Metabolic Acidosis Treatment as Part of a Strategy to Curb

Hindawi Publishing CorporationInternational Journal of InflammationVolume 2013, Article ID 601424, 4 pageshttp://dx.doi.org/10.1155/2013/601424

Review ArticleMetabolic Acidosis Treatment as Part of a Strategy toCurb Inflammation

Tales Rubens de Nadai, Mariane Nunes de Nadai,Agnes Afrodite Sumarelli Albuquerque, Marco Tulio Menezes de Carvalho,Andrea Carla Celotto, and Paulo Roberto Barbosa Evora

Department of Surgery and Anatomy, Ribeirao Preto Faculty of Medicine, University of Sao Paulo, Avenida Bandeirantes 3900,14048-Sao Paulo 900, 14015-120 Ribeirao Preto, SP, Brazil

Correspondence should be addressed to Paulo Roberto Barbosa Evora; [email protected]

Received 16 April 2013; Revised 22 May 2013; Accepted 22 May 2013

Academic Editor: Robert Clive Landis

Copyright © 2013 Tales Rubens de Nadai et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Abnormalities in systemic acid-base balance may induce significant changes in the immune response, and they may play asignificant role in the development or maintenance of immune dysfunction. Different forms of acidosis (metabolic and respiratory)and even different types of metabolic acidosis (hyperchloremic and lactic) may produce different effects on immune function. Ifalkalization has, or not, some effect on inflammation control is still a matter of speculation. Studies concerning these subjects arelimited justifying this paper.

1. Introduction

Abnormalities in systemic acid-base balance may cause sig-nificant changes in the immune response. The clinical signif-icance of these changes is not yet fully known, but its mag-nitude suggests that they may play a significant role in thedevelopment or maintenance of immune dysfunction. Thus,they represent attractive targets for curbing inflammation.

Metabolic acidosis is one of themost common abnormal-ities in patients suffering from serious diseases. There havenumerous etiologies and treatment of the underlying diseaseis the basis of therapy. However, there is a growing evidencesuggesting that acidosis itself has profound effects on thehost, particularly in immune function. Given the criticalimportance of immune function for the outcome of theillness, there is an overriding interest in elucidating the effectsof this condition.

In fact, recent evidence suggests that the different forms ofacidosis (metabolic and respiratory) and even different typesof metabolic acidosis (hyperchloremic and lactic) may pro-duce different effects on immune function.Theways in whichthese effects are applied to the clinical conditions have notbeen determined. Therefore, since acidosis is an extremely

common problem in intensive care units and that immunefunction is of vital importance, efforts to explain these rela-tions are fully justified [1]. However, it is necessary to notethat the publications linking acidosis with the inflammatoryresponse are limited, and studies on the alkalosis are virtuallynonexistent, justifying the current paper, at least as an opendiscussion (Figure 1).

2. Pathophysiology

The literature has reported in vitro experiments whereresearchers reduced intracellular pH (pHo) using differenttypes of acids. Notably, different patterns of expressionof mediator of inflammation occurred at different acids,despite the normalization of samples to the same pHo [1].Kellum et al. [2] demonstrated that different degrees ofhyperchloremic acidosis produce different effects on therelease of inflammatory mediators. By using electrophoreticmobility shift, these researchers have measured the bindingof NF-𝜅BDNA after exposure to different concentrations ofHCl. When compared to pHo 7.4, acidosis (7.0 pHo) signif-icantly increased the activation of NF-𝜅B induced by LPS,

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Figure 1: Metabolic acidosis and inflammation (Web of Science data).

while more severe acidosis (6.5 pHo) attenuated the activa-tion of NF-𝜅B, concluding that the degree of acidosis directlyinfluences the immune function.

Unlike HCl, lactic acid has been studied in an even morelimited way with even less convincing effects, and the mech-anisms by which the HCl and lactate exert effects oninnate immunity are unknown. Furthermore, the Kellumet al. investigation [2] evaluated the inflammatory responseinduced by LPS (E. coli toxin) associated with acidosis. Theinflammatory response through quantification of inflamma-tory markers (NO, IL6, and IL-10 binding with DNALPS),showed that HCl and lactic acid exhibit antagonisticresponses, and an immune response increases with HCL anddecreases with lactic acid. The basic conclusion is that dif-ferent types of acids produced different effects on cellularimmune function even when normalized to the same pH.

Evidently, the interrelationship between extracellular andintracellular pH on immune function cannot be ignored,especially in light of the numerous findings implicating arole for the Na/H exchanger prior to the activation of certainimmune activities, suggesting that the Na/H exchanger is asine qua non in generating a rapid intracellular alkaliniza-tion prior to the differential activation of certain immuneactivities [3]. However, a major criticism of the experimentalstudies is the strong acidification (pH 6.5–7.0), which showsmore clearly the role of inflammation, and these levels ofacidosis are rarely observed in the clinical setting. Moreover,it is difficult to differentiate between intracellular and extra-cellular acidosis, including possible “critical windows” andtheir relationship to inflammation.

3. Acid-Base Biomarkers and Inflammation

Farwell and Taylor conducted a survey about the relationshipbetween serum acid-base status and inflammation. Thisstudy examined the relationship between serum anion gap,bicarbonate levels, and inflammatory biomarkers in healthy

subjects. It was shown that a higher anion gap and a lowerlevel of serum bicarbonate (despite being within the normalrange) were associated with higher levels of several inflam-matory biomarkers, including leukocyte count and levelsof C-reactive protein. The cause of the observed relation-ship between higher serum anion gap and higher levels ofinflammatory markers in this apparently healthy people isunknown. These data raise the possibility that the increasedproduction of organic acids measured the chronic inflam-matory disease, which increases the risk of coronary heartdisease and cancer. More studies are necessary to deter-mine the effectiveness of alkali supplementation on levels ofinflammatory biomarkers [4].

Lactate clearance, a surrogate for the magnitude andduration of global tissue hypoxia, is used diagnostically, ther-apeutically, and prognostically. Nguyen and colleagues exam-ined the association of early lactate clearance with selectedinflammatory, coagulation, apoptosis response biomarkers,and organ dysfunction scores in severe sepsis and septicshock [5]. They carried out measurements of serum arteriallactate, and biomarkers (interleukin-1 receptor antagonist,interleukin-6, interleukin-8, interleukin-10, tumor necrosisfactor-alpha, intercellular adhesionmolecule-1, highmobilitygroup box1, D-dimer, and caspase-3). In addition, organdysfunction scores (Acute Physiology and Chronic HealthEvaluation II, Simplified Acute Physiology Score II, MultipleOrgan Dysfunction Score, and Sequential Organ FailureAssessment) were obtained in conjunction with a prospec-tive, randomized study. Lactate clearance was defined as thepercent change in lactate levels after six hours from a baselinemeasurement in the emergency department. The results ofthe statistical analysis showed that early lactate clearance asa surrogate for the resolution of global tissue hypoxia wassignificantly associated with decreased levels of biomarkers,improvement in organ dysfunction, and outcome in severesepsis and septic shock.This well-designed studywas selectedbecause it illustrates the relationship between metabolicacidosis and the inflammation reaction.

International Journal of Inflammation 3

4. Therapeutic Aspects

The various studies described above suggest that changes insystemic acid-base balance can also cause alterations in theimmune response through several different ways. Thus, fur-ther investigation of these changes may lead to valuable ther-apeutic targets in treating some potentially serious diseases.

Acidosis and changes in intracellular and extracellular pHmay influence endothelial function in different aspects. Inlarge arteries, intracellular acidosis is associated with vasodi-latation,whereas in small arteries, it leads to vasoconstriction.The pathogenic events of this response are not well known,but it was demonstrated that acidosis regulates not only theiNOSbut also the eNOS [6]. Nitric oxide can contribute to thecontrol of local blood flow during hypoxia/ischemia, whichpresents a close relationship with lactic acid production.Thisanalysis suggests that the pH regulation may represent apotential therapeutic target in curbing inflammation. Thisnew approach may attenuate endothelial dysfunction indiseases associated with acidosis [7].

Nowadays to consider what the best strategies to treatmetabolic acidosis, considering the inflammatory response isan exercise in speculation and hypotheses. For example, thereare advantages to seek alternative ways to treat intracellularacidosis, or just to know that it comes concomitant to theextracellular treatment? If have advantages, “resurrect” theTRIS buffer clinical use would be considered since thisbuffer is theoretically more effective to treat the intracellularacidosis, than ever questioned bicarbonate?

The “folk” thought that the patient died of multipleorgan failure with hemogasometry normal is particularlymetaphorical and capable of deep reflection. The correctionof metabolic acidosis as an isolated marker needs to beabandoned and considered being an essential part of thesystemic inflammatory response. Thus, administration ofpotent and selective NHE1 inhibitors afford protection fromthe whole body ischemia-reperfusion injury by attenuatingmyocardial dysfunction and improving organ blood flow andsystemic oxygen delivery, resulting in reduced proinflamma-tory response [8].

5. Conclusion

Most often, metabolic acidosis is present in acute systemicinflammatory response in which the control of acid-basebalance is part of the treatment protocol. Thus, evaluationof the role of metabolic acidosis is mandatory. One of mainconcerns about this paper is the difficulty to establish “whatthe chicken is and what the egg is.” In many cases, acuteacidosis is secondary to, for example, circulatory shock,and one could wonder whether, under those conditions, thecirculatory shock causes the inflammatory response or theacidosis related to the shock. The same reasoning can befollowed in patients who develop respiratory acidosis dueto ARDS or COPD, as the lung disease by itself will inducean inflammatory response. Perhaps the most unequivocaldata providing evidence for an impairment of the immune

response appear from the clinical studies of the organicacidosis and ketoacidosis. In general, the clinical acidemiasare accompanied by immunodeficiency, including a reduc-tion in white cell numbers, gamma globulins, mitogenicresponses, a diminution of the inflammatory response, anddelayed phagocytosis. In many cases, the immunodeficiencyis reversed on the correction of the acidosis. Despite thevaluable research carried out to date, a lack in the appreciationof extracellular acid-base effects on a wide range of otherimmune activities exists [3]. Therefore, the situations inwhich acidosis remains steadily, as chronic renal failure,would be more suitable for the evaluation of the treatmentto curb the spread of the inflammatory process.

It should be emphasized that the metabolic acidosis iscommon in critically ill patients and its presence can have adetrimental effect on clinical outcome.The administration ofbase, a common therapeutic maneuver, does not appreciablyimprove clinical outcome, even when acidosis is improved[9]. Is it better to consider “body acid-base imbalance” than“blood acid-base imbalance”?

Metabolic Acidosis and Inflammatory Response Key Points

(i) Metabolic acidosis is one of the most common abnor-malities in patients suffering from serious diseases,and there is a growing evidence suggesting that acido-sis itself has profound effects on the host, particularlyin immune function.

(ii) Recent evidence suggests that the different formsof acidosis (metabolic and respiratory) and evendifferent types of metabolic acidosis (hyperchloremicand lactic) may produce different effects on immunefunction.

(iii) Publications linking acidosis with the inflamma-tory response are limited, and a major criticism ofthe experimental studies is the strong acidification(pH 6.5–7.0), which shows more clearly the role ofinflammation, and these levels of acidosis are rarelyobserved in the clinical setting.

(iv) Anion gap, bicarbonate, and lactate are possiblebiomarkers of the inflammation response.

(v) Perhaps the most unequivocal data providing evi-dence of the immune response impairment emergefrom the clinical studies of the organic acidosisand ketoacidosis. In general, the clinical acidemiasare accompanied by immunodeficiency, including areduction in white cell numbers, gamma globulins,and mitogenic responses, a diminution of the inflam-matory response.

(vi) Nowadays, to consider what the best strategies to treatmetabolic acidosis, considering the inflammatoryresponse is an exercise in speculation and hypotheses.

(vii) The administration of selective inhibitors of NHE1minimizes the degree of cellular injury and improvessurvival.

4 International Journal of Inflammation

(viii) The correction of metabolic acidosis as an isolatedmarker needs to be abandoned and considered asbeing an essential part of the systemic inflammatoryresponse. Is it better to consider “body acid-base-imbalance” than “blood acid-base-imbalance”?

References

[1] J. A. Kellum, M. Song, and J. Li, “Science review: extracellularacidosis and the immune response: clinical and physiologicimplications,” Critical Care, vol. 8, no. 5, pp. 331–336, 2004.

[2] J. A. Kellum, M. Song, and J. Li, “Lactic and hydrochloric acidsinduce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells,” American Journal of Physiology,vol. 286, no. 4, pp. R686–R692, 2004.

[3] A. Lardner, “The effects of extracellular pH on immune func-tion,” Journal of Leukocyte Biology, vol. 69, no. 4, pp. 522–530,2001.

[4] W. R. Farwell and E. N. Taylor, “Serum anion gap, bicarbonateand biomarkers of inflammation in healthy individuals in anational survey,”CanadianMedical Association Journal, vol. 182,no. 2, pp. 137–141, 2010.

[5] H. B. Nguyen, M. Loomba, J. J. Yang et al., “Early lactate clear-ance is associated with biomarkers of inflammation, coagula-tion, apoptosis, organ dysfunction andmortality in severe sepsisand septic shock,” Journal of Inflammation, vol. 7, article 6, 2010.

[6] A. C. Celotto, C. B. A. Restini, V. K. Capellini, L. M. Bendhack,and P. R. B. Evora, “Acidosis induces relaxation mediated bynitric oxide and potassium channels in rat thoracic aorta,”European Journal of Pharmacology, vol. 656, no. 1–3, pp. 88–93,2011.

[7] E. Crimi, F. S. Taccone, T. Infante, S. Scolletta, V. Crudele, andC. Napoli, “Effects of intracellular acidosis on endothelial func-tion: an overview,” Journal of Critical Care, vol. 27, no. 2, pp. 108–118, 2012.

[8] D. Wu, J. A. Kraut, and W. M. Abraham, “Sabiporide improvescardiovascular function, decreases the inflammatory responseand reduces mortality in acute metabolic acidosis in pigs,” PLoSOne, vol. 8, no. 1, Article ID e53932, 2013.

[9] J. A. Kraut and I. Kurtz, “Metabolic acidosis of CKD: diagnosis,clinical characteristics, and treatment,” American Journal ofKidney Diseases, vol. 45, no. 6, pp. 978–993, 2005.

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Metabolic Acidosis Treatment as Part of a Strategy to Curb