Thomas Pernerstorfer

Heparin Blunts Endotoxin-Induced Coagulation Activation

BACKGROUND Lipopolysaccharide (LPS) is a major trigger of sepsis-induced disseminated intravascular coagulation (DIC) via the tissue factor (TF)/factor VIIa-dependent pathway of coagulation. Experimental endotoxemia has been used repeatedly to explore this complex pathophysiology, but little is known about the effects of clinically used anticoagulants in this setting. Therefore, we compared with placebo the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on LPS-induced coagulation. METHODS AND RESULTS In a randomized, double-blind, placebo-controlled trial, 30 healthy male volunteers received LPS 2 ng/kg IV followed by a bolus-primed continuous infusion of UFH, LMWH, or placebo. In the placebo group, activation of coagulation caused marked increases in plasma levels of prothrombin fragment F(1+2) (P<0.01) and polymerized soluble fibrin, termed thrombus precursor protein (TpP; P<0.01); TF-positive monocytes doubled in response to LPS, whereas levels of activated factor VII slightly decreased and levels of TF pathway inhibitor remained unchanged. UFH and LMWH markedly decreased activation of coagulation caused by LPS, as F(1+2) and TpP levels only slightly increased; TF expression on monocytes was also markedly reduced by UFH. TF pathway inhibitor values increased after either heparin infusion (P<0.01). Concomitantly, factor VIIa levels dropped by >50% at 50 minutes after initiation of either heparin infusion (P<0.01). CONCLUSIONS This experimental model proved the anticoagulatory potency of UFH and LMWH in the initial phase of experimental LPS-induced coagulation. Successful inhibition of thrombin generation also translates into blunted activation of coagulation factors upstream and downstream of thrombin.

Surgery and intensive care procedures affect the target site distribution of piperacillin.

Objective Therapeutic failure of antibiotic therapy has been ascribed to pharmacokinetic alterations in compromised patient populations. The present study, therefore, aimed at examining the influences of cardiac surgery and intensive care procedures on the postoperative target site distribution of piperacillin. For this purpose, the penetration of piperacillin to the interstitial space fluid, the relevant target site for most bacterial infections, was compared between patients after aortic valve replacement and healthy volunteers. Design Comparative study in two study populations. Setting The intensive care unit and research ward of a university hospital. Patients The study population included six otherwise healthy patients scheduled to undergo aortic valve replacement and a control group of six healthy male volunteers. Interventions After the administration of a single iv infusion of 4.0 g piperacillin, free piperacillin concentrations were measured in the interstitium of skeletal muscle and subcutaneous tissue by in vivo microdialysis and in venous serum. Piperacillin concentrations were assayed with reversed phase high-performance liquid chromatography. Measurements and Main Results Interstitial piperacillin concentrations in muscle and subcutaneous adipose tissue were significantly lower in patients compared with volunteers with the area under the curve for the interstitium/area under the curve for serum concentration ratios ranging from 0.25 to 0.27 and from 0.43 to 1.22 in patients and volunteers, respectively (p < .05 between groups). The terminal elimination half-life was markedly prolonged in patients, leading to a concomitant increase in t > minimal inhibitory concentration (MIC) values, the relevant surrogate for therapeutic success of therapy with &bgr;-lactam antibiotics, for strains with MIC50 <4 &mgr;g/mL. For strains with MIC50 >20 &mgr;l/mL, however, inadequate target site concentrations were attained in the patient population. Conclusions During the postoperative and intensive care periods, target site concentrations of piperacillin are markedly altered and decreased. This may also be true for other antibiotic agents and may have clinical implications in that current dosing guidelines may result in inadequate target site concentrations for high-MIC strains. Conceivably, this could lead to therapeutic failure in some patients.

Acetaminophen has greater antipyretic efficacy than aspirin in endotoxemia: a randomized, double-blind, placebo-controlled trial.

To compare the antipyretic efficacy of aspirin and acetaminophen (INN, paracetamol) in 30 male volunteers with the use of endotoxin (lipopolysaccharide) to elicit a standardized febrile response.

Inhaled Nitric Oxide Reduces Pulmonary Vascular Resistance More Than Prostaglandin E1 During Heart Transplantation

Heart transplantation in patients with increased pulmonary vascular resistance is often associated with postbypass right heart failure. We therefore compared the abilities of prostaglandin E1 (PGE1) and inhaled nitric oxide to reduce pulmonary vascular resistance during heart transplantation. Patients undergoing orthotopic heart transplantation for congestive heart failure were randomly assigned to either a PGE1 infusion at a rate of 8 ng · kg· −1min−1 starting 10 min before weaning from cardiopulmonary bypass (CPB) (n = 34) or inhalation of 4 ppm nitric oxide starting just before weaning from CPB (n = 34). Both treatments were increased stepwise, if necessary, and were stopped 6 h postoperatively. Hemodynamic values were recorded after the induction of anesthesia, 10 and 30 min after weaning from CPB, and 1 h and 6 h postoperatively. Immediately after weaning from CPB, pulmonary vascular resistance was nearly halved in the nitric oxide group but reduced by only 10% in the PGE1 group. Pulmonary artery pressure was decreased approximately 30% during nitric oxide inhalation, but only approximately 16% during the PGE1 infusion. Six hours after surgery, pulmonary vascular resistance and pulmonary artery pressure were similar in the two groups. The ratio between pulmonary vascular resistance and systemic vascular resistance was significantly less in the nitric oxide patients at all postbypass times. In contrast, the pulmonary-to-systemic vascular resistance ratio increased approximately 30% in the patients given PGE1. Cardiac output, heart rate, mean arterial pressure, right atrial pressure, and pulmonary wedge pressure did not differ between the groups. Weaning from CPB was successful in all patients assigned to nitric oxide inhalation; in contrast, weaning failed in six patients assigned to PGE1 (P = 0.03). Implications: Nitric oxide inhalation selectively reduces pulmonary vascular resistance and pulmonary artery pressure immediately after heart transplantation which facilitates weaning from cardiopulmonary bypass.

Endotoxin-induced activation of the coagulation cascade in humans: effect of acetylsalicylic acid and acetaminophen.

During Gram-negative septic shock, lipopolysaccharide (LPS, endotoxin) induces tissue factor (TF) expression. TF expression is mediated by nuclear factor kappaB and amplified by activated platelets. TF forms a highly procoagulant complex with activated coagulation factor VII (FVIIa). Hence, we hypothesized that aspirin, which inhibits LPS-induced, nuclear factor kappaB-dependent TF expression in vitro and platelet activation in vivo, may suppress LPS-induced coagulation in humans. Therefore, we studied the effects of aspirin on systemic coagulation activation in the established and controlled setting of the human LPS model. Thirty healthy volunteers were challenged with LPS (4 ng/kg IV) after intake of either placebo or aspirin (1000 mg). Acetaminophen (1000 mg) was given to a third group to control for potential effects of antipyresis. Neither aspirin nor acetaminophen inhibited LPS-induced coagulation. However, LPS increased the percentage of circulating TF(+) monocytes by 2-fold. This increase was associated with a decrease in FVIIa levels, which reached a minimum of 50% 24 hours after LPS infusion. Furthermore, LPS-induced thrombin generation increased plasma levels of circulating polymerized, but not cross-linked, fibrin (ie, thrombus precursor protein), whereas levels of soluble fibrin were unaffected. In summary, a single 1000-mg dose of aspirin did not decrease LPS-induced coagulation. However, our study showed, for the first time, that LPS increases TF(+) monocytes, substantially decreases FVIIa levels, and enhances plasma levels of thrombus precursor protein, which may be a useful marker of fibrin formation in humans.

Systemic inflammation increases shear stress‐induced platelet plug formation measured by the PFA‐100

The PFA‐100 measures platelet plug formation under shear stress and is strongly dependent on von Willebrand Factor (VWF) levels in plasma. We therefore hypothesized that elevated VWF levels, possibly as a result of acute inflammation, adversely influence PFA‐100 results. Healthy volunteers received either 2 ng/kg endotoxin or placebo in a randomized controlled trial. Four hours after endotoxin (but not placebo) infusion VWF levels increased by 85%, collagen epinephrine‐induced closure time (CT) decreased by 47% and collagen ADP‐CT decreased by 38% (P < 0·0001) respectively. In conclusion, systemic inflammation has a major impact on the results obtained by PFA‐100 and may confound interpretation of platelet function.

Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia.

ObjectiveCytokines and adhesion molecules have a decisive role in the development of early inflammatory response as well as the late sequelae of sepsis. Because L-selectin-deficient mice are protected from lethal endotoxemia, blockade of L-selectin may provide a useful therapeutic option in human sepsis. Heparin has immunomodulatory properties and effectively inhibits L- and P-selectin binding in vitro. We therefore investigated whether clinically applied doses of unfractionated or low-molecular-weight heparin affect early inflammatory response in human endotoxemia. DesignThe study was randomized, double-blinded, placebo-controlled, in three parallel groups consisting of 30 healthy male volunteers. SettingUniversity medical center. InterventionsAll subjects received a 2-ng/kg intravenous bolus of lipopolysaccharide and 10 mins later unfractionated heparin, low-molecular-weight heparin, or placebo as bolus primed continuous infusion for 6 hrs. Measurements and Main ResultsLipopolysaccharide infusion induced similar increases of tumor necrosis factor-&agr;, interleukin-6, interleukin-8, C-reactive protein, and soluble E-selectin levels in all treatment groups. CD11b expression increased by approximately 400%, but L-selectin decreased by 41% in the placebo arm 6 hrs after lipopolysaccharide infusion. Interestingly, both heparins (in particular unfractionated heparin) decreased L-selectin down-regulation as compared with placebo. Similarly, the decrease in lymphocyte counts was significantly less in the unfractionated heparin group during the first 24 hrs (p < .05 vs. placebo) ConclusionsHeparins displayed little effects on cytokine production and endothelial cell activation in endotoxemia. Of note, however, unfractionated heparin reduced L-selectin down-regulation and lymphocytopenia. These could present novel mechanisms of action of unfractionated heparin.

Excursions of the cervical spine during tracheal intubation: blind oral intubation compared with direct laryngoscopy

The most appropriate technique for performing tracheal intubation in patients with cervical spine injury is debatable. Recently, a new device enabling blind oral intubation (Augustine GuideTM) with the patients head and neck in the neutral position has been introduced. The aim of this study was to compare the extent of upper cervical spine movement during intubation with this device compared to direct laryngoscopy. Twelve patients (Mallampati I and II), without a cervical spine injury, were intubated using the Augustine GuideTM and afterwards by direct laryngoscopy. Both procedures were viewed radiographically. Extension in the upper cervical spine was determined at the point of the maximum excursion. By evaluating the joints occiput‐C3 together as a functional unit, blind oral intubation caused 17° (median) less extension compared to direct laryngoscopy (p < 0.01). The median differences observed for the individual joints were: 7° in occiput‐C1 (p < 0.05), 5° in C1‐2 (p < 0.01) and 6° in C2‐3 (p < 0.01) respectively. Since we assume that intubation‐induced excursions of the injured spine are even higher, blind oral intubation might be a safe alternative for airway management in this special group of trauma victims.

Effects of nitric oxide on platelet activation during plateletpheresis and in vivo tracking of biotinylated platelets in humans.

BACKGROUND: The use of platelet transfusions has risen considerably over the last few years, which leads to the collection and transfusion of a greater number of donor plateletpheresis units. Plateletpheresis activates platelets in platelet concentrates, which determines the degree of the storage lesion subsequently observed.

Stress response to tracheal intubation: direct laryngoscopy compared with blind oral intubation

Haemodynamic and hormonal responses to tracheal intubation can be profound and associated with serious cardiovascular and cerebral side effects. The Augustine Guide, a device enabling blind oral intubation, has been introduced recently. The aim of our study was to compare the haemodynamic and hormonal stress response of this method with direct laryngoscopy. Thirty five patients (ASA 1 and 2) were randomly assigned to undergo either direct laryngoscopy (n = 17), or blind oral intubation (n = 18). Haemodynamic responses and concentrations of adrenaline, noradrenaline and prolactin were determined prior to induction, before intubation and 5 min after intubation. The median duration of intubation was 22 s for direct laryngoscopy vs 46 s for blind oral intubation (p < 0.05). Between the groups, no significant differences were observed for heart rate, systolic or mean arterial blood pressure. Serum levels of adrenaline decreased slightly after induction and remained unaltered after intubation in both groups. Noradrenaline (1.01 vs 0.66 nmol.l‐1) and prolactin (5.2 vs 2.9 nmol.l‐1) levels were significantly higher after direct laryngoscopy compared to blind oral intubation. Although blind oral intubation took significantly longer to perform than direct laryngoscopy, hormonal stress response was less pronounced. Blind oral intubation should therefore not be withheld from patients with impaired cardiovascular reserve.