Systemic and local cytokine kinetics in musculoskeletal injury: a prospective study in patients with ankylosing spondylitis.

OBJECTIVE: Back surgery in patients with ankylosing spondylitis is a major trauma in individuals with tissue inflammation and joint destruction along the spine; we used surgery in these patients as a model in the study of systemic and local cytokine profiles in complicated trauma situations. MATERIAL AND METHODS: Blood was sampled before, during and after surgery in 10 patients operated on with extending osteotomy of the lumbar spine. Samples of arterial blood and local wound blood were analysed for proinflammatory and anti-inflammatory cytokines. RESULTS: Surgery induced no significant changes in systemic values of TNFalpha and IL-1beta. There were significant increments in systemic values of IL-6, IL-8 and sTNF-R1. A systemic increase in values of IL-10 was only noticed after 24 h. There were increments in local values of TNFalpha at 24 h and in local values of IL-1beta, IL-6, Il-8 and IL-10 at both 4 and 24 h postoperatively. The local values were in general significantly higher than the systemic values. CONCLUSIONS: This study indicates that a major musculoskeletal trauma principally is followed by significant increases in systemic levels of IL-6 with only modest systemic reactions in TNFalpha and IL-1beta, even in patients with an inflammatory disease. However, there are in general significantly increased local levels of IL-1beta, IL-6, IL-8 and IL-10, and our conclusion is that systemic cytokine levels might not reflect local reactions.

Systemic and local cytokine patterns during total hip surgery.

OBJECTIVE: Increased levels of inflammatory cytokines have been described in musculoskeletal injury. Total hip replacement is major musculoskeletal surgery, and in the present study this operation was used to investigate systemic and local cytokine patterns during musculoskeletal trauma. MATERIAL AND METHODS: Blood was sampled before, during and after surgery in 10 patients given total hip replacement. Samples of arterial blood and local blood from the femoral canal were analysed for proinflammatory and anti-inflammatory cytokines. RESULTS: Surgery induced significant increases in arterial and local levels of interleukin 6 (IL-6) (p = 0.000, respectively) with the highest levels at 4 h after operation. There were significantly higher local levels of IL-6 than arterial levels. Interleukin 1beta (IL-1beta) was not significantly influenced by surgery at any time (p = 0.800 and 0.300 for local and arterial levels, respectively), nor was tumour necrosis factor alpha (TNFalpha) (p = 0.375 and 0.547 for local and arterial levels, respectively). Local levels were higher than arterial levels for IL-1beta and for TNFalpha. At the end of the operation, local levels of interleukin 10 (IL-10) were significantly reduced (p = 0.036), while surgery did not influence the arterial levels of IL-10 (p = 0.235). There were no significant differences in local and arterial levels of IL-10 (p = 0.558). CONCLUSIONS: The study indicates that a major musculoskeletal operation on otherwise healthy patients is associated with fairly modest reactions of inflammation, both systemically and locally.

Reduced capacity of whole blood leucocytes to express tumour necrosis factor-alpha and interleukin-10 following major orthopaedic surgery.

BACKGROUND: Severe trauma is a challenge to the immune response and may cause reduced immune capacity. As a marker of decreased cellular activity, studies with ex vivo lipopolysaccharide (LPS) stimulation of whole blood or isolated mononuclear cells from injured patients have revealed reduced production of inflammatory cytokines. To gain further insight into immune alterations in orthopaedic surgery, we studied LPS-induced tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 in whole blood of patients during peri- and postoperative phases of total hip replacement. METHODS: Four females and 3 males undergoing elective total hip replacement were included in the study. Ex vivo LPS-induced TNF-alpha and IL-10 were measured in a whole blood assay before, during and at 1 and 6 days after operation. In addition, the counts of white blood cells were determined. RESULTS: During the operation, there were significant reductions in the number of monocytes, but at day 1 and 6 after surgery, there were significant increases as compared to the levels before surgery. The capacity of whole blood to express TNF-alpha and IL-10 did not change significantly during the operation and the following postoperative day. At day 6, however, there were significant reductions in expression of both TNF-alpha and IL-10 as compared to the levels before the operation. In relation to the values of monocytes, there was a significant reduction in the expression of TNF-alpha also at day 1 after operation. CONCLUSION: Our data indicate that in the course of at least 6 days after a major orthopaedic trauma, there is suppression of the whole blood capacity to express the inflammatory cytokine TNF-alpha and the anti-inflammatory cytokine IL-10 when exposed to LPS. During this time, then, the patient is particular susceptible to septic complications.

Fibrinolytic activity and postoperative salvaged untreated blood for autologous transfusion in major orthopaedic surgery.

OBJECTIVE: To evaluate the fibrinolytic activity in a closed surgical wound, in postoperatively drained blood, and during autologous transfusion. DESIGN: Prospective study. SETTING: National hospital, Norway. PATIENTS: 9 patients operated on for thoracic scoliosis. MAIN OUTCOME MEASURE: Concentrations of plasmin/antiplasmin (PAP), alpha2-antiplasmin, and D-dimers in drained, arterial, and mixed venous blood before, during, and after infusion of 10 ml/kg body weight of postoperatively drained, untreated blood. RESULTS: In drained blood the concentration of alpha2-antiplasmin was 31% of the preoperative arterial control value. Together with the increased concentrations of PAP to 18076 microg/L and D-dimers to 126 mg/L, this indicates extensive fibrinolytic activity in the closed wound. The postoperative autologous transfusion of drained, untreated blood increased the concentration of PAP from 507 to 2453 microg/L and of D-dimer from 0.7 mg/L to 15.3 mg/L in systemic blood. CONCLUSION: The systemic concentration of fibrin(ogen) degradation products, indicated by D-dimers, after recirculation of drained, untreated blood might impair coagulation. The extensive activation of plasmin might exhaust available alpha2-antiplasmin in the wound and result in postoperative rebleeding.

Tissue factor antigen and activity in serum of postoperatively shed blood used for autologous transfusion.

Orthopaedic surgery involves extensive dissection of connective and richly vascularised tissues rich in tissue factor (TF). It was, therefore, of interest to quantify the amount of TF antigen and activity in postoperatively drained, unwashed wound blood collected for the purpose of autologous transfusion. In nine young patients subjected to surgery for idiopathic thoracic scoliosis, samples were drawn postoperatively from collected shed blood, a pulmonary artery catheter and a radial arterial cannula prior to, during and after reinfusion of shed blood (10 ml/kg body weight), and analysed for TF antigen and activity. Preoperative arterial control samples contained 128 pg/ml TF antigen compared with 40 pg/ml postoperatively. During reinfusion of drained blood, arterial TF concentration rose to 96 pg/ml and dropped to 64 pg/ml after infusion. Arterial and mixed venous blood did not differ significantly in TF levels. Serum from drained blood contained high concentrations of TF antigen (773 pg/ml), but no TF activity was detected. It is concluded that the high concentrations of TF antigen in serum from postoperatively drained blood collected for autologous transfusion are devoid of procoagulant activity. The TF antigen in plasma of drained blood is suggested to be a soluble, proteolysed TF-apoprotein or a TF complex inactivated by the TF pathway inhibitor (TFPI).

Cytokine modulation in experimental endotoxemia: characterization of an ex vivo whole blood model.

A new model was developed to study cytokine regulation and modulation in whole blood ex vivo. The model is characterized by stable leukocyte counts and high leukocyte viability throughout the experimental period. Oxygen consumption per time decreased slowly, whereas carbon dioxide partial pressure increased accordingly throughout the experiment. In this model, the anti-inflammatory effects of recombinant human (rh) interleukin (IL)-4, rhIL-10 and rhIL-13 on lipopolysaccharide (LPS) stimulated (10 ng/ml) leukocytes were examined and compared by measuring their ability to inhibit the release and mRNA levels of tumor necrosis factor (TNF)alpha, IL-6 and IL-1beta. rhIL-10 potently inhibited the release of TNF-alpha, IL-6 and IL-1beta in a potent and dose-dependent manner, but did not influence the mRNA levels of these cytokines in CD14-positive cells. Also, rhIL-4 and rhIL-13 inhibited the release of IL-6 and IL-1beta in a potent and dose-dependent manner, however, stronger maximal inhibition of IL-1beta (85%) than of IL-6 (60%) was obtained. In contrast, rhIL-4 and rhIL-13 seemed to have both stimulatory and inhibitory effects on plasma values of TNF-alpha. The effects of 10 ng/ml LPS showed to be signalling through the CD14 receptor, since blood treated with a monoclonal anti-CD14 antibody did not produce any TNF-alpha. The whole blood model described in this study is in our opinion a useful tool for investigating immunomodulating effects on a mixed white blood cell population.

Fibrinogen, fibrin and its degradation products in drained blood after major orthopaedic surgery.

The aim of this study was to evaluate the fibrinogen enzymatic conversion in blood collected postoperatively from a surgical wound. Ten otherwise healthy patients (aged 11-28 years) in need of surgical treatment for thoracic scoliosis were included in the study. Arterial blood preoperatively and at wound closure were compared with samples of drained blood from the wound at closure and from a collection system for autologous transfusion 2.8 +/- 1.1 h later. There was a decrease in the fibrinogen content in arterial blood from 2.17 +/- 0.35 g/l to 1.23 +/- 0.42 g/l, which followed a 40% haemodilution estimated from the blood loss of 1.6 +/- 0.9 l during the operation. Drained blood contained high concentrations of D-dimer (85 +/- 53 mg/l from the wound and 121 +/- 47 mg/l from the collection system), but no clottable fibrinogen. The Western immunoblots all visualized the same patterns; in drained blood there were split-products mainly from cross-linked fibrin, in contrast to arterial blood which contained only normal fibrinogen. This indicates a strong fibrinolysis in the surgical wound after closure, with concentrations of fibrin degradation products that may impair local coagulation, and if infused, might interfere with general haemostasis.

Inflammatory cytokines and their receptors in arterial and mixed venous blood before, during and after infusion of drained untreated blood.

Wound blood for postoperative autologous transfusion is drained through an area of damaged tissue, the surgical wound, and contains inflammatory mediators. The inflammatory cytokines interleukin-1-beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) and their modulators interleukin-1-receptor antagonist (IL-1Ra), interleukin 6 soluble receptor (IL-6sR), soluble tumour necrosis factor receptor 1 (sTNF-R1) and interleukin 10 (IL-10), together with white cell count (WCC) and white cell differential count were measured in arterial and mixed venous blood before, during and after infusion of postoperatively drained untreated blood in nine patients operated for thoracic scoliosis. We found a transient increase in IL-6, an increase in TNF-RI, an increase in IL-8 with granulocytosis and a decrease in IL-10 in the systemic circulation. The increase in IL-6 was higher in mixed venous than in arterial blood.

The cytokines IL-1beta and IL-1 receptor antagonist, IL-2 and IL-2 soluble receptor-alpha, IL-6 and IL-6 soluble receptor, TNF-alpha and TNF soluble receptor I, and IL10 in drained and systemic blood after major orthopaedic surgery.

OBJECTIVE: To measure the concentration of the cytokines interleukin-1beta (IL-1beta), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumour necrosis factor-alpha (TNF-alpha) and the modulators of their function interleukin-1 receptor antagonist (IL-1Ra), interleukin-2 soluble receptor alpha (IL-2 sRalpha), interleukin-6 soluble receptor (IL-6sR) and soluble tumour necrosis factor receptor I (sTNFR-I) in systemic and drained blood for the first six hours after a major orthopaedic operation. DESIGN: Prospective study. SETTING: University hospital, Oslo. PATIENTS: 8 patients operated on for thoracic scoliosis. MAIN OUTCOME MEASURE: Concentrations of IL-1beta, IL-2, IL-6, IL-10, TNF-alpha, IL-1Ra, IL-2 sRalpha , IL-6sR, and sTNFR-I were measured together with haemoglobin (Hb) concentration, white cell count (WCC), and differential count in arterial and drained blood at wound closure and 1, 2, 4, and 6 hours postoperatively. RESULTS: IL-1beta and IL-6 concentrations increased significantly in drained blood, whereas that of TNF-alpha increased only in arterial blood. The modulating factors IL-1Ra, sTNFR-I, and IL-10 were increased both in arterial and drained blood. IL-6sR had decreased slightly at 6 hours in drained blood. No IL-2 was found and IL-2 sRalpha decreased simultaneously with the haemodilution. In arterial blood there was a granulocytosis and in drained blood a relative lymphocytosis. CONCLUSION: Cytokine responses to surgical trauma include modulating factors such as soluble receptors and receptor antagonists that have different responses systemically and locally.

Complement activation and release of interleukin-6 and tumour necrosis factor-alpha in drained and systemic blood after major orthopaedic surgery.

OBJECTIVE: To measure the concentration of complement activation products C3bc and terminal complement complex (TCC) and the cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) in systemic and drained wound blood for the first six hours after a major orthopaedic operation. DESIGN: Prospective study. SETTING: University hospital, Norway. PATIENTS: 8 patients operated on for thoracic scoliosis. MAIN OUTCOME MEASURE: Concentrations of complement activation products, IL-6 and TNF-alpha in arterial (systemic) and drained (local) blood were measured at wound closure and 1, 2, 4, and 6 hours postoperatively. RESULTS: C3bc and TCC were 10 times higher, and IL-6 showed extreme values, in drained compared with arterial blood. The concentration of TNF-alpha did not increase significantly, either in drained or in arterial blood. The white cell count (WCC) increased threefold in both drained and arterial blood compared with arterial control values before operation. CONCLUSION: Complement activation and IL-6 release after surgical trauma differ significantly in local and systemic blood samples. Conclusions based only on systemic findings may be limited.

[Intraoperative and postoperative autologous transfusion in orthopedic surgery]. / Per- og postoperativ autolog transfusjon ved ortopedisk kirurgi.

Information was collected retrospectively on three comparable groups, 25 patients in each, who had been operated on for thoracic scoliosis. Group 1 received homologous transfusions only. Group 2 and group 3 were transfused postoperatively with drained whole blood (Solcotrans orthopaedics). Group 3 received in addition peroperatively washed packed red blood cells (Haemolite 2 Cell Saver) recirculated. The need for homologous transfusions was reduced from 119 units to 23 patients in group 1, to 36 units to 14 patients in group 2 and 34 units to 13 patients in group 3. Three of the first 15 patients in group 2 experienced chills and fever reactions in connection with the autologous transfusion. No reactions were seen after infusion when we scrapped the last 50 to 100 ml of drained blood.

Ultrasonographic screening for abdominal aortic aneurysm.

OBJECTIVE: To assess the prevalence of abdominal aortic aneurysm in a selected group of men over the age of 60, and define main risk factors. DESIGN: Population based screening study. SETTING: Private Norwegian health maintenance organisation. SUBJECTS: 500 men over the age of 60 years. INTERVENTIONS: General examination by a general practitioner, together with measurements of blood glucose and serum cholesterol concentrations. Abdominal scan with a B-mode ultrasound imager. MAIN OUTCOME MEASURES: An increase in the diameter of the aorta of more than 150% over the diameter at the origin of the superior mesenteric artery, or maximum diameter of more than 29 mm. Correlation with history of smoking, serum cholesterol concentration, and general health. RESULTS: 29 patients (5.8%) had small, and 12 (2.4%) had large, abdominal aortic aneurysms. There was a significant association between aortic aneurysm and history of smoking (p < 0.01), poor health (defined as coexistent hypertension, cardiovascular disease, or diabetes mellitus) (p < 0.01), and increasing age (p = 0.025). There was no association with hypercholesterolaemia. CONCLUSION: Ultrasonic screening of groups at risk followed by elective operation may reduce mortality of abdominal aortic aneurysm.

[Ultrasonography for early diagnosis of abdominal aortic aneurysm]. / Ultrasonografi for tidlig diagnostikk av abdominalt aortaaneurisme.

2,654 males aged 60 years or older were invited to attend a screening examination using ultrasound to detect abdominal aortic aneurysm. 1,256 met up. A fee of NOK 150 was charged. 92 aneurysms were detected (7.3%) 69 were smaller than 40 mm and 23 were 40 mm or larger. During the observation period (18 months from start of the study and nine months after screening stopped) 17 of the patients with an abdominal aortic aneurysm of 40 mm or larger had elective operations. All patients survived without major complications. Owing to the high prevalence of abdominal aortic aneurysm, the low cost of screening, and the safety of elective surgery, it is suggested that screening for detection of abdominal aortic aneurysm should be carried out on a larger scale.