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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.

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.

The role of hypothermia in hemorrhagic shock is still a matter of debate [1]. Therefore, we studied the effects of deliberate, pre-emptive hypothermia on hemodynamics and organ function during long-term porcine hemorrhage and resuscitation.

Our goal was to evaluate the effect of hyperoxia on sublingual and ileostomal microcirculation during hemorrhagic and reperfusion shock in a porcine model simulating the rupture of an abdominal aortic aneurysm (AAA). We wanted to test the effect of hyperoxia on these two vascular beds because hyperoxia is known to cause different arteriolar responses [1].

In almost half of all sepsis patients, acute kidney injury (AKI) develops. However, the pathobiologic differences between sepsis patients with and without AKI are only poorly understood. We used a unique opportunity to examine dynamic inflammatory, renal hemodynamic, and microvascular changes in two clinically relevant large-animal models of sepsis. Our aim was to assess variability in renal responses to sepsis and to identify both hemodynamic and nonhemodynamic mechanisms discriminating individuals with AKI from those in whom AKI did not develop.Thirty-six pigs were anesthetized, mechanically ventilated, and instrumented. After a recovery period, progressive sepsis was induced either by peritonitis (n = 13) or by continuous intravenous infusion of live Pseudomonas aeruginosa (n = 15). Eight sham operated-on animals served as time-matched controls. All animals received standard intensive care unit (ICU) care, including goal-directed hemodynamic management. Before, and at 12, 18, and 22 hours of sepsis, systemic and renal (ultrasound flow probe) hemodynamics, renal cortex microcirculation (laser Doppler), inflammation (interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), oxidative stress (thiobarbituric acid reactive species (TBARS), nitrite/nitrate concentrations (NOx), and renal oxygen kinetics and energy metabolism were measured.In 14 (50%) pigs, AKI developed (62% in peritonitis, 40% in bacteria infusion model). Fecal peritonitis resulted in hyperdynamic circulation, whereas continuous bacteria infusion was associated with normodynamic hemodynamics. Despite insults of equal magnitude, comparable systemic hemodynamic response, and uniform supportive treatment, only those pigs with AKI exhibited a progressive increase in renal vascular resistance. This intrarenal vasoconstriction occurred predominantly in the live-bacteria infusion model. In contrast to AKI-free animals, the development of septic AKI was preceded by early and remarkable inflammatory response (TNF-α, IL-6) and oxidative stress (TBARS).The observed variability in susceptibility to septic AKI in our models replicates that of human disease. Early abnormal host response accompanied by subsequent uncoupling between systemic and renal vascular resistance appear to be major determinants in the early phase of porcine septic AKI. Nonuniform and model-related renal hemodynamic responses that are unpredictable from systemic changes should be taken into consideration when evaluating hemodynamic therapeutic interventions in septic AKI.

Introduction Mechanical ventilation (MV) can injure the lungs and contribute to an overwhelming inflammatory response, leading to acute renal failure (ARF). We previously showed that poly(adenosine diphosphate-ribose) polymerase (PARP) is involved in the development of ventilator-induced lung injury (VILI) and the related ARF, but the mechanisms underneath remain unclear. In the current study we therefore tested the hypothesis that renal blood flow and endothelial, functional and tissue changes in the kidney of rats with lipopolysaccharide (LPS)-induced lung injury aggravated by MV, is caused, in part, by activation of PARP by peroxynitrite. Methods Anesthetized Sprague Dawley rats (n = 31), were subjected to intratracheal instillation of lipopolysaccharide at 10 mg/kg followed by 210 min of mechanical ventilation at either low tidal volume (6 mL/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (19 mL/kg) with zero positive end-expiratory pressure in the presence or absence of a peroxynitrite decomposition catalyst, WW85 or a PARP inhibitor, PJ-34. During the experiment, hemodynamics and blood gas variables were monitored. At time (t) t = 0 and t = 180 min, renal blood flow was measured. Blood and urine were collected for creatinine clearance measurement. Arcuate renal arteries were isolated for vasoreactivity experiment and kidneys snap frozen for staining. Results High tidal volume ventilation resulted in lung injury, hypotension, renal hypoperfusion and impaired renal endothelium-dependent vasodilation, associated with renal dysfunction and tissue changes (leukocyte accumulation and increased expression of neutrophil gelatinase-associated lipocalin). Both WW85 and PJ-34 treatments attenuated lung injury, preserved blood pressure, attenuated renal endothelial dysfunction and maintained renal blood flow. In multivariable analysis, renal blood flow improvement was, independently from each other, associated with both maintained blood pressure and endothelium-dependent vasodilation by drug treatment. Finally, drug treatment improved renal function and reduced tissue changes. Conclusions The peroxynitrite-induced PARP activation is involved in renal hypoperfusion, impaired endothelium-dependent vasodilation and resultant dysfunction, and injury, in a model of lung injury.

Continuous renal replacement therapies (CRRT) are widely used for treatment of acute kidney injury in critically ill patients. Little attention has been paid to the potential adverse effects of CRRT related to extracorporeal circuit bioincompatibility. Limited available evidence suggests that intermittent dialysis may compromise hepatosplanchnic perfusion in acute renal failure patients. By contrast, there are no data on the bio(in)compatibility indices in patients treated by CRRT. To investigate this issue, we utilized a long-term porcine model allowing a broad insight into organ hemodynamic, microvascular, metabolic and other pathways not accessible in human medicine.

Introduction Our understanding of septic acute kidney injury (AKI) remains incomplete. A fundamental step is the use of animal models designed to meet the criteria of human sepsis. Therefore, we dynamically assessed renal haemodynamic, microvascular and metabolic responses to, and ultrastructural sequelae of, sepsis in a porcine model of faecal peritonitis-induced progressive hyperdynamic sepsis. Methods In eight anaesthetised and mechanically ventilated pigs, faecal peritonitis was induced by inoculating autologous faeces. Six sham-operated animals served as time-matched controls. Noradrenaline was administered to maintain mean arterial pressure (MAP) greater than or equal to 65 mmHg. Before and at 12, 18 and 22 hours of peritonitis systemic haemodynamics, total renal (ultrasound Doppler) and cortex microvascular (laser Doppler) blood flow, oxygen transport and renal venous pressure, acid base balance and lactate/pyruvate ratios were measured. Postmortem histological analysis of kidney tissue was performed. Results All septic pigs developed hyperdynamic shock with AKI as evidenced by a 30% increase in plasma creatinine levels. Kidney blood flow remained well-preserved and renal vascular resistance did not change either. Renal perfusion pressure significantly decreased in the AKI group as a result of gradually increased renal venous pressure. In parallel with a significant decrease in renal cortex microvascular perfusion, progressive renal venous acidosis and an increase in lactate/pyruvate ratio developed, while renal oxygen consumption remained unchanged. Renal histology revealed only subtle changes without signs of acute tubular necrosis. Conclusion The results of this experimental study argue against the concept of renal vasoconstriction and tubular necrosis as physiological and morphological substrates of early septic AKI. Renal venous congestion might be a hidden and clinically unrecognised contributor to the development of kidney dysfunction.

Extracorporeal blood purification techniques for the treatment of sepsis remain conceptually sound but are still an unresolved issue. Coupled plasma filtration adsorption (CPFA) enabling higher nonselective elimination of septic mediators represents a promising concept [1]. Its efficacy, however, has not been tested in a clinically relevant large animal model of septic shock. We therefore evaluated the biological effects of CPFA in a porcine long-term, hyperdynamic, peritonitis-induced septic shock model.

The widely held paradigm that renal vasoconstriction may not be a prerequisite for septic acute kidney injury (AKI) has recently been challenged [1]. Further research is needed to establish whether this concept is valid in other clinically relevant models of sepsis-induced AKI [2]. The aim of our study was therefore to dynamically assess the pattern of renal hemodynamics, microcirculation and energy balance during a hyperdynamic porcine model of progressive septic shock.

Increased microvascular permeability resulting in tissue edema is a hallmark of sepsis-related microcirculatory failure, and leukocyte–endothelium interaction is thought to assume major importance in this context. However, the role of nitric oxide (NO) in the interplay of inflammation, leukocyte–endothelium interaction and increased microcirculatory permeability is still a matter of debate. Hollenberg et al. now report, in the previous issue of Critical Care, that neither genetic deletion nor pharmacologic blockade of the inducible isoform of the NO synthase (iNOS) affected the sepsis-related aggravation of leukocyte rolling and adhesion, whereas iNOS inhibition attenuated microvascular permeability. The authors conclude that excess NO resulting from iNOS activation is important in modulating vascular permeability during sepsis, but that this effect is independent of its action on leukocytes.

We showed recently that both selective iNOS inhibition and the radical scavenger Tempol prevented live bacteria from causing key features of hemodynamic, microcirculatory and metabolic derangements in porcine sepsis [1,2]. Here we investigated the effects of combined selective iNOS inhibition (L-NIL) with a free radical scavenger (Tempol) on P. aeruginosa-induced endothelial and hemostatic stress.

A case report of a patient with hemophygocytic syndrome - a rare cause of life-threatening pancytopenia in the critical care.

We studied the medical personnel's power of distinction various types of respirators in CPAP and CPAP+pressure support (PS) modes.

Inhaled nitric oxide (NO) causes selective pulmonary vasodilation. In experiment, pulmonary arteries were shown to be primary site of NO effect. Our aim was to study the effect of inhaled NO on pulmonary vasculature in ARDS patients.

Vasopressor therapy is current practice for treatment of arterial hypotension associated with septic shock, but may result in gut dysfunction due to intestinal vasoconstriction. Therefore we compared the effects of vasopressor treatment with the nitric oxide synthase inhibitor L-NMMA with those of noradrenaline (NOR) on intestinal O2 transport as well as energy balance in a porcine hyperdynamic endotoxic shock model.

Inhibition of nitric oxide (NO) synthesis is currently investigated for the treatment of hypotension associated with septic shock. Since both endotoxin (ETX) and NO have been reported to influence gluconeogenesis we compared the effects of standard vasopressor therapy with noradrenaline (NOR) to L-NMMA on endogenous glucose release during long-term ETX induced shock.

Nitric oxide synthase (NOS) inhibition is currently investigated as a treatment of arterial hypotension associated with septic shock, but controversial data are available with respect to hepatic O2 balance. Therefore we studied the effect of NOS inhibition with L-NMMA on liver O2 transport as well as energy balance, in comparison to a standard treatment with noradrenaline (NOR) in a hyperdynamic endotoxin (ETX) shock model.

Objectives: To validate a porcine model of ruptured abdominal aortic aneurysm (rAAA) repair. Design: Experimental study. Methods: Ten experimental and five sham-operated pigs were studied. Instrumentation for cardiac output (CO) measurement, regional blood flow (renal-REN and portal-PORT) and blood sampling (inferior vena cava (IVC), renal and portal vein) was done. Microcirculation was visualised sublingually and in ileostoma. Protocol: simulation of rAAA with bleeding (mean arterial pressure (MAP) 45 mmHg) and increased abdominal pressure (25 mmHg) for 4 h; 2 h of infrarenal clamp with shed blood retransfusion; 11 h of post-surgery care. Results: Six experimental pigs completed the protocol and are presented. Bleeding decreased CO to 95%, PORT to 80% and REN to 10% of baseline. From clamping on CO and PORT increased above baseline whereas REN (47%) with creatinine clearance remained compromised till the end. Microcirculation was affected more in ileum than sublingually. Approximately threefold increase in cytokines (tumour necrosis factor-a (TNF-alpha), interleukin (IL)-6 and IL-10) and oxidative stress markers thiobarbituric acid-reactive substances (TBARs) and 4-hydroxy-2-trans-nonenal (HNE) was observed. Only mild increase in IL-6 and TBARs was observed in sham-operated animals. Organ histology did not reveal differences between groups. Conclusions: This near-lethal model of rAAA induced expected severe deterioration of haemodynamics and metabolism accompanied with a moderate inflammatory and oxidative stress response.

We have recently demonstrated that selective inducible nitric oxide (NO) synthase (iNOS) inhibition with 1400W attenuated the hemodynamic and metabolic alterations affiliated with hyperdynamic porcine endotoxemia. In contrast to endotoxemia, limited evidence is available to document a relationship between NO and organ dysfunction in large animal bacteremic models. Therefore, using the same experimental setup, we investigated the role of selective iNOS blockade in porcine bacteremia induced and maintained for 24 h with a continuous infusion of live Pseudomonas aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n = 8) or continuous infusion of selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysine (L-NIL; n = 8). Measurements were performed before, and 12, 18, and 24 h after P. aeruginosa infusion. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite concentrations and prevented hypotension without affecting cardiac output. Despite comparable hepatosplanchnic macrocirculation, L-NIL blunted the progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. L-NIL largely attenuated mesenteric and hepatic venous acidosis, significantly improved P. aeruginosa-induced impairment of hepatosplanchnic redox state, and mitigated the decline in liver lactate clearance. Furthermore, the administration of L-NIL reduced the hepatocellular injury and prevented the development of renal dysfunction. Finally, treatment with L-NIL significantly attenuated the formation of 8-isoprostane concentrations, a direct marker of lipid peroxidation. Thus, selective iNOS inhibition with L-NIL prevented live bacteria from causing key features of metabolic derangements in porcine hyperdynamic sepsis. Underlying mechanisms probably include reduced oxidative stress with improved microcirculatory perfusion and restoration of cellular respiration.

The pathophysiology and molecular mechanisms involved in sepsis are complex and poorly understood. We performed a proteomics study to characterize early host responses to sepsis as determined by altered plasma proteome in a porcine model of peritonitis-induced sepsis.

Hypercapnic acidosis (HCA) that accompanies lung-protective ventilation may be considered permissive (a tolerable side effect), or it may be therapeutic by itself. Cardiovascular effects may contribute to, or limit, the potential therapeutic impact of HCA; therefore, a complex physiological study was performed in healthy pigs to evaluate the systemic and organ-specific circulatory effects of HCA, and to compare them with those of metabolic (eucapnic) acidosis (MAC). In anesthetized, mechanically ventilated and instrumented pigs, HCA was induced by increasing the inspired fraction of CO2 (n = 8) and MAC (n = 8) by the infusion of HCl, to reach an arterial plasma pH of 7.1. In the control group (n = 8), the normal plasma pH was maintained throughout the experiment. Hemodynamic parameters, including regional organ hemodynamics, blood gases, and electrocardiograms, were measured in vivo. Subsequently, isometric contractions and membrane potentials were recorded in vitro in the right ventricular trabeculae. HCA affected both the pulmonary (increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR)) and systemic (increase in mean arterial pressure (MAP), decrease in systemic vascular resistance (SVR)) circulations. Although the renal perfusion remained unaffected by any type of acidosis, HCA increased carotid, portal, and, hence, total liver blood flow. MAC influenced the pulmonary circulation only (increase in MPAP and PVR). Both MAC and HCA reduced the stroke volume, which was compensated for by an increase in heart rate to maintain (MAC), or even increase (HCA), the cardiac output. The right ventricular stroke work per minute was increased by both MAC and HCA; however, the left ventricular stroke work was increased by HCA only. In vitro, the trabeculae from the control pigs and pigs with acidosis showed similar contraction force and action-potential duration (APD). Perfusion with an acidic solution decreased the contraction force, whereas APD was not influenced. MAC preferentially affects the pulmonary circulation, whereas HCA affects the pulmonary, systemic, and regional circulations. The cardiac contractile function was reduced, but the cardiac output was maintained (MAC), or even increased (HCA). The increased ventricular stroke work per minute revealed an increased work demand placed by acidosis on the heart.