Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis

STUDY OBJECTIVE: To determine the effects of hyperchloremic acidosis, induced by dilute HCl infusion, on BP and circulating inflammatory mediators in an experimental model of severe sepsis in the rat. DESIGN: Randomized, open-label, controlled experiment. SETTING: University research laboratory. PARTICIPANTS: Twenty-four adult, male, Sprague-Dawley rats. INTERVENTION: Eighteen hours after inducing lethal sepsis by cecal ligation and puncture, animals were randomized and classified 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, infusions were continued for 8 h or until the animals died. MEASUREMENTS: We measured mean arterial pressure (MAP), arterial blood gases, electrolytes, plasma nitrate/nitrite, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 levels at 0 h, 3 h, 6 h, and 8 h. RESULTS: MAP remained stable in group 1 but decreased in groups 2 and 3 (p < 0.001), such that at 8 h MAP was much higher in group 1 (94 +/- 9.2 mm Hg) [+/- SD] compared to either group 2 (71.6 +/- 20.1 mm Hg) or group 3 (49.4 +/- 33.2 mm Hg) [p = 0.01]. This change in MAP correlated with the increase in plasma Cl(-) (R(2) = 0.50, p < 0.0001) and less well with the decrease in pH (R(2) = 0.24, p < 0.001). After 6 h of acidosis, plasma nitrite levels were significantly higher in group 2 animals compared to either group 1 or group 3 animals (p < 0.05). Plasma TNF-alpha, IL-6, or IL-10 levels were not significantly different from control animals. CONCLUSION: Moderate acidosis (SBE of 5 to 10 mEq/L), induced by HCl infusion, worsened BP and increased plasma nitrate/nitrite levels but had no effect on circulating cytokines in septic rats. However, severe acidosis (SBE of 10 to 15 mEq/L), while still causing hypotension, did not affect plasma nitrate/nitrite levels.     

Hyperchloremic metabolic acidosis after chlorine inhalation

Chlorine gas Inhalation is usually accompanied by pulmonary toxicity and hypoxemia; the associated acidemia, when present, has been attributed to lactic acidosis. This case report describes the development of hyperchloremic metabolic acidosis following accidental chlorine gas exposure. The mechanism postulated for the production of this acidosis is the absorption of hydrochloric acid following the reaction of chlorine gas with tissue water. This may be the first case of chlorine toxicity in which the mechanism of the acidosis has been determined.     

Hyperchloremic acidosis during the recovery phase of diabetic ketosis.

We have studied 35 patients to find the occurrence of hyperchloremic acidosis during the recovery phase of diabetic ketoacidosis. At admission the patients had typical normochloremic acidosis, with increased anion gap exactly balancing decreased serum bicarbonate. In contrast, in 18 patients with phenformin-induced lactic acidosis, the increase in anion gap at admission was much greater than the decrease in bicarbonate. The difference between lactic acidosis and ketoacidosis may be explained by a slower rate of excretion of lactate than of ketone anions. After the patients with ketoacidosis were treated, the acidosis became predominantly hyperchloremic with normal anion gap. Failure to normalize serum bicarbonate is attributed to excretion of ketone anions in the urine.     

Therapeutic immunoadsorption increases the level of circulating soluble HLA molecules

BACKGROUND AND OBJECTIVES: Immunoadsorption (IA) is an established procedure to remove Igs and immune complexes from peripheral blood. Since Igs reportedly bind to human leucocyte antigen (HLA) molecules, we were interested to know whether removal of Ig will also influence the plasma concentration of soluble HLA (sHLA). PATIENTS AND METHODS: Nine patients suffering from severe autoimmune disease and undergoing 17 single courses of IA treatment were monitored for their sHLA class I (sHLA-I) and sHLA-DR plasma levels. Plasma was separated by a hollow-fiber-type separator. Plasma samples were taken before therapy, after 15 min of recirculation (without operating the adsorber), after 1 and 2 liters of plasma adsorption, and 24 and 48 h after the end of IA. RESULTS: Before treatment the mean levels of sHLA-I and sHLA-DR were 0.37 (+/-0.06 SEM) and 0. 32+/-0.05 microg/ml, respectively. After 2 liters of plasma filtration, an increase in sHLA-DR (0.80+/-0.10 microg/ml) was observed (p<0.001), whereas sHLA-I was only slightly affected (mean: 0.45+/-0.06 microg/ml). sHLA concentrations returned to initial levels after 24 h. CONCLUSION: The significant increase in sHLA-DR may contribute to the immunomodulatory effect of IA.     

Arterial injury increases expression of inflammatory adhesion molecules in the carotid arteries of apolipoprotein-E-deficient mice

Recent studies demonstrate increased cellular adhesion molecule expression by neointimal endothelium overlying primary and restenotic atherosclerotic plaque. In this study, we developed an atherosclerotic mouse model of arterial injury and characterized adhesion molecule expression after injury. Sixteen apolipoprotein-E-(ApoE)-deficient mice fed a Western-type diet for 4 weeks underwent carotid artery wire denudation at week 2. For each segment, the extent of neointima formation and medial thickening, or adhesion molecule expression, were scored separately on a scale from 0 (no plaque/thickening or expression) to 3 (extensive plaque/thickening or expression) using Movat staining (n = 3) or immunohistochemical analysis (n = 13). Histology revealed significant medial thickening (1.8 +/- 0.9 vs. 0.3 +/- 0.5, p < 0. 001) versus controls and pronounced staining for monocytes/macrophages in the wall of injured vessels. Immunohistochemical analysis showed more robust expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the luminal surface of injured arteries versus controls (2.2 +/- 0.6 vs. 1.4 +/- 0.7, p < 0.01, and 2.5 +/- 0.5 vs. 1.2 +/- 0.6, p < 0.001, respectively). Injury increased adventitial ICAM-1 expression (2.6 +/- 0.5 vs. 1.6 +/- 0.5, p < 0.002) and medial VCAM-1 expression (2.2 +/- 0.6 vs. 1.2 +/- 0. 7, p < 0.004). Thus, carotid injury results in significant medial thickening and increases adhesion molecule expression beyond that induced in ApoE-deficient mice fed a Western diet alone. The observation of macrophage infiltration into the media at sites of increased ICAM-1 and VCAM-1 expression suggests that these molecules may mediate monocyte/macrophage trafficking into the wall of injured arteries.     

Unmeasured anion during severe sepsis with metabolic acidosis

It is assumed that the development of metabolic acidosis during sepsis is secondary to lactic acidosis. We assessed the composition of the anion gap during severe sepsis induced by cecal perforation in rats. In the first experiment, cardiac output, arterial blood gases, and arterial lactate were measured over a 6 hr interval in five septic rats and in five rats serving as sham-operated controls. The cardiac output decreased from 331 +/- 32 to 172 +/- 9 ml/kg/min (P less than 0.01) in the septic rats. Although the arterial lactate was increased to 2.1 +/- 0.2 mEq/L in septic rats compared to 0.8 +/- 0.1 mEq/L in sham rats (P less than 0.01), the HCO3- was decreased to 16.5 +/- 0.6 mEq/L in septic rats versus 23.8 +/- 1.10 mEq/L in sham rats (P less than 0.01). We further investigated this bicarbonate deficit in a second study in which arterial blood was sampled at 6 hr for blood gases, and plasma Na+, K+, Cl-, HCO3-, lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, citrate, creatinine, albumin, and amino acids in five septic and five sham rats. The serum anion gap was calculated as [(Na(+) + K+) - (Cl(-) + HCO3-)]. The anion gap was 21.6 +/- 1.6 mEq/L in the septic animals as compared to 13.2 +/- 0.5 mEq/L in the sham animals (P less than 0.01). There were no differences in the concentration of pyruvate, beta-hydroxybutyrate, acetoacetate, citrate, creatinine, albumin, or amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)     

The inflammatory balance in human sepsis

Summary Sepsis and its potential degradation into multiple organ failure, reflects a complex immunological process occurring system wide, fueled by local and systemic proinflammatory stimuli, the activity of which is only minimally reflected in the levels of pro- and anti-inflammatory mediators found in the blood. On a cellular level, sepsis encompasses the up-regulation of both pro- and anti-inflammatory pathways. Inflammation is augmented through activation of the intracellular promoter protein nuclear factor κB (NF-κB), which induces synthesis of mRNA coding for many of the pro-inflammatory mediators, including TNF-α, IL-8, and inducible nitric oxide synthase. Similarly, the same stimuli also produce parallel activation of the heat shock protein (hsp) pathways that inhibit NF-κB activation and minimize the inflammatory response. It is the balance between these two pathways that appears to determine the immune responsiveness of the cells both locally and system wide. By characterizing this immune responsiveness, one may understand better the determinants of the ultimate inflammatory response and potential immunotherapy. Received: 7. Juli 1998 Accepted: 2 November 1998     

The inflammatory balance in human sepsis

Sepsis and its potential degradation into multiple organ failure, reflects a complex immunological process occurring system wide, fueled by local and systemic proinflammatory stimuli, the activity of which is only minimally reflected in the levels of pro- and anti-inflammatory mediators found in the blood. On a cellular level, sepsis encompasses the up-regulation of both pro- and anti-inflammatory pathways. Inflammation is augmented through activation of the intracellular promoter protein nuclear factor κB (NF-κB), which induces synthesis of mRNA coding for many of the pro-inflammatory mediators, including TNF-α, IL-8, and inducible nitric oxide synthase. Similarly, the same stimuli also produce parallel activation of the heat shock protein (hsp) pathways that inhibit NF-κB activation and minimize the inflammatory response. It is the balance between these two pathways that appears to determine the immune responsiveness of the cells both locally and system wide. By characterizing this immune responsiveness, one may understand better the determinants of the ultimate inflammatory response and potential immunotherapy.     

Anti-complement strategies in experimental sepsis

Using the cecal ligation/puncture (CLP) model of sepsis in rodents, evidence was obtained for excessive activation of the complement system, which leads to nearly total loss of innate immune protective functions of blood neutrophils. These defects are associated with profound defects in chemotaxis, respiratory burst (H2O2 production) and phagocytosis. The molecular mechanisms of these defects are linked to the complement activation product C5a. In CLP rats and mice, the C5a receptor (C5aR) is widely up-regulated in organs, in part owing to the production of interleukin-6 (IL-6). The up-regulation of C5aR in the thymus is linked to C5a-dependent induction of apoptosis in thymocytes, as revealed by caspase activation, increased binding of C5a and DNA laddering. Such events in thymocytes are prevented if rats first are treated with anti-C5a or with anti-C5aR at the time of CLP. Treatment of CLP rats and mice with anti-C5a, anti-IL-6 or anti-C5aR dramatically improves survival rates after CLP, indicating a linkage between C5a and C5aR in the harmful outcomes of sepsis in rodents. Studies are underway in humans with sepsis to determine whether similar mechanisms are in play.     

Age-related increases in circulating inflammatory markers in men are independent of BMI, blood pressure and blood lipid concentrations

ObjectiveTo examine whether age-related increase in concentrations of circulating inflammatory mediators is due to concurrent increases in cardiovascular risk factors or is independent of these.Methods and resultsCytokines (IL-6, IL-18), chemokines (6Ckine, MCP-1, IP-10), soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin) and adipokines (adiponectin) were measured in the plasma of healthy male subjects aged 18–84 years (n = 162). These were related to known cardiovascular risk factors (age, BMI, systolic and diastolic blood pressure, plasma total cholesterol, LDL cholesterol, HDL cholesterol and triacylglycerol concentrations) in order to identify significant associations. Plasma concentrations of sVCAM-1, sE-selectin, IL-6, IL-18, MCP-1, 6Ckine, IP-10 and adiponectin, but not sICAM-1, were significantly positively correlated with age, as well as with several other cardiovascular risk factors. The correlations with other risk factors disappeared when age was controlled for. In contrast, the correlations with age remained significant for sVCAM-1, IL-6, MCP-1, 6Ckine and IP-10 when other cardiovascular risk factors were controlled for.ConclusionsPlasma concentrations of some inflammatory markers (sVCAM-1, IL-6, MCP-1, 6Ckine, IP-10) are positively correlated with age, independent of other cardiovascular risk factors. This suggests that age-related inflammation may not be driven by recognised risk factors.     

Intramucosal acidosis and the inflammatory response in acute pancreatitis

OBJECTIVE: The aim of this study was to assess the host response and diminished bowel perfusion during acute pancreatitis. METHODS: A total of 19 patients admitted with established diagnoses of acute pancreatitis on the basis of clinical findings, elevated serum amylase to more than four times the upper limit or by contrast radiology. Patients were stratified into mild and severe pancreatitis using the Atlanta criteria. Blood samples were obtained from in-dwelling lines or direct venipuncture within 12 h of admission and 24 hourly thereafter for measurements of plasma endotoxin, EndoCab immunoglobulin (Ig)G and IgM antibodies, tumor necrosis factor (TNF), p55 TNF receptor, and IL-6. A gastric tonometer was inserted in place of a nasogastric tube for intramucosal pH evaluation. RESULTS: Episodes of endotoxaemia were more common and endotoxin concentration significantly higher at presentation in the severe group compared to the mild group of patients. A greater consumption of IgM antibody was found in those with severe disease. The decrease in IgM antibody concentration was shown to be a specific host response, as a fall in concentration of antibodies to a neutral antigen, tetanus toxoid, was not observed. Significantly greater elevations were found in p55 TNF receptor and IL-6 concentrations in the severe group in comparison to those suffering mild pancreatitis. Significant correlations were found between gastric intramucosal pH and EndoCab IgM antibody, p55 TNF receptor, and IL-6. CONCLUSIONS: These results suggest that endotoxemia, an acute inflammatory response, and a reduction in bowel perfusion may occur in severe acute pancreatitis. The endotoxemia and inflammatory response may be due to the permeation of bacteria and their breakdown products across a disrupted bowel mucosal barrier.     

Up-regulation of circulating adhesion molecules in bronchiectasis.

Adhesion molecules are expressed on the surface of endothelial cells and leukocytes and are responsible for mediating the migration of intravascular leukocytes into inflamed tissue. Intensive recruitment of neutrophils into the airways occurs in bronchiectasis, although little is known about the role of adhesion molecules in this process. The authors, therefore, determined serum levels of E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 in stable bronchiectasis patients (n=37) and healthy control subjects (n=17), and evaluated their relationship with clinical markers of disease severity in bronchiectasis. Serum levels of E-selectin, ICAM-1 and VCAM-1 in bronchiectasis patients were significantly higher than those in control subjects (p=0.02, <0.0001 and 0.0002 respectively). Both E-selectin and ICAM-1 levels were inversely related to forced expiratory volume in one second (FEV1)% predicted (r=-0.57, p<0.001; and r=-0.53, p=0.001 respectively), and FVC% predicted (r=-0.52, p=0.002; and r=-0.46, p=0.005). This was not the case for VCAM-1 levels. There was a correlation between serum ICAM-1 levels and 24 h sputum volume (r=0.34, p= 0.04). Serum E-selectin and ICAM-1, but not VCAM-1, levels showed correlation with the number of lung lobes affected by bronchiectasis (r=0.35, p=0.04 and r=0.34, p=0.04 respectively). These original observations strongly suggest that E-selectin, intercellular adhesion molecule-1 and Vascular adhesion molecule-1 could play a significant role in the pathogenesis of bronchiectasis.     

Physiological increases in circulating noradrenaline are antinatriuretic in man

Low-dose (0.025 micrograms/kg per min) noradrenaline infusion, resulting in a physiological plasma increment (280 pg/ml), was antinatriuretic in normal salt-replete male subjects. The reduction in sodium excretion (-20%, P less than 0.01) occurred without any change in the glomerular filtration rate but was associated with a significant (P less than 0.02) decline in lithium clearance. These results suggest that changes in circulating noradrenaline, within the physiological range, can decrease sodium excretion in man by enhancing proximal tubular sodium reabsorption. These findings extend previous investigations in man which used pharmacological doses of noradrenaline and are in agreement with animal evidence for a renal tubular antinatriuretic effect of the sympathetic nervous system.     

Liver in sepsis and systemic inflammatory response syndrome

In patients with sepsis and SIRS, the liver has two opposing roles: a source of inflammatory mediators and a target organ for the effects of the inflammatory mediators. The liver is pivotal in modulating the systemic response to severe infection, because it contains the largest mass of macrophages (Kupffer cells) in the body; these macrophages can clear the endotoxin and bacteria that initiate the systemic inflammatory response. This article summarizes the functional changes that take place in the liver during sepsis and systemic inflammatory response syndrome and discusses the cellular and molecular mechanisms that underlie clinical outcomes.     

Fluid loading increases oxygen consumption in septic patients with lactic acidosis

We prospectively evaluated 20 patients with systemic sepsis and signs of circulatory failure to determine if fluid loading was associated with increases in systemic oxygen delivery (DO2) and consumption (VO2). Fluid loading led to an increase in DO2 in 14 patients (70%). Patients who demonstrated increased DO2 with a corresponding increase in VO2 (Group A, n = 8) had significantly higher (p less than 0.05) initial blood lactate levels (4.9 +/- 2.9 mmol/L, mean +/- SD) than did patients without an increase in VO2 (Group B, n = 6, 1.9 +/- 1.0 mmol/L). A decrease in DO2 that was attributed to hemodilution was noted in the remaining 6 patients (Group C). Group C exhibited elevated lactate levels (5.1 +/- 2.4 mmol/L) and no significant changes in VO2. We conclude that lactic acidosis, a marker of anaerobic metabolism, predicts increases in VO2 in septic patients who respond to fluid loading with an increase in DO2.