Written by: Philip Jackson, MD (NUEM ‘20) Edited by: Katie Colton, MD (NUEM ‘19) Expert Commentary by: Benjamin Singer, MD
Introduction
Until recently, there has been a paucity of high-quality data to inform the use of intravenous sodium bicarbonate in severe metabolic acidosis. This has resulted in a lack of universal practice guidelines to inform clinicians in emergency medicine and other specialties when caring for some of their sickest patients.
Historically there have been two camps of thought when approaching the use of sodium bicarbonate in the sick, acidotic patient. Severe acidemia results in protein dysfunction, potentially leading to arrhythmia, cardiovascular collapse, multi-organ failure and eventual death. [1-6] Thus, correcting acidemia with alkalotic bicarbonate solutions could prevent these compounding complications. However, growing evidence suggests that the deleterious effects associated with profound acidemia may be more strongly associated with the underlying physiological insult than the acidosis itself. Therefore, treating the acidemia without addressing the underlying pathology may expose the patient to side effects including hypernatremia, hypocalcemia, and exacerbation of CNS cellular acidosis (due to increased levels of carbon dioxide) without resulting in a net benefit. [1,2]
The BICAR-ICU Trial
A recent randomized, prospective, multi-center trial by Jaber et al. evaluated the effects of bicarbonate administration to ICU patients with metabolic acidemia. The study randomized 389 ICU patients with severe metabolic acidemia (pH ≤7⋅20, PaCO ≤45 mm Hg, and sodium bicarbonate concentration ≤20 mmol/L), a total Sequential Organ Failure Assessment score of 4 or more or an arterial lactate concentration of 2 mmol/L or more into a treatment group receiving 4.2% sodium bicarbonate (<1L per day) or a control group receiving an equivalent volume of standard crystalloid solution.
There was no significant difference between the two groups in the primary outcome, a composite of all-cause mortality at day 28 and the presence of organ failure at day 7. Interestingly, bicarbonate administration decreased the need for renal replacement therapy (RRT) and in a sub-group of patients with acute kidney injury bicarbonate infusion improved mortality and decreased vasopressor requirements.
It is important to note that the study excluded patients with significant urinary or digestive tract losses of bicarbonate (two important causes of non-anion gap metabolic acidosis) and patients that had already been treated with bicarbonate or RRT. Furthermore, a significant proportion of patients in the control group (24%) received bicarbonate at some point during the study and only 60% of the treatment group actually maintained the goal pH of >7.30. These factors skew the study towards a negative outcome, as they presumably blunt the effects of administration of bicarbonate. Thus, it is possible that more of a benefit may have been observed without these disruptions.
The study did not differentiate between etiologies of metabolic acidemia, though ketoacidosis was also excluded, and thus it is difficult to draw conclusions on the value of bicarbonate in various pathologic conditions. There was no specific protocol regarding timing of administration or concentration, making the study difficult to replicate in the emergency setting. Nevertheless, it was essentially the first large, multi-center RCT evaluating this topic and so some practical conclusions can be drawn; these should be interpreted in the context of each individual patient.
Practice recommendations in special situations
Anion Gap Metabolic Acidosis: The human body maintains an essentially neutral net electrical charge through the retention and excretion of ions (notably H+) and anions (notably Cl- and HCO3-). Addition or retention of other anions will increase the anion gap and cause a net negative charge, causing retention of H+ ions and leading to a metabolic acidosis. In general, administration of bicarbonate to this scenario will balance the pH but will not remove the additional anions that are the root cause of the pathologic acidosis and would presumably provide little benefit to patient outcomes.
Lactic Acidosis: Previous to the BICAR-ICU trial, most available data suggests no benefit of bicarbonate. Notably two small prospective physiological studies of 14 and 10 patients, respectively, demonstrated no hemodynamic response or difference in response to catecholamines. [7,8] Additional retrospective and observational studies did not result in clear conclusions. [9,10] The BICAR-ICU trial did not specifically evaluate this population and thus current guidelines recommend against bicarbonate administration unless pH falls below 7.15 or bicarbonate falls below 5 mEq/L (at which point small changes in bicarbonate concentration can lead to potentially fatal changes in pH). [11]
In general, DON’T GIVE IT
Diabetic and Alcoholic Ketoacidosis: A prospective RCT of 21 patients in severe DKA showed no benefit of bicarbonate therapy. [12] Limited data in pediatric DKA and adult AKA populations show similar findings. [13,14] There is evidence that bicarb administration is associated with worse outcome in pediatric patients. It is feasible to give bicarbonate to patients in extremis (pH<6.9) in the adult population to theoretically prevent cardiovascular collapse.
In general, DON’T GIVE IT except when pH<6.9 and with extreme caution in the pediatric patient
Toxic Ingestions (methanol, ethylene glycol, toluene, salicylates, etc.): In general, along with specific therapies, bicarbonate infusion is a mainstay of therapy as systemic and urinary alkalinization removes these anions through ion trapping of metabolites. [15]
GIVE IT, along with specific antidotes and possible dialysis
Uremic Acidosis: Uremic acidosis results from the inability of the injured kidney to excrete anions such as phosphates, sulfates, and nitrates and so removal of these substances is the mainstay of therapy. Administration of bicarbonate does not directly impact this end, and data supporting its use is limited. [16] However, it is the current practice of many nephrologists to treat uremic acidosis with bicarbonate infusion to prevent the need for RRT. It is intuitive that bicarbonate can prevent RRT as bicarbonate therapy both corrects pH and also temporarily improves hyperkalemia (depending on the concentration of the solution). This was again demonstrated in the BICAR-ICU trial with a reduced need for RRT in the treatment group, as well as a mortality benefit in a subgroup with AKI. Though further investigation is needed, it is reasonable to give bicarbonate in this population in consultation with nephrology.
GIVE IT, judiciously in severe acidemia and in consultation with a nephrologist
Non-Anion Gap Metabolic Acidosis: In general, this results from loss of total body bicarbonate or retention of additional chloride. It is thus, theoretically reasonable to treat this population with bicarbonate because you are directly addressing the underlying pathophysiology. [1,2]
Renal Losses, including Renal Tubular Acidosis (RTA): Several types exist, but the pathophysiology lies in the inability of the kidneys to re-absorb bicarbonate resulting in increased urinary losses. The mainstay of therapy is bicarbonate, both oral and IV if severe. [17]
GIVE IT
Gastrointestinal Losses (pancreatic fistula, diarrhea, uretal diversion, etc.): Excessive loss of bicarbonate through the GI tract causes a systemic acidosis. Removing the offending pathology (repairing the fistula) is the mainstay of therapy with bicarbonate replacement as a temporizing measure. [18,19]
GIVE IT, in severe cases
Hyperchloremic Metabolic Acidosis: Usually, as the result of iatrogenic over-administration of chloride rich fluids (normal saline). Therapy involves stopping administration of high chloride content fluids and/or switching to a more pH neutral solution such as Lactated Ringer’s or sodium bicarbonate in dextrose. [20,21]
GIVE IT, in severe cases
Conclusions
• Administration of sodium bicarbonate is recommended along with therapies targeting specific etiologies of acidemia in severe cases of non-anion gap metabolic acidosis and anion gap metabolic acidosis secondary to most toxic ingestions.
• Bicarbonate administration is reasonable in severe metabolic acidemia secondary to uremic acidosis and in patients with both AKI and acidemia. Further research is needed to elucidate protocols and to clearly demonstrate benefits.
• Bicarbonate administration is rarely recommended in both ketoacidosis and lactic acidosis unless the patient is in extremis as it has shown no clear benefit and may cause harm.
Expert Commentary
In this trial there was no attempt to differentiate the cause of acidosis a priori, but the type of metabolic acidosis matters when considering bicarb administration. Why?
a) Metabolic acidosis without elevation in the anion gap is more likely to respond to bicarb administration than acidosis with an elevated anion gap. You can think of non-gap acidosis as bicarb deficiency; by administering bicarb, you are repleting bicarb.
b) The trial supports the use of bicarb for uremic acidosis, which tends to be a mix of non-gap- and gap-associated phenomena (renal tubular acidosis combined with an increase in unmeasured anions). Note that the number-needed-to-treat was six patients to prevent one of them from going on dialysis in the AKI subgroup.
c) Lactic acidosis is a misnomer in that the process that creates an elevation in blood lactate anions is physiologically separate from the process generating protons. [1,2] Lactate elevation occurs because of shunting of glycolysis-generated pyruvate away from oxidative metabolism and toward lactate production. This shunting can occur in states of hypoxia (oxidative metabolism shut down, usually Type A) or normoxia (so-called aerobic glycolysis, usually Type B). Lactate is a weak base, so why is there often an associated acidosis? The proton comes from hydrolysis of ATP, which cannot be rapidly replenished under conditions that also favor lactate production (e.g., hypoxia).
So, why does bicarb administration not work well for lactic acidosis? Because even if you titrate off those extra protons using huge amounts of bicarb, you will not rebalance hydrolysis and re-generation of ATP until you fix the underlying problem (ischemia, sepsis, etc.). The rationale for avoiding bicarb in ketoacidosis is similar. Hence, I agree with the recommendation to use bicarb in patients with severe non-uremic anion-gap-associated acidemia only as a temporizing measure while working to reverse the underlying cause.
References
1. Mizock BA. Controversies in lactic acidosis. Implications in critically ill patients. JAMA. 1987;258:497-501.
2. Andersen LW, Mackenhauer J, Roberts JC, Berg KM, Cocchi MN, Donnino MW. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc. 2013;88:1127-1140. PMCID: PMC3975915.
Benjamin Singer, MD
Assistant Professor of Medicine
Pulmonary and Critical Care
Biochemistry and Molecular Genetics
Northwestern University
How To Cite This Post:
[Peer-Reviewed, Web Publication] Jackson, P. Colton, K. (2020, Nov 16). The BICAR-ICU Trial and Practical Use of Bicarb in Metabolic Acidosis. [NUEM Blog. Expert Commentary by Singer, B]. Retrieved from http://www.nuemblog.com/blog/BICAR-ICU-trial.
Other Posts You May Enjoy
References
1. Adams, J, et al. Emergency Medicine: Clinical Essentials. 2013; 2nd edition: 1363-1378.
2. Arbo, J, et al. Decision Making in Emergency Critical Care: An Evidence-Based Handbook. 2015; 1: 496-499.
3. Jaber S, Paugam C, Futier E, et al. Sodium bicarbonate therapy for patients with severe metabolic acidemia in the intensive care unit (BICAR-ICU): a multi-center, open-label, randomized controlled, phase 3 trial. Lancet. June 2018.
4. Berend K, de Vries APJ. Physiological approach to assessment of acid–base disturbances. N Engl J Med 2014; 371: 1434–45.
5. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med 2014; 371: 2309–19.
6. Jung B, Rimmele T, Le Goff C, et al. Severe metabolic or mixed acidemia on intensive care unit admission: incidence, prognosis and administration of buffer therapy: a prospective, multiplecenter study. Crit Care 2011; 15: R238.
7. Cooper DJ, Walley KR, Wiggs BR, Russell JA. Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study. Ann Intern Med 1990; 112: 492–98.
8. Mathieu D, Neviere R, Billard V, Fleyfel M, Wattel F. Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study. Crit Care Med 1991; 19: 1352–56.
9. ElSolh AA, Abou Jaoude P, Porhomayon J. Bicarbonate therapy in the treatment of septic shock: a second look. Intern Emerg Med 2010; 5: 341–47.
10. Kim HJ, Son YK, An WS. Effect of sodium bicarbonate administration on mortality in patients with lactic acidosis: a retrospective analysis. PLoS One 2013; 8: e65283.
11. Gauthier P, Szerlip H. Metabolic acidosis in the intensive care unit. Crit Care Clin. 2002; 18: 289-308.
12. Morris LR, Murphy MB, Kitabchi AE: Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med. 1986; 105: 836-840.
13. Green SM, Rothrock SG, Ho JD, et al.: Failure of adjunctive bicarbonate to improve outcome in severe pediatric diabetic ketoacidosis. Ann Emerg Med. 1998; 31: 41-48
14. Hojer J: Severe metabolic acidosis in the alcoholic: differential diagnosis and management. Hum Exp Toxicol. 1996; 15: 482-488.
15. O’Malley G. Emergency department management of the salicylate-poisoned patient. Emerg Med Clin North Am. 2007; 25(2): 333-346
16. Roderick PJ, Willis NS, Blakeley S, Jones C, Tomson C. Correction of chronic metabolic acidosis for chronic kidney disease patients. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD001890. DOI: 10.1002/14651858.CD001890.pub3
17. Morris C, Low J. Metabolic acidosis in the critically ill: Part 2. Causes and treatment. Anesthesia. 2008; 63: 396-411.
18. Callery M, et al. Prevention and management of pancratic fistula. J Gastrointest Surg. 2009; 13(1): 163-173
19. Davidson T, et al. Long-term metabolic and nutritional effects of urinary diversion. Urology. 1995; 46: 804-809.
20. Kellum J. Saline induced hyperchloremic metabolic acidosis. Crit Care Med. 2002; 30: 259-261.
21. Prough D, Bidani A. Hyperchloremic metabolic acidosis is a predictable consequence of intraoperative infusion of 0.9% saline. Anesthesiology. 1999; 90: 1247-1249.