Search

The aim of the current paper is to summarize the results of the International CytoSorb Registry. Data were collected on patients of the intensive care unit. The primary endpoint was actual in-hospital mortality compared to the mortality predicted by APACHE II score. The main secondary endpoints were SOFA scores, inflammatory biomarkers and overall evaluation of the general condition. 1434 patients were enrolled. Indications for hemoadsorption were sepsis/septic shock (N = 936); cardiac surgery perioperatively (N = 172); cardiac surgery postoperatively (N = 67) and “other” reasons (N = 259). APACHE-II-predicted mortality was 62.0±24.8%, whereas observed hospital mortality was 50.1%. Overall SOFA scores did not change but cardiovascular and pulmonary SOFA scores decreased by 0.4 [-0.5;-0.3] and -0.2 [-0.3;-0.2] points, respectively. Serum procalcitonin and C-reactive protein levels showed significant reduction: -15.4 [-19.6;-11.17] ng/mL; -17,52 [-70;44] mg/L, respectively. In the septic cohort PCT and IL-6 also showed significant reduction: -18.2 [-23.6;-12.8] ng/mL; -2.6 [-3.0;-2.2] pg/mL, respectively. Evaluation of the overall effect: minimal improvement (22%), much improvement (22%) and very much improvement (10%), no change observed (30%) and deterioration (4%). There was no significant difference in the primary outcome of mortality, but there were improvements in cardiovascular and pulmonary SOFA scores and a reduction in PCT, CRP and IL-6 levels. Trial registration: ClinicalTrials.gov Identifier: NCT02312024 (retrospectively registered).

Introduction: Extracorporeal life support is an increasingly used technique for respiratory and cardiocirculatory support. Besides primary organ dysfunction, an excessive systemic hyperinflammatory response can be the underlying cause for acute organ failure necessitating extracorporeal life support therapy, or it may be associated with the extracorporeal life support itself. Controlling this overwhelming inflammatory response using CytoSorb® hemoadsorption has been shown to be associated with improved hemodynamics and restored metabolic balance resulting in preserved organ functions. Methods: In this retrospective case series, we describe 23 patients undergoing extracorporeal life support therapy and CytoSorb hemoadsorption. Cytokine levels were monitored, hemodynamic and metabolic variables were recorded, and outcome measures such as duration of organ support, intensive care unit mortality, and hospital mortality were noted. Results: CytoSorb treatment was associated with a trend toward a reduction in plasma cytokine levels (first treatment median interleukin-6 pre 595 vs post 350 pg/mL (n.s.); second treatment median interleukin-6 317 vs 108 pg/mL, p Conclusion: Hemoadsorption may offer a potentially promising therapeutic option for critically ill patients undergoing extracorporeal life support therapy, with cytokine reduction and a consecutively mitigated inflammatory response, decreased vasoplegia, and improved organ function as seen in our patients.

A 46-year-old woman on oral contraceptives developed an intrahepatic hematoma due to a benign hepatic tumor. As an incidental finding, a computed tomography showed a pulmonary embolism. Unfractionated heparin was given in a prophylactic dosing in an attempt to balance the risk of further intrahepatic bleeding with that of thrombosis. Ten days later, the patient developed a second pulmonary embolism along with acute right heart failure requiring cardiopulmonary resuscitation. As a sufficient circulation and oxygenation could not be reestablished, a veno-arterial extracorporeal membrane oxygenation (ECMO) was installed. An ELISA-Test, detecting PF4-Heparin associated antibodies, resulted in a positive result for a type II heparin induced thrombocytopenia even in the absence of thrombocytopenia. After hemodynamic and pulmonary stabilization, six days after ECMO-support the cannula was scheduled to be removed. On removal of the venous cannula the patient developed another massive pulmonary embolism with cardiac arrest which led to immediate reinstallation of va-ECMO. Under therapeutic anticoagulation using argatroban the ECMO support continued until the patient was on day 17 successfully weaned.

The acute respiratory distress syndrome (ARDS) remains a clinically relevant disease and causes high morbidity and mortality (1). Various treatment approaches exist to cope with the most critical patient courses. In the last decades therapeutic options for primary or secondary pulmonary failures were enlarged by the increasing spread and use of ECMO. The rate of treatments of severe respiratory failure with veno-venous extracorporeal membrane oxygenation (VV-ECMO) is rapidly increasing counting more than 15,600 adult treatments in the Extracorporeal Life Support Organization Registry in February 2018. In the treatment of ARDS, the VV-ECMO is a meanwhile established therapeutic approach despite ongoing discussion regarding evidence (2). Although there are consented parameters for indication of VV-ECMO (2), we are still lacking suitable prognostic parameters, that give us an arbitration about the potential success of ECMO treatment and about outcome of treated patients.

Introduction Infective endocarditis is a serious disease condition. Depending on the causative microorganism and clinical symptoms, cardiac surgery and valve replacement may be needed, posing additional risks to patients who may simultaneously suffer from septic shock. The combination of surgery bacterial spreadout and artificial cardiopulmonary bypass (CPB) surfaces results in a release of key inflammatory mediators leading to an overshooting systemic hyperinflammatory state frequently associated with compromised hemodynamic and organ function. Hemoadsorption might represent a potential approach to control the hyperinflammatory systemic reaction associated with the procedure itself and subsequent clinical conditions by reducing a broad range of immuno-regulatory mediators. Methods We describe 39 cardiac surgery patients with proven acute infective endocarditis obtaining valve replacement during CPB surgery in combination with intraoperative CytoSorb hemoadsorption. In comparison, we evaluated a historical group of 28 patients with infective endocarditis undergoing CPB surgery without intraoperative hemoadsorption. Results CytoSorb treatment was associated with a mitigated postoperative response of key cytokines and clinical metabolic parameters. Moreover, patients showed hemodynamic stability during and after the operation while the need for vasopressors was less pronounced within hours after completion of the procedure, which possibly could be attributed to the additional CytoSorb treatment. Intraoperative hemoperfusion treatment was well tolerated and safe without the occurrence of any CytoSorb device-related adverse event. Conclusions Thus, this interventional approach may open up potentially promising therapeutic options for critically-ill patients with acute infective endocarditis during and after cardiac surgery, with cytokine reduction, improved hemodynamic stability and organ function as seen in our patients.

Extracorporeal life support is an increasingly used technique for respiratory and cardiocirculatory support. Besides primary organ dysfunction, an excessive systemic hyperinflammatory response can be the underlying cause for acute organ failure necessitating extracorporeal life support therapy, or it may be associated with the extracorporeal life support itself. Controlling this overwhelming inflammatory response using CytoSorbIn this retrospective case series, we describe 23 patients undergoing extracorporeal life support therapy and CytoSorb hemoadsorption. Cytokine levels were monitored, hemodynamic and metabolic variables were recorded, and outcome measures such as duration of organ support, intensive care unit mortality, and hospital mortality were noted.CytoSorb treatment was associated with a trend toward a reduction in plasma cytokine levels (first treatment median interleukin-6 pre 595 vs post 350 pg/mL (n.s.); second treatment median interleukin-6 317 vs 108 pg/mL, p 0.05), a reduced vasoplegic response resulting in a reduction in vasopressor requirements (first treatment median norepinephrine pre 0.15 vs post 0.02 µg/kg/min (n.s.); second treatment median norepinephrine 0.1 vs 0.02 µg/kg/min, p 0.05) as well as rebalancing of deranged metabolic parameters (first treatment median lactate pre-treatment 6 vs post-treatment median lactate 2 mmol/L, p 0.05). The hemoperfusion treatment was well tolerated and safe, without the occurrence of any CytoSorb device-related adverse events.Hemoadsorption may offer a potentially promising therapeutic option for critically ill patients undergoing extracorporeal life support therapy, with cytokine reduction and a consecutively mitigated inflammatory response, decreased vasoplegia, and improved organ function as seen in our patients.

A 46-year-old woman on oral contraceptives developed an intrahepatic hematoma due to a benign hepatic tumor. As an incidental finding, a computed tomography showed a pulmonary embolism. Unfractionated heparin was given in a prophylactic dosing in an attempt to balance the risk of further intrahepatic bleeding with that of thrombosis. Ten days later, the patient developed a second pulmonary embolism along with acute right heart failure requiring cardiopulmonary resuscitation. As a sufficient circulation and oxygenation could not be reestablished, a veno-arterial extracorporeal membrane oxygenation (ECMO) was installed. An ELISA-Test, detecting PF4-Heparin associated antibodies, resulted in a positive result for a type II heparin induced thrombocytopenia even in the absence of thrombocytopenia. After hemodynamic and pulmonary stabilization, six days after ECMO-support the cannula was scheduled to be removed. On removal of the venous cannula the patient developed another massive pulmonary embolism with cardiac arrest which led to immediate reinstallation of va-ECMO. Under therapeutic anticoagulation using argatroban the ECMO support continued until the patient was on day 17 successfully weaned.Bei einer 46-jährigen Patientin zeigt sich neben einem neu aufgetretenen Leberhämatom zusätzlich noch eine Lungenarterienembolie, so dass eine Antikoagulation mit Heparin begonnen wird. Daraufhin kommt es zu einer heparininduzierten Thrombozytopenie Typ II mit fulminanter Lungenarterienembolie, die eine Therapie mit einer venoarteriellen extrakorporalen Membranoxygenierung (va-ECMO) notwendig macht.

Background/Aims: During continuous renal replacement therapy, relevant losses of nutritional substrates, vitamins, and trace elements via the filter may occur. We investigated filter lifetime efficiency during a 72-h treatment period. Methods: This prospective study included 40 patients undergoing citrate continuous veno-venous hemodialysis (CVVHD). The elimination rates were measured at 24, 48, and 72 h. To assess the influence of filter lifetime, we determined substrate loss every 24 h over a 72-h interval. Results: Filter lifetime did not affect the loss of ionized calcium, inorganic phosphate, magnesium, zinc, folic acid, and vitamin B12. Nevertheless, we did observe clinically significant loss of ionized calcium and inorganic phosphate during CVVHD that required supplementation. Conclusions: CVVHD leads to significant loss of ionized calcium and inorganic phosphate that is independent of the filter lifetime.

During continuous renal replacement therapy, achievement of recommended treatment dose is important. However, relevant substrate loss may occur and recommended nutrition during critical illness could not be sufficient for higher dialysis doses. We investigated the correlation of dialysis dose and substrate loss for a broad range of dialysis doses. Forty critically ill patients with acute kidney injury undergoing citrate CVVHD were included in this prospective study. Three different corresponding blood flow (BF) and dialysate flow (DF) rates were applied (BF/DF: 100 ml/min, 2000 ml/h; 80 ml/min, 1500 ml/h; 120 ml/min, 2500 ml/h). Delivered effluent flow rate (DEFR) was calculated and correlated with losses of vitamins, electrolytes, and trace elements during recommended nutritional supplementation. For folic acid, vitamin B12, zinc, inorganic phosphate, and magnesium, no correlation of losses and DEFR was detected. For ionized calcium, a correlation was observed and additional substitution was required. Clinically relevant loss of folic acid, vitamin B12, zinc, inorganic phosphate, and magnesium was not observed for differently used dialysis doses of CVVHD, and the loss was covered sufficiently by daily recommended nutritional supplementation. Increased loss of ionized calcium for higher dialysis doses occurred during citrate CVVHD. Therefore, a strict protocol must maintain calcium homeostasis to avoid calcium depletion.

Protamine is a protein mainly used to reverse anticoagulant effects of heparin during cardiac or vascular surgery with extracorporeal circulation. Adverse events after protamine administration are rare but if they occur they can be catastrophic. Based on a case report with an elective cardiac surgery patient with known allergy to fish, we discuss the related events and risk factors for an adverse reaction after protamine. The patient management and its outcome are presented.

The use of cardiopulmonary bypass (CPB) in cardiothoracic surgery results in a well-known activation of the immunologic response. In some cases, however, this triggered immunologic response may be excessive, leading to a severe systemic inflammatory response syndrome (SIRS) and induced organ dysfunction. For example, patients frequently develop hemodynamic instability with hypotension and low systemic vascular resistance. To date, different therapeutic approaches, such as steroids, have been tried to control this maladaptive postoperative SIRS response, yet definitive proof of clinical efficacy is missing. A new cytokine adsorber device (CytoSorb; CytoSorbents) may be a useful approach to control hyperinflammatory systemic reactions by reducing a broad range of proinflammatory cytokines and other inflammatory mediators. This may, in turn, help to reestablish a physiologic immune response and help to restore deranged clinical parameters in these patients. In this retrospective case series study, we describe 16 cardiac surgery patients following prolonged CPB with post-CPB SIRS and subsequent acute kidney injury, who were then treated with hemoadsorption using CytoSorb in combination with continuous renal replacement therapy (CRRT). Treatment of patients with CytoSorb who presented with severe post-CPB SIRS resulted in a reduction of elevated cytokine levels, which was associated with a clear stabilization of deranged hemodynamic, metabolic, and organ function parameters. Treatment was well tolerated and safe, with no device-related adverse events occurring. CytoSorb therapy combined with CRRT is a potentially promising new treatment approach to achieve hemodynamic stability, cytokine reduction, and improved organ function in cardiac surgery patients who develop post-CPB SIRS.

Die Rezidivblutung ist die haufigste Ursache fur das Versterben nach spontaner Subarachnoidalblutung und hat eine Letalitat von 90%. Die Prognose ist am schlechtesten bei Aneurysmen im hinteren Kreislauf, hier betragt die Letalitat annahernd 100%. Weitere Pradiktoren des Versterbens sind Komaeintritt, zentraler Atemstillstand und eine grose Blutmenge im Subarachnoidalraum. Der Fallbericht beschreibt einen Patienten mit Zusammentreffen all dieser Pradiktoren und einem dennoch guten Behandlungsergebnis.

OBJECTIVE We investigated hypovolaemia induced by bloodletting, accompanied by statistically significant, but clinically irrelevant increase of heart rate together with unchanged blood pressure, with regard to hepatic glucose production as well as alanine and glycerol turnover rates. METHODS Healthy male volunteers (n = 18) were bled 15 ml/kg body weight over 20 min and remained hypovolaemic for 60 minutes. Heart rate was recorded by ECG and blood pressure by an oscillometric device. Before and after bloodletting hepatic glucose production as well as alanine and glycerol turnover rates were determined using the stable isotopes 6.6-D2-glucose, 15N-alanine and D5-glycerol as tracers. Simultaneously, the blood concentrations of adrenaline, noradrenaline, free fatty acids and glycerol were measured. RESULTS Bleeding did not change the mean arterial blood pressure, but increased the heart rate significantly from 61 +/- 9 to 70 +/- 13 1/ min. Noradrenaline levels increased significantly from 1.16 +/- 0.41 to 2.15 +/- 0.69 nmol/l. Hepatic glucose production (HGP) as well as alanine (AlaTO) and glycerol turnover (GlyTO) decreased significantly during hypovolaemia. HGP fell from 2.72 +/- 0.29 to 2.56 +/- 0.28 mg/kg/min, AlaTO from 0.71 +/- 0.27 to 0.53 +/- 0.25 mg/kg/min and GlyTO from 4.9 +/- 2.1 to 3.8 +/- 1.4 mumol/kg/min, respectively. The blood levels of adrenaline, free fatty acids and glycerol did not change during the study. DISCUSSION In respect of clinical signs, the cardiovascular status of the volunteers was stable after bleeding. In contrast, the decrease of HGP as well as the drop in alanine and glycerol turnover rates might be interpreted as a sign of an altered functional status of single organs, induced by changes of regional perfusion.

Bei Mehrfachverletzungen mit todlichem Ausgang ist das Thoraxtrauma unverandert in 25% der Falle die Todesursache. Anhand eines Falles mit letalem Ausgang wird die Problematik dargestellt und unter Berucksichtigung der aktuellen Literatur diskutiert. Ein 49-jahriger Motorradfahrer wurde nach Frontalkollision mit einem Pkw in einem auswartigen Haus erstversorgt und bei schwerer Thoraxverletzung mit Verdacht auf Perikarderguss und zum Ausschluss einer aortalen Verletzung sekundar in unsere Abteilung verlegt. Die Initialdiagnostik (Rontgen, CT-Thorax, Sonographie Abdomen, Echokardiographie) zeigte eine Rippenserienfraktur links, eine Skapulafraktur links, einen Hamatopneumothorax links, Lungenkontusionen beidseits, Mantelpneumothorax rechts, einen geringen Perikarderguss und ein kleines Milzhamatom. Bei zunachst stabiler Situation kam es nach 12 h zu einer respiratorischen Verschlechterung, als deren Ursache sich eine Verlegung des Bronchialsystems mit Sekret, eine Zunahme des Lungenparenchymschadens im CT sowie die Vergroserung des Perikardergusses zeigte. Dies zwang am Folgetag zu einer Perikardiotomie, was jedoch die klinische Situation nicht verbesserte. Im weiteren Verlauf benotigte der Patient ein zunehmend invasiveres Beatmungsmuster (PEEP>10, FiO2>0,5). Eine nicht stillbare Blutung aus dem linken Unterlappen zwang am 3. Tag zu einer Notfallthorakotomie mit Lobektomie. Trotz dieser Masnahme blieb der Patient instabil und verstarb nach 2-maliger Reanimation 95 h nach dem Unfall. Im vorliegenden Fall zeigt sich, dass die Schwere einer Thoraxverletzung sowohl klinisch, als auch in der Bildgebung haufig initial nicht mit dem tatsachlichen Ausmas des Parenchymschadens korreliert. Der Verlauf zeigt, dass trotz unverzuglichem und zeitgerechten Vorgehen der letale Ausgang nicht verhindert werden konnte. Der Fall bestatigt die Bedeutung des Thoraxtraumas als wichtige Todesursache beim Mehrfachverletzten.

The main clinical characteristics of sepsis and septic shock are derangements of cardiocirculatory and respiratory function. Additionally, profound alterations in metabolic pathways occur leading to hypermetabolism, enhanced energy expenditure, and insulin resistance. The clinical hallmarks are hyperglycemia, hyperlactatemia, and enhanced protein catabolism. These metabolic alterations are even more pronounced during sepsis as a result of cytokine release and subsequent induction of inflammatory pathways. Increased oxygen demands from mitochondrial oxygen utilization and oxygen consumption related to oxygen radical formation may contribute to hypermetabolism. In addition, mitochondrial dysfunction with impaired cellular respiration may be present. Mainstay therapeutic interventions for hemodynamic stabilization are adequate volume resuscitation and vasoactive agents, which, however, have additional impact on metabolic activity. Therefore, beyond hemodynamic effects, specific drug-related metabolic alterations need to be considered for optimal treatment during sepsis. This review gives an overview of the typical metabolic alterations during sepsis and septic shock and highlights the impact of vasoactive therapy on metabolism.

Hohes Aortenclamping geht im proximalen Stromgebiet mit ausgepragter Hypertension und deren potenziellen Komplikationen einher. Daruber hinaus sind die betroffenen Patienten durch die perioperativ unumgangliche Ischamie-Reperfusions-Situation im distalen Stromgebiet gefahrdet. Unterschiedliche Ansatze zur Vermeidung dieser Komplikationen werden kontrovers diskutiert. Eine wissenschaftlich und klinisch einheitliche Bewertung dieser Masnahmen steht aus. Ziel der vorliegenden Arbeit ist es als Grundlage zur systematischen Bewertung von adjuvanten Methoden in der Aortenchirurgie ein klinikrelevantes Grostiermodell zu etablieren. An Schweinen wurde durch 30-minutiges Klemmen der Aorta unmittelbar distal der linken A. subclavia eine Ischamie der distalen sowie eine Hypertension der proximalen Korperpartie induziert. Metabolische und funktionelle Parameter fur den Gesamtorganismus sowie insbesondere fur die Teilkreislaufe des Intestinums und der Leber wurden vor, wahrend und nach Clamping der thorakalen Aorta erhoben. Wahrend des hohen Aortenclampings kommt es im Rahmen einer deutlichen endogenen Katecholaminausschuttung zu einer Verdoppelung des Herzzeitvolumens mit ausgepragter Tachykardie. Vergleichbar mit der klinischen Situation lasst sich der supraaortale Mitteldruck mit Hilfe von Nitroprussidnatrium (Nipruss) innerhalb der Ausgangswerte halten. Das Declamping fuhrt zu einem Abfall des systemischen Gefaswiderstands, der sich erst nach 4 h dem Ausgangswert annahert. Wahrend es in der Clampingphase zu einer Halbierung des Sauerstoffverbrauchs kommt, steigt dieser nach Declamping an und bleibt bis zum Ende des Versuchs erhoht. Die Ischamie des portalen Stromgebiets fuhrt nach Declamping zu einer ausgepragten reaktiven Perfusionssteigerung. Dennoch bleibt die Mikrozirkulation insbesondere der Dunndarmmukosa trotz erhohter regionaler Blutflusse uber das Versuchsende hinaus deutlich kompromittiert. In dieser Studie konnten wir ein kliniknahes Grostiermodell zur Beschreibung pathophysiologischer Veranderungen wahrend und nach thorakalem Aortenclamping darstellen. Im Zentrum des Modells stehen die Reaktion des Gesamtkreislaufs auf der einen, sowie die Stoffwechselreaktionen in den Teilkreislaufen des intestinalen und hepatischen Stromgebiets auf der anderen Seite. Basierend auf diesen Daten sollen systematisch adjuvante Verfahren in der Aortenchirurgie uberpruft werden.

Particular research interest is currently focusing on the resuscitation of the gastrointestinal tract, because the gut is regarded to be both the "canary of the body", i.e. a sentinel organ during situations of compromised oxygen or substrate supply, as well as the "motor of multiple organ failure". Several therapeutic strategies have recently been proposed for the resuscitation of this organ system, aimed primarily at the augmentation of blood flow and oxygenation but also integrating nutritional or metabolic support and antioxidant administration.

Objective: We compared the effects of thromboxane receptor antagonist and synthase inhibitor DTTX30 on systemic and liver blood flow, oxygen (O2) exchange and energy metabolism during 24 h of hyperdynamic endotoxemia with untreated endotoxemia. Design: Prospective, randomized, experimental study with repeated measures. Setting: Investigational animal laboratory. Subjects: Twenty-seven domestic pigs: 16 during endotoxemia with volume resuscitation alone; 11 with endotoxemia, volume resuscitation and treatment with DTTX30. Interventions: Continuous infusion of Escherichia coli lipopolysaccharide (LPS) for 24 h together with volume resuscitation. After 12 h of endotoxemia, DTTX30 was administered as a bolus of 0.12 mg kg–1 followed by 12 h continuous infusion of 0.29 mg kg–1 per h. Measurements and results: DTTX30 effectively counteracted the endotoxin-associated increase in TXB2 levels and increased 6-keto-PGF1α with a significant shift of the thromboxane/prostacyclin ratio towards predominance of prostacyclin. DTTX30 prevented the significant progressive endotoxin-induced decrease of mean arterial pressure (MAP) below baseline while maintaining cardiac output (CO), and increased the fractional contribution of liver blood flow to CO without an effect on either hepatic O2 delivery or O2 uptake. The mean capillary hemoglobin O2 saturation (HbO2) on the liver surface and HbO2 frequency distributions remained unchanged as well. Conclusions: DTTX30 significantly attenuated the endotoxin-induced derangements of cellular energy metabolism as reflected by the diminished progressive decrease in hepatic lactate uptake rate and a blunted increase in hepatic venous lactate/pyruvate ratios. While endotoxin significantly increased the endogenous glucose production (EGP) rate, EGP returned towards baseline levels in the DTTX30-treated group. Thus, in our model DTTX30 resulted in hemodynamic stabilization concomitant with improved hepatic metabolic performance.

Objective: To investigate whether an increased ileal-mucosal-arterial PCO2 gap (ΔPCO2) during hyperdynamic porcine endotoxemia is associated with impaired villus microcirculation. Design: Prospective, randomized, controlled, experimental study. Setting: Animal research laboratory. Animals: Twenty-two domestic pigs. Interventions: After baseline measurements, anesthetized and ventilated pigs received continuous i.v. endotoxin (ETX, n=12) for 24 h or placebo (SHAM, n=10). Measurements and results: Before, as well as 12 and 24 h after, the start of endotoxin or saline portal venous blood flow (QPV, ultrasound flow probe) and lactate/pyruvate ratios (L/P), the ileal-mucosal-arterial ΔPCO2 (fiberoptic sensor) and bowel-wall capillary hemoglobin O2 saturation (%Hb-O2-cap, remission spectrophotometry) were assessed together with intravital video records of the ileal-mucosal microcirculation (number of perfused/heterogeneously perfused/unperfused villi) using orthogonal polarization spectral imaging (CYTOSCAN A/R) via an ileostomy. At 12 and 24 h endotoxin infusion, about half of the evaluated villi were heterogeneously or unperfused which was paralleled by a progressive significant increase of the ileal-mucosal-arterial ΔPCO2 and portal venous L/P ratios, whereas QPV as well as both the mean %Hb-O2-cap and the %Hb-O2-cap frequency distributions remained unchanged. By contrast, in the SHAM-group, mucosal microcirculation was well-preserved, and none of the other parameters were influenced. Conclusions: We conclude that an increased ileal-mucosal-arterial ΔPCO2 during porcine endotoxemia is related to impaired villus microcirculation. A putative contribution of disturbed cellular oxygen utilization resulting from "cytopathic hypoxia" may also assume importance.

Objective: To compare the effects of a 12 h continuous infusion of iloprost, a stable prostacyclin analogue, on hepatic blood flow (Qliv), O2 exchange, and energy metabolism during a 24 h hyperdynamic, porcine endotoxemia with volume resuscitation alone. Design: Prospective, randomized, experimental study with repeated measures. Setting: Investigational animal laboratory. Subjects: Twenty-eight domestic pigs: 16 animals during endotoxemia with volume resuscitation alone (ETX), 12 with endotoxemia, volume resuscitation, and treatment with iloprost (ILO). Interventions: Endotoxemia was initiated by continuous infusion of E. coli lipopolysaccharide. Animals were resuscitated with hetastarch, aimed at maintaining a MAP of >60 mmHg. After 12 h of endotoxemia, iloprost was administered for 12 h in the treatment group, titrated to avoid pharmacologically induced hypotension (MAP

Objectives: To compare the effects of norepinephrine (NOR) and the nonselective nitric oxide synthase inhibitor, N G -monomethyl-L-arginine (L-NMMA), on intestinal blood flow, oxygen exchange, and energy metabolism over 24 hrs of hyperdynamic, normotensive porcine endotoxic shock. Design: Prospective, randomized, experimental study with repeated measures. Setting: Investigational animal laboratory. Subjects: Twenty-seven pigs were divided into three groups: seven animals received no vasopressor therapy (ETX) during endotoxic shock; ten animals were treated with NOR; and ten animals were treated with L-NMMA. Interventions: Pigs were anesthetized, mechanically ventilated, and instrumented. Eight hours later, endotoxic shock was initiated by an infusion of Escherichia coli lipopolysaccharide. Animals were resuscitated by hetastarch directed to maintain the intrathoracic blood volume and a mean arterial pressure (MAP) of >60 mm Hg. Twelve hours after the start of the endotoxin infusion, NOR or L-NMMA was administered for 12 hrs in the treatment groups to maintain a MAP at preshock levels. Measurements and Main Results: ETX caused a continuous fall in MAP, despite a sustained increase in the cardiac output achieved by fluid resuscitation. NOR maintained MAP at preshock levels because of a further rise in cardiac output, whereas hemodynamic stabilization during L-NMMA resulted from systemic vasoconstriction. NOR increased portal venous blood flow concomitant with decreased intestinal oxygen extraction, whereas L-NMMA influenced neither portal venous blood flow nor intestinal oxygen extraction. Mean capillary hemoglobin oxygen saturation of the ileal mucosa as well as the frequency distributions reflecting microcirculatory oxygen availability remained unchanged as well. Nevertheless, portal venous pH similarly decreased and portal venous lactate/pyruvate ratios increased in all three groups. The arterial-ileal mucosal Pco 2 gap progressively increased in the ETX and L-NMMA groups, whereas NOR blunted this response. Conclusions: Neither treatment could reverse the ETX-induced derangements of cellular energy metabolism as reflected by the increased portal venous lactate/pyruvate ratios. The NOR-induced attenuation of ileal mucosal acidosis was possibly caused by a different pattern of blood flow redistribution compared with L-NMMA.

Sepsis und SIRS sind charakterisiert durch gesteigerten Blutfluss und Sauerstofftransport im Hepato-Splanchnikusgebiet, hervorgerufen durch eine Steigerung der Stoffwechselanforderungen mit dem Ergebnis einer erhohten O2-Aufnahme. In Folge des Sepsis-induzierten Hypermetabolismus kann es zu einem Missverhaltnis zwischen vorhandener Sauerstoffverfugbarkeit und aktuellem Sauerstoffbedarf kommen und daraus potentiell eine pathologische Abhangigkeit zwischen Sauerstoffverfugbarkeit und -bedarf resultieren. Als Ursache fur den Hypermetabolismus wird unter anderem die gesteigerte hepatische Glukoneogenese diskutiert, die als Folge einer gesteigerten Aufnahmerate von vermehrt peripher freigesetzten Glukoseprakursoren angesehen wird. Dieser gesteigerte Fluss von Glukoseprakursoren wiederum ist durch reaktiv freigesetzte Zytokine mitbedingt. Bezuglich therapeutischer Interventionen muss beachtet werden, dass Effekte auf Hamodynamik und Sauerstofftransport im Splanchnikusgebiet der entsprechenden Stoffwechselantwort angepasst sein mussen, um eine zusatzliche Imbalanz zwischen regionalen Blutfluss, Sauerstoff- und Substratfluss einerseits und den regionalen Anforderungen andererseits zu vermeiden. Deshalb ist das Verstandnis sowohl der Gewebeperfusion und -oxygenierung als auch der wesentlichen Stoffwechselaktivitat unerlasslich, um Behandlungskonzepte einzuordnen und bewerten zu konnen.

We investigated hepatic blood flow, O2 exchange and metabolism in porcine endotoxic shock (Control, n = 8; Endotoxin, n = 10) with administration of hydroxyethylstarch to maintain arterial pressure (MAP)>60 mmHg. Before and 12, 18 and 24 h after starting continuous i.v. endotoxin we measured portal venous and hepatic arterial blood flow, intracapillary haemoglobin O2 saturation (Hb-O2%) of the liver surface and arterial, portal and hepatic venous lactate, pyruvate, glycerol and alanine concentrations. Glucose production rate was derived from the plasma isotope enrichment during infusion of [6,6-2H2]-glucose. Despite a sustained 50% increase in cardiac output endotoxin caused a progressive, significant fall in MAP. Liver blood flow significantly increased, but endotoxin affected neither hepatic O2 delivery and uptake nor mean intracapillary Hb-O2% and Hb-O2% frequency distributions. Endotoxin nearly doubled endogenous glucose production rate while hepatic lactate, alanine and glycerol uptake rates progressively decreased significantly. The lactate uptake rate even became negative (P

The effect of daily human growth hormone (hGH) injections (3 I.U./m2/day) on tissue anabolism was determined in six patients with Ullrich-Turner syndrome (XO) (8.7-19 years of age) using novel techniques such as whole body leucine kinetics during continuous infusion of L-(Methyl-2H3)-leucine and urinary pseudouridine (5-ribosyluracil) excretion on the one hand and traditional methods like serum urea and amino acid concentrations on the other. Pseudouridine is only found in ribonucleic acid (RNA) and is neither reincorporated nor catabolically broken down and is therefore considered an ideal index of whole body RNA turnover. The mean L-(Methyl-2H3)-leucine turnover of the six XO patients before hGH was 1.90 +/- 0.15 mumoles/kg per minute. After 3 months of hGH-treatment it had increased in three patients, whereas it had decreased in the other three. The results obtained with the stable isotope technique were correlated with the urinary pseudouridine concentrations (r = 0.68; P0.01). The growth rates were positively correlated with leucine turnover (r = 0.63; P0.02) and urinary pseudouridine concentration (r = 0.73; P0.006) as well as negatively correlated with the serum urea concentrations r = -0.62; P0.03). The decrease in the individual serum urea concentrations were tightly correlated with the hGH induced change in growth rate (r = -0.90; P0.01). The individual bone ages were negatively correlated with the hGH induced changes in leucine turnover (r = -0.77; P0.003) as well as with the urinary pseudouridine concentrations (r = -0.87; P0.0002). The hGH effect on leucine and RNA turnover, showing effectiveness only until a developmental age between 11 and 12 years, leads the discussion of the ideal moment of oestrogen supplementation when girls with Ullrich-Turner syndrome are treated with hGH in early adolescence.The protein metabolism of patients with Ullrich-Turner syndrome is influenced by hGH in an age dependent manner. In a clinical setting, pseudouridine, an easily determined derivative of ribonucleic acids, may be able to replace the tedious work with expensive stable isotopes when questions related to tissue anabolism are to be answered.

To determine the magnitude and time course of adrenergic effects on metabolism in volunteers and possible implications for the use of sympathomimetics in the critically ill.Descriptive laboratory investigation.7 volunteers.Primed continuous infusions of stable isotope tracers ([15N2]-urea, [6,6-D2]-glucose, [methyl-D3]-L-leucine, [15N]-L-alanine) were used. After isotopic steady state had been reached an infusion of adrenaline (0.1 microgram/kg/min) was administered (4 h). Isotopic enrichment was measured using gas chromatography-mass spectrometry and the corresponding rates of appearance were calculated.Glucose production increased from 14.1 +/- 1.2 to 21.5 +/- 2.0 mumol/kg/min (p0.05) after 80 min of adrenergic stimulation and then decreased again to 17.9 +/- 1.2 mumol/kg/min after 240 min. Leucine and ketoisocaproate (KIC) fluxes were 2.3 +/- 0.2 and 2.6 +/- 0.2 mumol/kg/min, respectively, at baseline and gradually decreased to 1.8 +/- 0.2 and 2.2 +/- 0.1 mumol/kg/min, respectively, after 240 min of adrenaline infusion (both p0.05). Alanine flux increased from 3.7 +/- 0.5 to 6.9 +/- 0.9 mumol/kg/min (p0.05) after 80 min of adrenergic stimulation. Urea production slightly decreased from 4.8 +/- 0.9 to 4.3 +/- 0.8 mumol/kg/min during adrenaline (p0.05).Adrenaline induced an increase in glucose production lasting for longer than 240 min. The decrease in leucine and KIC flux suggests a reduction in proteolysis, which was supported by the decrease in urea production. The increase in alanine flux is therefore most likely due to an increase in de-novo synthesis. The ammonia donor for alanine synthesis in peripheral tissues and the target for ammonia after alanine deamination in the liver remain to be investigated. These results indicate that adrenaline infusion most probably will not promote already enhanced proteolysis in critically ill patients. Gluconeogenesis is an energy consuming process and an increase may deteriorate hepatic oxygen balance in patients.

Published lethality rates of esophageal perforation (EP) vary depending on patient- and disease-related factors. This study was designed to evaluate how these factors impact death. Furthermore, we calculated the predictive accuracy of the Mortality Prediction Model (MPM II) and the Simplified Acute Physiology Score (SAPS II) for in-hospital death. Conclusions about treatment decisions were drawn based on our data and analysis of recent literature. Every patient who was treated for EP at our department from December 2001 to July 2008 is included in this study. Logistic regression analyses of various risk factors, such as etiology, time interval, size, comorbidities, localization, type of treatment, and preexisting pathologies of the esophagus on death, were performed. Of the 41 patients diagnosed with EP, nine died (21%). The most important risk factor concerning death was cirrhosis of the liver (0 vs. 89% mortality; odds ratio, 208; P

The tonometric measurement of the arterial-intramucosal PCO2-difference and the calculation of the intramucosal pH is currently the only parameter which is available in the clinical routine for the assessment of perfusion, oxygen kinetics and metabolic activity of the patho-splanchnic region. Since this region with its unique both parallel and serial blood supply net comprises several organs with different metabolic performance, among which moreover the synthetic activity of the liver has to be taken into account, tonometric data have to be interpreted independently from blood flow and oxygen transport and uptake in this region. In fact, tonometry is an integrative parameter for perfusion, oxygenation and cellular energy balance. Therefore, it more completely reflects the complex anatomical and physiological conditions.

After adequate volume resuscitation, the mainstay of therapy in critically ill patients with shock is treatment with vasoactive substances to restore haemodynamics or to improve regional perfusion. These agents include adrenoceptor agonists with inotropic combined with either vasoconstricting or vasodilating effects, and predominantly vasodilating drugs such as prostacyclin and related compounds. However, vasoactive agents not only affect the cardiovascular system, but also have profound metabolic effects. The interdependence of vasoactive drugs with metabolism may be relevant regarding adequate oxygen and substrate delivery to cover actual organ needs. Therefore, the profiles of these metabolic effects have to be considered during their therapeutic administration.

The pathologic state of shock is characterized by profound changes in tissue perfusion and metabolism. The main consequence of such pathophysiologic changes clearly affects the hierarchy of priority among the various organs, but which of these changes are adaptive or deleterious is still a question not completely answered. Therefore interfering with some of the main features of shock, such as low blood pressure, may have different consequences according to the flow redistribution and/or to the associated specific metabolic consequences. Vasopressor administration is one of the mainstay treatment approaches for various shock states. Catecholamines are the most widely used vasopressors in this context. In particular during septic shock there are various concepts about the use of adrenergic agents depending on the specific adrenoceptor profile of either endogenous and synthetic catecholamines [1]. The recommendations for the use of catecholamines consider primarily their efficacy in restoring or maintaining adequate systemic hemodynamics but also try to implement effects on regional blood flow and metabolism. Adrenergic agents may also be associated, however, with marked metabolic effects not necessarily linked to their hemodynamic effects [2].

The objective of the present study was to evaluate the effects of norepinephrine (n = 9) and dobutamine (n = 7) on carbohydrate and protein metabolism in healthy volunteers in comparison with a control group (n = 9). Norepinephrine (0.1 microg/kg min), dobutamine (5 microg/kg min), or placebo was infused for 240 min. The plasma concentration of glucose, lactate, epinephrine, norepinephrine, insulin, and glucagon were determined. Glucose and urea production and leucine flux were measured using a tracer technique. Norepinephrine caused a persisting rise in plasma glucose concentration, whereas the increase in glucose production was only transient. A minor increase in plasma lactate concentration was observed, but it did not exceed the physiological range. No change in leucine flux, urea production, or plasma concentration of insulin, glucagon, or epinephrine was found. Dobutamine slightly decreased glucose production, whereas the plasma concentration of glucose and lactate did not change. The reduction in leucine flux was paralleled by a decrease in urea production. No change in the plasma concentration of insulin, glucagon, or the catecholamines was observed. In conclusion, both norepinephrine and dobutamine have only minor metabolic effects. Because glucose production is enhanced by alpha1- and beta2-adrenoceptor stimulation, we conclude that dobutamine is only a weak agonist at these adrenoceptors. These minor metabolic actions may make both compounds suitable for critically ill patients because no further increase in metabolic rate should be caused.

During continuous renal replacement therapy (CRRT), relevant losses of nutritional substrates, vitamins and trace elements due to diffusive transport and elimination via the filter may occur. We investigated the amount of these losses with regard to treatment dose during a 72-hour treatment period.

We have previously demonstrated that non-selective nitric oxide synthase (NOS) inhibition did not reverse the LPS-induced deterioration of hepato-splanchnic energy status in porcine endotoxic shock. Therefore, this study investigated the effect of selective inducible NOS (iNOS) inhibition using 1400 W on intestinal and liver perfusion, O2 kinetics, and energy metabolism during hyperdynamic porcine endotoxemia. Intravenous E. Coli LPS was continuously infused over 24 h concomitant with fluid resuscitation. After 12 h of endotoxemia, continuous intravenous infusion of 1400 W was started until the end of the experiment and was titrated to maintain mean blood pressure (MAP) at baseline levels. Twelve, 18, and 24 h after starting LPS, we measured hepatic arterial and portal venous blood flow, ileal mucosal-arterial PCO2 gap, portal as well as hepatic venous lactate/pyruvate ratios, and endogenous glucose production rate. Expired NO and plasma nitrate levels were assessed as a measure of NO production. 1400 W decreased LPS-induced increase in expired NO and allowed for the maintenance of MAP without modification of cardiac output. Despite unchanged regional macrocirculation, 1400 W prevented the progressive rise of ileal mucosal-arterial PCO2 gap, significantly improved the LPS-induced impairment of hepato-splanchnic redox state, and blunted the decline in liver lactate clearance. Increased glucose production rate was not influenced. Thus, the selective iNOS inhibition with 1400 W prevented circulatory failure and largely attenuated otherwise progressive LPS-induced deterioration of intestinal and hepatocellular energy metabolism.

We investigated the effect of mercaptoethylguanidine (MEG, 3 mg kg -1 h -1 ), a combined selective inducible nitric oxide synthase (iNOS) inhibitor, a peroxynitrite and oxygen free radical scavenger with cyclooxygenase-inhibitor properties on intestinal and hepatic perfusion, O 2 exchange, and metabolism during long-term hyperdynamic porcine endotoxemia. MEG was started 12 h after onset of endotoxemia. At baseline and after 12, 18, and 24 h of endotoxemia, hepatic arterial and portal venous blood flow, ileal mucosal-arterial PCO 2 gap, portal and hepatic venous lactate/pyruvate ratio, free glutathione (GSH), and 8-isoprostanes were measured. Expired NO and plasma nitrate levels were assessed as well. MEG blunted the endotoxin-induced increase in expired NO and prevented the progressive fall in blood pressure without affecting cardiac output. It attenuated both systemic and regional venous acidosis without influencing the impairment of hepatosplanchnic metabolism nor counteracting the increase in GSH levels. In our model MEG failed to beneficially affect variables of oxidative stress.

Objective: To investigate the effects of nicotinamide (NIC), an inhibitor of poly(ADP-ribose) synthetase (PARS), on intestinal and liver perfusion, O2 kinetics, and energy metabolism over 24 h of hyperdynamic porcine endotoxemia. Design: Prospective, randomized, controlled experimental study with repeated measures. Setting: Animal laboratory in a university hospital. Subjects: Sixteen pigs, divided into two groups: nine endotoxemic animals without therapy (CON); seven animals treated with NIC. Interventions: Pigs were anesthetized, mechanically ventilated, and instrumented. Intravenous E. Coli LPS was continuously infused over 24 h concomitant with fluid resuscitation. After 12 h of endotoxemia continuous i.v. infusion of NIC (10 mg/kg per hour) was administered until the end of the experiment. Measurements and results: All animals developed hyperdynamic circulation with sustained increase in cardiac output and progressive fall in mean arterial pressure. NIC maintained blood pressure without affecting CO. Hepato-splanchnic macrocirculation was not modified by the treatment. Nevertheless, although NIC attenuated the progressive rise of ileal mucosal-arterial PCO2 gap, it failed to improve portal venous L/P ratio, a marker of the overall energy state of the portal venous drained viscera. Similarly, neither the increased hepatic venous L/P ratio nor the simultaneous drop in hepatic lactate uptake were influenced by NIC. Conclusions: Although NIC maintained hemodynamic stabilization during long-term endotoxemia, it was unable to improve LPS-induced deterioration of the hepato-splanchnic energy metabolism. More potent and selective PARS inhibitors are needed to elucidate the role of a PARS-dependent pathway in a clinically relevant models of sepsis.

Objectives: Total hepatic venous blood flow is determined by the common hepatic arterial blood flow and the venous outflow from stomach, spleen, pancreas, small intestine, and bowel, collected by the portal vein, and thus represents overall splanchnic perfusion. We investigated whether transesophageal echography (TEE) can provide a method for bedside assessment of hepatic venous blood flow useful as a noninvasive method for measuring splanchnic perfusion in clinical practice. Design and setting Experimental study in 15 anesthetized and ventilated pigs in an animal research laboratory. Interventions: TEE-derived calculations of hepatic venous blood flow were compared with liver blood flow measurements using perivascular ultrasound flow probes surgically positioned on portal vein and common hepatic artery. Parameters were determined at baseline and after modulating splanchnic perfusion by either PEEP maneuver (15 cmH2O) or intravenous epinephrine (0.1 µg kg–1 min–1). Measurements and results: Diameter (d) and velocity time integral (VTI) of all three hepatic veins were determined by TEE, heart rate (HR) was derived from electrocardiography and flow subsequently calculated as Q=π·(d/2)2·0.57·VTI·HR. Regression analysis of matched TEE and flow probe values showed a significant linear relationship (r 2=0.698). Bias analysis revealed a systematic underestimation of liver blood flow by TEE, possibly due to use of 0.57 as correction factor for mean velocity, while changes in liver blood flow were reliably detected. Conclusion: TEE offers a noninvasive approach for monitoring hepatic perfusion and may be used in patients.

Sepsis may lead to deranged thromboxane-prostacyclin ratio with consecutive organ dysfunction. Because of the suggested role of the gut in the pathogenesis of septic shock and multiple organ failure, we investigated the effects of the novel dual thromboxane synthase inhibitor and receptor antagonist DTTX-30 (TRASI) on intestinal tissue perfusion, O2 kinetics, and energy metabolism over 24 h of hyperdynamic, normotensive porcine endotoxemia. Before, 12, 18, and 24 h after starting continuous i.v. endotoxin (LPS), we measured portal venous (PV) blood flow, intestinal oxygen extraction (iO2ER), intracapillary hemoglobin O2 saturation (HbO2%) of the ileal wall, intramucosal ileal PCO2, PV lactate-pyruvate (L-P) ratio, and plasma levels of thromboxane and prostacyclin. Treatment with TRASI (0.12 mg/kg i.v. bolus injection followed by an infusion of 0.29 mg/kg/h) initiated after 12 h of LPS infusion markedly reduced the plasma thromboxane levels and attenuated the LPS-induced fall in systemic vascular resistance, resulting in hemodynamic stabilization. TRASI did not influence the LPS-induced increase in PV blood flow nor intracapillary HbO2%, thus reflecting unchanged microcirculatory O2 availability and decreased iO2ER, possibly because of reduced O2 requirements. Nevertheless, TRASI prevented the LPS-induced increase in the PV L-P ratio, attenuated the progression of the ileal mucosal-arterial PCO2 gap, and tended to attenuate the gradual fall of PV pH. Hence, compounds like TRASI may beneficially influence LPS-related derangements of gut energy metabolism.

We compared the effects of norepinephrine (NOR; n = 11) and the nonselective nitric oxide synthase inhibitor Nomega-monomethyl-L-arginine (L-NMMA; n = 11) on hepatic blood flow (Q liv), O2 exchange, and energy metabolism over 24 h of hyperdynamic, normotensive porcine endotoxic shock. Endotoxin (ETX; n = 8) caused a continuous fall in mean arterial pressure (MAP) despite a sustained 50% increase in cardiac output (Q) achieved by adequate fluid resuscitation. NOR maintained MAP at preshock levels owing to a further rise in Q, while the comparable hemodynamic stabilization during L-NMMA infusion resulted from systemic vasoconstriction, increasing the systemic vascular resistance (SVR) about 30% from shock level after 6 h of treatment concomitant with a reduction in Q to preshock values. Whereas NOR also increased Q liv and, hence, hepatic O2 delivery (hDO2), but did not affect hepatic O2 uptake (hVO2), L-NMMA influenced neither Q liv nor hDO2 and hVO2. Mean capillary hemoglobin O2 saturation (HbScO2) on the liver surface as well as HbScO2 frequency distributions, which mirror microcirculatory O2 availability, remained unchanged as well. Neither treatment influenced the ETX-induced derangements of cellular energy metabolism reflected by the progressive decrease in hepatic lactate uptake rate and increased hepatic venous lactate/pyruvate ratios. ETX nearly doubled the endogenous glucose production (EGP) rate, which was further increased with NOR, whereas L-NMMA nearly restored EGP to preshock levels. Nevertheless, despite the different mechanisms in maintaining blood pressure neither treatment influenced ETX-induced liver dysfunction.