Katja Baumgart

Glucose metabolism and catecholamines.

Until now, catecholamines were the drugs of choice to treat hypotension during shock states. Catecholamines, however, also have marked metabolic effects, particularly on glucose metabolism, and the degree of this metabolic response is directly related to the &bgr;2-adrenoceptor activity of the individual compound used. Under physiologic conditions, infusing catecholamine is associated with enhanced rates of aerobic glycolysis (resulting in adenosine triphosphate production), glucose release (both from glycogenolysis and gluconeogenesis), and inhibition of insulin-mediated glycogenesis. Consequently, hyperglycemia and hyperlactatemia are the hallmarks of this metabolic response. Under pathophysiologic conditions, the metabolic effects of cate-cholamines are less predictable because of changes in receptor affinity and density and in drug kinetics and the metabolic capacity of the major gluconeogenic organs, both resulting from the disease per se and the ongoing treatment. It is also well-established that shock states are characterized by a hypermetabolic condition with insulin resistance and increased oxygen demands, which coincide with both compromised tissue microcirculatory perfusion and mitochondrial dysfunction. This, in turn, causes impaired glucose utilization and may lead to inadequate glucose supply and, ultimately, metabolic failure. Based on the landmark studies on intensive insulin use, a crucial role is currently attributed to glucose homeostasis. This article reviews the effects of the various catecholamines on glucose utilization, both under physiologic conditions, as well as during shock states. Because, to date (to our knowledge), no patient data are available, results from relevant animal experiments are discussed. In addition, potential strategies are outlined to influence the catecholamine-induced effects on glucose homeostasis.

Serum amyloid A versus C-reactive protein in acute pancreatitis: clinical value of an alternative acute-phase reactant.

Objectives: The acute‐phase reactant C‐reactive protein (CRP) is currently the serum variable of choice for an early, accurate, and cost‐effective severity assessment of acute pancreatitis in the daily clinical routine. Serum amyloid A (SAA) proteins comprise a family of apolipoproteins that constitute another major acute‐phase reactant and thus could be a potential alternative to CRP assessment. In the present study we investigated the clinical usefulness of SAA determinations in acute pancreatitis using an automated immunoassay technique. Design: Cohort study, comparing patients with complicated and mild acute pancreatitis; control groups included individuals with further abdominal disorders and healthy volunteers. Setting: A collaborative study between the department of general surgery and the routine laboratory of the department of clinical chemistry/pathobiochemistry. Patients: We enrolled 66 patients with acute pancreatitis in the present study. Control groups consisted of healthy subjects (n = 30), patients with chronic pancreatitis (n = 20), patients with pancreatic carcinoma (n = 20), and patients with acute appendicitis (n = 20). Interventions: Blood samples were collected during 14 consecutive days in patients with acute pancreatitis. A single blood specimen was taken in all control groups after the diagnosis was established. Measurements and Main Results: SAA concentrations were 3 mg/L (median; range, 3‐93) in healthy subjects. Although SAA and CRP both reached their maximum within 4 days after onset of symptoms in patients with acute pancreatitis, SAA concentrations rose faster above normal ranges and reached 676 mg/L (median; range, 12‐1880), higher than CRP, which reached 313 mg/L (median; range, 29‐613). As observed for CRP, SAA was significantly higher in patients who developed complications such as necrosis, infection of necrosis, or multiple organ dysfunction syndrome or in patients who died. SAA achieved best results in discriminating between necrotizing pancreatitis and interstitial edematous pancreatitis. However, CRP provided an earlier differentiation between both entities and a significantly better overall accuracy, as shown by receiver operating characteristics analysis. SAA concentrations in patients with chronic pancreatitis were 6 mg/L (median; range, 3‐756). In patients with pancreatic carcinoma, SAA concentrations were 7 mg/L (median; range, 3‐492), and in patients with acute appendicitis, they were 50 mg/L (median; range, 3‐2140). Conclusion: SAA is a nonspecific and rapidly produced variable in inflammatory abdominal disorders with a wider dynamic range than CRP. The current assay technique renders SAA an applicable and readily available variable under clinical routine conditions. In cases of acute pancreatitis, however, CRP is still superior to SAA for early and accurate stratification of patients with a complicated course.

Clinical relevance of caspase-1 activated cytokines in acute pancreatitis: high correlation of serum interleukin-18 with pancreatic necrosis and systemic complications.

ObjectivesThere is recent experimental evidence that caspase-1 activation plays an instrumental role in the pathomechanism of severe acute pancreatitis. Besides interleukin-1&bgr;, interleukin-18, a recently described proinflammatory cytokine, is cleaved into its biologically active form by caspase-1 as well. Interleukin-18 is known to have potent properties concerning the activation of the Th1-lymphocyte subset via costimulation of interferon-&ggr; production. In contrast to interleukin-1&bgr;, little is known about the clinical impact of interleukin-18 in the course of acute pancreatitis. DesignCohort study comparing patients with mild and severe acute pancreatitis associated with local and systemic complications during the course of the disease. SettingSurgical and anesthesiological intensive care unit as well as wards of the department of general surgery. PatientsWe included 68 patients with acute pancreatitis in the present study. In terms of local complications, pancreatic necrosis was present in 37 patients, of whom 21 developed pancreatic infections. Systemic complications included pulmonary, renal, or cardiocirculatory insufficiency and were observed in 40, 18, and 25 patients, respectively. Severe multiple-organ dysfunction syndrome involving all three organ systems occurred in 18 patients, all suffering from pancreatic necrosis. InterventionsSerum samples were collected over 14 consecutive days after study inclusion. Ascites or peripancreatic exudate was obtained by ultrasound-guided fine needle aspiration in 14 cases. Sera and local aspirates were stored at −70°C until analysis. Measurements and Results Interleukin-18 and interferon-&ggr; were measured by commercially available enzyme-linked immunosorbent assays. Interleukin-18 concentrations were significantly increased after the fourth day of disease onset until the end of the observation period in patients who developed pancreatic necrosis and systemic complications such as pulmonary, renal, and cardiocirculatory failure as well as severe multiple-organ dysfunction syndrome. However, no correlation was found between the development of pancreatic infections and interleukin-18 concentrations. In contrast with interleukin-18, interferon-&ggr; concentrations did not show any significant difference with respect to the presence or absence of either systemic or local complications. Local interleukin-18 concentrations in ascites or peripancreatic exudate were up to 20-fold higher than systemic concentrations, whereas interferon-&ggr; concentrations did not differ. ConclusionsSerum interleukin-18 concentrations are significantly elevated in patients with acute pancreatitis complicated by pancreatic necrosis and remote organ failure. The present data suggest an important role of caspase-1 dependent cytokine activation in the pathomechanism of severe acute pancreatitis beyond the experimental setting. In this context, interleukin-18 may serve as a potential target for new therapeutic approaches.

Cardiac and metabolic effects of hypothermia and inhaled hydrogen sulfide in anesthetized and ventilated mice.

Objective: To test the hypothesis whether inhaled hydrogen sulfide amplifies the effects of deliberate hypothermia during anesthesia and mechanical ventilation as hypothermia is used to provide organ protection after brain trauma or circulatory arrest. Awake mice inhaling hydrogen sulfide exhibit reduced energy expenditure, hypothermia, and bradycardia despite unchanged systolic heart function. In rodents, anesthesia alone causes decreased metabolic rate and thus hypothermia and bradycardia. Design: Prospective, controlled, randomized study. Setting: University animal research laboratory. Subjects: Male C57/B6 mice. Interventions: After surgical instrumentation (central venous, left ventricular pressure-conductance catheters, ultrasound flow probes on the portal vein and superior mesenteric artery), normo- or hypothermic animals (core temperature = 38°C and 27°C) received either 100 ppm hydrogen sulfide or vehicle over 5 hrs (3 hrs hydrogen sulfide during normothermia). Measurements and Main Results: During normothermia, hydrogen sulfide had no hemodynamic or metabolic effect. With or without hydrogen sulfide, hypothermia decreased blood pressure, heart rate, and cardiac output, whereas stroke volume, ejection fraction, and end-diastolic pressure remained unaffected. Myocardial and hepatic oxidative deoxyribonucleic acid damage (comet assay) and endogenous glucose production (rate of appearance of 1,2,3,4,5,6-13C6-glucose) were similar in all groups. Hypothermia comparably decreased CO2 production with or without inhaled hydrogen sulfide. During hypothermia, inhaled hydrogen sulfide increased the glucose oxidation rate (derived from the expiratory 13CO2/12CO2 ratio). This shift toward preferential carbohydrate utilization coincided with a significantly attenuated responsiveness of hepatic mitochondrial respiration to stimulation with exogenous cytochrome-c-oxidase (high-resolution respirometry). Conclusions: In anesthetized and mechanically ventilated mice, inhaled hydrogen sulfide did not amplify the systemic hemodynamic and cardiac effects of hypothermia alone. The increased aerobic glucose oxidation together with the reduced responsiveness of cellular respiration to exogenous cytochrome-c stimulation suggest that, during hypothermia, inhaled hydrogen sulfide improved the yield of mitochondrial respiration, possibly via the maintenance of mitochondrial integrity. Hence, inhaled hydrogen sulfide may offer metabolic benefit during therapeutic hypothermia.

The Clinical Value of Procalcitonin in the Prediction of Infected Necrois in Acute Pancreatitis

ObjectiveInfection of pancreatic necrosis (IN) has a major impact on management and outcome in acute pancreatitis (AP). Currently, guided fine-needle aspiration (FNA) is the only means for an accurate diagnosis of IN. Procalcitonin (PCT), a 116 amino acid pro-peptide of calcitonin has been found in high concentrations in patients with sepsis. In the present study we analyzed the clinical value of serum PCT for predicting IN in AP and compared the results to guided FNA.DesignClinicaly study.SettingA collaborative study between the Departments of General Surgery and Clincal Chemistry/ Pathobiochemistry of the University of Ulm, Germany.Patients61 patients with AP entered this study and were stratified into three groups according to morphological and bacteriological data: I. 22 patients with edematous pancreatitis (AIP), II. 18 patients with sterile necrosis (SN), III. 21 patients with IN.Measurements and ResultsDuring an observation period of 14 days PCT was measured by immuonluminometry, CRP was determined by lasernephelometry on a routine base. In patients with IN overall PCT concentrations were significantly higher than in those with SN, whereas CRP levels did not differ in both groups. In contrast, only low concentrations of both parameters were found in patients with AIP. By ROC analysis the best PCT cut-off level for predicting IN or persisting pancreatic sepsis was obtained at ≥1.8 ng/ml. If this cut-off was reached on at least two consecutive days, IN could be predicted with a sensitivity of 95%, a specificity, of 88%, and an accuracy of 90%. Guided FNA achieved a sensitivity, specificity, and accuracy of 91%. 79%, and 84% in differentiating IN from SN, respectively. After surgical treatment of IN median PCT values continued to be significantly higher in patients with persisting pancreatic sepsis (n=12) compared to those with an uneventful postoperative course (n=7). Our results demonstrate that monitoring of serum PCT could serve as a noninvasive and accurate method to predict IN in AP as well as to select patients with persisting septic complications after surgical debridement

Differential Effects of Caspase-1/Interleukin-1β–Converting Enzyme on Acinar Cell Necrosis and Apoptosis in Severe Acute Experimental Pancreatitis

There is recent experimental evidence that inhibition of caspase-1/interleukin-1β converting enzyme (ICE) significantly ameliorates overall severity and survival in severe acute experimental pancreatitis. However, little is known about the effects of this approach on the dynamics and mechanisms of local acinar cell damage, which we aimed to investigate in the present study. Severe acute pancreatitis (SAP) was induced by retrograde infusion of 4% sodium taurocholate in rats treated with isotonic saline or a highly selective, irreversible inhibitor of ICE. After 3, 6, and 24 hours, 3 and 7 days, acinar cell death by necrosis and apoptosis, as well as intrapancreatic and systemic interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) expression, was assessed. Treatment with the ICE inhibitor significantly reduced the extent of acinar cell necrosis accounting for major parenchymal destruction. In contrast, apoptosis was confined to the postacute course of the disease and was closely related to tubular complex formation, both remaining unchanged. Whereas intrapancreatic IL-1β mRNA expression was highly up-regulated in both treated and untreated animals, active IL-1β protein expression and subsequent neutrophil tissue infiltration was dramatically decreased in the ICE-inhibited group. Parallel to the onset of enhanced apoptotic acinar cell death and tubular complex formation, TNF-α mRNA and protein expression was up-regulated, with levels being lower in ICE inhibitor-treated rats. We conclude that activation of caspase-1/ICE plays a central role in the progression of acinar cell death by necrosis in SAP. Herein, IL-1β–mediated neutrophil infiltration seems to be a crucial step in enhanced cellular destruction. In contrast, acinar cell apoptosis contributes to ductal transformation and is independent of this mechanism, but may be influenced by TNF-α

Applying gases for microcirculatory and cellular oxygenation in sepsis: effects of nitric oxide, carbon monoxide, and hydrogen sulfide.

Purpose of review Nitric oxide, carbon monoxide, and hydrogen sulfide (H2S) are gases that have received attention as signaling molecules regulating many biological processes. All of them were reported to have beneficial effects in inflammatory states, in particular for microcirculatory perfusion and tissue energy balance. Thus, this review will highlight the most important results with a focus on resuscitated, clinically relevant experimental models and, if available, human studies. Recent findings There is ample evidence that nitric oxide, carbon monoxide, and H2S may exert cytoprotective effects in shock states due to their vasomotor, antioxidant, and anti-inflammatory properties as well as their potential to induce a hibernation-like metabolic state called ‘suspended animation’ resulting from inhibition of cytochrome-c-oxidase. It must be emphasized, however, that the three molecules may also be cytotoxic, not only because of their inhibition of cellular respiration but also because of their marked pro-inflammatory effects. Summary It is still a matter of debate whether manipulating nitric oxide, carbon monoxide, or H2S tissue concentrations, either by using the inhaled gas itself or by administering donor molecules or inhibitors of their endogenous production, is a useful therapeutic approach to improve microcirculatory blood flow, tissue oxygenation, and cellular respiration. This is mainly due to their ‘friend and foe character’ documented in various experimental models, but also to the paucity of data from long-term, resuscitated large animal experiments that fulfil the criteria of clinically relevant models.

The effect of superoxide dismutase overexpression on hepatic gluconeogenesis and whole-body glucose oxidation during resuscitated normotensive murine septic shock.

ABSTRACT Besides excess cytokine and NO production, enhanced oxygen radical formation was referred to contribute to the impaired hepatic gluconeogenesis during sepsis or endotoxemia. Therefore, we tested the hypothesis that genetic overexpression of the Cu/Zn-superoxide dismutase (SOD-1) may restore the sepsis-related lack of the norepinephrine-induced increase in hepatic gluconeogenesis and whole-body glucose oxidation. Anesthetized, ventilated, and instrumented wild-type control, and heterozygous and homozygous SOD-1-overexpressing mice received hydroxyethyl starch and norepinephrine to maintain normotensive hemodynamics measured at 18, 21, and 24 h after cecal ligation and puncture (CLP) or sham operation. Hepatic gluconeogenesis and whole-body glucose oxidation were calculated from liver tissue isotope and expiratory 13CO2 enrichments during continuous i.v. 1,2,3,4,5,6-13C6-glucose. Superior mesenteric artery and portal vein flows (ultrasound flow probes) and hepatic microcirculatory perfusion (Laser Doppler flowmetry) and O2 saturation (remission spectrophotometry) were comparable in the CLP and sham-operated animals, without any difference related to the mouse strain. Despite continuous i.v. norepinephrine necessary in the CLP mice, both glycemia and hepatic gluconeogenesis were similar, irrespective of the presence of sepsis and the genetic strain. Glucose oxidation rate progressively increased in the CLP groups, again without difference between the genetic strains. The surgery- and CLP-induced increase in liver cell oxidative DNA damage (tail moment in the comet assay) was less pronounced in the homozygous mice. Heterozygous nor homozygous SOD-1 overexpression did not improve the sepsis-related impairment of carbohydrate metabolism, possibly because of the lacking increase of the tissue catalase and the mitochondrial SOD activity, and the ongoing i.v. norepinephrine.

Year in review 2006: Critical Care - Multiple organ failure,sepsis, and shock.

In 2006, Critical Care provided important and clinically relevant research data in the field of multiple organ failure, sepsis, and shock. This review summarizes the results of the experimental studies and clinical trials and discusses them in the context of the relevant scientific and clinical background.

Cardioprotection by hydrogen sulfide: suspended animation, inflammation, and apoptosis.

In a landmark experiment, Blackstone et al. (1) demonstrated in awake, spontaneously breathing mice that inhaling H2S produced a Bsuspended animation-like[ metabolic status characterized by pronounced hypothermia and reduced oxygen demand, which in turn protected against otherwise lethal hypoxia (2). Formerly mainly considered as a poisonous gas and environmental pollutant, H2S has been recognized as an inorganic mediator with broad therapeutic potential (3), in particular, in the heart (4). In fact, in several models of myocardial I/R injury, both endogenous and exogenous H2S reduced myocardial injury and improved heart function (5Y8), and the beneficial effects of chronic garlic consumption on the cardiovascular system have recently been attributed to H2S release (9). Various mechanisms are responsible for these protective properties of H2S-related, that is, activation of myocardial KATP channels (5, 6), reduction of oxidative stress (10), inhibition of leukocyte adhesion to the endothelium (11), and preservation of mitochondrial integrity and function and, thereby, cellular respiration (7). Being a small, easily diffusible molecule, H2S resembles the other two gaseous NO and CO, and, thus, it is not surprising that it shares many of the Bfriend-and-foe[ characteristics of the latter. In fact, H2S is also referred to as a mediator of inflammation (12), and in various models of shock and inflammation, exogenous H2S caused oxidative DNA damage, aggravated tissue inflammation and enhanced apoptosis by activating both the mitochondrial and the death receptor pathways, and resulted in aggravated organ injury (for review, see Ref. [3]). Inhibition of H2S production reversed these effects (13). In this issue of Shock, Sivarajah et al. (14) now describe studies aimed at elucidating the mechanisms of the H2Srelated cardioprotection. The authors investigated the effects of the H2S donor sodium hydrogen sulfide (NaHS) on infarct size and apoptosis after regional myocardial I/R in rats. Sodium hydrogen sulfide indeed reduced cardiomyocyte apoptosis in the Barea at risk[ adjacent to the infarct zone, which was reduced as well, and this response coincided with attenuated tissue oxidative and nitrosative stress as measured by malondialdehyde content and nitrotyrosine staining, respectively. In addition, the I/R-induced inflammatory response was markedly reduced as well, most likely as a result of the blunted activation of the nuclear transcription factor nuclear factor .B. In the present study, these beneficial effects of NaHS were not affiliated with any difference in the measured parameters of left heart hemodynamics, whereas other authors have recently reported markedly improved systolic contractility after administration of another H2S donor, Na2S, during myocardial ischemia in rats and swine (7, 8). Because the NaHS-induced protection was abolished by the mitochondrial KATP channel blocker 5-hydroxydecanoate, these results are well in line with the data by Elrod et al. (7), showing that the cardioprotection exerted by Na2S was concomitant with reduced mitochondrial morphologic damage and a markedly improved recovery of mitochondrial respiration. These improved cellular energetics were affiliated with reduced tissue inflammation, inhibition of neutrophil migration into the reperfused tissue, and cardiomyocyte apoptosis. The findings by Sivarajah et al. are fascinating, but several questions remain open. First, what is the role of an H2Sinduced drop in energy expenditure and/or body temperature? It is well established that hypothermia assumes major importance for any Bsuspended animation[Yrelated organ protection (15). Although rodents can rapidly drop their core temperature due to their large surface areaYmass ratio, this response is much smaller in larger animals and humans. In fact, short-term exposure to inhaled H2S did not produce any hypometabolism in sedated sheep (16), whereas infusing Na2S during 10 hours in swine markedly reduced energy expenditure (17). In the rodent studies (7, 14), the cardioprotective effects were apparent without a change in core body temperature, although it is possible that localized metabolic effects may have contributed to the protection (7). The relationship between the metabolic effects of sulfide and the effects on KATP channels also remains to be investigated. Is it possible that the effects of sulfide on membrane channels are secondary to the effects elicited on cellular metabolic status? Second, the preferred route of therapeutic H2S administration remains a crucial issue. Although inhaling gaseous H2S probably allows easily titrating target blood concentrations, it is well established that it directly causes airway irritation.