Eric Wiel

Endothelial cell dysfunction and coagulation.

Objectivesa) To review endothelial properties and to establish how these unperturbed properties contribute to the maintenance of endothelium anticoagulant activity; b) to better understand the relative contributions of endothelial cells and monocytes in sepsis-induced altered coagulation. Data SourcesA summary of published literature from MEDLINE search files and other original articles and reviews published on endothelial cell and monocyte functions and modifications owing to sepsis. Data Extraction and Synthesis Unperturbed endothelial cells provide anticoagulant properties; exposure to inflammatory and/or septic stimuli can rapidly lead to procoagulant behavior. Sepsis alters endothelial cell surface and induces tissue factor synthesis at the endothelial and subendothelial levels. During endotoxemia, endothelial cells generate adhesion molecules that bind leukocytes and monocytes, increasing local procoagulant reactions. Tissue factor expression is also increased at the level of the monocyte; the relative importance of endothelial injury and monocyte activation in coagulation disorders was recently assessed. Endothelium protection before induction of septic shock was not associated with any reduction in monocyte tissue factor expression, suggesting that altered coagulation was present despite normal endothelial cell function. On the other hand, decreased monocyte tissue factor expression was associated with a marked reduction in endothelial injury, increased endothelium-derived relaxation, and improved survival rate in treated animals. ConclusionsThis review suggests that monocyte activation and tissue factor expression may be of paramount importance in sepsis-associated injuries and that coagulation activation may contribute to the endothelial cell injury observed during sepsis. Endothelial injury, in turn, exacerbates sepsis-induced coagulation abnormalities.

Beneficial effect of glycoprotein IIb/IIIa inhibitor (AZ-1) on endothelium in Escherichia coli endotoxin-induced shock.

Objective To investigate the effects of AZ-1, a murine monoclonal antiglycoprotein-IIb/IIIa antibody, on endothelium and on hemostasis in a rabbit endotoxic shock model. Design Prospective laboratory study. Setting University laboratory. Subjects Thirty-five male New-Zealand rabbits. Interventions In vitro vascular reactivity, endothelium CD31-PECAM1 immunohistochemistry, plasma coagulation factors, and monocyte tissue factor determination were performed 1 day and/or 5 days after onset of endotoxic shock (0.5 mg/kg, intravenous bolus, Escherichia coli lipopolysaccharide) with or without treatment by AZ-1 (0.5 mg/kg intravenously) given 1 hr after lipopolysaccharide injection. Measurements and Main Results Metabolic acidosis and coagulation activation confirmed the presence of shock. AZ-1 treatment improved endothelial-dependent relaxation at 1 day (maximal effect = 87.2 ± 4.0% vs. 60.9 ± 5.2% in the nontreated group, p < .05) and at 5 days (maximal effect = 84.5 ± 3.5% vs. 56.6 ± 8.2% in the nontreated group, p < .05). Endotoxin-induced endothelial injury was decreased significantly by AZ-1 at 1 day (6.4 ± 1.9% vs. 10.3 ± 0.8% in the nontreated group, p < .05) and at 5 days (6.3 ± 2.0% vs. 20.2 ± 1.2% in the nontreated group, p < .05). Monocyte tissue factor expression was significantly reduced at 5 days. Conclusions These data indicate that potent inhibition of platelet function via antiglycoprotein-IIb/IIIa receptor blockade can inhibit coagulation activation and protect against endothelial dysfunction and histologic injury in endotoxin-induced shock.

Extracorporeal Life Support in Out-of-Hospital Refractory Cardiac Arrest

Out-of-Hospital refractory Cardiac Arrest (OHrCA) has a mortality rate between 90 and 95%. Since 2009, French medical academic societies have recommended the use of extracorporeal life support (ECLS) for OHrCA. According to these guidelines, patients were eligible for ECLS support if vital signs were still present during cardiopulmonary resuscitation (CPR), or if cardiac arrest was secondary to intoxication or hypothermia (≤32°C). Otherwise, patients would receive ECLS if (i) no-flow duration was less than 5 min; (ii) time delays from CPR to ECLS start (low flow) were less than 100 min; and (iii) expiratory end tidal CO2 (ETCO2 ) was more than 10 mm Hg 20 min after initiating CPR. We have reported here our experience with ECLS in OHrCA according to the previous guidelines. We retrospectively analyzed mortality rates of patients supported with ECLS in case of OHrCA. From December 2009 to December 2013, 183 patients were assisted with ECLS, among which 32 cases were of OHrCA. Mean age for the OHrCA patients was 43.6 years. Over two-thirds were male (71.9%). Causes of OHrCA included intoxication, isolated hypothermia <32°C, acute coronary syndrome, pulmonary edema, and other cardiac pathology. Despite adherence to protocols, only two patients (6.2%) with hypothermia and acute myocardium ischemia, respectively, could be discharged from hospital after cardiac recovery. Causes of death were brain death and multiple organ failure. Despite ECLS support setting in accordance with French guidelines in case of refractory OHrCA, mortality rates remained high. French ECLS support recommendations for OHrCA due to presumed cardiac cause should be re-examined through new studies. Low flow duration should be improved by a shorter time of CPR before hospital transfer.

Activated protein C increases sensitivity to vasoconstriction in rabbit Escherichia coli endotoxin-induced shock

IntroductionThe aim of this study was to investigate the effects of activated protein C (aPC) on vascular function, endothelial injury, and haemostasis in a rabbit endotoxin-induced shock model.MethodThis study included 22 male New Zealand rabbits weighing 2.5 to 3 kg each. In vitro vascular reactivity, endothelium CD31-PECAM1 immunohistochemistry, plasma coagulation factors and monocyte tissue factor (TF) expression were performed 5 days (D5) after onset of endotoxic shock (initiated by 0.5 mg/kg intravenous bolus of Escherichia coli lipopolysaccharide (LPS)) with or without treatment with aPC injected as an intravenous 2 mg/kg bolus 1 hour after LPS (LPS+aPC group and LPS group, respectively).ResultsLPS decreased the sensitivity to phenylephrine (PE) in aortic rings without endothelium (E-) when compared to E- rings from the control group (p < 0.05). This was abolished by NG-nitro-L-arginine methyl ester and not observed in E- rings from aPC-treated rabbits. Although aPC failed to decrease monocyte TF expression in endotoxinic animals at D5, aPC treatment restored the endothelium-dependent sensitivity in response to PE (2.0 ± 0.2 μM in rings with endothelium (E+) versus 1.0 ± 0.2 μM in E- rings (p < 0.05) in the LPS+aPC group versus 2.4 ± 0.3 μM in E+ rings versus 2.2 ± 0.2 μM in E- rings (p value not significant), in the LPS group). Endotoxin-induced de-endothelialisation was reduced by aPC at D5 (28.5 ± 2.3% in the LPS+aPC group versus 40.4 ± 2.4% in the LPS group, p < 0.05).ConclusionThese data indicate that aPC increased the sensitivity to a vasoconstrictor agent (PE) associated with restoration of endothelial modulation, and protected against endothelial histological injury in endotoxin-induced shock. It failed to inhibit TF expression at D5 after LPS injection.

Traitements non infectieux du choc septique

Points essentiels Le “sepsis severe″ est une dysfonction ou une hypoperfusion d’un organe induite par une infection. Le “choc septique″ se definit par une hypotension arterielle, refractaire au remplissage, associee a une dysfonction ou hypoperfusion d’organes. La mortalite du “sepsis severe″ et du “choc septique″ est elevee. Des recommandations ayant pour but d’aider les praticiens a ameliorer les chances de survie de patients atteints de sepsis severe s’integrent dans un projet international intitule Surviving Sepsis Campaign et reprennent les innovations therapeutiques fondees sur un monitorage tourne vers la prise en charge globale de l’oxygenation tissulaire (saturation veineuse centrale en oxygene ou SvcO2). Elles se basent sur le concept d’optimisation therapeutique initiale precoce dans les 6 premieres heures du sepsis severe pendant lesquelles le remplissage vasculaire ne souffre aucun retard. En cas de choc septique, le remplissage doit etre rapidement accompagne de l’administration de catecholamines vasoconstrictrices. La noradrenaline est preferee a la dopamine. La dobutamine est recommandee lorsque l’index cardiaque est L’existence d’une insuffisance surrenalienne relative au cours du choc septique fait recommander la prescription de corticoides apres realisation d’un test au Synacthene®. La proteine C activee est la seule molecule issue de la biotechnogie, a ce jour, permettant de diminuer la mortalite du sepsis severe. Une prise en charge globale integree dans des referentiels de soins en reanimation doit etre instauree. Elle concerne, entre autres, la sedation, la ventilation, le controle strict de la glycemie et la prophylaxie de la thrombose veineuse et de l’ulcere de stress.

Board 357 - Research Abstract Validation of Anesthesia Protocols Designed for Space Exploration Missions using a Human Patient Simulator (Submission #1156)

Introduction/Background Research focusing on anesthesia delivery for future interplanetary space missions is scarce, partly because no existing human model on Earth is able to reproduce the vast and specific physiological changes occurring in response to microgravity. Using the Meti Human Patient Simulator (HPS), a prospective comparative study was conducted with the objective of defining the best anesthesia protocol for space exploration missions, suitable for the drastic technical and human constraints and the altered physiological state of an astronaut. Methods Five experts in anesthesia and/or simulation were enrolled in the study. The HPS was programmed to reproduce the physiological alterations experienced by crewmembers during long-duration spaceflight, in particular the cardiovascular deconditioning. Blood volume, left and right ventricular contractility, baroreflex and systemic vascular resistance were set at levels measured in actual astronauts during long-duration spaceflight. Two general anesthesia protocols (with spontaneous ventilation and oro-tracheal intubation) were tested in two scenarios, comparing three different anesthetics (propofol, etomidate and ketamine). One of the scenarios was complicated with an additional 1000 ml haemorrhage. Results Mean arterial pressure 60 seconds after induction was significantly lower in the groups propofol (mean +/- SD: 56.1 +/- 4.5 mmHg) and etomidate (54.4 +/- 3.5 mmHg) compared to the group ketamine (72.3 +/- 4.7 mmHg, p<0.0003). The groups propofol and etomidate required significantly more intravenous fluids (respectively 1450 +/- 598 mL and 1400 +/- 658 mL) compared to the group ketamine (800 +/- 349 mL, p<0.01). Significantly more vasoconstrictors boluses (phenylephrine) were administered in the groups propofol (2 +/- 0.44) and etomidate (2 +/- 0) compared to the group ketamine (0, p<0.01). Contrary to the propofol and etomidate groups, none of the trials in the ketamine group developed cardiovascular collapse, required large volumes of intravenous fluids nor received vasoconstrictors. Conclusion For the first time, the complex physiological and pharmacological algorithms of the HPS were used to accurately reproduce the altered physiology of an astronaut, and test the tolerance to hypovolemia and general anesthesia. The Results confirmed the superiority of ketamine in this situation, which should become the anesthetic drug of choice for the preparation of future space exploration missions. Disclosures None.