allergy

Allergic reactions are a common occurrence with sulfa‐containing antibiotics (SCA) and reports estimates the incidence to be approximately 3% to 5%.43, 44

One misbelief is that patients who are allergic to SCAs should not receive sulfa containing diuretics or other sulfa‐containing medications.45 This leads some physicians to substitute commonly used diuretics (such as furosemide or thiazides) for ethacrynic acid. The use of ethacrynic acid has several challenges: the limited supply of the intravenous form, the discontinuation of the oral form, the increased cost, and the risk of permanent ototoxicity.

The evidence for potential allergic cross‐reactivity among medications containing the sulfa moiety has been primarily derived from Case Reports.4649

The molecular structures of sulfamethoxazole and furosemide are shown below. The allergic antigen is most often the N1 component,45 and sometimes N4 but not the sulfa moiety. Both of the incriminated antigens are not present in the furosemide structure (as well as all other sulfa containing diuretics) (Figures 4 and 5).

Figure 4

Figure 5

Experimental data showed that serum from patients allergic to SCAs did not bind to diuretics.50 In addition, clinical reports failed to demonstrate cross‐reactivity.5153 In a large clinical trial, Strom et al.53 showed that although there was a higher risk for allergic reaction to sulfa containing medications (SCM) in patients allergic to SCA (compared to those who were not), it was lower among patients with an allergy to sulfa antibiotic than among patients with a history of hypersensitivity to penicillins, suggesting this was due to a predisposition to allergic reactions in general rather than true cross‐reactivity. In another report, patients who were receiving ethacrynic acid for many years were successfully and uneventfully switched to furosemide.54

Taken together, these findings suggest that there is no evidence for withholding sulfa nonantibiotics in patients allergic to sulfa containing antibiotics.

Conclusion

Hypothyroidism, unlike myxedema, is not a cause of hyponatremia (although it can be sometimes seen in conjunction with the latter) and additional investigations should be done to determine its etiology. Sodium bicarbonate is effective for treatment of hyperkalemia by enhancing renal potassium elimination, rather than from shifting potassium into cells. The 5‐oxoprolinuria is a newly recognized cause of high anion‐gap metabolic acidosis and should be considered in patients who have taken acetaminophen. Furosemide (and sulfa containing diuretics) can be used safely in patients with an allergy to SCA.

There are many controversial topics relating to renal disease in hospitalized patients. The aim of this review is to shed light on some important and often debated issues. We will first discuss topics related to electrolytes disorder commonly seen in hospitalized patients (hyponatremia, hyperkalemia, metabolic acidosis) then the use of diuretics in patients with allergy to sulfa containing antibiotics.

Hypothyroidism and Hyponatremia

Hyponatremia is common in hospitalized patients and is associated with worse outcomes.1 It can be seen with a variety of conditions ranging from congestive heart failure to volume depletion. Careful history and physical examination are paramount and the initial work‐up usually includes serum and urine osmolality and urine sodium concentration.

For euvolemic hyponatremia, the differential diagnosis includes the syndrome of inappropriate adenine dinucleotide (ADH) secretion (SIADH), hypoadrenalism, and beer potomania. Additionally, many authorities also include hypothyroidism.

Although the simultaneous finding of hypothyroidism and hyponatremia can occur in patients as both diseases are widely prevalent in the general population, causation has yet to be convincingly demonstrated.

ADH is released in response to effective volume depletion; consequently when hypothyroidism is encountered in the setting of complete pituitary failure there is often hyponatremia.2, 3 Alternatively, with myxedema, the ability of the kidney to handle a water load and concentrate urine can be impaired.4

However, the observation that thyroid hormone administration did not raise sodium values in newborns with congenital hypothyroidism or in adults supports the absence of causal effect.5, 6And in addition, large studies done in the hospital and outpatient setting showed no differences between the serum sodium values of hypothyroid patients and that of controls.7, 8 In the study of outpatients, among those with hypothyroidism, for every increase of 10 mU/L of thyroid‐stimulating hormone (TSH), there was a drop of only 0.14 mmol/L of Na concentration.8 Thus, the elevation of TSH required for a clinically meaningful drop in sodium to occur was considerable.

Hence in patients with hyponatremia, the hospitalist should look for etiologies other than hypothyroidism and should only consider thyroid hypofunction as a culprit in cases of myxedema, or panhypopituitarism.

Sodium Bicarbonate for Hyperkalemia

Hyperkalemia is one of the most feared electrolyte disorders encountered in hospitalized patients and can lead to dire outcomes.9, 10

Potassium (K+) homeostasis is maintained in the body by 2 complimentary systems: a short‐term system that regulates K+ variation by modifying translocation across the cellular membrane and a long‐term system that adjusts overall K+ balance. The translocation system is regulated primarily by insulin and ‐2 stimulation. Overall K+ balance is mainly controlled by the kidney (90‐95%) although the gastrointestinal (GI) tract can have a more preponderant role in anephric patients.

Hyperkalemia can ensue by either a dysregulation of the translocation system (as in diabetic Ketoacidosis secondary to insulin deficiency) or impairment of K+ elimination.

Acid‐base status was previously thought to have a prominent influence on K+ concentration, based on studies that demonstrated that. However, studies looking at metabolic acidosis revealed that contrary to the effect of mineral acidosis (excess of nonmetabolizable anions)11 where there is an inverse correlation between potassium concentration and pH; organic acidosis (excess of metabolizable anions)11 was not associated with hyperkalemia.1214 However, organic acidosis can be seen simultaneously and induced by a same underlying disease (such as organ ischemia with lactic acidosis or insulin deficiency complicated by ketoacidosis). Also, when changes in pH are induced by respiratory variations or with alkalosis, the impact on serum K+ concentration is less remarkable.15 Hence, it seems that it is the nature of the acid‐base disturbance that impacts K+ concentration more than the change in pH itself.

In the kidney, the main site for regulation of K+ balance is the collecting duct. Factors that affect elimination include urinary sodium delivery, urine flow, and aldosterone.16 In order to adequately eliminate K+ these factors must be optimized in conjunction.

Treatment of hyperkalemia includes the sequential administration of agents that stabilize the cardiac membrane (calcium gluconate), shift the potassium intracellularly (insulin, ‐2 agonists), and remove the potassium (diuretics, sodium polystyrene, or dialysis).

The use of sodium bicarbonate for treatment of hyperkalemia has been long advocated.17 It was thought to act by translocation of potassium hence could be used to quickly lower K+ concentration. However, this dogma has been challenged recently.

To assess the true impact of sodium bicarbonate on potassium translocation, studies have been conducted on anephric patients with hyperkalemia. Bicarbonate infusion failed to elicit a significant rapid change in serum K+ concentration despite increase in bicarbonate concentration, arguing against a translocation mechanism.1821 After 60 minutes of treatment, neither isotonic nor hypertonic bicarbonate infusion affected Serum K+ levels in end‐stage renal disease (ESRD) patients.19, 20 On the contrary, hypertonic sodium bicarbonate increased the K+ concentration after 180 minutes of treatment,20 and it took a prolonged infusion of 4 hours to see a significant decrease in K+ concentration (0.6 mmol/L); half of which could be accounted for solely by volume administration. Moreover, this reduction was highly variable.

Rather, sodium bicarbonate seems to enhance potassium elimination by increasing sodium delivery to the distal tubule, increasing urinary pH and negative luminal charge and potentiating the action of diuretics.23 In an elegant study on normovolemic patients, the induction of bicarbonaturia practically doubled potassium excretion.23 However, such an effect is heterogeneous and usually takes place over 4 hours to 6 hours.17

At the cellular level, 2 ion exchange pumps cooperate to handle Na/K/H movement across the cellular membrane: an Na⁺/H⁺ exchanger (NHE) and the Na⁺/K⁺ ATP‐ase pump (Figure 1). The NHE is normally inactive and is only upregulated in cases of severe intracellular acidosis.24 The infusion of sodium bicarbonate to patients with severe metabolic acidosis could possibly decrease the serum potassium concentration by translocation if the NHE was significantly upregulated. However, this treatment can be associated with a drop in the ionized calcium level, a worsening of the intracellular acidosis, and a decreased peripheral oxygen delivery.25 Thus, the benefits should be balanced with the potential adverse effects and, even in cases of severe metabolic acidosis with hyperkalemia, we would advise the clinician to restrictively administer sodium bicarbonate.

Figure 1

In addition, in ESRD patients, the administration of sodium bicarbonate can be problematic owing to the osmotic and volume burden it carries. It should also be avoided in patients who are volume overload or in those with decreased ability to eliminate potassium.

When treating hyperkalemic patients, hospitalists should use sodium bicarbonate to potentiate urinary elimination of potassium and should consider administering it either with acetazolamide or a loop diuretic, anticipating a lowering effect after a few hours.26 It should be avoided in patients with volume overload and anuria. Immediate translocation of potassium into cells is best achieved by insulin and ‐2 agonists.

5‐Oxoprolinuria: A Newly Recognized Cause of High Anion Gap Metabolic Acidosis

There are several causes of metabolic high anion gap acidosis in hospitalized patients. However, despite careful investigations, the cause of that disorder is not always apparent.27 Recently, 5‐oxoprolinuria (also called pyroglutamic acidosis) has become increasingly recognized as a potential etiology.2832

The metabolism of glutamate (though the ‐Glutamyl cycle) generates glutathione which provides negative feedback to the ‐Glutamyl‐cysteine synthetase enzyme. The depletion of glutathione increases 5‐oxoproline production owing to the loss of that inhibition (Figures 2 and 3). Low glutathione levels can be seen with liver disease,33 chronic alcohol intake,34 acetaminophen use,35 malnutrition,36 renal dysfunction,29 use of vigabatrim (an antiepileptic that received Food and Drug Administration [FDA] approval for use in April 2009)37 and sepsis.38 Most of the reported cases were female and had more than one risk factor.39

Figure 2

Figure 3

Typically, patients present with high anion gap acidosis (often more than 20)28 with normal acetaminophen levels and all usual tests being negative. A history of chronic acetaminophen use with or without other risk factors can frequently be found. The true independent impact of this type of acidosis on outcomes is difficult to determine as all of the reported cases had many confounding factors.

A urinary organic acid level is diagnostic and will reveal increased levels of pyroglutamic acid. Alternatively, the finding of a positive urinary anion gap (U_Na +U_K U_Cl) with a positive urinary osmolar gap (Uosm_measured‐Uosm_calculated) in the appropriate clinical setting (unexplained high anion gap acidosis with negative workup and presence of risk factors for 5‐oxoproliniuria) can point towards the diagnosis.40

A study of patients with unexplained metabolic acidosis did not find any cases of 5‐oxoprolinuria.41 Although this might suggest that the incidence of this disease is low, very few of those patients were actually taking acetaminophen (therefore had a reduced propensity for developing pyroglutamic acidosis).41 Thus, the actual incidence of 5‐oxoprolinuria is hard to determine.

Once recognized, acetaminophen should be withheld and N‐acetylcysteine (NAC) can be used to replete glutathione levels although there is no convincing evidence for this use.42 It is important for hospitalists to be aware of this disorder as it can pose a diagnostic challenge (negative usual work‐up), is easy to treat by stopping acetaminophen, and can (possibly) negatively affect outcomes.

Furosemide and Patients With Sulfa Allergy

Allergic reactions are a common occurrence with sulfa‐containing antibiotics (SCA) and reports estimates the incidence to be approximately 3% to 5%.43, 44

One misbelief is that patients who are allergic to SCAs should not receive sulfa containing diuretics or other sulfa‐containing medications.45 This leads some physicians to substitute commonly used diuretics (such as furosemide or thiazides) for ethacrynic acid. The use of ethacrynic acid has several challenges: the limited supply of the intravenous form, the discontinuation of the oral form, the increased cost, and the risk of permanent ototoxicity.

The evidence for potential allergic cross‐reactivity among medications containing the sulfa moiety has been primarily derived from Case Reports.4649

The molecular structures of sulfamethoxazole and furosemide are shown below. The allergic antigen is most often the N1 component,45 and sometimes N4 but not the sulfa moiety. Both of the incriminated antigens are not present in the furosemide structure (as well as all other sulfa containing diuretics) (Figures 4 and 5).

Figure 4

Figure 5

Experimental data showed that serum from patients allergic to SCAs did not bind to diuretics.50 In addition, clinical reports failed to demonstrate cross‐reactivity.5153 In a large clinical trial, Strom et al.53 showed that although there was a higher risk for allergic reaction to sulfa containing medications (SCM) in patients allergic to SCA (compared to those who were not), it was lower among patients with an allergy to sulfa antibiotic than among patients with a history of hypersensitivity to penicillins, suggesting this was due to a predisposition to allergic reactions in general rather than true cross‐reactivity. In another report, patients who were receiving ethacrynic acid for many years were successfully and uneventfully switched to furosemide.54

Taken together, these findings suggest that there is no evidence for withholding sulfa nonantibiotics in patients allergic to sulfa containing antibiotics.

Conclusion

Hypothyroidism, unlike myxedema, is not a cause of hyponatremia (although it can be sometimes seen in conjunction with the latter) and additional investigations should be done to determine its etiology. Sodium bicarbonate is effective for treatment of hyperkalemia by enhancing renal potassium elimination, rather than from shifting potassium into cells. The 5‐oxoprolinuria is a newly recognized cause of high anion‐gap metabolic acidosis and should be considered in patients who have taken acetaminophen. Furosemide (and sulfa containing diuretics) can be used safely in patients with an allergy to SCA.

Lactic acidosis (LA) is common in hospitalized patients and is associated with a high mortality.1, 2 Commonly, it is defined as a lactic acid concentration greater than 5 mmol/L with a pH less than 7.35.3 There are no evidence‐based guidelines for the treatment of LA despite progress in our understanding of its pathophysiology.36 This is not surprising, given the uncertainty regarding the impact of LA itself on clinical outcomes. In this regard, it is interesting to note that, despite its well‐recognized role as a marker of tissue hypoxia, lactate accumulation appears to have beneficial effects and may function as an adaptive mechanism. This raises the possibility that therapy directed at altering this adaptation may be detrimental. Pursuing correction of the pH in LA has been shown to have untoward physiologic effects. These and other ambiguities in the pathophysiology and treatment of LA are the focus of this review.

Lactate Metabolism

The body produces approximately 1400 mmol of lactate daily.7 Lactate is derived from the metabolism of pyruvate through an anaerobic reaction that occurs in all tissues (Figure 1). The liver is the primary site of lactate clearance and can metabolize up to 100 mmol per hour under normal conditions.8 There, lactate is converted to glucose to serve as an energy source during periods of hypoxia (Figure 2).9

Figure 1

Figure 2

Approximately 20% to 30% of the daily lactate load is metabolized by the kidneys.10, 11 Renal clearance is increased in acidosis12 and is maintained even in the presence of low renal perfusion.10, 12, 13 Renal lactate clearance is primarily through metabolism and not excretion.10, 14

LA Subtypes

Generally, lactic acid accumulation results from excess lactic acid production and not from reduced clearance.15 In cases of fulminant liver failure, it is due to a combination of decreased clearance and tissue hypoxia.16 In the setting of tissue hypoxia, an impairment of mitochondrial oxidative capacity results in the accumulation of pyruvate and generation of lactate. Lactic acid accumulation through this mechanism has historically been described as Type A LA.7 Hence, in critically ill patients lactate has traditionally been viewed as a marker of tissue hypoxia.15, 1721 Hyperlactatemia without tissue hypoxia has been referred to as type B LA. This is seen in a variety of circumstances. In sepsis, for example, several studies have shown lactic acid accumulation, despite adequate oxygen delivery.2224

Hyperlactatemia may also occur in cases of pure mitochondrial dysfunction, which can be induced by commonly prescribed medications such as the biguanides, nucleoside analog reverse‐transcriptase inhibitors (NRTIs), and linezolid.2527 Alternatively, lactate generation from metabolism of agents such as propylene glycol is possible. Finally, excessive lactate generation may occur following stress due to altered carbohydrate metabolism, or with respiratory alkalosis.2831

Lactate: A Metabolic Adaptation

Lactate was traditionally considered only as a marker of tissue hypoxia and anaerobic metabolism.17 This is certainly the case in situations of poor perfusion such as cardiogenic,15, 18 vasopressor‐resistant,19 or hypovolemic shock.20, 21

Alternative explanations for lactic acid accumulation, without tissue hypoperfusion, include catecholamine‐induced alterations in glycolysis,32, 33 mitochondrial disturbances,3436 and increased pyruvate production combined with increased glucose entry into cells.24, 37 In addition, the activity of an enzyme regulating lactate metabolism, pyruvate dehydrogenase kinase, increases in sepsis.38 This enzyme inactivates the pyruvate dehydrogenase (PDH) complex, which metabolizes pyruvate. Pyruvate and lactate may accumulate as a result. These changes partly explain the generation of LA in sepsis, independent of any effect of diminished tissue perfusion.

Recognizing the body's tendency toward homeostasis, it is appealing to speculate that lactate accumulation is adaptive.9 A number of findings support this. For example, lactate may act to shuttle energy between organs, or between cell types in the same organ. The astrocyteneuron lactate shuttle and the spermatogenic lactate shuttle are 2 examples of lactate's valuable effects on cellular metabolism.39 In the astrocyteneuron lactate shuttle, astrocytes support the increased metabolic demands of neurons through lactic acid production.40 Specifically, the neurotransmitter glutamate is released by the neurons and taken up by the astrocytes. Astrocytes produce lactate, which then moves back to the neuron to be used as an energy source. Glutamine, also released by the astrocytes, leads to the regeneration of glutamate and the potential to restart the cycle.39

Animal and human studies have suggested that, in periods of stress, lactate is the preferential energy substrate in the brain.4144 The usefulness of increased lactate production routinely seen in sepsis may thus represent multiple adaptive processes aimed primarily at improving the delivery of energy substrates. Thus, therapeutic strategies aimed specifically at lowering lactic acid levels may prove to have deleterious effects on cellular metabolism.

Impact of LA on Morbidity and Mortality

The poor prognosis in patients with LA is well recognized.2, 4548 For example, in a study of 126 patients with various causes of LA, the median survival was 38.5 hours and 30‐day survival was 17%.2

Studies have revealed that LA with low pH is associated with adverse effects on the cardiovascular system, particularly a decrease in cardiac contractility.49, 50 This effect is particularly prominent with a pH below 7.20. In contrast, acidosis in animal models has been shown to limit myocardial infarct size after reperfusion.51, 52 Variable effects of LA on cell death have been found. A worsening of apoptosis in myocytes has been noted;53 alternatively, protection from hypoxic injury in hepatocytes and myocardium has been observed.52, 54 Thus, although LA is associated with poor outcomes in human studies,2, 4547 it is still unclear to what extent lactic acid accumulation is a marker of severe illness, an independent effector of pathology, or a mechanism with the potential to serve a protective role.

Available data indicate that lactate itself is not harmful. Studies on infusion of lactate solutions to postoperative patients was shown to be safe.55 Also, the fact that lactate generation in states of respiratory alkalosis, stress, or altered carbohydrate metabolism without sepsis is not associated with worse outcomes supports the fact that lactic acid alone may not be maladaptive.2831

Similarly, low pH is not necessarily maladaptive. In the postictal state,56 diabetic ketoacidosis,57 spontaneous respiratory acidosis,58 or permissive hypercapnia,59 low blood pH is not deleterious.

In summary, LA is associated with poor outcomes, and indirect evidence suggests that it is the underlying causative condition rather than the low pH or the lactate that is responsible for the dire outcomes.

Treatment of LA with Sodium Bicarbonate

Since excessive lactic acid generation is accompanied by consumption of plasma bicarbonate and a fall in plasma pH, sodium bicarbonate has been long proposed as a treatment for LA. While theoretically appealing, this strategy has not been validated by studies in animals or humans. Indeed, bicarbonate administration in LA often has been shown to be detrimental.60, 61 The adverse effects of bicarbonate administration in LA, while initially paradoxical, have a number of possible explanations.

First, bicarbonate administration can induce a reduction in intracellular pH.60, 62, 63 The mechanism involves bicarbonate's effect to increase carbon dioxide (CO₂) generation through mass action effect. Because the cell membrane is more permeable to CO₂ than to bicarbonate, intracellular pH falls.64, 65 In sepsis, this intracellular/extracellular pH discrepancy may be more pronounced due to alterations in blood flow.66 Other reports on outcomes of intracellular pH with bicarbonate therapy show variable effects.6772

Second, to the extent that bicarbonate administration raises extracellular pH, it is associated with a reduction in ionized calcium concentration, since the binding of calcium to albumin is pH dependent.73 A sodium bicarbonate load administered to patients with LA was associated with a significant fall in ionized calcium concentration, whereas a sodium chloride load was not.1 This can affect cardiac function, as the latter varies proportionally with calcium levels.74

Third, bicarbonate administration may reduce tissue oxygen delivery since the affinity of hemoglobin for oxygen increases as pH rises (Bohr effect).75 The administration of bicarbonate worsened systemic oxygen consumption in one study76 and decreased oxygen delivery in another.75

Fourth, bicarbonate administration may indirectly increase intracellular calcium concentration. Low intracellular pH (see above) stimulates proton efflux by way of proton transporters and exchangers, increasing intracellular sodium content.77 A high cell sodium content then may increase intracellular calcium, through the Na/Ca exchanger, impairing cellular function.7779 Compounding this, the reduced function of the Na/H ATPase as a regulator of intracellular sodium in sepsis may not be adequate to limit cell swelling.77

Against this background of mechanistic concerns with the use of bicarbonate treatment, it is not surprising that clinical outcomes have been inconsistent at best. In animal models of LA, the use of sodium bicarbonate has either negative effects on cardiac output60, 72 or no significant hemodynamic effect when compared to sodium chloride infusion.67, 80, 81 One animal study did show some benefit with sodium bicarbonate compared to saline, though all animals subsequently died.50

In humans, sodium bicarbonate was studied in 2 randomized trials of sepsis‐induced LA.1, 82 In a study by Cooper et al.,1 14 critically‐ill patients received sequential infusions of sodium bicarbonate or sodium chloride. Neither solution was superior to the other in terms of hemodynamic improvement. No benefit was noted even when analysis was limited to those with very low pH (<7.2). Mathieu et al.82 randomized 10 critically‐ill patients to sequential infusion of either sodium bicarbonate or sodium chloride. Similarly, no significant difference in hemodynamic variables was noted.

When taken together, these studies evaluating sodium bicarbonate in LA fail to show convincing benefit and raise serious questions about its detrimental effects. Extracellular pH may be a misleading marker of success in the treatment of LA, given its direct influence by sodium bicarbonate administration.

Treatment of LA and Use of Other Buffers

Other buffers (Carbicarb, dichloroacetate, and tromethamine [THAM]) have been studied for treatment of LA. Human studies have not shown superiority of any of the buffers as far as improving pH,83, 84 hemodynamics, or survival.85

Treatment of LA by Renal Replacement Therapy

Renal replacement therapy (RRT; dialysis and its variants) has been studied for the treatment of severe acidosis. RRT has a number of theoretical advantages over purely medical therapies in the treatment of LA: it can deliver large quantities of base without contributing to volume overload; it can directly remove lactate from the plasma; and it can mitigate the effect of alkalinization on ionized calcium concentration by delivering calcium.

In critically ill patients with intact liver function, continuous venovenous hemofiltration (CVVH) appears to contribute very little (less then 3%) to overall lactate clearance.86 While outcome studies are limited, continuous dialysis modalities consistently show improved resolution of acidosis of various types when compared to intermittent modalities.87, 88 As described above, this is related to base administration and is not a surprising finding. There are no studies comparing RRT and medical therapy with respect to clinical outcomes in patients with LA.

Special Situations

Conclusions

Many studies note the association between LA and adverse outcomes.2, 4547 Though metabolic acidosis from elevated lactate levels may negatively affect organ function, the evidence supporting therapy specifically aimed at increasing pH in these settings is consistently poor.3, 127 Limitations have included small numbers of subjects,1, 82 variable outcomes studied, and the inability to assess intracellular metabolic stability.1, 61 When taking these factors into account it is hard to justify aggressive treatment of LA with mechanisms aimed at raising pH. Literature on the treatment of patients with LA and very low pH (below 7.2) is even more limited.

Moreover, lactate elevations may not represent tissue hypoperfusion. Lactate may have an important role in improving energy metabolism. This represents 1 additional reason to be hesitant when attempting to normalize pH in LA; we may be disrupting the body's physiologic response to sepsis. A conflict for clinicians emerges, however, as lactate is often used to define tissue ischemia. Obviously, more specific markers of tissue hypoperfusion would be ideal.

Bicarbonate therapy is an understandably attractive means to improve the acidemia, but there are serious mechanistic concerns with it use. Moreover, neither animal nor human studies, limited as they may be, show a convincing benefit. LA in the setting of acute kidney injury may be best treated with renal replacement therapy with bicarbonate‐based buffers, but controlled trials are lacking.

A number of commonly used drugs can cause LA. A heightened awareness on the part of clinicians will lead to prompt recognition of these cases, and timely treatment.

Lactic acidosis (LA) is common in hospitalized patients and is associated with a high mortality.1, 2 Commonly, it is defined as a lactic acid concentration greater than 5 mmol/L with a pH less than 7.35.3 There are no evidence‐based guidelines for the treatment of LA despite progress in our understanding of its pathophysiology.36 This is not surprising, given the uncertainty regarding the impact of LA itself on clinical outcomes. In this regard, it is interesting to note that, despite its well‐recognized role as a marker of tissue hypoxia, lactate accumulation appears to have beneficial effects and may function as an adaptive mechanism. This raises the possibility that therapy directed at altering this adaptation may be detrimental. Pursuing correction of the pH in LA has been shown to have untoward physiologic effects. These and other ambiguities in the pathophysiology and treatment of LA are the focus of this review.

Lactate Metabolism

The body produces approximately 1400 mmol of lactate daily.7 Lactate is derived from the metabolism of pyruvate through an anaerobic reaction that occurs in all tissues (Figure 1). The liver is the primary site of lactate clearance and can metabolize up to 100 mmol per hour under normal conditions.8 There, lactate is converted to glucose to serve as an energy source during periods of hypoxia (Figure 2).9

Figure 1

Figure 2

Approximately 20% to 30% of the daily lactate load is metabolized by the kidneys.10, 11 Renal clearance is increased in acidosis12 and is maintained even in the presence of low renal perfusion.10, 12, 13 Renal lactate clearance is primarily through metabolism and not excretion.10, 14

LA Subtypes

Generally, lactic acid accumulation results from excess lactic acid production and not from reduced clearance.15 In cases of fulminant liver failure, it is due to a combination of decreased clearance and tissue hypoxia.16 In the setting of tissue hypoxia, an impairment of mitochondrial oxidative capacity results in the accumulation of pyruvate and generation of lactate. Lactic acid accumulation through this mechanism has historically been described as Type A LA.7 Hence, in critically ill patients lactate has traditionally been viewed as a marker of tissue hypoxia.15, 1721 Hyperlactatemia without tissue hypoxia has been referred to as type B LA. This is seen in a variety of circumstances. In sepsis, for example, several studies have shown lactic acid accumulation, despite adequate oxygen delivery.2224

Hyperlactatemia may also occur in cases of pure mitochondrial dysfunction, which can be induced by commonly prescribed medications such as the biguanides, nucleoside analog reverse‐transcriptase inhibitors (NRTIs), and linezolid.2527 Alternatively, lactate generation from metabolism of agents such as propylene glycol is possible. Finally, excessive lactate generation may occur following stress due to altered carbohydrate metabolism, or with respiratory alkalosis.2831

Lactate: A Metabolic Adaptation

Lactate was traditionally considered only as a marker of tissue hypoxia and anaerobic metabolism.17 This is certainly the case in situations of poor perfusion such as cardiogenic,15, 18 vasopressor‐resistant,19 or hypovolemic shock.20, 21

Alternative explanations for lactic acid accumulation, without tissue hypoperfusion, include catecholamine‐induced alterations in glycolysis,32, 33 mitochondrial disturbances,3436 and increased pyruvate production combined with increased glucose entry into cells.24, 37 In addition, the activity of an enzyme regulating lactate metabolism, pyruvate dehydrogenase kinase, increases in sepsis.38 This enzyme inactivates the pyruvate dehydrogenase (PDH) complex, which metabolizes pyruvate. Pyruvate and lactate may accumulate as a result. These changes partly explain the generation of LA in sepsis, independent of any effect of diminished tissue perfusion.

Recognizing the body's tendency toward homeostasis, it is appealing to speculate that lactate accumulation is adaptive.9 A number of findings support this. For example, lactate may act to shuttle energy between organs, or between cell types in the same organ. The astrocyteneuron lactate shuttle and the spermatogenic lactate shuttle are 2 examples of lactate's valuable effects on cellular metabolism.39 In the astrocyteneuron lactate shuttle, astrocytes support the increased metabolic demands of neurons through lactic acid production.40 Specifically, the neurotransmitter glutamate is released by the neurons and taken up by the astrocytes. Astrocytes produce lactate, which then moves back to the neuron to be used as an energy source. Glutamine, also released by the astrocytes, leads to the regeneration of glutamate and the potential to restart the cycle.39

Animal and human studies have suggested that, in periods of stress, lactate is the preferential energy substrate in the brain.4144 The usefulness of increased lactate production routinely seen in sepsis may thus represent multiple adaptive processes aimed primarily at improving the delivery of energy substrates. Thus, therapeutic strategies aimed specifically at lowering lactic acid levels may prove to have deleterious effects on cellular metabolism.

Impact of LA on Morbidity and Mortality

The poor prognosis in patients with LA is well recognized.2, 4548 For example, in a study of 126 patients with various causes of LA, the median survival was 38.5 hours and 30‐day survival was 17%.2

Studies have revealed that LA with low pH is associated with adverse effects on the cardiovascular system, particularly a decrease in cardiac contractility.49, 50 This effect is particularly prominent with a pH below 7.20. In contrast, acidosis in animal models has been shown to limit myocardial infarct size after reperfusion.51, 52 Variable effects of LA on cell death have been found. A worsening of apoptosis in myocytes has been noted;53 alternatively, protection from hypoxic injury in hepatocytes and myocardium has been observed.52, 54 Thus, although LA is associated with poor outcomes in human studies,2, 4547 it is still unclear to what extent lactic acid accumulation is a marker of severe illness, an independent effector of pathology, or a mechanism with the potential to serve a protective role.

Available data indicate that lactate itself is not harmful. Studies on infusion of lactate solutions to postoperative patients was shown to be safe.55 Also, the fact that lactate generation in states of respiratory alkalosis, stress, or altered carbohydrate metabolism without sepsis is not associated with worse outcomes supports the fact that lactic acid alone may not be maladaptive.2831

Similarly, low pH is not necessarily maladaptive. In the postictal state,56 diabetic ketoacidosis,57 spontaneous respiratory acidosis,58 or permissive hypercapnia,59 low blood pH is not deleterious.

In summary, LA is associated with poor outcomes, and indirect evidence suggests that it is the underlying causative condition rather than the low pH or the lactate that is responsible for the dire outcomes.

Treatment of LA with Sodium Bicarbonate

Since excessive lactic acid generation is accompanied by consumption of plasma bicarbonate and a fall in plasma pH, sodium bicarbonate has been long proposed as a treatment for LA. While theoretically appealing, this strategy has not been validated by studies in animals or humans. Indeed, bicarbonate administration in LA often has been shown to be detrimental.60, 61 The adverse effects of bicarbonate administration in LA, while initially paradoxical, have a number of possible explanations.

First, bicarbonate administration can induce a reduction in intracellular pH.60, 62, 63 The mechanism involves bicarbonate's effect to increase carbon dioxide (CO₂) generation through mass action effect. Because the cell membrane is more permeable to CO₂ than to bicarbonate, intracellular pH falls.64, 65 In sepsis, this intracellular/extracellular pH discrepancy may be more pronounced due to alterations in blood flow.66 Other reports on outcomes of intracellular pH with bicarbonate therapy show variable effects.6772

Second, to the extent that bicarbonate administration raises extracellular pH, it is associated with a reduction in ionized calcium concentration, since the binding of calcium to albumin is pH dependent.73 A sodium bicarbonate load administered to patients with LA was associated with a significant fall in ionized calcium concentration, whereas a sodium chloride load was not.1 This can affect cardiac function, as the latter varies proportionally with calcium levels.74

Third, bicarbonate administration may reduce tissue oxygen delivery since the affinity of hemoglobin for oxygen increases as pH rises (Bohr effect).75 The administration of bicarbonate worsened systemic oxygen consumption in one study76 and decreased oxygen delivery in another.75

Fourth, bicarbonate administration may indirectly increase intracellular calcium concentration. Low intracellular pH (see above) stimulates proton efflux by way of proton transporters and exchangers, increasing intracellular sodium content.77 A high cell sodium content then may increase intracellular calcium, through the Na/Ca exchanger, impairing cellular function.7779 Compounding this, the reduced function of the Na/H ATPase as a regulator of intracellular sodium in sepsis may not be adequate to limit cell swelling.77

Against this background of mechanistic concerns with the use of bicarbonate treatment, it is not surprising that clinical outcomes have been inconsistent at best. In animal models of LA, the use of sodium bicarbonate has either negative effects on cardiac output60, 72 or no significant hemodynamic effect when compared to sodium chloride infusion.67, 80, 81 One animal study did show some benefit with sodium bicarbonate compared to saline, though all animals subsequently died.50

In humans, sodium bicarbonate was studied in 2 randomized trials of sepsis‐induced LA.1, 82 In a study by Cooper et al.,1 14 critically‐ill patients received sequential infusions of sodium bicarbonate or sodium chloride. Neither solution was superior to the other in terms of hemodynamic improvement. No benefit was noted even when analysis was limited to those with very low pH (<7.2). Mathieu et al.82 randomized 10 critically‐ill patients to sequential infusion of either sodium bicarbonate or sodium chloride. Similarly, no significant difference in hemodynamic variables was noted.

When taken together, these studies evaluating sodium bicarbonate in LA fail to show convincing benefit and raise serious questions about its detrimental effects. Extracellular pH may be a misleading marker of success in the treatment of LA, given its direct influence by sodium bicarbonate administration.

Treatment of LA and Use of Other Buffers

Other buffers (Carbicarb, dichloroacetate, and tromethamine [THAM]) have been studied for treatment of LA. Human studies have not shown superiority of any of the buffers as far as improving pH,83, 84 hemodynamics, or survival.85

Treatment of LA by Renal Replacement Therapy

Renal replacement therapy (RRT; dialysis and its variants) has been studied for the treatment of severe acidosis. RRT has a number of theoretical advantages over purely medical therapies in the treatment of LA: it can deliver large quantities of base without contributing to volume overload; it can directly remove lactate from the plasma; and it can mitigate the effect of alkalinization on ionized calcium concentration by delivering calcium.

In critically ill patients with intact liver function, continuous venovenous hemofiltration (CVVH) appears to contribute very little (less then 3%) to overall lactate clearance.86 While outcome studies are limited, continuous dialysis modalities consistently show improved resolution of acidosis of various types when compared to intermittent modalities.87, 88 As described above, this is related to base administration and is not a surprising finding. There are no studies comparing RRT and medical therapy with respect to clinical outcomes in patients with LA.

Special Situations

Conclusions

Many studies note the association between LA and adverse outcomes.2, 4547 Though metabolic acidosis from elevated lactate levels may negatively affect organ function, the evidence supporting therapy specifically aimed at increasing pH in these settings is consistently poor.3, 127 Limitations have included small numbers of subjects,1, 82 variable outcomes studied, and the inability to assess intracellular metabolic stability.1, 61 When taking these factors into account it is hard to justify aggressive treatment of LA with mechanisms aimed at raising pH. Literature on the treatment of patients with LA and very low pH (below 7.2) is even more limited.

Moreover, lactate elevations may not represent tissue hypoperfusion. Lactate may have an important role in improving energy metabolism. This represents 1 additional reason to be hesitant when attempting to normalize pH in LA; we may be disrupting the body's physiologic response to sepsis. A conflict for clinicians emerges, however, as lactate is often used to define tissue ischemia. Obviously, more specific markers of tissue hypoperfusion would be ideal.

Bicarbonate therapy is an understandably attractive means to improve the acidemia, but there are serious mechanistic concerns with it use. Moreover, neither animal nor human studies, limited as they may be, show a convincing benefit. LA in the setting of acute kidney injury may be best treated with renal replacement therapy with bicarbonate‐based buffers, but controlled trials are lacking.

A number of commonly used drugs can cause LA. A heightened awareness on the part of clinicians will lead to prompt recognition of these cases, and timely treatment.

Lactic acidosis (LA) is common in hospitalized patients and is associated with a high mortality.1, 2 Commonly, it is defined as a lactic acid concentration greater than 5 mmol/L with a pH less than 7.35.3 There are no evidence‐based guidelines for the treatment of LA despite progress in our understanding of its pathophysiology.36 This is not surprising, given the uncertainty regarding the impact of LA itself on clinical outcomes. In this regard, it is interesting to note that, despite its well‐recognized role as a marker of tissue hypoxia, lactate accumulation appears to have beneficial effects and may function as an adaptive mechanism. This raises the possibility that therapy directed at altering this adaptation may be detrimental. Pursuing correction of the pH in LA has been shown to have untoward physiologic effects. These and other ambiguities in the pathophysiology and treatment of LA are the focus of this review.

Lactate Metabolism

The body produces approximately 1400 mmol of lactate daily.7 Lactate is derived from the metabolism of pyruvate through an anaerobic reaction that occurs in all tissues (Figure 1). The liver is the primary site of lactate clearance and can metabolize up to 100 mmol per hour under normal conditions.8 There, lactate is converted to glucose to serve as an energy source during periods of hypoxia (Figure 2).9

Figure 1

Figure 2

Approximately 20% to 30% of the daily lactate load is metabolized by the kidneys.10, 11 Renal clearance is increased in acidosis12 and is maintained even in the presence of low renal perfusion.10, 12, 13 Renal lactate clearance is primarily through metabolism and not excretion.10, 14

LA Subtypes

Generally, lactic acid accumulation results from excess lactic acid production and not from reduced clearance.15 In cases of fulminant liver failure, it is due to a combination of decreased clearance and tissue hypoxia.16 In the setting of tissue hypoxia, an impairment of mitochondrial oxidative capacity results in the accumulation of pyruvate and generation of lactate. Lactic acid accumulation through this mechanism has historically been described as Type A LA.7 Hence, in critically ill patients lactate has traditionally been viewed as a marker of tissue hypoxia.15, 1721 Hyperlactatemia without tissue hypoxia has been referred to as type B LA. This is seen in a variety of circumstances. In sepsis, for example, several studies have shown lactic acid accumulation, despite adequate oxygen delivery.2224

Hyperlactatemia may also occur in cases of pure mitochondrial dysfunction, which can be induced by commonly prescribed medications such as the biguanides, nucleoside analog reverse‐transcriptase inhibitors (NRTIs), and linezolid.2527 Alternatively, lactate generation from metabolism of agents such as propylene glycol is possible. Finally, excessive lactate generation may occur following stress due to altered carbohydrate metabolism, or with respiratory alkalosis.2831

Lactate: A Metabolic Adaptation

Lactate was traditionally considered only as a marker of tissue hypoxia and anaerobic metabolism.17 This is certainly the case in situations of poor perfusion such as cardiogenic,15, 18 vasopressor‐resistant,19 or hypovolemic shock.20, 21

Alternative explanations for lactic acid accumulation, without tissue hypoperfusion, include catecholamine‐induced alterations in glycolysis,32, 33 mitochondrial disturbances,3436 and increased pyruvate production combined with increased glucose entry into cells.24, 37 In addition, the activity of an enzyme regulating lactate metabolism, pyruvate dehydrogenase kinase, increases in sepsis.38 This enzyme inactivates the pyruvate dehydrogenase (PDH) complex, which metabolizes pyruvate. Pyruvate and lactate may accumulate as a result. These changes partly explain the generation of LA in sepsis, independent of any effect of diminished tissue perfusion.

Recognizing the body's tendency toward homeostasis, it is appealing to speculate that lactate accumulation is adaptive.9 A number of findings support this. For example, lactate may act to shuttle energy between organs, or between cell types in the same organ. The astrocyteneuron lactate shuttle and the spermatogenic lactate shuttle are 2 examples of lactate's valuable effects on cellular metabolism.39 In the astrocyteneuron lactate shuttle, astrocytes support the increased metabolic demands of neurons through lactic acid production.40 Specifically, the neurotransmitter glutamate is released by the neurons and taken up by the astrocytes. Astrocytes produce lactate, which then moves back to the neuron to be used as an energy source. Glutamine, also released by the astrocytes, leads to the regeneration of glutamate and the potential to restart the cycle.39

Animal and human studies have suggested that, in periods of stress, lactate is the preferential energy substrate in the brain.4144 The usefulness of increased lactate production routinely seen in sepsis may thus represent multiple adaptive processes aimed primarily at improving the delivery of energy substrates. Thus, therapeutic strategies aimed specifically at lowering lactic acid levels may prove to have deleterious effects on cellular metabolism.

Impact of LA on Morbidity and Mortality

The poor prognosis in patients with LA is well recognized.2, 4548 For example, in a study of 126 patients with various causes of LA, the median survival was 38.5 hours and 30‐day survival was 17%.2

Studies have revealed that LA with low pH is associated with adverse effects on the cardiovascular system, particularly a decrease in cardiac contractility.49, 50 This effect is particularly prominent with a pH below 7.20. In contrast, acidosis in animal models has been shown to limit myocardial infarct size after reperfusion.51, 52 Variable effects of LA on cell death have been found. A worsening of apoptosis in myocytes has been noted;53 alternatively, protection from hypoxic injury in hepatocytes and myocardium has been observed.52, 54 Thus, although LA is associated with poor outcomes in human studies,2, 4547 it is still unclear to what extent lactic acid accumulation is a marker of severe illness, an independent effector of pathology, or a mechanism with the potential to serve a protective role.

Available data indicate that lactate itself is not harmful. Studies on infusion of lactate solutions to postoperative patients was shown to be safe.55 Also, the fact that lactate generation in states of respiratory alkalosis, stress, or altered carbohydrate metabolism without sepsis is not associated with worse outcomes supports the fact that lactic acid alone may not be maladaptive.2831

Similarly, low pH is not necessarily maladaptive. In the postictal state,56 diabetic ketoacidosis,57 spontaneous respiratory acidosis,58 or permissive hypercapnia,59 low blood pH is not deleterious.

In summary, LA is associated with poor outcomes, and indirect evidence suggests that it is the underlying causative condition rather than the low pH or the lactate that is responsible for the dire outcomes.

Treatment of LA with Sodium Bicarbonate

Since excessive lactic acid generation is accompanied by consumption of plasma bicarbonate and a fall in plasma pH, sodium bicarbonate has been long proposed as a treatment for LA. While theoretically appealing, this strategy has not been validated by studies in animals or humans. Indeed, bicarbonate administration in LA often has been shown to be detrimental.60, 61 The adverse effects of bicarbonate administration in LA, while initially paradoxical, have a number of possible explanations.

First, bicarbonate administration can induce a reduction in intracellular pH.60, 62, 63 The mechanism involves bicarbonate's effect to increase carbon dioxide (CO₂) generation through mass action effect. Because the cell membrane is more permeable to CO₂ than to bicarbonate, intracellular pH falls.64, 65 In sepsis, this intracellular/extracellular pH discrepancy may be more pronounced due to alterations in blood flow.66 Other reports on outcomes of intracellular pH with bicarbonate therapy show variable effects.6772

Second, to the extent that bicarbonate administration raises extracellular pH, it is associated with a reduction in ionized calcium concentration, since the binding of calcium to albumin is pH dependent.73 A sodium bicarbonate load administered to patients with LA was associated with a significant fall in ionized calcium concentration, whereas a sodium chloride load was not.1 This can affect cardiac function, as the latter varies proportionally with calcium levels.74

Third, bicarbonate administration may reduce tissue oxygen delivery since the affinity of hemoglobin for oxygen increases as pH rises (Bohr effect).75 The administration of bicarbonate worsened systemic oxygen consumption in one study76 and decreased oxygen delivery in another.75

Fourth, bicarbonate administration may indirectly increase intracellular calcium concentration. Low intracellular pH (see above) stimulates proton efflux by way of proton transporters and exchangers, increasing intracellular sodium content.77 A high cell sodium content then may increase intracellular calcium, through the Na/Ca exchanger, impairing cellular function.7779 Compounding this, the reduced function of the Na/H ATPase as a regulator of intracellular sodium in sepsis may not be adequate to limit cell swelling.77

Against this background of mechanistic concerns with the use of bicarbonate treatment, it is not surprising that clinical outcomes have been inconsistent at best. In animal models of LA, the use of sodium bicarbonate has either negative effects on cardiac output60, 72 or no significant hemodynamic effect when compared to sodium chloride infusion.67, 80, 81 One animal study did show some benefit with sodium bicarbonate compared to saline, though all animals subsequently died.50

In humans, sodium bicarbonate was studied in 2 randomized trials of sepsis‐induced LA.1, 82 In a study by Cooper et al.,1 14 critically‐ill patients received sequential infusions of sodium bicarbonate or sodium chloride. Neither solution was superior to the other in terms of hemodynamic improvement. No benefit was noted even when analysis was limited to those with very low pH (<7.2). Mathieu et al.82 randomized 10 critically‐ill patients to sequential infusion of either sodium bicarbonate or sodium chloride. Similarly, no significant difference in hemodynamic variables was noted.

When taken together, these studies evaluating sodium bicarbonate in LA fail to show convincing benefit and raise serious questions about its detrimental effects. Extracellular pH may be a misleading marker of success in the treatment of LA, given its direct influence by sodium bicarbonate administration.

Treatment of LA and Use of Other Buffers

Other buffers (Carbicarb, dichloroacetate, and tromethamine [THAM]) have been studied for treatment of LA. Human studies have not shown superiority of any of the buffers as far as improving pH,83, 84 hemodynamics, or survival.85

Treatment of LA by Renal Replacement Therapy

Renal replacement therapy (RRT; dialysis and its variants) has been studied for the treatment of severe acidosis. RRT has a number of theoretical advantages over purely medical therapies in the treatment of LA: it can deliver large quantities of base without contributing to volume overload; it can directly remove lactate from the plasma; and it can mitigate the effect of alkalinization on ionized calcium concentration by delivering calcium.

In critically ill patients with intact liver function, continuous venovenous hemofiltration (CVVH) appears to contribute very little (less then 3%) to overall lactate clearance.86 While outcome studies are limited, continuous dialysis modalities consistently show improved resolution of acidosis of various types when compared to intermittent modalities.87, 88 As described above, this is related to base administration and is not a surprising finding. There are no studies comparing RRT and medical therapy with respect to clinical outcomes in patients with LA.

Special Situations

Conclusions

Many studies note the association between LA and adverse outcomes.2, 4547 Though metabolic acidosis from elevated lactate levels may negatively affect organ function, the evidence supporting therapy specifically aimed at increasing pH in these settings is consistently poor.3, 127 Limitations have included small numbers of subjects,1, 82 variable outcomes studied, and the inability to assess intracellular metabolic stability.1, 61 When taking these factors into account it is hard to justify aggressive treatment of LA with mechanisms aimed at raising pH. Literature on the treatment of patients with LA and very low pH (below 7.2) is even more limited.

Moreover, lactate elevations may not represent tissue hypoperfusion. Lactate may have an important role in improving energy metabolism. This represents 1 additional reason to be hesitant when attempting to normalize pH in LA; we may be disrupting the body's physiologic response to sepsis. A conflict for clinicians emerges, however, as lactate is often used to define tissue ischemia. Obviously, more specific markers of tissue hypoperfusion would be ideal.

Bicarbonate therapy is an understandably attractive means to improve the acidemia, but there are serious mechanistic concerns with it use. Moreover, neither animal nor human studies, limited as they may be, show a convincing benefit. LA in the setting of acute kidney injury may be best treated with renal replacement therapy with bicarbonate‐based buffers, but controlled trials are lacking.

A number of commonly used drugs can cause LA. A heightened awareness on the part of clinicians will lead to prompt recognition of these cases, and timely treatment.