Bicarbonate Therapy for Critically Ill Patients with Metabolic Acidosis: A Systematic Review

The management of acid-base disorders always calls for precise diagnosis and treatment of the underlying disease. Sometimes additional means are necessary to combat systemic acidity itself. In this systematic review, we discuss the concept and some specific aspects of bicarbonate therapy for critically ill patients with metabolic acidosis (i.e., patients with blood pH < 7.35). We conducted a systematic literature review of three online databases (PubMed, Google Scholar, and Cochrane) in November 2018 to validate usage of bicarbonate therapy for critically ill patients with metabolic acidosis. Twelve trials and case series were included in the final analysis, from which we assessed population, intervention, comparison, and outcome data. The current literature suggests limited benefit from bicarbonate therapy for patients with severe metabolic acidosis (pH < 7.1 and bicarbonate < 6 mEq/L). However, bicarbonate therapy does yield improvement in survival for patients with accompanying acute kidney injury.

underlying disease. Sometimes it requires additional means to combat abnormal systemic acidity. In this systematic review, we review the concept and some specific aspects of bicarbonate therapy for critically ill patients with metabolic acidosis.

Review Material and methods
Two authors individually performed a systematic literature review of three online databases (PubMed/MEDLINE, Google Scholar, and Cochrane) till November 2018 with the following search terms: "bicarbonate" OR "bicarbonate therapy" AND "metabolic acidosis" OR "lactic acidosis" OR "ketoacidosis" OR "intensive care unit". Inclusion criteria were (i) reporting on bicarbonate usage in metabolic acidemia, (ii) article in English. Exclusion criteria were (i) conference abstract, reports and similar (ii) participants younger than 18 years. After the search, 3,008 articles were screened by title and abstract. Of those, 128 relevant articles underwent a detailed review of relevance for full-text. The disagreements were resolved by mutual discussion (Figure 1). During the research, we identified 12 articles on bicarbonate therapy for critically ill patients with metabolic acidosis. To identify other relevant studies, we manually scanned reference lists from the identified trials and review articles. Our review follows the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [10].

Results
Twelve trials and case series were included in the final analysis. We extracted population, intervention, comparison, and outcome (PICO) data from the 12 included articles. Summaries of the relevant studies are presented in Table 1

Discussion
Metabolic acidosis is an acid-base disorder characterised by low serum pH from reduced HCO3levels following a compensatory decrease in PaCO2 [1][2]. When blood pH is < 7.20, acidosis is severe [1][2]. There are two main mechanisms underlying metabolic acidosis: a deficit in HCO3-(loss by kidneys or gastrointestinal system) or addition of strong acids, where lactic acidosis and ketoacidosis are the two most common causes of severe metabolic acidosis [2,[22][23].
Capnography is the primary diagnostic method of metabolic acidosis in spontaneously breathing patients referred to the emergency wards. However, arterial blood gas is the gold standard tool for diagnosis, the results of which guide the treatment [24]. Metabolic acidosis affects the cardiovascular, respiratory, metabolic, cerebral, renal, haematological, endocrine, musculoskeletal, and immunological systems [25][26][27][28][29].

Bicarbonate Therapy
Buffers are substances that counteract changes in pH [9], and sodium bicarbonate is the most frequently used buffer [30][31]. The main reason to commence sodium bicarbonate therapy is to prevent or reverse the effects of metabolic acidemia, especially in the cardiovascular system [25]. For bicarbonate therapy to be effective, plasma HCO3-levels must be increased to 8 mmol/L to 10 mmol/L. There are no guidelines stating exactly how to achieve these levels given a variety of influencing factors (e.g., vomiting, renal failure) [25].
When a patient is given bicarbonate, the production of lactate is stimulated in lactic acidosis [32][33][34] diabetic ketoacidosis [35], and hemorrhagic shock [36]. Sodium bicarbonate should be dispensed as an infusion over several hours. In cases of severe acidemia, a bolus may be considered. The clinical effect can be assessed at least 30 minutes after infusion [25].

Complications of Bicarbonate Therapy
Sodium bicarbonate infusions may result in hypernatremia and hyperosmolality. However, the addition of sodium chloride and 5% dextrose creates an isotonic solution and will help prevent these adverse effects [25]. Extracellular-fluid volume overload is another negative consequence of bicarbonate therapy, and the risk is higher among patients with congestive heart failure and/or renal failure. To prevent extracellular-fluid volume overload, loop diuretics (e.g., furosemide) should be used. In worst-case scenarios, hemofiltration and/or dialysis may be needed [25].
In cases of lactic acidosis or ketoacidosis, the simulation of 6-phosphofructokinase activity and organic acid production should be considered, as the overproduction of organic acid may limit the effects of alkalizing agents [25].

Bicarbonate Therapy for Patients with Metabolic Acidosis
Three recent studies on 150 patients with metabolic acidemia (pH ≤ 7.35) and increased lactate concentrations (serum lactate > 2.45 or 5 mmol/L) failed to prove sodium bicarbonate offered a limited benefit on mortality and hemodynamic variables [11][12][13]. In another study, Fang et al. evaluated a cohort of 94 patients with sepsis assigned into three groups receiving 5 mL/kg normal saline, 5 mL/kg 3.5% sodium chloride, and 5 mL/kg 5% sodium bicarbonate. They reported no differences in cardiac output, mean arterial pressure heart rate or respiratory rate eight hours following infusion, and no significant differences were observed in mortality rate after 28 days. However, patients receiving sodium bicarbonate showed improved hemodynamic parameters earlier than those in other groups [14].
Kraut et al. surveyed nephrologists and critical care physicians on their use of bases in treating acute severe organic acidosis [37]. While results varied among individual physicians from both specialties, a larger percentage of nephrologists recommended administration of base for the treatment of lactic acidosis and ketoacidosis than critical care physicians (lactic acidosis, 86% vs.67%; ketoacidosis, 60% vs.28%). Sodium bicarbonate was the most utilized form of base used for treatment (> 75%) [37].
The first positive study on the benefits of sodium bicarbonate therapy was published in 2010 by El-Solh et al. [17].  35 to 55]; p = 0·0283 for controls). Additionally, the number of days free from renal-replacement therapy and vasopressors was higher. These findings suggest that unlike the overall population of patients with metabolic acidosis, those suffering from concomitant acute kidney injury may experience improved outcomes and a reduced rate of mortality from enrolment to day 28 with sodium bicarbonate infusion therapy [19]. Similarly, Zhang et al. studied 1718 septic patients (1218 controls and 500 patients who received sodium bicarbonate) and reported no significant mortality change in the overall population (hazard ratio [HR], 1.04; 95% CI, 0.86 to 1.26; p = 0.67], but bicarbonate proved to be beneficial in patients with acute kidney injury (HR, 0.74; 95% CI, 0.51 to 0.86; p = 0.021) [20].

Limitations
Our review had several limitations. Data were only searched in three databases, and the inclusion of other databases could increase the range of articles found. In addition, we limited our inclusion to studies published in English. Given our focus was gathering information regarding bicarbonate therapy, we did not evaluate the methodologic quality of the included studies. These limitations did not substantially alter the results. A meta-analysis was not conducted given the heterogeneity of the data.