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Original Research: CRITICAL CARE MEDICINE |

Hyperchloremic Acidosis Increases Circulating Inflammatory Molecules in Experimental Sepsis* FREE TO VIEW

John A. Kellum, MD, FCCP; Mingchen Song, MD, PhD; Eyad Almasri, MD
Author and Funding Information

*From the MANTRA Laboratory, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Correspondence to: John A. Kellum, MD, FCCP, University of Pittsburgh, School of Medicine, Department of Critical Care Medicine, 3550 Terrace St, Pittsburgh, PA 15261; e-mail: Kellumja@ccm.upmc.edu



Chest. 2006;130(4):962-967. doi:10.1378/chest.130.4.962
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Published online

Rationale: Hyperchloremic acidosis is common in the critically ill and is often iatrogenic. We have previously shown that hyperchloremic acidosis increases nuclear factor-κB DNA binding in lipopolysaccharide-stimulated RAW 264.7 cells. However, evidence that hyperchloremic acidosis leads to increased inflammation in vivo has been limited to nitric oxide.

Objectives: To determine if acidosis, induced by dilute hydrochloric acid (HCl) infusion, will increase circulating inflammatory mediator levels in an experimental model of severe sepsis in rats.

Methods: Eighteen hours after inducing lethal sepsis by cecal ligation and puncture in 20 adult, male, Sprague-Dawley rats, we randomized animals into three groups. In groups 2 and 3, we began an IV infusion of 0.1 N HCl to reduce the standard base excess (SBE) by 5 to 10 mEq/L and 10 to 15 mEq/L, respectively. In group 1, we infused a similar volume of lactated Ringer solution. In all groups infusion continued 8 h or until the animal died.

Measurements and main results: We measured arterial blood gases, whole-blood lactate, and chloride, tumor necrosis factor (TNF), interleukin (IL)-6, and IL-10 levels at 0 h, 4 h, and 8 h. All measured cytokines increased over time. Compared to group 1, animals in groups 2 and 3 exhibited greater increase in all three cytokines, with the greatest increases seen with severe acidosis.

Conclusion: Moderate (SBE, – 5 to – 10) and severe (SBE, – 10 to – 15) acidosis, induced by HCl infusion, increases circulating levels of IL-6, IL-10, and TNF in normotensive septic rats.

Figures in this Article

Metabolic acidosis commonly complicates various forms of critical illness. In sepsis, metabolic acidosis results from hyperlactatemia and hyperchloremia, as well as from unmeasured anions. Hyperchloremic metabolic acidosis may be avoidable in many cases because the etiology is often saline solution resuscitation. Large-volume saline solution infusion produces metabolic acidosis by increasing the plasma chloride concentration relative to the plasma sodium concentration.16 The result is a reduction in the plasma strong ion difference, the difference between positive and negative charged electrolytes, which in turn produces an increase in free hydrogen ion concentration.7However, the clinical consequences of metabolic acidosis are not well understood. In a study8of experimental endotoxic shock, we found that 0.9% saline solution resuscitation resulted in a decreased survival time and reduced the standard base excess (SBE) by 5 to 10 mEq/L compared to a balanced colloid solution. Although survival time was inversely correlated with the increase in plasma chloride, the effects of hyperchloremic acidosis itself could not be assessed directly. Therefore, in a subsequent study,9we induced hyperchloremic acidosis in normotensive, septic rats, by infusing dilute hydrochloric acid (HCl) and found that increasing acidosis resulted in worsening degrees of hypotension. However, circulating concentrations of inflammatory cytokines varied significantly among animals regardless of whether HCl was infused or not. Inflammatory cytokine release appeared to be influenced more by the presence of shock than by the amount of acidosis per se. Thus, we designed the present study to test the hypothesis that, in the absence of shock, hyperchloremic metabolic acidosis will influence the circulating cytokine response to sepsis. Our hypothesis was formulated on the basis of studies12 using isolated cells exposed to lipopolysaccharide (LPS) in the presence or absence of metabolic acids. Although the results of these studies differ somewhat, all show that acidosis has important effects on cytokine secretion. Thus, we sought to determine if these effects occur in vivo under experimental conditions that more closely resemble human sepsis.

Surgical Preparation

Following approval by the Animal Care and Use Committee of the University of Pittsburgh, we anesthetized 28 adult (24 to 28 weeks old), male, Sprague-Dawley rats with pentobarbital sodium (40 mg/kg intraperitoneally). We performed cecal ligation and puncture (CLP) as previously described9 using a 25% ligation13 and 18-gauge needle, three-puncture technique. This protocol is associated with a control group mortality of 70 to 90% at 72 h. Eighteen hours after CLP, we reanesthetized the animals and intubated them with a beveled 16-guage angiocatheter and ventilated them with room air using a Harvard rodent ventilator (Holliston, MA) at a tidal volume of 6 mL/kg and a frequency sufficient to maintain an arterial Pco2 between 35 and 45 mm Hg. We isolated the right carotid artery and the left femoral vein by dissection and cannulated each with 1.27-mm PE-90 tubing. The femoral vein catheter was advanced into the inferior vena cava.,9

Experimental Protocol

Eighteen hours after CLP and prior to randomization, we measured mean arterial pressure (MAP) and arterial whole-blood lactate. Animals were excluded if they met criteria for shock as defined by Rivers et al14: specifically, MAP ≤ 60 mm Hg or arterial blood lactate ≥ 4 mmol/L. The remaining animals were randomized and classified into three groups. In groups 2 and 3, we began an IV infusion of 0.1 N HCl via the femoral vein to reduce the SBE by 5 to 10 mEq/L and 10 to 15 mEq/L, respectively. We sampled the arterial blood for blood gas measurements (0.2 mL each sample) every 1 to 2 h as dictated by the variation in arterial pH between sampling. We adjusted the rate of HCl infusion as needed to achieve the target SBE. In group 1, we infused lactated Ringer solution at 2 mL/h. In all groups, infusions were continued for 8 h or until the animals died. We administered additional pentobarbital sodium (5 mg/kg intraperitoneally) when needed to maintain anesthesia for the entire protocol.

Measurements and Calculations

MAP was measured continuously and recorded in real time on a strip-chart recorder (Gould; Cleveland, OH). Blood assays including blood gas analysis, whole-blood lactate and chloride, plasma nitrate/nitrite, tumor necrosis factor (TNF), interleukin (IL)-6, and IL-10 levels were obtained at baseline (time 0) and at 4 h and 8 h. SBE was calculated as previously described.15

Cytokine and NO Assays

Cytokine enzyme-linked immunosorbent assay assays were performed as recommended by the manufacturer. Enzyme-linked immunosorbent assay kits for TNF, IL-6, and IL-10 were obtained from R&D Systems (Minneapolis, MN). Total nitrite was measured using cadmium-mediated reduction of NO3 to NO2 followed by the Griess reagent as previously described.1617

Statistical Analysis

Our primary analysis was between the two experimental groups (HCl) and the control (lactated Ringer solution) group and was based on plasma cytokines concentrations. Mean differences between and within groups were analyzed by analysis of variance adjusted for multiple comparisons (Student-Newman-Keuls) for all pairwise comparisons. Trend analysis for dose effect was performed using linear regression. Statistical analysis was performed using statistical software (MedCalc v 7.6; MedCalc; Mariakerke, Belgium); p < 0.05 was considered statistically significant.

Prior to randomization, we excluded 8 of 28 animals because of shock (MAP ≤ 60 mm Hg or lactate ≥ 4 mmol/L). Two additional animals died before completing the 8-h protocol. One animal in group 2 died soon after baseline blood samples were obtained prior to any subsequent sampling; this animal was excluded from further analysis. Another animal in group 3 died just prior to 6 h; this animal was included in the analysis for time 0 and 4 h. We administered a mean volume of 16.3 mL of 0.1 N HCl to group 2 animals and 19.5 mL to group 3 animals; while control animals received 16 mL of lactated Ringer solution (p = not significant).

Acid-base variables at each time point are depicted in Figure 1 . After 8 h, the arterial pH was significantly lower in HCl-treated animals (7.16 ± 0.04 and 7.08 ± 0.12 for groups 2 and 3, respectively) compared to control animals (7.27 ± 0.07) [p = 0.002]. Similarly, SBE was lower in HCl-treated animals (− 11.0 ± 3.7 mEq/L and − 13.1 ± 1.9 mEq/L for groups 2 and 3, respectively) compared to control animals (− 6.9 ± 4.4 mEq/L) [p = 0.017]. Whole-blood chloride increased with HCl (118.5 ± 5.0 mmol/L and 131.0 ± 11.3 mmol/L vs 111.7 ± 3.5 mmol/L) [p = 0.02], while lactate and Pco2 were unchanged. MAP was stable among the three groups over time, as shown in Figure 2 .

Also by 8 h, plasma TNF, IL-6, and IL-10 levels were all significantly higher in both acidosis groups compared to control subjects (Fig 3 ). Indeed, there was a dose effect (beginning at 4 h for IL-10), whereby increasing severity of acidosis brought about an increase in cytokines. Unlike the cytokine response, plasma nitrite levels were not significantly different in the three groups. Slightly higher levels were seen in group 3 animals (32.1 ± 10.8 μmol/L) compared to either group 1 (26.2 ± 7.6 μmol/L) or group 2 animals (24.4 ± 7.2 μmol/L), but this difference was not significant.

Hyperchloremic acidosis, induced by dilute HCl infusion, significantly increased cytokine expression in a dose-dependent fashion in normotensive septic animals. Our results are consistent with an in vitro study10 showing that HCl influences cytokine production in LPS-stimulated RAW 264.7 cells. However, the nature of the effect is very different. Both proinflammatory (TNF, IL-6) and antiinflammatory (IL-10) mediators were increased by HCl infusion in vivo (at 8 h) and in roughly equal proportion, while in vitro both responses were decreased (at 24 h) with a much greater impact on IL-10 compared to IL-6.,10 These findings illustrate the important differences between models, especially whole animals vs cell culture experiments. Interestingly, in vitro studies,1011 have shown that HCl induces an increase in nuclear factor-κB DNA binding at pH in the range seen in our present study. This proinflammatory effect at the level of gene induction, despite a decrease in cytokine levels, might suggest that the effects of HCl are also highly time dependent.

Several potentially important differences between whole animal experiments compared to isolated cells include the effects of acidosis on various hormonal responses. Metabolic acidosis increases catecholamine synthesis18 and, in turn, catecholamines are known to induce inflammatory mediator production,1820 primarily through α-adrenergic action.18 Similarly, acidemia has been shown to stimulate vasopressin, adrenocorticotropic hormone, and aldosterone in experimental animal models.2123 All these effects may influence the inflammatory response and may also counteract any effect of acidosis on BP.2425 Moreover, our results are also somewhat different from our previous study9 using a similar in vivo model. In this earlier study,,9 we did not exclude animals with septic shock and, thus, shock itself may have confounded the effects of acidosis on the inflammatory response.26 Interestingly, unlike previous studies,9,2728 we could not demonstrate hypotension as a result of hyperchloremic acidosis. This may have been because our animals were more volume resuscitated. By excluding animals with septic shock (MAP < 60 mm Hg or lactate > 4 mmol/L), we found that larger volumes of dilute HCl were required to achieve similar biochemical end points compared to our previous study.9 This may have obscured any effects of acidosis on BP. However, we also failed to demonstrate an increase in NO with increasing acidosis. Although there was a trend toward greater nitric oxide (NO) release by 8 h in group 3, differences between groups were not significant at any time point. If, as some authors28 have suggested, the optimal pH for inducible NO synthase is near 7.0, we may not have achieved a change in pH associated with a changes in inducible NO synthase activity and NO production as seen previously.910

The mechanisms responsible for effects of hyperchloremic acidosis on inflammation are not known. A direct effect of pH on intracellular signaling seems unlikely given differences between HCl and lactic acid in LPS-stimulated RAW 264.7 cells,10 as well as differences seen between CO2 and “metabolic” acids.,29 Anion specific effects (eg, chloride vs lactate) therefore seem more likely but remain unproven.

However, regardless of the mechanism(s), the effects of hyperchloremic acidosis seen in this study occurred at levels of acidosis (SBE − 10) commonly seen clinically. Furthermore, the nature of hyperchloremic acidosis in the ICU is at least partially iatrogenic. Solutions that contain superphysiologic concentrations of chloride (ie, 0.9% saline solution) are routinely used for volume resuscitation. When administered rapidly and in large quantities, these solutions induce hyperchloremic metabolic acidosis,26 the magnitude of which is similar to the targets we chose in this investigation.8 Although the chemical mechanisms for these effects have been well described,1,7,30there is still controversy as to whether these effects are deleterious to patients.3132 Consistent with other reports,8,2728,33 our results suggest that hyperchloremic acidosis of the magnitude seen clinically might be harmful. For example, Pedoto and colleagues have demonstrated that hyperchloremic acidosis increases lung28 and intestinal injury27 in healthy rats. Comparing starch preparations in saline solution vs balanced electrolyte solution for elderly GI surgery patients, Wilkes and coworkers33described worse acid-base balance and more adverse events with the saline solution-based fluid. Similar findings have been reported with 0.9% saline solution compared to lactated Ringer solution.34Indeed, the side effect profile of saline solution-induced acidosis, nausea, vomiting, abdominal pain, headache, thirst, hyperventilation, and delayed urination is identical to what occurs with ammonium chloride administration.3536 Thus, while there is little evidence that treating metabolic acidosis improves clinical outcomes,32,37 there is mounting evidence that iatrogenic metabolic acidosis may be harmful. While animal studies are rarely sufficient to guide clinical practice, the prudent clinician might reasonably seek to avoid iatrogenic hyperchloremic acidosis perhaps by using alternative fluids for resuscitation. However, clinical studies are needed before specific strategies can be recommended.

Our study has several limitations. First, the common etiologies of hyperchloremic acidosis in the critically ill do not include HCl infusion. Whether from large-volume saline solution resuscitation or secondary to the effects of renal tubular dysfunction or loss of Donan equilibrium,30 clinical hyperchloremia may be very different from that induced experimentally using dilute HCl. However, our approach has the advantage of separating the potential effects of hyperchloremia from the confounding effects of volume shifts and/or renal dysfunction. While this reductionist approach may limit generalizability, it allows for a more careful dissection of the isolated effects of hyperchloremia. Indeed, studies in patients will be needed before the clinical importance of these animal observations can be determined. This study was intended to generate testable hypotheses and to develop a conceptual framework for future clinical studies.

Second, although we used an experimental model of sepsis that enjoys wide usage in laboratories that study sepsis, there are important differences from human sepsis even after species differences are considered. First, multiple perforations of the cecum do not spontaneously occur in otherwise healthy humans. Our use of older rats (24 to 28 weeks old, after breeding age) may help to more closely simulate the “typical clinical picture”; however, with the except of certain “fulminant” cases, patients do not often present to medical attention within hours of their infection. Furthermore, when they do present they are usually offered more than anesthesia, mechanical ventilation, and fluid resuscitation. We chose not to treat animals with antibiotics or source control surgery for the important reason that these therapies also alter the inflammatory response and may well have obscured any “signal.” However, we acknowledge that this is clearly a limitation of these kinds of experiments.

Finally, as already acknowledged, our study does not address the physiologic mechanisms responsible for the increases in cytokines seen with hyperchloremic acidosis. Although evidence from RAW 264.7 cells10and peritoneal macrophages11 have implicated gene induction through nuclear factor κ-B, this mechanism has not, to our knowledge, been examined in acidosis in vivo. Furthermore, given the range of cytokine effects involving both proinflammatory and antiinflammatory cytokines, multiple pathways are likely to be involved.

At clinically relevant levels, hyperchloremic metabolic acidosis increases circulating inflammatory cytokines in animals with sepsis but without shock. The mechanism(s) responsible for this effect are unknown.

Abbreviations: CLP = cecal ligation and puncture; HCl = hydrochloric acid; IL = interleukin; LPS = lipopolysaccharide; MAP = mean arterial pressure; NO = nitric oxide; SBE = standard base excess; TNF = tumor necrosis factor

Support for this project was provided, in part, by a grant the Laerdal Foundation for Acute Medicine.

The authors have no conflicts of interest to disclose.

Figure Jump LinkFigure 1. Changes in acid-base variables, arterial blood pH, lactate, SBE, Cl, and Pco2 for each group (mean ± SE) over time are shown. Solid line and diamonds correspond to group 1 (control); dashed line and squares correspond to group 2 (SBE, – 5 to – 10 mEq/L); and dotted line and triangles correspond to group 3 (SBE, –10 to –15 mEq/L). *Differences between groups were significant at 8 h (p < 0.05, analysis of variance).Grahic Jump Location
Figure Jump LinkFigure 2. Changes in MAP. Mean ± SE. Solid line and diamonds correspond to group 1 (control); dashed line and squares correspond to group 2 (SBE, – 5 to – 10 mEq/L); and dotted line and triangles correspond to group 3 (SBE, – 10 to – 15 mEq/L).Grahic Jump Location
Figure Jump LinkFigure 3. Changes in plasma concentrations for IL-6, IL-10, and TNF. Mean plasma concentrations for each mediator are shown for baseline, 4 h, and 8 h. Group 1 (control) are shown as open bars, group 2 (SBE, – 5 to – 10 mEq/L) are shown as cross-hatched bars, and group 3 (SBE, – 10 to – 15 mEq/L) are shown as solid gray bars. Error bars indicate SE. *Differences between groups 1 and 3 were significant by analysis of variance and by regression analysis for dose trend (p < 0.05).Grahic Jump Location

The authors wish to thank Greg Roberts and Jeff Schmigel for technical assistance.

Kellum, JA, Bellomo, R, Kramer, DJ, et al (1998) Etiology of metabolic acidosis during saline resuscitation in endotoxemia.Shock9,364-368. [CrossRef] [PubMed]
 
Scheingraber, S, Rehm, M, Sehmisch, C, et al Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery.Anesthesiology1999;90,1265-1270. [CrossRef] [PubMed]
 
Waters, JH, Miller, LR, Clack, S, et al Cause of metabolic acidosis in prolonged surgery.Crit Care Med1999;27,2142-2146. [CrossRef] [PubMed]
 
Waters, JH, Bernstein, CA Dilutional acidosis following hetastarch or albumin in healthy volunteers.Anesthesiology2000;93,1184-1187. [CrossRef] [PubMed]
 
Liskaser, FJ, Bellomo, R, Hayhoe, M, et al Role of pump prime in the etiology and pathogenesis of cardiopulmonary bypass-associated acidosis.Anesthesiology2000;93,1170-1173. [CrossRef] [PubMed]
 
Rehm, M, Orth, V, Scheingraber, S, et al Acid-base changes caused by 5% albumin versus 6% hydroxyethyl starch solution in patients undergoing acute normovolemic hemodilution: a randomized prospective study.Anesthesiology2000;93,1174-1183. [CrossRef] [PubMed]
 
Stewart, P Modern quantitative acid-base chemistry.Can J Physiol Pharmacol1983;61,1444-1461. [CrossRef] [PubMed]
 
Kellum, JA Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: improved survival and acid-base balance with a synthetic colloid in a balanced electrolyte solution compared to saline.Crit Care Med2002;30,300-305. [CrossRef] [PubMed]
 
Kellum, JA, Song, M, Venkataraman, R Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis.Chest2004;125,243-248. [CrossRef] [PubMed]
 
Kellum, JA, Song, M, Li, J Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells.Am J Physiol Regul Integr Comp Physiol2004;286,R686-R692. [CrossRef] [PubMed]
 
Bellocq, A, Suberville, S, Philippe, C, et al Low environmental pH is responsible for the induction of nitric-oxide synthase in macrophages: evidence for involvement of nuclear factor-κB activation.J Biol Chem1998;273,5086-5092. [CrossRef] [PubMed]
 
Jensen, JC, Buresh, C, Norton, JA Lactic acidosis increases tumor necrosis factor secretion and transcription in vitro.J Surg Res1990;49,350-353. [CrossRef] [PubMed]
 
Singleton, KD, Wischmeyer, PE Distance of cecum ligated influences mortality, tumor necrosis factor-α and interleukin-6 expression following cecal ligation and puncture in the rat.Eur Surg Res2003;35,486-491. [CrossRef] [PubMed]
 
Rivers, E, Nguyen, B, Havstad, S, et al Early goal-directed therapy in the treatment of severe sepsis and septic shock.N Engl J Med2001;345,1368-1377. [CrossRef] [PubMed]
 
Christiansen, TF An algorithm for calculating the concentration of the base excess of blood. Siggard-Andersen, O eds.Proceedings of the IFCC expert panel on pH and blood gases1981,77-81 Radiometer Medical A/S. Copenhagen, Denmark:
 
Vodovotz, Y Modified microassay for serum nitrite and nitrate.Biotechniques1996;20,390-394. [PubMed]
 
Green, LC, Wagner, DA, Glogowski, J, et al Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids.Anal Biochem1982;126,131-138. [CrossRef] [PubMed]
 
Tulzo, YL, Shenkar, R, Kaneko, D Hemorrhage increases cytokines expression in lung mononuclear cell in mice, involvement of catecholamines in nuclear factor-B regulation and cytokine expression.J Clin Invest1997;99,1516-1524. [CrossRef] [PubMed]
 
van der Poll, T, Jansen, J, Endert, E, et al Noradrenaline inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin 6 production in human whole blood.Infect Immun1994;62,2046-2050. [PubMed]
 
Severn, A, Rapson, NT, Hunter, CA, et al Regulation of tumor necrosis factor production by adrenaline and -adrenergic agonists.J Immunol1992;148,3441-3445. [PubMed]
 
Augustinsson, O, Forslid, A Aldosterone secretion during acute respiratory acidosis and NH4Cl-induced metabolic acidosis in the goat.Acta Physiol Scand1989;136,339-345. [CrossRef] [PubMed]
 
Faucher, DJ, Lowe, TW, Magness, RR, et al Vasopressin and catecholamine secretion during metabolic acidemia in the ovine fetus.Pediatr Res1987;21,38-43. [CrossRef] [PubMed]
 
Wood, CE, Chen, HG Acidemia stimulates ACTH, vasopressin, and heart rate responses in fetal sheep.Am J Physiol1989;257,R344-R349. [PubMed]
 
Al-Kharfy, KM, Kellum, JA, Matzke, GR Unintended immunomodulation: part II; Effects of pharmacological agents on cytokine activity.Shock2000;13,346-360. [CrossRef] [PubMed]
 
Al-Kharfy, KM, Kellum, JA, Matzke, G Unintended immunomodulation: part I; Effect of common clinical conditions on cytokine biosynthesis.Shock2000;13,333-345. [CrossRef] [PubMed]
 
Ayala, A, Perrin, MM, Chaudry, IH Defective macrophage antigen presentation following haemorrhage is associated with the loss of MHC class II (Ia) antigens.Immunol1990;70,33-39
 
Pedoto, A, Nandi, J, Oler, A, et al Role of nitric oxide in acidosis-induced intestinal injury in anesthetized rats.J Lab Clin Med2001;138,270-276. [CrossRef] [PubMed]
 
Pedoto, A, Caruso, JE, Nandi, J Acidosis stimulates nitric oxide production and lung damage in rats.Am J Respir Crit Care Med1999;159,397-402. [PubMed]
 
Laffey, JG, Kavanagh, BP Carbon dioxide and the critically ill-too little of a good thing?Lancet1999;354,1283-1286. [CrossRef] [PubMed]
 
Kellum, JA Determinants of blood pH in health and disease.Crit Care2000;4,6-14. [PubMed]
 
Prough, DS Acidosis associated with perioperative saline administration: dilution or delusion?Anesthesiology2000;93,1167-1169. [CrossRef] [PubMed]
 
Forsythe, SM, Schmidt, GA Sodium bicarbonate for the treatment of lactic acidosis.Chest2000;117,260-267. [CrossRef] [PubMed]
 
Wilkes, NJ, Woolf, R, Mutch, M, et al The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients.Anesth Analg2001;93,811-816. [CrossRef] [PubMed]
 
Williams, EL, Hildebrand, KL, McCormick, SA, et al The effect of intravenous lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers.Anesth Analg1999;88,999-1003. [PubMed]
 
Wilcox, CS Regulation of renal blood flow by plasma chloride.J Clin Invest1983;71,726-735. [CrossRef] [PubMed]
 
Bushinsky, DA, Coe, FL Hyperkalemia during acute ammonium chloride acidosis in man.Nephron1985;40,38-40. [CrossRef] [PubMed]
 
Cooper, D, Herbertson, M, Werner, H, et al Bicarbonate does not increase left ventricular contractility during L-lactic acidemia in pigs.Am Rev Respir Dis1993;148,317-322. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Changes in acid-base variables, arterial blood pH, lactate, SBE, Cl, and Pco2 for each group (mean ± SE) over time are shown. Solid line and diamonds correspond to group 1 (control); dashed line and squares correspond to group 2 (SBE, – 5 to – 10 mEq/L); and dotted line and triangles correspond to group 3 (SBE, –10 to –15 mEq/L). *Differences between groups were significant at 8 h (p < 0.05, analysis of variance).Grahic Jump Location
Figure Jump LinkFigure 2. Changes in MAP. Mean ± SE. Solid line and diamonds correspond to group 1 (control); dashed line and squares correspond to group 2 (SBE, – 5 to – 10 mEq/L); and dotted line and triangles correspond to group 3 (SBE, – 10 to – 15 mEq/L).Grahic Jump Location
Figure Jump LinkFigure 3. Changes in plasma concentrations for IL-6, IL-10, and TNF. Mean plasma concentrations for each mediator are shown for baseline, 4 h, and 8 h. Group 1 (control) are shown as open bars, group 2 (SBE, – 5 to – 10 mEq/L) are shown as cross-hatched bars, and group 3 (SBE, – 10 to – 15 mEq/L) are shown as solid gray bars. Error bars indicate SE. *Differences between groups 1 and 3 were significant by analysis of variance and by regression analysis for dose trend (p < 0.05).Grahic Jump Location

Tables

References

Kellum, JA, Bellomo, R, Kramer, DJ, et al (1998) Etiology of metabolic acidosis during saline resuscitation in endotoxemia.Shock9,364-368. [CrossRef] [PubMed]
 
Scheingraber, S, Rehm, M, Sehmisch, C, et al Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery.Anesthesiology1999;90,1265-1270. [CrossRef] [PubMed]
 
Waters, JH, Miller, LR, Clack, S, et al Cause of metabolic acidosis in prolonged surgery.Crit Care Med1999;27,2142-2146. [CrossRef] [PubMed]
 
Waters, JH, Bernstein, CA Dilutional acidosis following hetastarch or albumin in healthy volunteers.Anesthesiology2000;93,1184-1187. [CrossRef] [PubMed]
 
Liskaser, FJ, Bellomo, R, Hayhoe, M, et al Role of pump prime in the etiology and pathogenesis of cardiopulmonary bypass-associated acidosis.Anesthesiology2000;93,1170-1173. [CrossRef] [PubMed]
 
Rehm, M, Orth, V, Scheingraber, S, et al Acid-base changes caused by 5% albumin versus 6% hydroxyethyl starch solution in patients undergoing acute normovolemic hemodilution: a randomized prospective study.Anesthesiology2000;93,1174-1183. [CrossRef] [PubMed]
 
Stewart, P Modern quantitative acid-base chemistry.Can J Physiol Pharmacol1983;61,1444-1461. [CrossRef] [PubMed]
 
Kellum, JA Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: improved survival and acid-base balance with a synthetic colloid in a balanced electrolyte solution compared to saline.Crit Care Med2002;30,300-305. [CrossRef] [PubMed]
 
Kellum, JA, Song, M, Venkataraman, R Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis.Chest2004;125,243-248. [CrossRef] [PubMed]
 
Kellum, JA, Song, M, Li, J Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells.Am J Physiol Regul Integr Comp Physiol2004;286,R686-R692. [CrossRef] [PubMed]
 
Bellocq, A, Suberville, S, Philippe, C, et al Low environmental pH is responsible for the induction of nitric-oxide synthase in macrophages: evidence for involvement of nuclear factor-κB activation.J Biol Chem1998;273,5086-5092. [CrossRef] [PubMed]
 
Jensen, JC, Buresh, C, Norton, JA Lactic acidosis increases tumor necrosis factor secretion and transcription in vitro.J Surg Res1990;49,350-353. [CrossRef] [PubMed]
 
Singleton, KD, Wischmeyer, PE Distance of cecum ligated influences mortality, tumor necrosis factor-α and interleukin-6 expression following cecal ligation and puncture in the rat.Eur Surg Res2003;35,486-491. [CrossRef] [PubMed]
 
Rivers, E, Nguyen, B, Havstad, S, et al Early goal-directed therapy in the treatment of severe sepsis and septic shock.N Engl J Med2001;345,1368-1377. [CrossRef] [PubMed]
 
Christiansen, TF An algorithm for calculating the concentration of the base excess of blood. Siggard-Andersen, O eds.Proceedings of the IFCC expert panel on pH and blood gases1981,77-81 Radiometer Medical A/S. Copenhagen, Denmark:
 
Vodovotz, Y Modified microassay for serum nitrite and nitrate.Biotechniques1996;20,390-394. [PubMed]
 
Green, LC, Wagner, DA, Glogowski, J, et al Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids.Anal Biochem1982;126,131-138. [CrossRef] [PubMed]
 
Tulzo, YL, Shenkar, R, Kaneko, D Hemorrhage increases cytokines expression in lung mononuclear cell in mice, involvement of catecholamines in nuclear factor-B regulation and cytokine expression.J Clin Invest1997;99,1516-1524. [CrossRef] [PubMed]
 
van der Poll, T, Jansen, J, Endert, E, et al Noradrenaline inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin 6 production in human whole blood.Infect Immun1994;62,2046-2050. [PubMed]
 
Severn, A, Rapson, NT, Hunter, CA, et al Regulation of tumor necrosis factor production by adrenaline and -adrenergic agonists.J Immunol1992;148,3441-3445. [PubMed]
 
Augustinsson, O, Forslid, A Aldosterone secretion during acute respiratory acidosis and NH4Cl-induced metabolic acidosis in the goat.Acta Physiol Scand1989;136,339-345. [CrossRef] [PubMed]
 
Faucher, DJ, Lowe, TW, Magness, RR, et al Vasopressin and catecholamine secretion during metabolic acidemia in the ovine fetus.Pediatr Res1987;21,38-43. [CrossRef] [PubMed]
 
Wood, CE, Chen, HG Acidemia stimulates ACTH, vasopressin, and heart rate responses in fetal sheep.Am J Physiol1989;257,R344-R349. [PubMed]
 
Al-Kharfy, KM, Kellum, JA, Matzke, GR Unintended immunomodulation: part II; Effects of pharmacological agents on cytokine activity.Shock2000;13,346-360. [CrossRef] [PubMed]
 
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    Print ISSN: 0012-3692
    Online ISSN: 1931-3543