Anders Nordgren

Propofol (Diprivan-EDTA) counteracts oxidative injury and deterioration of the arterial oxygen tension during experimental septic shock.

PURPOSE Human septic shock can be replicated in the endotoxaemic pig. Endotoxaemia causes a multitude of events, including reduced PaO(2) and increased lipid peroxidation. This study was designed to evaluate the possible effects of a commonly used anaesthetic drug with known antioxidant properties (propofol) during porcine endotoxaemia. METHODS Ten pigs were anaesthetised and given a 6 h E. coli endotoxin infusion. The animals received, randomly, a supplementary continuous infusion of propofol emulsion (containing 0.005% EDTA) or the corresponding volume of vehicle (controls). Pathophysiologic responses were determined. Non-enzymatic (by measuring plasma 8-iso-PGF(2 alpha) and enzymatic (by measuring plasma 15-keto-dihydro-PGF(2 alpha)) lipid peroxidations were evaluated. Plasma levels of the endogenous antioxidants alpha- and gamma-tocopherols, were also analysed. RESULTS Endotoxaemia increased plasma levels of 8-iso-PGF(2 alpha) (1st-4th h) and 15-keto-dihydro-PGF(2 alpha) (1st-4th h) significantly more in controls than in the propofol+endotoxin group. PaO(2) was significantly less affected by endotoxin in the propofol treated animals (2nd-4th h). Mean arterial pressure (4th-6th h) and systemic vascular resistance (6th h) were reduced significantly more by endotoxin among the propofol-treated animals. Vitamin E (alpha-tocopherol) increased in all animals, significantly more in the propofol+endotoxin group (1/2-6th h) than in the control group. CONCLUSIONS Propofol reduced endotoxin-induced free radical mediated and cyclooxygenase catalysed lipid peroxidation significantly. The implication is that propofol counteracts endotoxin-induced deterioration of PaO(2).

Maximisation of cerebral blood flow during experimental cardiopulmonary resuscitation does not ameliorate post-resuscitation hypoperfusion

Continuous intra-aortic balloon occlusion has been reported to improve cerebral blood flow during cardiopulmonary resuscitation (CPR) but not to ameliorate the impaired blood recirculation occurring after restoration of spontaneous circulation (ROSC). Volume expansion with hypertonic solutions may improve recovery of brain function by enhancing post-resuscitation cerebral blood flow. We hypothesised that the combination of these treatments with open-chest CPR would improve cerebral blood flow during CPR, and attenuate post-resuscitation flow disturbances. In 32 anaesthetised piglets, catheters were placed for haemodynamic and blood gas monitoring. Open-chest CPR was initiated after 9 min of ventricular fibrillation. The piglets were treated either with 3 ml kg(-1) hypertonic saline and dextran (HSD) (n = 10), HSD and balloon occlusion (n = 10) or with normal saline (n = 12). After 7 min of CPR, internal defibrillatory shocks were administered to restore spontaneous circulation. Haemodynamic variables, continuous cerebral cortical blood flow, cerebral tissue pH and pCO2 and blood gas parameters were measured during CPR and up to 210 min after ROSC. Higher cerebral perfusion pressure was found in the balloon-HSD group during CPR. This group exhibited less arterial hypertension immediately after ROSC compared with the other groups. Thereafter, a fairly rapid decrease of the perfusion pressures was observed in all groups reaching a minimum level approximately 30 min after ROSC. Cerebral cortical blood flow was significantly higher and cerebral oxygen extraction ratio significantly lower in the balloon-HSD group during CPR, but not after ROSC. In conclusion, a combination of intra-aortic balloon occlusion and HSD administration improves cerebral blood flow and brain oxygen supply during experimental open-chest CPR. In contrast, cerebral blood flow after ROSC was not shown to be influenced by this treatment.

Effects of mechanical ventilation on platelet microparticles in bronchoalveolar lavage fluid

INTRODUCTION Mechanical ventilation (MV) is considered to contribute to lung injury. Platelet membrane-derived microparticles (PMPs) are procoagulant and participate in the inflammatory process. The bronchoalveolar space could, besides plasma, be a site of origin of these microparticles. We evaluated the presence of these PMPs and two prostaglandin-derived metabolites in bronchoalveolar lavage fluid (BALF) regarding their possible relation to MV. MATERIALS AND METHODS Before and after 1 h of MV, PMPs and prostaglandin metabolites were analyzed, in BALF from 14 anesthetized pigs, by flow cytometry and RIA, respectively. Tracheal mucus from five humans was analyzed for PMPs at extubation after surgery. RESULTS Activated PMPs and prostaglandin metabolites were present in all BALF samples. The time needed to count 5000 cellular events was prolonged six-fold after 1 h of mechanical ventilation (p<0.001). The relative content of PMPs was constant in all samples. The PMPs were thrombogenic, i.e. they were fibrinogen, p-selectin and von Willebrand factor positive. Lavage did not per se affect the period necessary to count 5000 cellular events. PMPs in human tracheal mucus were in the same range as in the pig after 1 h of MV aiming at a PaCO(2) between 5.0 and 5.5 kPa. CONCLUSIONS Activated PMPs are present in the pulmonary air-liquid interface. The prolongation of the time needed to count 5000 cellular events in BALF after MV indicates activation and adherence. Adherent microparticles bind neutrophils, which may aggravate pathological processes leading to pulmonary dysfunction. Evaluation of PMPs in BALF may be useful in evaluating strategies for lung-protective ventilator treatment.

Glutamine concentration and tissue exchange with intravenously administered α-ketoglutaric acid and ammonium: A dose-response study in the pig

OBJECTIVE We investigated the effects of an intravenous load of alpha-ketoglutaric acid, ammonium (NH(4)(+)), and metabolic acidosis on plasma concentration and splanchnic and hindleg tissue exchange of glutamine, glutamate, alanine, and arginine in postabsorptive, anesthetized pigs. METHODS Sixteen anesthetized piglets received a constant infusion of NH(4)Cl for 4 h and alpha-ketoglutaric acid in incremental dosages for 3 h (group 1, n = 8) or a constant infusion of alpha-ketoglutaric acid for 4 h and NH(4)Cl in incremental dosages for 3 h (group 2, n = 8). Plasma amino acids were analyzed and splanchnic blood flow was calculated according to the indocyanine green dye infusion technique. Femoral artery blood flow was measured with ultrasound flowmetry. Statistical evaluation of within-group differences was made with the Wilcoxon signed rank test. RESULTS Plasma glutamine levels increased dose-dependently in group 2 (P < 0.05) but not in group 1. Glutamate concentration increased, mainly in group 2 (P < 0.05), whereas the plasma concentration of alanine decreased in both groups (P < 0.05). Plasma concentration of arginine increased in both groups (P < 0.05). Splanchnic uptake and skeletal muscle release of glutamine did not change in either group compared with baseline values. Splanchnic glutamate release decreased (P < 0.05) in group 1 at 240 min; muscular uptake was unaffected in both groups. Splanchnic uptake and muscular release of alanine were unaffected in both groups. The significance level was set at 0.05. CONCLUSION Our findings indicate that the splanchnic bed or hindleg skeletal muscle was not the source of the increased plasma concentration of glutamine in this study.

Increased platelet microvesicle formation is associated with mortality in a porcine model of endotoxemia

Background: Gram‐negative sepsis in humans and endotoxemia in pigs induce the formation of platelet microvesicles. These microvesicles are active in homeostasis and may thus contribute to the outcome in patients with activated coagulation and fibrinolysis. We decided to prospectively evaluate the effects of endotoxemia on microvesicle formation and some common physiologic variables against survival in a porcine model.

Effects of melagatran, a novel direct thrombin inhibitor, during experimental septic shock

Sepsis and endotoxaemia initiate the generation of thrombin, which is responsible for the conversion of fibrinogen to fibrin, platelet aggregation and acts as an inflammatory mediator affecting numerous types of cells, including myocardial, smooth muscle and endothelial cells. Human Gram-negative septic shock, frequently seen in intensive care units, is a condition with high mortality. This condition can be replicated in the endotoxaemic pig. As many of the toxic effects of sepsis are due to thrombin generation, it was of interest to study, using this porcine experimental septic shock model, whether inhibition of thrombin could alleviate the effects of endotoxaemia. For this purpose melagatran, a direct synthetic thrombin inhibitor with a molecular weight of 429 Da, was employed. Melagatran does not significantly interact with any other enzymes in the coagulation cascade or fibrinolytic enzymes aside from thrombin. Furthermore, melagatran does not require endogenous co-factors such as antithrombin or heparin co-Factor II for its antithrombin effect, which is important, as these inhibitors are often consumed in septic patients. We have shown that melagatran exerts a beneficial effect on renal function, as evaluated by plasma creatinine and urinary output, during experimental septic shock. These effects were most pronounced during the later phase of the experimental period, after the infusion of melagatran had been discontinued. Prevention of intrarenal coagulation may be attributable to this finding. In addition, melagatran had beneficial effects on systemic haemodynamics (left ventricular stroke work index, pulmonary capillary wedge pressure and systemic vascular resistance index) in endotoxaemic pigs. This result may be explained by the ability of melagatran to inhibit thrombin, thereby counteracting thrombin’s cellular effects. Thus, it can be seen, using this experimental model of septic shock, that melagatran may help to alleviate some of the damaging effects of endotoxaemia, although more research is required to test this further.

Impact of Different Inspiratory Flow Patterns on Arterial C02- tension

Abstract Ventilation with decelerating inspiratory flow is known to reduce the dead space fraction and to decrease PaCO2. Constant inspiratory flow with an end-inspiratory pause (EIP) is also known to increase the removal of CO2. The aim of the study was to elucidate the effect of the pause/no-flow period while both the pattern and rate of inspiratory flow was unchanged, and when the lung was ventilated with sufficient PEEP to prevent end-expiratory collapse. Surfactant depleted piglets were assigned to decelerating or constant inspiratory flow with 24 breaths per minute (bpm) or 12 bpm, or to constant flow, without and with an end-inspiratory pause of 25%. By adding an EIP the total time without active inspiratory flow of the respiratory cycle was kept unchanged. Gas exchange, airway pressures, functional residual capacity (using sulfurhexafluoride) and haemodynamics (thermo-dye indicator dilution technique) were measured. Irrespective of ventilatory frequency, PaCO2 was lower and serial dead space reduced with decelerating flow, compared with constant inspiratory flow. With an end-inspiratory pause added to constant inspiratory flow, serial dead space was reduced but did not decrease PaCO2. The results of this study corroborate the assumption that total time without active inspiratory flow is important for arterial CO2-tension.

Ammonium chloride and α-ketoglutaric acid increase glutamine availability in the early phase of induced acute metabolic acidosis

Background:  Glutamine deficiency in critical illness is associated with increased morbidity and mortality. We hypothesized that ammonium chloride (NH4Cl) and α‐ketoglutaric acid (α‐KGA) infusions could increase glutamine availability possibly through de novo synthesis in the liver.

Effects of sustained pressure application on compliance and blood gases in healthy porcine lungs

Background: Short periods of sustained increase in airway pressures (Pressup) are believed to re‐open lung areas that collapsed upon induction of anaesthesia. Recruitment of alveolar surface is usually assessed in terms of changes in the pressure–volume (PV) curve. The purpose of this study was to analyse PV‐curves before and after a Pressup and to ascertain whether such changes are compatible with the concept of recruitment of lung volume.

An Inhibitor of Angiotensin Converting Enzyme (Enalapril) Augments Endotoxin-Induced Hypotension in the Pig

Septic shock causes an extensive inflammatory reaction including increased capillary leakage and a decrease in systemic blood pressure. Human septic shock can be replicated in the endotoxaemic pig. Angiotensin converting enzyme (ACE) is involved in the degradation of bradykinin, an inflammatory mediator, and in the regulation of blood pressure. Inhibition of ACE is a common approach to reduce hypertension as well as left ventricular insufficiency. Fifteen anaesthetised pigs received a continuous 3 h endotoxin infusion. The animals were randomly given an inhibitor of ACE (enalpril) [at a dose (0.5 mg x kg-1) that did not per se reduce mean arterial blood pressure (MAP); (n = 7)], or the corresponding volume of saline (n = 8). Another seven pigs were randomised for treatment with enalapril (0.5 mg x kg-1) + saline (n = 3). Four pigs were randomised to serve as untreated controls (saline + saline). Basic physiologic variables were registered. Endotoxaemia progressively reduced MAP. This decrease was significantly augmented by enalapril. Hypovolemia caused by increased permeability or salt/water excretion did not seem to explain this effect as neither blood haemoglobin nor plasma sodium differed between the two groups of endotoxaemic pigs. Inhibitors of ACE are known to potentiate the cardio-depressant effect of bradykinin. This may explain the reduction in MAP by enalapril during porcine endotoxaemia.