METABOLIC ACIDOSIS IN SEPSIS

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Metabolic Acidosis in Sepsis Article · September 2010 DOI: 10.2174/187153010791936900 · Source: PubMed

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Metabolic Acidosis in Sepsis Alexandre Toledo Maciel1, Danilo Teixeira Noritomi2 and Marcelo Park1,* 1

Intensive Care Unit, Emergency Department, Hospital das Clinicas, University of Sao Paulo Medical School, Sao Paulo, Brazil; 2Intensive Care Unit, Hospital Israelita Albert Einstein, Sao Paulo, Brazil Abstract: Metabolic acidosis is very common in critically ill septic patients. Acidosis may be a result of the underlying pathophysiology, but it also may be the result of the way in which those patients are managed. Chloride-associated acidosis is frequent and is potentially aggravated during fluid resuscitation. The severity of metabolic acidosis is associated with poor clinical outcomes; however, it remains uncertain whether or not there is a causal relationship between acidosis and the pathophysiology of septic syndromes. Several experimental findings have demonstrated the impact of acidosis modulation on the release of inflammatory mediators and cardiovascular function. Treatment of metabolic acidosis is based on control of the underlying process and support of organ dysfunction, although the use of intravenous chloridepoor balanced solutions seems an attractive option to prevent the worsening of metabolic acidosis during fluid resuscitation.

Keywords: Metabolic acidosis, sepsis, septic shock. INTRODUCTION Metabolic acidosis is very common in critically ill septic patients [1, 2]. It may be the result of the underlying pathophysiology or a result of the way in which we manage these patients [3]. Current recommendations support aggressive application of volume challenges to optimize hemodynamics and restore the oxygen transport / consumption adequacy in septic patients [4, 5]. However, metabolic acidosis worsening due to fluid infusion is very frequent [6]. The severity of metabolic acidosis is associated with poor clinical outcomes [7], although it remains uncertain whether or not there is a causal relationship between acidosis and the pathophysiology of septic syndromes. There are several techniques for approaching acid-base metabolism, all of them ultimately complementary [8]. To quantitatively describe the metabolic acidosis of critically ill patients, the physicochemical approach has been extensively used in the current literature [2, 7, 9-11]. In this review of septic syndromes and metabolic acidosis, we will discuss distinct approaches to acid-base metabolism, the sources of metabolic acidosis in septic patients, associated outcomes and organ dysfunction, effects on hemodynamics, renal physiology and release of inflammatory mediators, and general aspects of clinical management. APPROACH TO METABOLIC ACIDOSIS Metabolic acidosis, which results from the accumulation of non-volatile organic and/or inorganic acids in the circulation, represents a marker of disease severity [12] and has been proposed as a surrogate for organ dysfunction [13]. It seems that the worse the metabolic acidosis is, the worse is the prognosis. However, much controversy still remains regarding the understanding and management of metabolic *Address correspondence to this author at the Rua Francisco Preto, 46, bloco 3, apto 64 Sao Paulo – Brazil, ZIP 05623010; Tel; ?????????????????; Fax: 55-11-30697221; E-mail: [email protected] 1871-5303/10 $55.00+.00

acidosis. First, different approaches have been proposed to define and quantify metabolic acidosis [14]. Besides the classical descriptive approach based on the HendersonHasselbalch equation and focused on bicarbonate concentration, two other approaches are frequently used in the intensive care unit setting. One of them is based on standard base excess (SBE) and is known as the “Copenhagen approach”; the other one is based on the strong ion difference (SID) and total concentration of non-volatile weak acids (Atot) and is called the “physicochemical approach” [15]. SBE is the amount of acid or base needed to restore the pH to 7.4 while maintaining fixed values of PCO2 (40 mmHg) and temperature (37 oC) and standardized to a hemoglobin value of 5 g/dL, which seems to increase SBE accuracy in vivo and (almost) independently of acute PCO2 variations [16, 17]. Metabolic acidosis is said to be present when the SBE value is negative, usually below -2 mEq/L [18]. SID is the net difference between strong cations (basically, Na+, K+, Mg2+, Ca2+) and anions (Cl- and lactate-) in plasma, with the most relevant non-volatile weak acids being dissociated albumin and phosphate. Metabolic acidosis is the result of decreases in SID or increases in weak acids. Besides increases in chloride and lactate, decreases in SID can be attributed to an increase in the strong ion gap (SIG), which is the variable that quantifies the presence of unmeasured anions in the physicochemical approach. A more extensive review of this approach can be found elsewhere [19, 20]. SOURCES OF METABOLIC ACIDOSIS IN SEPTIC SYNDROMES Metabolic acidosis in patients with septic syndromes can occur due to several ion disturbances, mainly hyperchloremia, hyperlactatemia and the accumulation of unmeasured anions. Each of them can be the result of a different pathophysiological process. Hyperchloremia seems to be the most important ion disturbance responsible for metabolic acidosis in septic patients. In a descriptive study, the authors demonstrated that most of the SBE negative deviation can be © 2010 Bentham Science Publishers Ltd.

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Maciel et al.

explained by the increase in the chloride serum level in comparison to normal volunteers [2]. This result was in accordance with Weil et al. [1]. In addition, the authors have shown this increase to be greater in non-survivors [2].

although hypercapnic acidosis caused a decrease in contractility, thoracolumbar epidural anesthesia increased this depression considerably by blocking sympathetic activity [31].

The sources of hyperchloremic acidosis in critically ill patients, including septic ones, have traditionally been attributed to the infusion of chloride-rich solutions such as normal saline (NS). Several studies have correlated the amount of NS infusion with the degree of hyperchloremia [21, 22]. However, recent evidence suggests that this is not the only source of hyperchloremia. Applying simple stoichiometric calculations, Kellum et al. demonstrated that in endotoxemic animals the degree of hyperchloremia could not be solely explained by NS infusion [23]. This study postulated that a shift in chloride could occur between fluid compartments, e.g., from intracellular to intravascular. Interestingly, this shift does not seem to happen in normal animals [23].

Chloride is implicated in impaired renal function, with hyperchloremia resulting in less natriuresis than might be expected after a saline infusion when compared to Hartmann‘s, a chloride depleted solution [32]. This difference may reflect the tonicity of the respective solutions and the amount of free water, particularly in normovolemic healthy volunteers in whom the responses to alterations in osmolality or in renal vascular tone are more pronounced. Hyperchloremia may also influence coagulation [32]. In aortic aneurysm surgery, it was shown that an infusion of chloriderich solution (NS) was associated with increased blood product requirements [21, 33]. Thromboelastography indicates that saline has more effects on coagulation and platelet function than does a balanced salt solution [34].

Hyperlactatemia has been extensively studied in critically ill patients, mainly because of its prognostic importance [7, 24]. In clinical practice, hyperlactatemia has been traditionally attributed to poor tissue perfusion or a tissue oxygen debt. This association can be the case in some circumstances and in a landmark study the augmentation of oxygen delivery was associated with faster lactate clearance and an improvement in prognosis [4]. However, it has been known for several years that lactate is generated even in situations of no oxygen debt, such as accelerated glycolysis, metabolic alkalosis, and decreased lactate clearance [25]. Unmeasured anions are responsible for a significant amount of metabolic acidosis in septic patients [2, 26]. Furthermore, unmeasured anions seem to be the major acid charge in patients with hyperlactatemia [27]. Forni et al. tried to elucidate which anions constitute the unmeasured anions or SIG and the results pointed to several anions in very small concentrations, most related to the Krebs’ cycle [26]. In addition, the increase in unmeasured anions measured by the SIG can be explained by an exogenous source: the infusion of gelatins that contain organic anions not measured by routine clinical tests [28]. METABOLIC ACIDOSIS, ORGAN DYSFUNCTION AND OUTCOMES OF SEPTIC SYNDROMES The effect of metabolic acidosis on organ function is uncertain to date. In clinical practice, it is very difficult to differentiate the possible effects of metabolic acidosis in organ function from the effect of the underlying pathophysiological process [29]. We will briefly discuss the known effects of acidosis and the role of its mainly causative ions on organ function and clinical outcomes. The most studied effect of acidosis is the reduction in cardiac contractility. In humans, these effects may be counterbalanced by increased catecholamine and calcium production. The impaired response to catecholamines during acidosis is a commonly observed phenomenon. Diminished ventricular performance at low pH has been attributed to a reduced response to catecholamines [30]. Conversely, it can be shown that the contractility changes caused by acidosis are offset by increased catecholamine production. This concept was supported by the observation in rabbits that

The role of lactate may also be important. In experimental hemorrhagic shock in which dichloroacetate was used to block lactate, the subsequent reduction of lactate availability impaired cardiac function [35]. This finding suggests an important protective role for lactate. Indeed, a study has shown that the myocardium prefers lactate to other substrates [36]. Metabolic acidosis is clearly associated with bad clinical outcomes [37]. Smith et al. have demonstrated that patients with a SBE < - 4 mEq/L at ICU admission have a bad prognosis, especially when they are not able to increase this SBE in the next 48 hours [38]. It seems that some types of acidosis have a better prognosis in some scenarios. In a large population of critically ill patients, Gunnerson et al. demonstrated that the worst prognosis was associated with lactic acidosis while the best prognosis (similar to no acidosis) was seen in predominantly hyperchloremic acidosis patients. Intermediate results were observed with SIG acidosis. Particularly in septic patients, hyperchloremia was independently associated with bad prognosis [2]. EFFECTS OF METABOLIC ACIDOSIS ON HEMODYNAMICS Metabolic acidosis has important effects in the cardiovascular system. These effects vary according to the acidosis severity. Mild acidosis activates the sympathetic system, release catecholamines and induces myocardial depression [39]. In more severe acidemias, myocardial depression predominates and hypotension occurs due to peripheral resistance to catecholamines. In sepsis, nitric oxide (NO) production is increased and is thought to be one of the main mechanisms of sepsis-induced hypotension because NO has potent vasodilatory properties. However, Pedoto et al. [40] have suggested that metabolic acidosis by itself stimulates NO production so that metabolic acidosis has a direct arteriolar vasodilatory effect (although vasoconstriction occurs in venous and pulmonary beds induced by acidosis) [39]. Most of these studies are animal experiments and it is difficult to distinguish metabolic acidosis effects from pH effects. It is important to remember that metabolic acidosis may be present with normal pH and this finding is common in critically

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ill patients. In terms of prognosis, metabolic acidosis severity may be the most relevant piece of data, as is retrieved from studies demonstrating that in patients with permissive hypercarbia and respiratory acidosis, non-survivors were the patients with more metabolic acidosis [39]. The fact that the greater the severity of metabolic acidosis the worse the prognosis does not mean that metabolic acidosis is always negative and undesired. It is frequently an epiphenomenon of the underlying deadly pathologic process (shock, for example). In many situations metabolic acidosis can be viewed as an adaptative process. It may decrease ATP turnover and oxygen demand as well as increase oxygen delivery by decreasing oxygen-hemoglobin affinity. Lactate, usually viewed as a marker of poor outcome as occurs with metabolic acidosis, may in fact be part of a metabolic adaptation and even an alternative source of energy [41]. This finding probably explains, at least in part, the deleterious (or not beneficial) effects of the direct correction of metabolic acidosis with sodium bicarbonate, especially when the cause of metabolic acidosis and hyperlactatemia is a cellular energy deficit [42]. This situation is different from metabolic acidosis due to hyperchloremia in which the underlying mechanism is usually excessive exogenous chloride load, renal tubular acidosis or gastrointestinal losses of bicarbonate. EFFECTS OF METABOLIC ACIDOSIS ON RENAL PHYSIOLOGY The kidneys play a major role in acid-base homeostasis. In response to an excessive acid load or production, normal kidneys are able to increase the urinary excretion of ammonium (NH4+), which is accompanied by increased chloride urinary excretion. Routinely, ammonium excretion is not directly measured but it is inferred by a decreased urinary anion gap or, more recently, a urinary strong ion difference (in practice the terms are synonymous) [43]. Urinary strong ion difference (SIDu) is equal to Na+ + K+ – Cl-. The normal value of SIDu is approximately 42 mEq/l, which is similar to plasma SID. In metabolic acidosis not primarily caused by renal dysfunction (most of which decreases plasma SID), the kidneys also produce urine with low SID. These alterations in urine composition are also found in respiratory acidosis. Chronic obstructive pulmonary disease patients frequently have decreased chloremia [44], which is probably due to an increased chloriuresis and, hence, a low SIDu. In healthy pigs we were able to verify that seven hours of induced hypercapnia were sufficient to induce a significant drop in chloremia (unpublished data). However, how do the kidneys experience acidosis? Are they able to distinguish between metabolic and respiratory acidosis? Studies in mice have shown that plasma pH alterations lead to the activation of several complex signaling pathways via receptors on the basolateral surface of kidney tubule cells, resulting in increased glutamine uptake, metabolism and ammonia (NH3) synthesis [45]. NH3 diffuses into the urine and becomes ammonium (NH4+) in the tubular lumen (mainly the proximal tubule) or is actively transported to the tubular lumen in the form of NH4+ by apical Na+/H + exchangers. Patients with many forms of renal tubular acidosis into which the kidneys are not able to adequately acidify urine have alterations in some pathways of this complex cascade.

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Plasma chloride concentrations seem to be relevant in terms of renal physiology. Hyperchloremia is frequently seen in patients with acute renal failure and is generally considered to be, at least in part, caused by kidney dysfunction. However, some ancient studies in animals have pointed out that the chloride concentration may modulate renal vascular tone. Hyperchloremia may actually increase the renal vascular responsiveness to vasoconstrictor agents such as angiotensin II and arginine vasopressin, with the opposite occurring in the presence of low chloride levels [46]. Chloremia’s influence on renal blood flow and glomerular filtration rate is mediated by prostaglandins and thromboxane A2 [47, 48]. The vasoconstrictor effect of hyperchloremia is independent of the renal nervous system, related to tubular chloride reabsorption and specific to renal vessels [47]. Unfortunately, the literature on hyperchloremia and renal vasoconstriction is restricted to animal studies. The possible role of chloriderich solutions and hence hyperchloremic metabolic acidosis as a potential cause of oliguria in human beings still needs to be clarified because a fluid challenge is usually the first measure to correct low urine output and actually may worsen it. EFFECTS OF METABOLIC INFLAMMATORY MEDIATORS

ACIDOSIS

ON

Septic syndromes are correlated with increased concentrations of inflammatory mediators with pro and antiinflammatory properties [49]. The infusion of these proinflammatory mediators in experimental models or in humans can reproduce many alterations similar to the septic syndromes [50]. Classically, metabolic acidosis has been considered an epiphenomenon of systemic inflammation [4, 51]; however there are several pieces of experimental evidence demonstrating that the reduction of pH in the blood through the reduction of SBE (metabolic acidosis) in the extracellular medium can induce inflammatory mediator release [3]. In contrast, the pH reduction via carbon dioxide elevation (respiratory acidosis) does not have the same pathophysiological impact [52]. This former finding points out that the cause of acidosis rather than the acidosis per se is driving the association with clinical outcomes [3]. Currently, there are several experimental studies documenting the effects of metabolic acidemia basically induced by hyperchloremia or hyperlactatemia on the synthesis and release of inflammatory mediators, especially tumor necrosis factor (TNF) and interleukin-6 (IL-6). Addressing hyperchloremic-associated acidosis in the resident alveolar macrophages of rabbits, the progressive reduction of the preconditioned media pH from 7.4 to 5.0 with chloride and phosphate solutions is associated with a linear reduction in TNF release stimulated by constant doses of endotoxin [53]. The effect of extracellular pH on inflammatory mediator release in resident macrophages occurs due to reduced production and in part due to intracellular retention of synthesized interleukin [54]. Besides this fact, when exposed to pH = 7.0 media, Sprague-Dawley peritoneal macrophages acidified with chloridric acid in inflammatory lesions, leads to the up-regulation of iNOS activity through the activation of NFkB [55]. In Sprague-Dawley rats, Kellum et al. induced normotensive lethal sepsis by cecal ligation and puncture,

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and moderate (SBE, -5 to -10 mEq/L) and severe (SBE, -10 to -15 mEq/L) acidosis, induced by HCl infusion, increased circulating levels of IL-6, IL-10, and TNF [56]. In contrast, in the same rat model including hypotensive septic shock animals, moderate hyperchloremic acidosis (SBE of -5 to -10 mEq/L), worsened arterial blood pressure and increased plasma nitrate/nitrite levels and had no effect on circulating cytokines. However, severe acidosis (SBE of -10 to -15 mEq/L), while still causing hypotension, did not affect plasma nitrate/nitrite levels [57]. There is a paucity of studies on the effects of lactic acidosis on inflammatory mediators and immune response [3]. The exposure of rat peritoneal macrophages to lactic acid in pH = 6.75 is associated with an increase in TNF release when endotoxin is added to the media [58]. In contrast, lactate has been considered an energy shuttle for neurons during hypoxia, prolonging cell viability [59]. In an elegant study, Kellum showed in endotoxin-stimulated RAW 264.7 murine macrophages-like cells that decreasing the medium pH with different acids can result in a different pattern of inflammatory mediator release in spite of normalization to the same pH [60]. These results are compatible with a proinflammatory role for metabolic acidosis related to HCl and a neutral or anti-inflammatory effect of metabolic acidosis related to lactic acid. In this study, in pH = 7.0, the activity of NF-kB was only increased in the acidemia related to HCl [60]. The metabolic effect of lactic acid as an energy shuttle is still valid [59, 61], without in vitro pro-inflammatory effects. Based on actual data from the literature, we can conclude that alterations in the extracellular pH are associated with different patterns of inflammatory mediator release. The main determinant of these different patterns is the etiology (hyperchloremia or hyperlactatemia) of the metabolic acidosis. MANAGEMENT OF METABOLIC ACIDOSIS Metabolic acidosis is associated with adverse outcomes both in general [62] and in septic critically ill patients [7]. Chronic metabolic acidosis with acidemia may produce bone disease and protein catabolism [63]. However, clinical evidence for the benefits of treating acute metabolic acidosis in critically ill patients is still leaking [42, 64-66]. Actually, metabolic acidosis might be beneficial for oxygen delivery and metabolism [3, 41]. In this way, the surviving sepsis campaign only recommends the treatment of acute metabolic acidosis with sodium bicarbonate if pH < 7.1 in severe sepsis and septic shock patients [5]. The early-goal resuscitation of severe sepsis and septic shock patients is associated with better outcomes than the conventional resuscitation. Moreover, volemic expansion with normal saline is the mainstay of the therapy [4]. The use of high amounts of normal saline is associated with hyperchloremic metabolic acidosis [67]. From this standpoint, the presence of metabolic acidosis deserves a correct diagnosis, and the use of balanced solutions (chloride-poor) can avoid further hyperchloremic-related metabolic acidosis [67]. When implemented at the beginning of severe sepsis and septic shock syndromes, early goal-directed therapy is asso-

Maciel et al.

ciated with an improvement of metabolic acidosis as shown by the base deficit [4]. However, if the metabolic acidosis has already began, severe acidemia can be treated conventionally with sodium bicarbonate [68]. There are some alternatives to treating severe academia, even though none of these alternatives are associated with improved clinical outcomes: 1. Carbicarb is an equimolar mixture of sodium bicarbonate and sodium carbonate and has a superior alkalinizing effect as compared to sodium bicarbonate due to the potential reduction of tissue CO2 generation [69, 70]; 2. Tris (hydroxymethyl) aminomethane (THAM or Tromethamine) is a weak amino alcohol base with more buffer power than sodium bicarbonate (pKa = 7.82 versus 6.1). It is effective for both metabolic and respiratory acidosis. It is excreted by the kidneys and does not increase the production of CO2; its facilitated cellular diffusion translates into a potential to increase intracellular pH [71]. There is evidence for the reversal of myocardial depression induced by hypercapnia when using THAM as a buffer [72]; 3. Sodium hydroxide has been used experimentally as a component of hemofiltration replacement solutions in experimental models, allowing the reduction of minute ventilation. This solution has a potential tool to reduce tidal volume in acute lung injury patients on mechanical ventilation [73]; and 4. Renal replacement therapy can strongly affect acid–base disorders and can be used to correct severe metabolic acidosis [74]. Anion gap and lactate-associated metabolic acidosis are potentially caused by high-weight molecules [26]; in this way, when the patient is on continuous renal replacement therapy, convective clearance might be associated with major clearance of such molecules. By contrast, while patients are still on continuous renal replacement therapy, hyperchloremic metabolic acidosis is easily corrected with convective and diffusional clearance [75]. Intermittent modes of renal replacement therapy are capable of effectively correcting lactate, anion gap or hyperchloremic-associated acidosis [76]. In habitual dosing of renal replacement therapy, the continuous mode is more effective for correcting metabolic acidosis than are intermittent modes [11, 77]. In conclusion, the pharmacologic correction of metabolic acidosis is not associated with an improvement in clinical outcomes, although the recognition of such a situation can avoid the worsening of acidosis secondary to volume changes. Currently, the treatment of metabolic acidosis with a buffer other than sodium bicarbonate needs further clinical evaluation. CONCLUSIONS Complex metabolic acidosis is common in critically ill septic patients. Furthermore, its severity is associated with poor clinical outcomes and organ dysfunction. The real effect of metabolic acidosis on organ function and sepsis pathophysiology is still uncertain; however, there are several pieces of experimental evidence on the acidosis modulation of inflammatory compounds and cardiovascular function. The treatment of metabolic acidosis is based on the control of the underlying process and support for organ dysfunction, although the use of chloride-poor balanced solutions in fluid intake seems attractive in the way of preventing worsening of acidosis during hemodynamic resuscitation or hydration of critically ill patients.

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Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010, Vol. 10, No. 3

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Received: 08 January, 2010

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Accepted: 20 January, 2010

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