Konstantinos Kalimeris

Global Consequences of Liver Ischemia/Reperfusion Injury

Liver ischemia/reperfusion injury has been extensively studied during the last decades and has been implicated in the pathophysiology of many clinical entities following hepatic surgery and transplantation. Apart from its pivotal role in the pathogenesis of the organs post reperfusion injury, it has also been proposed as an underlying mechanism responsible for the dysfunction and injury of other organs as well. It seems that liver ischemia and reperfusion represent an event with “global” consequences that influence the function of many remote organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organs injury may lead to the multiple organ dysfunction syndrome, frequently encountered in these patients. Remote organ injury seems to be in part the result of the oxidative burst and the inflammatory response following reperfusion. The present paper aims to review the existing literature regarding the proposed mechanisms of remote organ injury after liver ischemia and reperfusion.

Propofol prevents lung injury following intestinal ischemia-reperfusion.

BACKGROUND The antioxidant properties of propofol have been shown to improve ischemia/reperfusion injury. We investigated whether anesthesia with propofol can ameliorate remote lung injury induced by intestinal ischemia-reperfusion (IIR). MATERIALS AND METHODS Thirty male Wistar rats were randomly allocated in three groups (n = 10 each): animals in group Sham were anesthetized with ketamine and xylazine and then laparotomy and sham IIR followed. Animals in group IIR received ketamine and xylazine and were then subjected to clamping of the superior mesenteric artery for 45 min and reperfusion for 4 h. Group IIR+P received anesthesia with propofol and then IIR was induced, as in group IIR. Blood samples for blood gases and malondialdehyde measurements were drawn at the end of reperfusion. Bronchoalveolar lavage fluid (BALF) was obtained to measure cell counts, total protein, and phospholipids levels. RESULTS Induction of IIR resulted in deteriorated oxygenation, acidemia, and inflammatory cells sequestration, along with increased BALF protein content and increased proportions of small surfactant aggregates. Anesthesia with propofol alleviated intestinal injury and efficiently prevented lipid oxidation. In group IIR+P inflammatory cell infiltration and pulmonary histologic changes were significantly limited. The increase in BALF total protein and the changes in surfactant aggregates were prevented, leading to normal systemic oxygenation. CONCLUSION Using propofol to induce and maintain anesthesia efficiently prevented IIR-induced lung injury. Systemic antioxidant protection, improvement of intestinal injury, inhibition of the inflammatory response, and preservation of the alveolar-capillary permeability seem to be crucial mediating mechanisms for this simple and clinically relevant intervention.

Influence of propofol and volatile anaesthetics on the inflammatory response in the ventilated lung

Background: The immunomodulatory effects of volatile anaesthetics in vitro and the protective effect of propofol in lung injury spurred us to study the effects of volatile anaesthetics and propofol on lung tissue in vivo.

Development of a Porcine Model of Post-Hepatectomy Liver Failure

BACKGROUND The aim of this study was to develop a porcine model of post-operative liver failure (POLF) that could accurately reproduce all the neurological and metabolic parameters of the corresponding clinical syndrome that may develop after extensive liver resections. METHODS In our model, we induced POLF by combining extended left hepatectomy and ischemia of the small liver remnant of 150 min duration. Subsequently, the remnant liver parenchyma was reperfused and the animals were closely monitored for 24 h. MATERIALS Twelve Landrace pigs (weight 25-30 kg) were randomly assigned in two groups; eight of them constituted the experimental group, in which POLF was induced (POLF group, n = 8), whereas the rest of them (n = 4) were included in the control group (sham laparotomy without establishment of POLF). RESULTS (MEANS ± SD): All POLF animals gradually developed neurological and biochemical signs of liver failure including, among many other parameters, elevated intracranial pressure (24.00 ± 4.69 versus 10.17 ± 0.75, P = 0.004) and ammonia levels (633.00 ± 252.21 versus 51.50 ± 9.49, P = 0.004) compared with controls. Histopathologic evaluation of the liver at the end of the experiment demonstrated diffuse coagulative necrosis and severe architectural distortion of the hepatic parenchyma in all POLF animals. CONCLUSION Our surgical technique creates a reproducible porcine model of POLF which can be used to study the pathophysiology and possible therapeutic interventions in this serious complication of extensive hepatectomies.

Cognitive Function and Oxidative Stress After Carotid Endarterectomy: Comparison of Propofol to Sevoflurane Anesthesia

OBJECTIVE To examine the antioxidant role of propofol in ischemia-reperfusion during carotid endarterectomy (CEA) and its influence on cognitive dysfunction after CEA. DESIGN A randomized prospective study. SETTING Single-center study in a university hospital. PARTICIPANTS Forty-four patients. INTERVENTIONS Patients underwent elective CEA under general anesthesia with either sevoflurane (group S, n = 21) or propofol (group P, n = 23). MEASUREMENTS AND MAIN RESULTS Cognitive function was assessed with the Mini-Mental State Examination (MMSE) before CEA, 1 hour after CEA, and 24 hours after CEA. Blood samples from the radial artery and the internal jugular vein were drawn before carotid clamping and 5 minutes following unclamping, and peripheral blood was obtained 24 hours postoperatively. Samples were analyzed for lactate, S100B, and P-selectin concentrations and for the antioxidative markers malondialdehyde/low-density lipoprotein ratio and nitrate + nitrite concentrations. Compared with group S, patients in group P exhibited a greater increase in their MMSE values 24 hours postoperatively. Patients who had their MMSE performance reduced at 24 hours also were significantly fewer in group P (13% v 43% in group S, p<0.05). Significantly lower levels of lactate and S100B were observed in arterial and jugular vein samples in group P. In addition, the jugular vein-arterial differences of malondialdehyde-to-low-density lipoprotein ratio and nitrates + nitrites concentrations were lower during propofol anesthesia. CONCLUSIONS Propofol seemed to improve cognitive performance after CEA. This improvement was associated with decreased indices of ischemic cerebral damage and seemed to be due to antioxidative effect in the ischemic cerebral circulation.

Do different substitution patterns or plant origin in hydroxyethyl starches affect blood coagulation in vitro

The effect of hydroxyethyl starches (HES) on blood coagulation is affected by their molecular weight, their molar substitution and the C2/C6 ratio. The solutions of 6% HES 130/0.4 and 6% HES 130/0.42 have similar molecular weight and molar substitution but different C2/C6 ratio and plant origin. In the present study, the comparative effect of 6% HES 130/0.4 versus 6% HES 130/0.42 on blood coagulation was investigated in vitro. Thirty milliliter of blood was obtained from 10 healthy volunteers and was diluted by 10, 30 and 50% using either 6% HES 130/0.4 or HES 130/0.42, respectively. Blood coagulation was assessed using thrombelastography measurements (clotting time, clot formation time, maximal clot firmness and alpha-angle). The assessment of platelet function was performed with whole blood aggregometry after adding thrombin–receptor-activating protein. No differences were noted between respective dilutions of the two HES. Both colloids produced significant reductions below the reference values range in clotting time at 10, 30 and 50% dilutions. The 50% dilution of both colloids resulted in significant reduction of maximal clot firmness, alpha-angle and platelet aggregation. The present study showed that the corn-derived 6% HES 130/0.4 and the potato-derived 6% HES 130/0.42 have the same effect on blood coagulation in vitro.

Reversal of Experimental Posthepatectomy Liver Failure in Pigs: A New Application of Hepatocyte Bioreactors

Postoperative liver failure remains a major cause of morbidity and mortality after extensive hepatectomies. This study aims to evaluate the effectiveness of a hepatocyte bioreactor in the treatment of experimental post-hepatectomy liver failure. Our experimental model included a combination of a side-to-side portacaval shunt, occlusion of the hepatoduodenal ligament for 150 min, 70% hepatectomy, and reperfusion. Following the development of liver failure, 12 pigs were randomized into a control group (n = 6) and a treatment group (n = 6). Both groups underwent extracorporeal perfusion through a plasma separation device, a membrane oxygenator, and two parallel bioreactors. In the latter group, the bioreactors were loaded with 10 billion fresh hepatocytes, isolated from a donor pig. Following hepatocyte treatment, all animals were maintained for 24 h under mechanical ventilation, with intravenous fluid and glucose supplementation. Hemodynamic parameters, intracranial pressure, and biochemical parameters were measured. Liver biopsies were obtained during the 24-h autopsy. The extracorporeal circuit was well-tolerated hemodynamically. Treated animals had lower intracranial pressure compared with controls (at 24 h, 15 ± 3.1 vs. 22 ± 3.5 mm Hg, P = 0.006). Plasma ammonia in treated animals was lower compared with controls at 12 h (100 ± 29 vs. 244 ± 131 µmol, P = 0.026). Liver histological study showed decreased necrosis and increased regeneration activity in treated animals compared with controls. Treatment through an extracorporeal hepatocyte bioreactor attenuates brain edema and improves histological and functional parameters of the liver remnant of pigs with posthepatectomy liver failure.

Early myocardial injury is an integral component of experimental acute liver failure – a study in two porcine models

Introduction There is accumulating clinical evidence that acute liver failure may be regularly associated with myocardial injury. To test this hypothesis in a standardized experimental setting, we used two porcine models of ALF. Material and methods In 14 domestic pigs ALF was induced by either a) surgical devascularization of the liver (DV group, n = 7), or b) partial (70-75%) hepatectomy and ischaemia/reperfusion of the liver remnant for 150 min (I/R group, n = 7). Four additional animals constituted the sham operation group. All animals were monitored for a 12-h period, at the end of which their hearts were harvested. Plasma troponin I (cTnI) and malondialdehyde (MDA) were measured before the operation (baseline) and at 6 h and 12 h postoperatively. The harvested hearts were histologically analysed, appointing a score from 0 (no injury) to 3 (maximum injury) to selected injury indicators. Results In the sham group, all cTnI measurements and total myocardial injury score were zero in all animals. In both ALF groups, plasma cTnI levels increased by the 6th and remained elevated up to the 12th postoperative hour (p < 0.01 vs. sham animals). Total myocardial injury score and total histological score revealed some extent of myocardial injury. The rise of MDA levels suggests an underlying oxidative mechanism. Conclusions Our study provides direct evidence of early myocardial injury in the setting of acute liver failure in pigs. The mechanism of injury remains to be elucidated.

Iron chelation prevents lung injury after major hepatectomy

Aim:  Oxidative stress has been implicated in lung injury following ischemia/reperfusion and resection of the liver. We tested whether alleviating oxidative stress with iron chelation could improve lung injury after extended hepatectomy.

Mannitol and Renal Dysfunction After Endovascular Aortic Aneurysm Repair Procedures: A Randomized Trial

OBJECTIVE Endovascular aortic aneurysm repair (EVAR) may result in deterioration of renal function. Mannitol has renovascular and antioxidant properties that could prove beneficial in this respect. DESIGN A randomized prospective study. SETTING Attikon University Hospital, single institution. PARTICIPANTS Eighty-six patients undergoing elective EVAR under regional anesthesia. METHODS Patients received hydration alone (controls) or hydration plus mannitol (0.5 g/kg). MEASUREMENTS AND MAIN RESULTS Creatinine, serum cystatin-C, urine neutrophil-gelatinase-associated lipocalin (NGAL), albuminuria and serum urea were measured 24 hours and 72 hours after the procedure (baseline NGAL was measured in 19 randomly selected patients). Serum creatinine also was measured at the followup of the patients. Serum creatinine and cystatin-C were lower in the mannitol group at 24 hours postoperatively (creatinine, mannitol [n=43]; 1.07±0.26 [CI95%: 0.99-1.15] v controls [n=43]; 1.20±0.30 [CI95%: 1.11-1.30]), but not at 72 hours (creatinine, mannitol [n=43]; 1.13±0.29 [CI95%: 1.04-1.22] v controls [n=43]; 1.26±0.41 [CI95% 1.15-1.38]). Urine NGAL increased substantially at 24 hours without differences between groups. At followup (controls: 13±7 months; mannitol: 12±7 months), there were no differences between creatinine or creatinine clearance (creatinine: controls [n=28]; 1.15±0.39 [CI95% 1.02-1.29] v mannitol [n=23]; 1.05±0.27 [CI95%: 0.95-1.17]). The overall changes of creatinine and creatinine clearance with time were significant in controls but not in the mannitol group. The classification according to the RIFLE criteria yielded 4 patients at risk for renal injury and 2 with renal injury in the control group and 6 patients at risk with no patients with injury in the mannitol group, but the difference of renal dysfunction between the 2 groups was not statistically significant. CONCLUSIONS Mannitol plus hydration during EVAR provides a small but significant benefit for renal function. Future preventive protocols aiming at greater restoration of renal function after EVAR could include mannitol as a useful component.