Platelet activation and increased tissue factor expression on monocytes in reperfusion injury following orthotopic liver transplantation.

Platelets have been implicated in the pathogenesis of liver damage after orthotopic liver transplantation (OLT). Early graft dysfunction is frequently caused by reperfusion injury subsequent to cold ischemia (IRI). Therefore, we investigated activation of the pivotal haemostatic cells, platelets and monocytes, from patients with elevated markers of IRI and from patients with uneventful course (control-group), respectively during the first week after OLT. Flow cytometry analysis of citrate anticoagulated blood samples revealed that platelets from IRI patients became significantly activated within 48 h after OLT in vivo, with increased surface presentation of P-selectin, CD40L, thrombospondin-1 and tissue-factor. Platelet activation in IRI patients on post-transplant day 2 was accompanied by significantly enhanced tissue-factor expression on peripheral blood monocytes, significant elevated levels of C-reactive protein and hepatocellular damage. Towards post-transplant day 4, levels of platelet-derived microparticles rose significantly in IRI patients if contrasted to control patients. Thus, activated cellular haemostasis is involved in the early inflammatory response of hepatocellular damage subsequent to reperfusion of the transplanted liver. Targeting distinct activation patterns of platelets and monocytes in an early phase of hepatic grafting may counteract the extent of IRI via inhibition of micro-thrombus formation and inflammation without exacerbating the existing bleeding risk.

Employing dobutamine as a useful agent to reverse the terlipressin-linked impairments in cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep.

Although arginine vasopressin and terlipressin have been identified as useful nonadrenergic agents to increase systemic blood pressure in catchecholamine-resistant septic shock, the impairments in cardiac index (CI) and global oxygen transport may limit their clinical applicability. The present study was designed as a prospective controlled laboratory experiment to investigate the effects of dobutamine as an adjunct to terlipressin infusion on cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep. Nine adult ewes were instrumented for chronic study using an established protocol. After a baseline measurement in the healthy state had been performed, 1 mg terlipressin was given as bolus infusion. Thirty minutes later, dobutamine was continuously infused at incremental doses (2 and 5 microg x kg(1) x min(1), each for 1 h). After 24 h of recovery, a hypotensive-hyperdynamic circulation was induced and maintained by a continuous infusion of Salmonella typhosa endotoxin (10 ng x kg(1) x min(1)). After 16 h of endotoxemia, the six surviving sheep received terlipressin and dobutamine according to the same protocol that was used in healthy sheep. Compared with baseline, terlipressin infusion was associated with a significant increase in MAP that, however, occurred at the expense of a compromised CI, oxygen delivery index (DO(2)I), and mixed venous oxygen saturation (SvO(2), each P < 0.05). Dobutamine infusion was followed by a dose-dependent increase in CI, DO(2)I, and SvO(2) in both health and endotoxemia (each P < 0.05). Although the higher dosage of dobutamine exerted favorable effects, such as a decrease in pulmonary vascular resistance index (P < 0.05), the associated onset of tachycardia (P < 0.05) and arterial hypotension (P < 0.05) may limit its therapeutic use under septic conditions. This study provides evidence that dobutamine in a dosage of 2 microg x kg(1) x min(1) is useful to reverse the terlipressin-linked depressions in CI, DO(2)I and SvO(2) in ovine endotoxemia without obvious side effects.

Nicotinamide increases systemic vascular resistance in ovine endotoxemia.

OBJECTIVE: The nuclear enzyme Poly(ADP-Ribose)-Polymerase (PARP) has been hypothesized as playing a major role in various forms of inflammation. PARP activation is induced by DNA strand breakage and can result in intracellular energy depletion and, ultimately, cell death. Further, it is thought to influence cardiovascular function and organ failure in endotoxemia. Here, we investigated the effect of the PARP inhibitor nicotinamide on cardiovascular and liver function in healthy and chronically endotoxemic sheep. DESIGN: Prospective controlled trial. SETTING: University research laboratory. SUBJECTS: 12 female adult sheep. INTERVENTIONS: Six healthy sheep, instrumented for chronic study, received nicotinamide intravenously as a bolus of 40 mg/kg followed by a continuous infusion of 10 mg.kg(-1).h(-1); six animals received the vehicle. One hour after bolus application, a continuous infusion of endotoxin ( Salmonella typhosa, 10 ng.kg(-1).min(-1)) was started. Hemodynamic parameters were determined before and during endotoxemia. MEASUREMENTS AND RESULTS: Treatment with nicotinamide resulted in a significantly higher systemic vascular resistance index and lower cardiac index in endotoxemic animals, but not in controls. It also attenuated endotoxin-induced increase in gamma-glutamyl transferase. CONCLUSIONS: The PARP inhibitor nicotinamide attenuates impairment of cardiovascular function during endotoxemia. In addition, PARP activation may be involved in endotoxin-induced liver injury.

Heat shock protein 72 and apoptosis indicate cardiac decompensation during early multiple organ failure in sheep.

OBJECTIVE: Inducible heat shock protein 72 (HSP 72) preserves myocardial function and prevents apoptosis. We investigated the expression and localization of HSP 72 and apoptosis in our previously described new model of multiple organ failure. DESIGN: Eighteen adult-instrumented sheep and three healthy controls were randomly assigned to one of three groups: (a) norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO); (b) norfenefrine-masked hypovolemia without endotoxemia (NMH); (c) recurrent endotoxemia during normovolemia (ENDO); and (d) normovolemia without endotoxemia (CONTROLS). MEASUREMENTS AND RESULTS: Hearts were analyzed by light microscopy, Western blots, immunohistochemistry, and TUNEL staining. HSP 72 expression was approximately threefold increased in NMH+ENDO compared with the other groups ( p<0.05) and was localized mainly in left ventricular cardiomyocytes. HSP 72 was elevated in animals with norfenefrine-refractory shock compared to survivors ( p=0.015). TUNEL-positive cells in the left ventricle were significantly elevated in the NMH+ENDO group ( p=0.05) and correlated with HSP 72 expression (r=0.51, p=0.018). HSP 72 correlated positively with heart rate (r=0.76, p<0.0001), the prefinal hourly dose of norfenefrine (r=0.88, p<0.0001), and negatively with left ventricular stroke work index (r=-0.52, p=0.028). Double staining revealed TUNEL-positive cells with and without HSP 72 expression. Micronecroses were only detectable in NMH and NMH+ENDO without intergroup difference or correlations with hemodynamics. CONCLUSION: HSP 72 overexpression and apoptosis, but not necrosis, indicate cardiovascular decompensation and poor outcome during early multiple organ failure.

[The cardiac risk patient: introduction and epidemiology]. / Der kardiale Risikopatient. Einführung und Epidemiologie.

Preexisting cardiovascular diseases are the most important risk factors in the perioperative period. They can cause complications that have a major impact on the morbidity and mortality of surgical patients. The current issue of AINS thus presents the actual state of knowledge about the pathophysiology, preoperative evaluation, and perioperative management of cardiac risk diseases in three practice-orientated review articles. Only sound knowledge of the pathophysiological background together with the diagnostic and therapeutic possibilities will allow the clinically active anesthesiologist to adapt the available therapeutic and preventative options in the best possible way to the individual patient and to avoid not only medical but also economically unnecessary and/or potentially harmful interventions.

Cerebral response to norepinephrine compared with fluid resuscitation in ovine traumatic brain injury and systemic inflammation.

OBJECTIVE: Traumatic brain injury is frequently accompanied by a systemic inflammatory response. Systemic inflammation was associated with cerebral hyperperfusion uncoupled to global oxygen metabolism in ovine head trauma. The present study investigated the cerebral effects of cerebral perfusion pressure (CPP) management performed by either fluid resuscitation or vasopressor treatment of low CPP induced by systemic inflammation. DESIGN: Nonrandomized experimental study. SETTING: University hospital laboratory. SUBJECTS: A total of 12 adult sheep. INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Sheep were anesthetized and ventilated throughout the experimental period (13 hrs). After baseline measurements (hour 0), blunt head trauma was induced by a nonpenetrating stunner. After postinjury measurements (hour 2), all animals received continuous endotoxin infusion. At hour 10, one group (n = 6) was infused with hydroxyethyl starch until CPP reached 60-70 mm Hg. A second group (n = 6) received norepinephrine for CPP elevation. In the norepinephrine group, blood was isovolemically exchanged by hydroxyethyl starch to achieve comparable hematocrit levels. Head trauma increased intracranial pressure and decreased brain tissue oxygen tension. Endotoxemia induced a hyperdynamic cardiovascular response with increased internal carotid blood flow in the presence of systemic hypotension and decreased CPP. Hydroxyethyl starch infusion further increased internal carotid blood flow from (mean +/- sd) 247 +/- 26 (hour 10) to 342 +/- 42 mL/min (hour 13) and intracranial pressure from 20 +/- 4 (hour 10) to a maximum of 25 +/- 3 mm Hg (hour 12) but did not significantly affect brain tissue oxygen tension, sinus venous oxygen saturation and oxygen extraction fraction. Norepinephrine increased internal carotid blood flow from 268 +/- 19 to 342 +/- 58 mL/min and intracranial pressure from 22 +/- 11 to 24 +/- 11 mm Hg (hour 10 vs. hour 13) but significantly increased sinus venous oxygen saturation from 49 +/- 4 (hour 10) to a maximum of 59 +/- 6 mm Hg (hour 12) and decreased oxygen extraction fraction. The increase in brain tissue oxygen tension during norepinephrine treatment was not significant. CONCLUSION: We conclude that despite identical carotid blood flows, only CPP management with norepinephrine reduced the cerebral oxygen deficit in this model.

Cine and tagged magnetic resonance imaging in short-term stunned versus necrotic myocardium.

We investigated the potential of Cine and 2D Tagged Cardiac Magnetic Resonance (CMR) Imaging to distinguish stunned from necrotic left ventricular (LV) myocardium in the early postischemic phase in an open-chest animal model (N = 12). Reversible and permanent occlusion of the LAD coronary artery resulted in global LV dysfunction in both groups without significant differences. LAD perfused segments revealed significant higher values for end systolic wall thickening (ESWT) and percentual systolic wall thickening in animals with stunned myocardium. Analysis of strain parameters showed significant regional differences (maximal principal strain lambda1, deviation angle beta) between postischemic and remote myocardium within both groups, however results were not significantly different comparing animals with stunned myocardium to animals with myocardial necrosis. In conclusion, at rest neither global LV functional nor regional strain parameters derived from Cine and 2D Tagged CMR Imaging can distinguish animals with short-term stunned myocardium from respective animals with necrotic myocardium. Diagnostic value of ESWT is limited due to the spatial resolution of the gradient-echo sequence used.

Arteriovenous carboxyhemoglobin difference in critical illness: fiction or fact?

It is still unclear whether the paradoxical arteriovenous carboxyhemoglobin (COHb) difference found in critical illness is due to increased COHb production by the lung, or whether this gradient is caused by technical artifacts using spectrophotometry. In healthy and matched endotoxemic sheep, blood gases were analyzed with a standard ABL 625 and the updated version, an ABL 725. The latter one was accurately calibrated for COHb wavelengths (SAT 100) to eliminate the FCOHb dependency on oxygen tension. All endotoxemic sheep exhibited a hypotensive-hyperdynamic circulation and a pulmonary hypertension. Interestingly, arteriovenous COHb difference occurred in both healthy and endotoxemic sheep (P<0.001 each). Arterial and central venous COHb concentrations determined with the ABL 625 were significantly lower than those measured with the ABL 725 (P<0.001 each). We conclude that (a) arteriovenous COHb difference per se does not reflect critical illness and (b) measurements with an ABL 625 underestimate COHb concentrations.