Trude Aspelin

Increased activation of coagulation and formation of late deep venous thrombosis following discontinuation of thromboprophylaxis after hip replacement surgery

Hip replacement surgery (HRS) is associated with a high frequency of deep vein thrombosis (DVT). At the same time there is a substantial systemic and local activation of coagulation. This study indicates that discontinuation of thromboprophylaxis one week after surgery may allow a second wave of coagulation and fibrinolysis activation to occur. An almost parallel increase in plasma TAT and D-dimer levels between the 6th and the 35th postoperative day may indicate late DVT formation. Repeated bilateral ascending venography is though to be necessary to evaluate the suitability of using selected activation markers of the coagulation and fibrinolytic systems as indices of DVT formation.

The role of bone traumatization in the initiation of proximal deep vein thrombosis during cemented hip replacement surgery in pigs

Hip arthroplasty is associated with a high frequency of postoperative solitary proximal deep vein thrombosis which seems most frequently observed when bone cement is used for prosthesis fixation. Eighteen pigs underwent hemiarthroplasty, eight with cement-fixed prostheses and eight with non-cement prosthesis installation. Levels of thrombin—antithrombin (TAT) complexes, tissue plasminogen activator (t-PA) activity and plasminogen activator inhibitor 1 (PAI-1) activity were determined in femoral vein blood from both limbs during and after surgery. On the operated side, TAT increased during bone traumatization followed by a substantial rise in t-PA activity and a gradual decline in PAI-1 activity. This indicates a local per-and post-operative sequential activation of coagulation and fibrinolysis followed by a fibrinolytic shutdown, all reflected in femoral vein blood on the operated side. In the animals receiving noncemented hip prostheses, the same pattern of activation of coagulation and fibrinolysis occurred on the operated side. This was, however, less marked than with the cement-fixed prostheses. Postoperative scanning electron microscopic (SEM) examination of the femoral veins showed thrombi on the operated side in 62% of the animals in the cement group and 25% in the non-cement group. In an additional study with eight animals undergoing cement-anchored hip prosthesis operations the levels of TAT, t-PA and PAI-I were analysed in femoral vein blood, mixed venous blood and arterial blood. Significantly higher levels were found in femoral vein blood compared with mixed venous blood while no significant change was found in arterial blood compared with mixed venous blood. The hyperthermia induced by curing bone cement was effectively conducted by the implanted prosthesis and did not seem to exert major influence on the activation of coagulation. Extreme rotation of the limbs during surgery did not in itself induce visible vein wall damage as judged by SEM. These studies indicate that traumatization of bone marrow during hip surgery induce a marked local activation of coagulation and a high incidence of deep vein thrombosis in proximal veins, in particular if bone cement is used for prosthesis fixation.

Effects of doxazosin and atenolol on circulating endothelin-1 and von Willebrand factor in hypertensive middle-aged men.

Elevated levels of endothelin-1 (ET-1) and von Willebrand factor (vWF), both markers indicative of endothelial function, are associated with hypertension. In a randomized open study we investigated the effect of antihypertensive treatment with the alpha-blocker doxazosin (n = 23) or the beta-blocker atenolol (n = 22) for 22 weeks on circulating levels of ET-1 and vWF in middle-aged men with essential hypertension. Blood pressure reduction was satisfactorily achieved with both drugs, although the decrease in the atenolol group was larger than that in the doxazosin group. A reduction in the levels of vWF occurred in both groups, being more pronounced in the alpha-blocker group compared with the decrease on beta blockers, p = 0.004 and p = 0.056, respectively. In the alpha-blocker group, there was a significant correlation (r = 0.50, p = 0.022) between the reduction in diastolic blood pressure and the decline in vWF. A highly significant decrease in plasma ET-1 was obtained during beta blockade (p = 0.007), whereas no significant change occurred within the alpha-blocker group. There was, however, no correlation between the decrease in blood pressure and the reduction in ET-1. The different favorable effects of alpha and beta blockers on endothelial function expressed as vWF and ET-1, could indicate that the effects are probably related not only to the blood pressure per se, but also to the different pharmacologic mechanisms of the drugs.

Intramedullary nailing of femoral shaft fractures in polytraumatized patients. a longitudinal, prospective and observational study of the procedure-related impact on cardiopulmonary- and inflammatory responses

BackgroundEarly intramedullary nailing (IMN) of long bone fractures in severely injured patients has been evaluated as beneficial, but has also been associated with increased inflammation, multi organ failure (MOF) and morbidity. This study was initiated to evaluate the impact of primary femoral IMN on coagulation-, fibrinolysis-, inflammatory- and cardiopulmonary responses in polytraumatized patients.MethodsTwelve adult polytraumatized patients with femoral shaft fractures were included. Serial blood samples were collected to evaluate coagulation-, fibrinolytic-, and cytokine activation in arterial blood. A flow-directed pulmonary artery (PA) catheter was inserted prior to IMN. Cardiopulmonary function parameters were recorded peri- and postoperatively. The clinical course of the patients and complications were monitored and recorded daily.ResultsMean Injury Severity Score (ISS) was 31 ± 2.6. No procedure-related effect of the primary IMN on coagulation- and fibrinolysis activation was evident. Tumor necrosis factor alpha (TNF-α) increased significantly from 6 hours post procedure to peak levels on the third postoperative day. Interleukin-6 (IL-6) increased from the first to the third postoperative day. Interleukin-10 (IL-10) peaked on the first postoperative day. A procedure-related transient hemodynamic response was observed on indexed pulmonary vascular resistance (PVRI) two hours post procedure. 11/12 patients developed systemic inflammatory response syndrome (SIRS), 7/12 pneumonia, 3/12 acute lung injury (ALI), 3/12 adult respiratory distress syndrome (ARDS), 3/12 sepsis, 0/12 wound infection.ConclusionIn the polytraumatized patients with femoral shaft fractures operated with primary IMN we observed a substantial response related to the initial trauma. We could not demonstrate any major additional IMN-related impact on the inflammatory responses or on the cardiopulmonary function parameters. These results have to be interpreted carefully due to the relatively few patients included.Trial RegistrationClinicalTrials.gov: NCT00981877

Coagulation, fibrinolysis and cytokine responses to intramedullary nailing of the femur: an experimental study in pigs comparing traditional reaming and reaming with a one-step reamer-irrigator-aspirator system.

INTRODUCTION Operations in trauma patients represent a second insult and the extent of the surgical procedures influences the magnitude of the inflammatory response. Our hypothesis was that a reamer-irrigator-aspirator (RIA) system would cause a lesser inflammatory response than traditional reaming (TR). MATERIALS AND METHODS Coagulation, fibrinolysis and cytokine responses were studied in Norwegian landrace pigs during and after intramedullary nailing (IMN) with two different reaming systems using ELISA and chromogenic peptide substrate assays. The TR (n=8) and the RIA (n=7) reaming systems were compared to a control group (n=7). The animals were followed for 72 h. Arterial, mixed venous and femoral vein blood were withdrawn simultaneously peroperatively and until 2 h after the nail was inserted for demonstration of local, pulmonary and systemic activation of the cascade systems. At 6 h, 24 h, 48 h and 72 h postoperatively arterial blood samples were withdrawn. RESULTS Significantly procedure-related increased levels were found for thrombin-antithrombin (TAT) and tissue plasminogen activator (t-PA) in the TR group and TAT in the RIA group. The local and the pulmonary activation of coagulation and fibrinolysis were more pronounced in the TR than in the RIA group, the difference reached significance for plasminogen activator inhibitor-1 (PAI-1) (arterial blood). The cytokine response, mainly represented by IL-6 increase, was more pronounced in the TR than the RIA group, and was significant for IL-6 in femoral vein blood. The arterial levels of IL-6 exceeded the mixed venous levels indicating an additional pulmonary activation of IL-6. Two animals in the TR group, who died of pulmonary embolism (PE) prior to planned study end point, had a more pronounced response compared to the rest of the TR group. CONCLUSION A procedure-related coagulation and fibrinolytic response was demonstrated in both reaming groups, with more pronounced response in the TR than in the RIA group. Elevated levels of cytokines were demonstrated related to reaming and nailing, with significantly higher IL-6 levels in the TR than in the RIA group.

Aminoethyl-isothiourea Inhibits The Increase In Plasma Endothelin-1 Caused By Serogroup A Streptococci And Prolongs Survival In Rat Peritoneal Sepsis

To elucidate the possible roles of nitric oxide (NO), endothelin-1 (ET-1), and reactive oxygen species (ROS) in the pathophysiology of serogroup A streptococcal (GAS) peritoneal sepsis, we investigated the effects of aminoethylisothiourea (AE-ITU), an inducible NO synthase (iNOS) inhibitor, and a ROS scavenger, and the ET-1 receptor antagonist bosentan. In rats, live GAS inocula, 3 x 10(8) and 1 x 10(9) cfu/kg, entailed a 24-h mortality of 10% and 90%, respectively. GAS caused increases in tissue iNOS activity (9 h), in serum nitrite/nitrate (9-24 h), and in intracellular leukocyte ROS levels (3-6 h). These changes were all prevented by the pre-treatment with AE-ITU. A novel finding was that AE-ITU also prevented the GAS-induced marked increase in plasma ET-1 at 6 h. Short-term (7-h) survival was improved by both AE-ITU and by bosentan. The mechanism(s) for the beneficial effects of AE-ITU may possibly be a combined mode of action; iNOS inhibition, ROS scavenging, and inhibition of the increase in plasma ET-1 caused by GAS.

Different cardiac tissue plasminogen activator release patterns by local stimulation of the endothelium and sympathetic nerves in pigs.

Myocardial ischemia induces cardiac tissue plasminogen activator (tPA) release, declining by repeated periods of ischemia. However, the mechanisms and cellular sources are unknown. Sympathetic nerve stimulation (SS) and bradykinin (BK), an endogenous inducer of endothelial tPA release, may play roles, potentially involving different sources or mechanisms revealed by different release patterns. Therefore, we compared the cardiac tPA release patterns during repeated coronary BK infusions and SS, both with an ensuing period of local myocardial ischemia/reperfusion (I/R). Nine pigs were subjected to four periods of coronary BK infusion (4 min) and another nine animals to four periods of SS (4 min). Finally, 10 min of I/R was induced in both groups. The single-peaked BK-induced tPA release declined toward baseline by repeated infusions, but tPA release reappeared during I/R. In contrast, total tPA release during repeated SS and subsequent I/R was more stable, and SS-induced total tPA and norepinephrine (NE) releases were strongly correlated. Surprisingly, the instantaneous SS-induced tPA release was biphasic with a stable first peak, and a second peak declining toward baseline by repeated stimulations. The fluctuations in cardiac release of plasminogen activator inhibitor-1 and the endogenous BK inhibitor angiotensin-converting enzyme, could not explain the diverging tPA release patterns. Different tPA release patterns were demonstrated during SS and BK stimulation, as well as diverging responses to repeated stimulations and subsequent I/R. This study demonstrates strong association between tPA and NE during SS and possibly two different sources or mechanisms for SS-induced tPA release.

Perfluorochemical Liquids Do Not Stimulate Endothelin-1 or Nitric Oxide Production in Human Blood Leukocytes

The purpose of these studies was to examine if perfluorochemical (PFC) liquids stimulate blood leukocytes to secrete nitric oxide (NO) and/or endothelin-1 (ET-1). As such, NO and ET-1 may modulate broncho- and vascular dilatation and constriction, respectively, and thereby influence the clinical condition of a patient in respiratory distress with persistent pulmonary hypertension. Blood leukocytes in their natural habitat (whole blood) were incubated in the presence of two different perfluorochemicals (perflubron and perfluorodecalin). The overall response in ET-1 or NO (indirectly measured as nitrite/nitrate) production was examined at increasing PFC percentages (wt/vol) of PFC/whole blood. The lowest proportion used, 0.001% (wt/vol), was relevant to serum concentrations of PFC observed in liquid-ventilated individuals, whereas the highest proportion PFC, 50% (wt/vol), would mimic a situation where leukocytes are presented to PFC-filled airways. Plasma levels of freshly drawn blood, similar to levels of incubated (6 h) non-PFC-supplemented cultures, were ET-1 0.59 ± 0.07 pg/ml (6 h, mean ± SEM) and NO–2/NO–3 50 ± 9 µM (6 h). Perflubron or perfluorodecalin did not induce significant differences in ET-1 or NO–2 /NO–3 levels as function of PFC type or dose. In conclusion, PFC liquids do not stimulate production in leukocytes in vitro of substances that may modulate constriction or dilatation in the vascular and respiratory tract systems.

Reduced release of vasoconstrictors from the porcine heart after repeated periods of ischemia

Objective To examine if the decline in post-ischemic hyperemic flow after repeated brief periods of myocardial ischemia is accompanied by augmented cardiac release of the vasoconstrictors endothelin-1 (ET-1) and norepinephrine (NE). Design Mid-LAD (left anterior descending coronary artery) was occluded for 10 min with 30 min intervals a total of four times in six anesthetized pigs. Blood from the anterior interventricular coronary vein was drained through a shunt to the right atrium to facilitate blood sampling. Plasma concentrations of ET-1 and NE were repeatedly measured in arterial and coronary venous blood to estimate cardiac vasoconstrictor release. Results Plasma concentrations of ET-1 and NE remained unaltered, but cardiac release of both vasoconstrictors rose briefly during reperfusion due to the hyperemia. However, release declined progressively after repeated periods of ischemia and reperfusion and amounted to 53% (NE) and 17% (ET-1) of initial release after the fourth period of ischemia. Conclusion The decline in post-ischemic hyperemia after repeated brief periods of myocardial ischemia is not accompanied by a progressive accentuation of cardiac ET-1 and NE release.

Combined administration of dextran 70 and dalteparin does not increase perioperative blood loss compared to dextran 70 alone in major orthopedic surgery.

A prospective open-labeled clinical study was carried out to compare the safety of dextran 70 and low molecular weight heparin (dalteparin; DD group) versus dextran 70 alone (D group) in patients subjected to elective hip replacement surgery. Dalteparin, 5,000 IU/day and dextran 70, 500 ml during surgery and on the first postoperative day were administered to 214 patients. Dextran 70 alone was infused in 44 patients, 500 ml during surgery and on the 1st, 3rd and 5th postoperative day. Mean total blood loss during the operation and until the 2nd postoperative day was 1,708 ml in the DD group and 1,712 ml in the D group (p = 0.79). During the 1st postoperative week, no group differences were found in the relative number of patients that received packed red blood cells (p = 0.95), the amount of transfused packed red blood cells (p = 1.0) and changes in hemoglobin concentrations (p = 0.69). The present results suggest that dextran 70 and dalteparin can be combined in recommended doses without significantly increasing perioperative bleeding in patients undergoing hip replacement surgery. Bone traumatization and insufficient plugging of surgical traumatized bone surfaces with bone cement favor bleeding. Further well-designed studies are needed to evaluate the safety and efficacy of this regimen.