Selective ß2-Adrenoceptor Agonists and Relevant Hyperlactatemia: Systematic Review and Meta-Analysis

Selective ß2-agonists have been imputed as potential cause of l-hyperlactatemia since the 1970s. To document the prevalence of hyperlactatemia associated with selective ß2-agonists and to investigate the predisposing factors, we searched for published articles until April 2019 pertaining to the interplay of administration of selective ß2-agonists and circulating l-lactic acid in the Excerpta Medica, Web of Science, and the U.S. National Library of Medicine databases. Out of the 1834 initially retrieved records, 56 articles were included: 42 papers reporting individual cases, 2 observational studies, and 12 clinical trials. Forty-seven individual patients receiving a selective ß2-agonist were found to have l-lactatemia ≥5.0 mmol/L, which decreased by ≥3.0 mmol/L or to ≤2.5 mmol/L after discontinuing (N = 24), reducing (N = 17) or without modifying the dosage of the selective ß2-agonist (N = 6). Clinical trials found that l-lactic acid significantly increased in healthy volunteers administered a ß2-agonist. l-lactatemia ≥5.0 mmol/L was observed in 103 (24%) out of 426 patients with asthma or preterm labor managed with a selective ß2-agonist and was more common in patients with asthma (30%) than in premature labor (5.9%). A significant relationship was also noted between l-lactate level and intravenous albuterol dose or its circulating level. In conclusion, relevant l-hyperlactatemia is common on high dose treatment with a selective ß2-agonist.


Introduction
Excess (≥2.5 mmol/L) blood lactic acid level and, less frequently, lactic acidosis, may result from poor tissue oxygen delivery, from inherited or acquired metabolic defects and from drugs such as biguanides, some antiretrovirals, the antibiotic linezolid, and the hypnotic sedative propofol [1,2]. Selective ß 2 -adrenoceptor agonists are worldwide prescribed to manage bronchial obstruction, to prevent premature delivery and, less frequently, to treat hyperkalemia. ß 2 -adrenoceptor activation increases lactic acid synthesis in skeletal muscle cells [3]. Unsurprisingly, therefore, selective ß 2 -adrenoceptor agonists have been imputed as a cause of hyperlactatemia since the second half of the 70s [4].
Available guidelines do not mention the association of management with selective ß 2 -adrenoceptor agonists and hyperlactatemia [5][6][7]. The aim of this study was to document the prevalence and predisposing factors for hyperlactatemia associated with selective ß 2 -agonists.

Literature Search Strategy
A systematic search of scientific articles investigating the prevalence and predisposing factors for hyperlactatemia associated with selective ß 2 -agonists was performed by using the Excerpta Medica, Web of Science, and the U.S. National Library of Medicine databases (PROSPERO REGISTRATION NUMBER: CRD42019139789). The literature search was conducted until April 2019. The search algorithm used was a combination of different key words and Medical Subject Heading terms: (hyperlactatemia OR lactate OR lactic acid OR lactic acidosis OR metabolic acidosis) AND (albuterol OR bitolterol OR carmoterol OR fenoterol OR formoterol OR indacaterol OR metaproterenol OR procaterol OR rimiterol OR ritodrine OR salbutamol OR salmeterol OR terbutaline OR ß 2 -adrenoceptor agonist OR beta-2-agonist). Reports published in Dutch, English, French, German, Italian, Portuguese, or Spanish after 1970 as full-length articles or letters on the topic of interest were considered. We also scanned the references of all included articles for additional reports. We employed the principles underlying the U.K. Economic and Social Research Council guidance on the conduct of narrative synthesis and the "Preferred Reporting Items for Systematic reviews and Meta-Analyses" (PRISMA) statement.

Selection Criteria and Data Extraction
We included reports detailing individual subjects with clinically relevant hyperlactatemia (≥5.0 mmol/L) after taking either an intravenous or a nebulized selective ß 2 -agonist and a decrease in lactate level by ≥3.0 mmol/L or to a level of ≤2.5 mmol/L after discontinuing the ß 2 -agonist or reducing its dosage. Individual cases of relevant hyperlactatemia that improved without discontinuing or reducing the selective ß 2 -agonist were also included. Observational studies and clinical trials addressing the prevalence of relevant hyperlactatemia or the interplay between the metabolism of ß 2 -agonists and that of lactic acid were also retained. Cases managed with biguanides, antiretrovirals, linezolid, or propofol, or with inherited enzyme defects responsible for excess of this acid were excluded.
From each included report, information on demographics, drug name and route of administration of the selective ß 2 -agonist, co-medication with corticosteroids, ipratropium, theophylline, and underlying clinical condition was also collected. If needed, authors of original articles were contacted to provide missing data or verify the accurateness of reported information.
Literature selection and data extraction were performed independently by two investigators. When results were incongruent, conflicts were resolved by reaching a consensus and, if the discrepancy stood, a third researcher was consulted.

Study Quality Assessment
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) score, which may be very low, low, moderate, or high, was used to appraise the quality of the observational and clinical trials included in this review.

Analysis
Continuous data are presented as median and interquartile range or as 'box and whisker plot', dichotomous data as relative frequency and confidence interval. The Cohen index was used to assess the agreement between investigators on the application of the inclusion and exclusion criteria, the Kruskal-Wallis test to compare continuous variables and the Fisher test to compare dichotomous variables.
We performed a pooled analysis about the prevalence of significant hyperlactatemia in patients receiving a selective ß 2 -agonist using data retrieved from the selected observational studies and clinical trials. A random-effects model was used for statistical pooling of the data, taking into account the heterogeneity among studies. The different weight of each study in the pooled analysis was related to the different sample size. Pooled data were presented with their respective 95% confidence interval (95% CI) values, and data were displayed using plots. Heterogeneity was estimated by using the I 2 index, which describes the percentage of variation across studies that is due to heterogeneity rather than chance. Publication bias was assessed through the Egger's test. Statistical analyses were performed using the StatsDirect software version 3 (StatsDirect Ltd., Cambridge, UK) and the Meta-analyse Software (Brown University, Providence, RI, USA).
Anticipating the possible occurrence of a significant heterogeneity (I 2 index > 50%), subgroup analyses based on the type of studied population (a. healthy subjects, b. adults with asthma, c. children with asthma, and d. females with premature labor) or route of administration (a. intravenous or subcutaneous, b. nebulized, c. both intravenous and nebulized) were planned. Statistical significance was assigned at p < 0.05.

Observational Studies and Clinical Trials
The interplay between the metabolism of a selective ß2-agonist and that of lactic acid was investigated in two observational studies [
A substantial heterogeneity among studies (I 2 index = 94.2%) was detected. A similar heterogeneity was also observed when clinical trials and observational studies were separately considered (Figure 4).
Among the different types of study populations, circulating lactic acid significantly increased in healthy volunteers [49,50] administered intravenous (N = 4; by about 2.0 mmol/L) or nebulized (N = 14; by about 0.8 mmol/L) albuterol. A significant increase in circulating lactate was also observed in 6 healthy volunteers after intravenous ritodrine [51]. In this study population, hyperlactatemia was relevant (≥5.0 mmol/L) only in a small, not significant minority of cases (N = 3; 13%). A total of 426 patients (214 adults and 212 children) with acute asthma (N = 324) or preterm labor (N = 102) managed with nebulized, intravenous, subcutaneous, or both nebulized and intravenous albuterol (N = 324), ritodrine (N = 62) or terbutaline (N = 40) were investigated in the 12 clinical trials. Relevant hyperlactatemia was observed in 103 (24%) cases and was significantly (p < 0.0001) more common in asthma patients (N = 97; 30%) than in females with premature labor (N = 6; 5.9%). Among the 324 aforementioned patients affected by acute asthma, the prevalence of relevant hyperlactatemia was identical in patients ≤18 years of age (63 out of 212, 30%) and in older subjects (34 out of 112, 30%). In 42 pediatric subjects managed with intravenous albuterol, a significant (p < 0.02) correlation was observed between intravenous albuterol dose and lactate level [61]. In addition, in 65 adult patients, a significant (p < 0.0001) positive correlation was noted between circulating albuterol and lactate level [62]. Finally, Radwan et al. found significantly higher lactic acid levels in children with more severe asthma attacks [58]. The subgroup analysis of the pooled prevalence of relevant hyperlactatemia taking into account the different studied population disclosed an I 2 index of 44% in the group of women with premature labor (Figure 5). This index was >50% in the remaining three subgroups.  A substantial heterogeneity among studies (I 2 index = 94.2%) was detected. A similar heterogeneity was also observed when clinical trials and observational studies were separately considered ( Figure 4). A total of seven studies included subjects managed exclusively with intravenous or subcutaneous ß2-agonists (N = 112), three studies included subjects managed exclusively with nebulized ß 2 -agonists (N = 64), and four studies included subjects managed both with intravenous and nebulized ß 2 -agonists (N = 274). The subgroup analysis taking into account the route of administration disclosed an I 2 index of 22% in the group of subjects managed with nebulized ß 2 -agonists and >50% in the remaining two groups ( Figure 6). A substantial heterogeneity among studies (I 2 index = 94.2%) was detected. A similar heterogeneity was also observed when clinical trials and observational studies were separately considered (Figure 4).  Among the different types of study populations, circulating lactic acid significantly increased in healthy volunteers [49,50] administered intravenous (N = 4; by about 2.0 mmol/L) or nebulized (N = 14; by about 0.8 mmol/L) albuterol. A significant increase in circulating lactate was also observed in 6 healthy volunteers after intravenous ritodrine [51]. In this study population, hyperlactatemia was relevant (≥5.0 mmol/L) only in a small, not significant minority of cases (N = 3; 13%). A total of 426 patients (214 adults and 212 children) with acute asthma (N = 324) or preterm labor (N = 102) managed with nebulized, intravenous, subcutaneous, or both nebulized and intravenous albuterol (N = 324), ritodrine (N = 62) or terbutaline (N = 40) were investigated in the 12 clinical trials. Relevant hyperlactatemia was observed in 103 (24%) cases and was significantly (p < 0.0001) more common in asthma patients (N = 97; 30%) than in females with premature labor (N = 6; 5.9%). Among the 324 aforementioned patients affected by acute asthma, the prevalence of relevant hyperlactatemia was identical in patients ≤18 years of age (63 out of 212, 30%) and in older subjects (34 out of 112, 30%). In 42 pediatric subjects managed with intravenous albuterol, a significant (p < 0.02) correlation was observed between intravenous albuterol dose and lactate level [61]. In addition, in 65 adult patients, a significant (p < 0.0001) positive correlation was noted between circulating albuterol and lactate level [62]. Finally, Radwan et al. found significantly higher lactic acid levels in children with more severe asthma attacks [58]. The subgroup analysis of the pooled prevalence of relevant hyperlactatemia taking into account the different studied population disclosed an I 2 index of 44% in the group of women with premature labor (Figure 5). This index was >50% in the remaining three subgroups.  A total of seven studies included subjects managed exclusively with intravenous or subcutaneous ß2-agonists (N = 112), three studies included subjects managed exclusively with nebulized ß2-agonists (N = 64), and four studies included subjects managed both with intravenous and nebulized ß2-agonists (N = 274). The subgroup analysis taking into account the route of administration disclosed an I 2 index of 22% in the group of subjects managed with nebulized ß2agonists and >50% in the remaining two groups ( Figure 6).

Discussion
The results of the first systematic review and meta-analysis on selective ß2-agonist associated hyperlactatemia can be summarized as follows. First, administration of either an intravenous or a nebulized ß2-agonist may be followed by an increased lactic acid level in healthy volunteers, in both pediatric and adult patients with an acute bronchial obstruction or hyperkalemia, in women with preterm labor, and following voluntary intoxication. The effect on lactic acid of albuterol, the most frequently prescribed ß2-agonist, is dose-dependent and correlates with its blood level. Second, management with a high dose of a short-acting ß2-agonist is associated with clinically relevant hyperlactatemia (≥5.0 mmol/L) in every third patient with asthma admitted to an intermediate or intensive care unit. Third, hyperlactatemia has been found to resolve after stopping, reducing, or even continuing the ß2-agonist.

Discussion
The results of the first systematic review and meta-analysis on selective ß 2 -agonist associated hyperlactatemia can be summarized as follows. First, administration of either an intravenous or a nebulized ß 2 -agonist may be followed by an increased lactic acid level in healthy volunteers, in both pediatric and adult patients with an acute bronchial obstruction or hyperkalemia, in women with preterm labor, and following voluntary intoxication. The effect on lactic acid of albuterol, the most frequently prescribed ß 2 -agonist, is dose-dependent and correlates with its blood level. Second, management with a high dose of a short-acting ß 2 -agonist is associated with clinically relevant hyperlactatemia (≥5.0 mmol/L) in every third patient with asthma admitted to an intermediate or intensive care unit. Third, hyperlactatemia has been found to resolve after stopping, reducing, or even continuing the ß 2 -agonist.
Acute asthma and chronic obstructive pulmonary disease, the most common indications for management with selective ß 2 -agonists, may per se be associated with hyperlactatemia. Poor tissue oxygen delivery might contribute to hyperlactatemia in this setting [63,64]. However, a severely impaired oxygen delivery is required to cause hyperlactatemia [63,64]. As a consequence, it is currently assumed that hyperlactatemia predominantly results from lactic acid overproduction by respiratory muscles performing increased work and, to a lesser extent, from its reduced elimination caused by liver hypoperfusion [63,64]. In vitro and in vivo studies have elucidated the mechanism by which ß 2 -agonists cause lactic acid generation: ß 2 -adrenoceptor activation stimulates production of lactic acid in skeletal muscle (but not in other tissues) through exaggerated aerobic glycolysis [3,65].
In the past, an increased ratio of lactate to pyruvate concentration in blood has been deemed to distinguish hyperlactatemia due to poor tissue oxygen delivery from that without [66]. Since recent observations demonstrate that this ratio may be an inaccurate marker of tissue oxygen delivery, this information was not addressed in this review [66].
In asthma exacerbation managed with high dose selective ß 2 -agonists, tachypnea represents a diagnostic challenge. Given the high prevalence of relevant hyperlactatemia on treatment with these drugs, tachypnea may result from airway obstruction, Kussmaul breathing caused by lactic acidosis, or both. In this setting, serial physical examination (and perhaps, in older children and adults, peak flow measurement) are advised to appreciate airway obstruction. Many currently available point-of-care blood gas analyzers also assess lactic acid. In our opinion, however, the determination of this acid in severe asthma managed with a ß 2 -agonist is likely to be currently underappreciated.
Our analysis complements the results of a very recent review which included patients ≥13 years of age with hyperlactatemia associated with the administration of both selective and non-selective ß 2 -agonists [2].
This report has at least three limitations. First, the main limitation of our study was the detected heterogeneity. The subgroup analyses taking into account the route of drug administration showed a reduced statistical heterogeneity among the studies. Therefore, this finding points out that the different route of drug administration is a significant cause of heterogeneity among the included studies. In addition, the heterogeneity observed in healthy subjects and in patients with asthma is likely due to the variable doses of selective ß 2 -agonists. Furthermore, in asthma patients, excess lactic acid level may occur as a consequence of increased respiratory muscle work (even without treatment with a ß 2 -agonist). Regrettably, all but one report did not assess asthma exacerbation severity, making it impossible to correlate circulating lactic acid level with disease severity. Second, available data can sketch out the management of hyperlactatemia only in very broad terms. Third, the literature does not permit to identify the role of co-medication with corticosteroids, ipratropium, or theophylline in the occurrence of ß 2 -agonist-associated hyperlactatemia.

Conclusions
The potential of selective ß 2 -agonists to produce hypocalcemia, hypomagnesemia, hypophosphatemia, and especially hypokalemia and hyperglycemia is well recognized but often overlooked in clinical practice [2,[67][68][69]. The present review of the literature points out that relevant hyperlactatemia is also common (about 20%) on high dose treatment with these agents. In patients with acute asthma, healthcare providers might misinterpret relevant hyperlactatemia as worsening of respiratory disease.
Author Contributions: P.B.F. had full access to all of the data in the study and takes responsibility for the integrity of the data; A.G.L., G.P.M., S.A.G.L., M.G.B., and P.B.F. conceptualized the study design, contributed to data analysis and wrote the manuscript; A.G.L. and V.G. performed the literature search and study selection. G.T. performed the data analysis; C.A., A.G.L., V.G., and P.B.F. gave a significant contribution in the interpretation of results. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.

Conflicts of Interest:
The authors declare no conflict of interest.