The inflammatory response and its consequence for the clinical outcome following aortic aneurysm repair.

OBJECTIVE: to review published studies on the outcome of the inflammatory response after abdominal aortic aneurysm (AAA) repair. METHODS: a literature search on PubMed was performed. All studies that determined the inflammatory response (cytokine release) after AAA repair were included. The results of the studies and differences between open and endoluminal repair were compared and evaluated. RESULTS: seventeen studies were identified. In most studies the investigated cytokines were TNF-alpha and IL-6. Determination of IL-1 beta, IL-8, TNFsr1 and TNFsr2 were less often performed. TNF-alpha may reflect, but not strictly predict, the clinical outcome in patients with ruptured AAA. IL-6 levels correlate well with the surgical trauma per se. Variations in recorded cytokine release during endovascular AAA repair may depend on the times of blood sampling. CONCLUSION: both open and endovascular AAA repair provoke a cytokine response. This response is greater during open repair than during endovascular aortic aneurysm exclusion.     

Cytokines, their genetic polymorphisms, and outcome after abdominal aortic aneurysm repair.

BACKGROUND: Excessive cytokine production has been implicated in the development of organ failure. Polymorphic sites in cytokine genes have been shown to affect levels of production in vitro and may influence cytokine production in vivo. The aims of this study were to determine if cytokines or their genetic polymorphisms were related to outcome after abdominal aortic aneurysm (AAA) repair. METHODS: A prospective study of 135 patients undergoing open AAA repair. Plasma levels of TNF-alpha, IL-1beta, IL-6 and IL-10 were measured 24 h post-operatively and genotypes for the TNF-alpha -308, IL-1beta+3953, IL-6 -174, IL-10 -1082 and IL-10 -592 polymorphisms were determined for each patient. RESULTS: After elective AAA high levels of IL-10 were associated with both prolonged critical care (P<0.001) and hospital stay (P=0.001). The presence of a G allele at the IL-6 -174 locus was associated with a higher incidence of organ failure (P=0.04) and an A allele at TNF-alpha -308 with prolonged critical care stay (P=0.03). After ruptured AAA the development of multi-organ failure was associated with high levels of IL-6 (P=0.01) and TNF-alpha (P=0.04). High TNF-alpha levels were also associated with mortality (P=0.01). CONCLUSION: Post-operative cytokine levels are related to outcome after AAA repair. Cytokine gene polymorphisms may provide a method for determining which patients are at high risk of complications.     

Release of anti-inflammatory mediators after major torso trauma correlates with the development of postinjury multiple organ failure

BACKGROUND: Soluble tumor necrosis factor receptor (sTNFr) and interleukin-1 receptor antagonist (IL-1ra) have been identified as endogenous inhibitors of TNF-alpha and IL-1beta. While TNF-alpha and IL-1beta levels are not systematically elevated in postinjury patients who developed multiorgan failure (MOF), their involvement at the tissue level has been suggested. Our study hypothesis was that levels of sTNFr-I and IL-1ra would discriminate patients at risk for postinjury MOF. METHODS: Serial plasma levels of sTNFr and IL-1ra were measured in 29 trauma patients at high risk for postinjury MOF. RESULTS: sTNFr-I levels were higher in MOF compared with non-MOF patients at 12, 84, and 132 hours postinjury. MOF patients also had higher IL-1ra values 36, 60, 84, and 132 hours postinjury. CONCLUSIONS: Anti-inflammatory mechanisms are activated after trauma. Since increased levels of sTNFr and IL-1ra correlate with postinjury MOF, they may contribute to our understanding of the pathogenesis as well as prediction of outcome. High levels of antagonists to TNF-alpha and IL-1beta suggest tissue level involvement of these cytokines in postinjury hyperinflammation.     

Cytokine gene polymorphisms and the inflammatory response to abdominal aortic aneurysm repair

BACKGROUND: Cytokines are key mediators of the inflammatory response to surgery and polymorphic sites in their genes have been shown to affect cytokine production in vitro. The aim of this study was to determine whether cytokine gene polymorphisms affect cytokine production in vivo in patients undergoing abdominal aortic aneurysm (AAA) repair. METHODS: One hundred patients admitted for elective AAA repair had plasma levels of interleukin (IL) 1beta, IL-6, IL-10 and tumour necrosis factor (TNF) alpha measured at induction of anaesthesia and 24 h after operation. Genotypes for each patient were determined using induced heteroduplex genotyping for the following loci: IL-1beta + 3953, IL-6 - 174, IL-10 - 1082/-592 and TNF-alpha - 308. RESULTS: Patients with an IL-10 - 1082 A allele had a significantly higher IL-10 response to surgery than those without an A allele (P = 0.030) and there was also a significant difference in IL-10 response between patients with IL-10 - 1082 AA genotypes and those with GG genotypes (P = 0.030). CONCLUSION: Elective AAA repair results in a measurable cytokine response. In this study the magnitude of this response was not affected by the individual patient's cytokine gene polymorphisms.     

Comparison of systemic cytokine levels in patients with acute respiratory distress syndrome, severe pneumonia, and controls

BACKGROUND: The inflammatory response has been widely investigated in patients with acute respiratory distress syndrome (ARDS) and pneumonia. Studies investigating the diagnostic values of serum cytokine levels have yielded conflicting results and only little information is available for the differential diagnosis between ARDS and pneumonia. METHODS: Clinical and physiological data, serum concentrations of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, and quantitative cultures of lower respiratory tract specimens were obtained from 46 patients with ARDS and 20 with severe pneumonia within 24 hours of the onset of the disease and from 10 control subjects with no inflammatory lung disease. Cytokine concentrations were compared between groups and determinants in addition to the diagnosis were tested. RESULTS: Serum TNF-alpha levels were significantly higher in ARDS patients (67 (57) pg/ml) than in patients with severe pneumonia (35 (20) pg/ml; p = 0.031) or controls (17 (8) pg/ml; p = 0.007). For IL-1beta and IL-6 the observed differences were not statistically significant between patients with ARDS (IL-1beta: 34 (65) pg/ml; IL-6: 712 (1058) pg/ml), those with severe pneumonia (IL-1beta: 3 (4) pg/ml, p = 0.071; IL-6: 834 (1165) pg/ml, p = 1.0), and controls (IL-1beta: 6 (11) pg/ml, p = 0.359; IL-6: 94 (110) pg/ml, p = 0.262). TNF-alpha (standardised coefficient beta = 0.410, p<0.001) and IL-1beta (standardised coefficient beta = 0.311, p = 0.006) were most strongly associated with the degree of lung injury, even when the diagnostic group was included in the statistical model. CONCLUSIONS: Serum TNF-alpha levels were higher in patients with ARDS than in those with severe pneumonia or in control subjects. Multivariate results suggest that the levels of systemic TNF-alpha and IL-1beta reflect the severity of the lung injury rather than the diagnosis.     

Decreased progression of postinjury lung dysfunction to the acute respiratory distress syndrome and multiple organ failure

BACKGROUND: Postinjury organ dysfunction is a result of unbridled systemic hyperinflammation. According to the two-event construct, patients are resuscitated into an early vulnerable window of systemic hyperinflammation (primed) in which a second otherwise innocuous event precipitates uncontrolled hyperinflammation, leading to secondary organ damage and dysfunction (activated). Recent efforts to decrease postinjury morbidity have focused on limiting the potential of second events and systemic inflammation. We hypothesized that the collective effects of recently implemented therapeutic strategies have resulted in decreased activation of the systemic inflammatory response relative to priming in recent years. METHODS: Data were collected prospectively on trauma patients at risk for postinjury multiple organ failure (MOF). Inclusion criteria were age >15 years, trauma intensive care unit admission, Injury Severity Score >15 and survival >48 hours. Isolated head injuries and head injuries with an extracranial abbreviated injury score <2 were excluded. Daily physiologic and laboratory data were collected through surgical intensive care unit day 28, and clinical events were recorded thereafter until death or hospital discharge. Organ failure was characterized with the use of the Denver MOF Scale. Acute respiratory distress syndrome (ARDS) was defined according to the consensus definition. RESULTS: Over a 6.5-year period 897 patients were studied; 271 (31%) developed ARDS, and 226 (25%) developed MOF. Early lung dysfunction, as a measure of systemic priming, did not change over the study period. In contrast, the incidence of ARDS and MOF decreased from 43% to 25% and 33% to 12%, respectively. The incidence of early MOF decreased from 22% to 7% over the study period. CONCLUSIONS: Priming of the postinjury inflammatory response is an early event and is primarily influenced by the injury itself. Recent advances in postinjury care such as judicious blood transfusion, lung protective ventilation, treatment of adrenal insufficiency, and tight glucose control are known to attenuate systemic inflammation. Step-wise adoption of these therapies is coincident with a decrease in the destructive processes resulting in ARDS and MOF. The global effect is a decrease in activation of the systemic inflammatory response over recent years.     

Aortic aneurysm repair is associated with a lower inflammatory response compared with surgery for inflammatory bowel disease

BACKGROUND: Since the plasma cytokine profile reflects the body's inflammatory response to injury, this study was designed to prospectively observe the plasma cytokine levels in response to the degree of different sorts of abdominal surgical trauma. METHODS: Plasma levels of TNF-alpha, type I TNF receptor (p55), type II TNF receptor (p75), IL-6, IL-8, IL-10, phospholipase A(2) (PLA(2)), and haptoglobin were measured peri-operatively in patients undergoing bowel resection for inflammatory bowel disease or diverticulitis (IBD) (n = 9), elective repair of abdominal aortic aneurysm (AAA) (n = 9), or laparoscopic cholecystectomy (lap chole) (n = 9). RESULTS: The IBD patients showed a significant (p < 0.05) post-operative elevation in plasma IL-6, p55, p75, and PLA(2) levels, but no significant change in TNF-alpha, IL-8, IL-10 or haptoglobin levels. The AAA patients had a significant post-operative rise in IL-10 levels and a significant decrease in plasma haptoglobin levels, but no significant change of TNF-alpha, IL-6, IL-8, p55, p75, or PLA(2) concentrations. The lap chole patients demonstrated no significant change in any of these parameters. CONCLUSION: These data show that IL-6, IL-10, p55, and p75 are markers to measure the degree of inflammatory stress associated with abdominal operative procedures and demonstrate the relative lack of a cytokine response to laparoscopic cholecystectomy.     

Cytokine pattern in aneurysmal and occlusive disease of the aorta.

BACKGROUND: Prominent inflammatory infiltrates of macrophages and T-lymphocytes are found in both aortic occlusive disease (AOD) and abdominal aortic aneurysms (AAA). These cells secrete different cytokines that might affect matrix turnover through modulation of matrix metalloproteinase expression. A different cytokine pattern might account for the evolution of AOD vs AAA. MATERIALS AND METHODS: Six different cytokines were examined to determine whether AOD and AAA could be characterized by unique cytokine patterns. AOD (n = 8) and AAA (n = 8) tissues were collected and serially treated with salt, dimethyl sulfoxide, and urea buffers to extract the soluble matrix or cell-bound cytokines. Levels of IL-1 beta, TNF-alpha, IL-10, IL-12, and IFN-gamma were measured by immunoenzymatic methods. Additionally, RNA levels of IL-12 and IFN-gamma were measured. RESULTS: AAA tissue contained higher levels of IL-10 compared to AOD tissue (P < 0.05). Higher levels of the proinflammatory cytokines IL-1 beta, TNF-alpha, and IL-6 were found in AOD (P < 0.05). mRNA levels of IL-12 and IFN-gamma did not differ between the diseases. Aortic tissues contained large amounts of matrix or cell-bound cytokines. CONCLUSIONS: AAA is characterized by greater levels of IL-10 while IL-1 beta, TNF-alpha, and IL-6 are higher in AOD. Targeted deletion of these cytokines in animal models might help in identifying their role in the progression of AAA.     

Abdominal aortic aneurysm and aortic occlusive disease: a comparison of risk factors and inflammatory response.

OBJECTIVE: to compare patients with abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD) with regard to risk factors for atherosclerosis, co-morbid conditions and inflammatory activity. PATIENTS AND METHODS: a total of 155 patients undergoing abdominal aortic surgery between January 1993 and October 1997: 82 (53%) had aneurysmal disease and 73 (47%) had occlusive disease. Principal risk factors were compared: age; gender; smoking; hypertension; hyperlipidaemia; diabetes mellitus; severe peripheral vascular disease (PVD) and ischaemic heart disease. Aortic wall tissue samples were obtained during surgery. A prospective blind analysis was performed for the presence of inflammatory cytokines TNF-alpha, IL-1 beta, IL-6 and TGF-beta. RESULTS: the average age of AAA patients was 74 years (50-88), while that of AOD patients was 61 years (43-82) (p<0.0001). Diabetes mellitus was found to be much more prevalent in the AOD group (p<0.001), while hypertension and severe PVD were more prevalent in the AAA group (p<0.001). No differences were found concerning any of the risk factors. Inflammatory cytokine activity: AAA tissue samples contained significantly higher mean TNF-alpha and IL-6 levels compared to the AOD samples (5.6+/-2.7 x 10 E-4 vs. 4.4+/-2.7 x 10 E-5 atmoles/microl (p=0. 01), and 0.6+/-0.4 vs. 0.01+/-0.006 atmoles/microl (p=0.02) respectively). No differences were found related to IL-1 beta and TGF-beta. CONCLUSIONS: (1) Patients with AAA have fewer atherosclerotic risk factors than do patients with AOD. (2) Patients with AAA and AOD have significantly different inflammatory activity. (3) The data supports the hypothesis that AAA and AOD are probably two different pathological entities.     

Cytokine Levels (IL-4, IL-6, IL-8 and TGFβ) as Potential Biomarkers of Systemic Inflammatory Response in Trauma Patients

Purpose

Much research is now being conducted in order to understand the role of cytokines in the development of the inflammatory response following trauma. The purpose of this study was to evaluate whether serum levels of certain cytokines, measured immediately after initial injury, can be used as potential biomarkers for predicting the development and the degree of severity of the systemic inflammatory response (SIRS) in patients with moderate and severe trauma.

Methods

We conducted a prospective study with 71 individuals of whom 13 (18.3 %) were healthy controls and 58 (81.7 %) were traumatized orthopaedic patients who were categorized into two groups: 31 (43.6 %) with moderate injuries and 27 (38.1 %) patients with severe orthopaedic trauma. Thirty cc of heparinized blood were drawn from each individual within a few hours after the injury. Serum levels of pro-inflammatory, regulatory and anti-inflammatory cytokines were measured in each individual participant.

Results

High levels of pro-inflammatory cytokines IL-1β,-6,-8,-12, tumour necrosis factor alpha and interferon gamma were found in all injured patients compared to healthy controls. Only IL-6 and IL-8 were significantly higher in the injured patients. Levels of the regulatory cytokines, transformed growth factor beta (TGF-β) and IL-10 were higher in the injured patients, but significant only for TGF-β. Levels of IL-4 were significantly lower in the injured groups as compared to the controls.

Conclusions

Secretion of large amounts of pro-inflammatory cytokines and decreased level of anti-inflammatory cytokines during the acute phase of trauma may lead to the development of systemic inflammatory response syndrome (SIRS) in unstable polytraumatized patients. SIRS may result in life threatening conditions as acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF). High levels of IL-6, IL-8, TGFβ and low levels of IL-4 were found to be reliable markers for the existence of immune reactivity in trauma patients. More research is needed to study pattern of cytokine levels along the acute period of injury, after surgical interventions and during recovery.     

Metabolic correlates of oxygen debt predict posttrauma early acute respiratory distress syndrome and the related cytokine response

BACKGROUND: The purpose of this study was to quantify the relationship between negative base excess (base deficit) and lactate as correlates of oxygen debt and the probability of the early acute respiratory distress syndrome (ARDS) response and with regard to the mediator and metabolic response characteristic of this disease. METHODS: Eighty patients with multiple trauma were studied (514 samples) during their intensive care unit courses (Injury Severity Score 27.6+/-8.8, 36% deaths). Simultaneous samples of arterial base excess and lactate as correlates of oxygen debt, and enzyme-linked immunosorbent assay-measured mixed venous cytokines were obtained daily. At each sample period, the patient was categorized as having ARDS or non-ARDS. RESULTS: Twenty-nine patients (36%; 19 deaths) developed ARDS over the period studied: 17 in postinjury days 1 to 4 (EARLY ARDS) and 12 in postinjury days 5 or later (LATE ARDS). Patients subsequently developing ARDS had evidence of ischemic acidosis on or within the first 24 hours after hospital admission (lower base excess -7.1 mmol/L and higher lactate 5.2 mmol/L in ARDS versus base excess -3.8 mmol/L and lactate 3.6 mmol/L in non-ARDS; p < 0.05). Patients with EARLY ARDS showed even lower (p < 0.05) initial 24 hour mean base excess and higher lactate (base excess -9.1 mmol/L and lactate 6.4 mmol/L) compared with LATE ARDS (base excess -4.3 mmol/L and lactate 3.3 mmol/L). In EARLY ARDS, this degree of ischemic acidosis was followed by a greater mean IL-6 response in the postinjury days 1 to 4 (323 pg/mL) compared with the LATE ARDS response (141 pg/mL) (p < 0.05) or compared with the non-ARDS IL-6 response (67 pg/mL; p < 0.001). In addition, in EARLY ARDS, mean IL-8 levels in postinjury days 1 to 4 (264 pg/mL) were higher than in LATE ARDS (168 pg/mL) (p < 0.05) and the mean IL-1 response in postinjury days 1 to 4 of EARLY ARDS (65 pg/mL) was greater than non-ARDS (32 pg/mL) (p < 0.05). Derivation of probability curves suggests a critical threshold of base excess -6.6 mmol/L or greater for an increased risk of EARLY ARDS. CONCLUSION: These data suggest that the maximum posttrauma oxygen debt (quantified by the ischemia correlates of negative base excess and lactate) is a critical primary determinant of the later fulminant autoinflammatory EARLY ARDS response mediated by the host's endogenous cytokine mediators.     

Urinary albumin:creatinine ratio (ACR) and the prediction of postoperative complications after abdominal aortic aneurysm repair.

INTRODUCTION: Open repair of abdominal aortic aneurysm (AAA) requires aortic clamping. This results in an ischaemia-reperfusion injury (IRI) which can lead to the development of the systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF). We investigated the use of urinary albumin:creatinine ratio (ACR) as a simple predictor of the development of complications (SIRS) postoperatively. METHODS: Forty-four patients undergoing elective infrarenal AAA repair and 10 control patients undergoing major abdominal surgery had fresh urine samples taken before, immediately after and 24 h after the procedure. Urinary ACR was calculated on all samples, and daily SIRS scores were calculated for all patients postoperatively. Systemic interleukin-6 (IL-6) levels were measured intraoperatively to measure the cytokine response to surgery. RESULTS: AAA patients demonstrated a characteristic pattern of ACR levels during the three time points, with a significant increase in the ACR immediately postoperatively and with normalisation by 24 h (P<0.001 Wilcoxon signed ranks test). In comparison, control patients did not demonstrate any changes in their ACR (P=0.45 Wilcoxon signed ranks test) suggesting the increased ACR in AAA patients to occur as a result of IRI. ACR did not correlate with the development of SIRS postoperatively or with the systemic IL-6 response. CONCLUSIONS: Infrarenal AAA repair is associated with a temporary and reversible renal injury. ACR could not, however, be used as a predictor of complications postoperatively.     

Anti-inflammatory cytokine response and the development of multiple organ failure in severe sepsis

BACKGROUND: The production of proinflammatory cytokines activates the systemic inflammatory response in sepsis. Patients also develop a compensatory anti-inflammatory reaction, which may have an important down-regulatory effect on the overactive inflammation. However, the role of this anti-inflammatory response in sepsis is not completely clarified. In this prospective study, we investigated the relationship between the pro- and anti-inflammatory cytokine profiles in severe sepsis and their role in the development of multiple organ failure (MOF). METHODS: Thirty-eight patients meeting the criteria for severe sepsis were studied. MOF was defined as a maximum SOFA score of 10 or higher. Serial measurements of the proinflammatory IL-6 and IL-1beta and the anti-inflammatory IL-10 and IL-1ra were used. The cytokine samples were taken at the onset of sepsis and on the third and fifth day during the ICU period. RESULTS: The initial IL-10 and IL-1ra responses were identical in patients with or without MOF. The anti-inflammatory cytokine levels remained elevated in the MOF patients, whereas in patients without MOF the levels declined. The IL-6/IL-10 ratio was significantly higher in the MOF patients on days 1 and 3 compared with patients without MOF. CONCLUSIONS: We could not demonstrate overproduction of anti-inflammatory IL-10 in MOF patients. On the contrary, the high IL-6/IL-10 ratio indicates that IL-10 deficiency may contribute to the development of MOF in severe sepsis.     

Obesity increases risk of organ failure after severe trauma

BACKGROUND: Obesity is an independent risk factor for a variety of diseases, including postinjury morbidity and mortality. Obesity is associated with a proinflammatory state that could affect the postinjury inflammatory response and increase risk of organ dysfunction. The purpose of this study was to determine the relationship between obesity and postinjury multiple organ failure (MOF). STUDY DESIGN: A prospective observational study of patients at risk for postinjury MOF. Inclusion criteria were age older than 15 years, Injury Severity Score > 15, ICU admission within 24 hours of injury, and survival longer than 48 hours after injury. Isolated head injuries were excluded. Organ dysfunction was assessed using the Denver multiple organ failure score. RESULTS: Data were collected on 716 severely injured patients, 70% were men and 83% were victims of blunt trauma. There was no relationship between body mass index and injury severity or the amount of blood transfused within 12 hours of injury. Postinjury MOF was observed in 123 of 564 (22%) nonobese patients and 56 of 152 (37%) obese patients. Obesity was independently associated with MOF (odds ratio, 1.8; 95% CI, 1.2-2.7) after adjusting for patient age, injury severity, and amount of blood transfused during resuscitation. In this study population, obesity was also associated with increased length of ICU and hospital stay but not death. CONCLUSIONS: Obese patients are at increased risk of postinjury MOF. Study of the obesity-related inflammatory profile could provide additional insight into the pathogenesis of organ dysfunction and identify therapeutic targets for both obese and nonobese patients. Increased morbidity and length of stay in obese trauma patients implies greater resource allocation for this population.     

The systemic inflammatory response syndrome,organ failure,and mortality after abdominal aortic aneurysm repair

BACKGROUND: Organ failure is a major cause of morbidity and mortality after abdominal aortic aneurysm (AAA) repair. The aim of this study was to determine the relationships between the systemic inflammatory response syndrome (SIRS), organ failure, and mortality after AAA repair and to determine whether the clinical monitoring of SIRS was a useful adjunct to clinical method. METHODS: One hundred consecutive patients undergoing open AAA repair were prospectively studied. Patients were divided into three groups: those undergoing elective AAA repair, those with symptomatic but nonruptured AAA, and those with ruptured AAA. The presence of SIRS and organ failure was recorded on a daily basis for each patient until discharge or death. RESULTS: Most patients had SIRS develop during the postoperative period: 89% of the elective group, 92% of the emergency nonruptured (urgent) group, and 100% of the ruptured group. Multiorgan failure occurred in 3.8% of the elective group, 38% of the urgent group, and 64% of the ruptured AAA group. After ruptured AAA repair, the concurrent absence of both SIRS and any organ failure for 48 hours had a sensitivity of 93% and a specificity of 91% as a predictive indicator of subsequent survival to hospital discharge. Patients in whom multiorgan failure developed after ruptured AAA repair had a significantly higher mortality rate (69%) than those who did not (0%; P =.001; 95% CI for the difference, 30.2% to 85.8%). CONCLUSION: The differences in the incidence rate of multiorgan failure between the patient groups compared with the high incidence rate of SIRS in all patient groups supports the two-hit hypothesis of multiorgan failure. The presence of multiorgan failure after ruptured AAA repair is associated with poor outcome. The absence of SIRS and organ failure in these patients is a good predictive indicator of survival.     

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.     

TNF Alpha−308 Genotype and Renin–Angiotensin System in Hemodialysis Patients: An Effect on Inflammatory Cytokine Levels?

BACKGROUND: Renin-angiotensin system (RAS) was suggested to modulate inflammatory cytokine production. Angiotensin II was consistently shown to increase production of tumor necrosis factor alpha (TNF-alpha). However, inflammatory cytokines and RAS were modulated by genetic polymorphisms such as TNF-alpha-308 G > A and angiotensin-converting enzyme (ACE) I/D gene polymorphisms. The aim of this study was to investigate the effects of ACE and TNF-alpha genotypes on inflammatory cytokines in hemodialysis (HD) patients. METHODS: ACE I/D and TNF-alpha-308 G > A genotypes, pre- and postdialysis plasma renin activity (PRA), serum ACE, interleukin-1 beta (IL-1beta), and TNF-alpha levels were determined in 22 HD patients. RESULTS: Predialysis serum ACE activity is correlated with TNF-alpha (r = 0.63; P = 0.01), and PRA was correlated with IL-1beta levels (r = 0.49; P = 0.02). Pre/postdialysis IL-1beta and TNF-alpha were similar in DD and II/ID ACE genotypes. Predialysis TNF-alpha and IL-1beta (32.4 +/- 5; 35.1 +/- 4.2 vs. 28.1 +/- 3.7; 26.5 +/- 6.2 pg/mL; P < 0.05) and postdialysis TNF-alpha levels (30.4 +/- 1.4 vs. 28.4 +/- 0.82 pg/mL; P < 0.05) were significantly higher in TNF1/2 than TNF1/1 patients. CONCLUSION: ACE and TNF-alpha-308 G > A (1/2) gene polymorphisms may contribute to modulation of proinflammatory cytokine production and hence chronic inflammation in HD patients.     

A 12-year prospective study of postinjury multiple organ failure: has anything changed?

HYPOTHESIS: The incidence and severity of postinjury multiple organ failure (MOF) has decreased over the last decade. DESIGN: A prospective 12-year inception cohort study ending December 31, 2003. SETTING: Regional academic level I trauma center. PATIENTS: One thousand three hundred forty-four trauma patients at risk for postinjury MOF. Inclusion criteria were aged older than 15 years, admission to the trauma intensive care unit, an Injury Severity Score higher than 15, and survival for more than 48 hours after injury. Isolated head injuries were excluded from this study. Previously identified risk factors for postinjury MOF were age, Injury Severity Score, and receiving a blood transfusion within 12 hours of injury. MAIN OUTCOME MEASURES: Multiple organ failure was defined by a Denver MOF score of 4 or more for longer than 48 hours after injury. Multiple organ failure severity was defined by the maximum daily MOF score and the number of MOF free days within the first 28 postinjury days. RESULTS: Multiple organ failure was diagnosed in 339 (25%) of 1244 patients. The mean age and Injury Severity Scores increased and the use of blood transfusion during resuscitation decreased over the 12-year study period. After adjusting for age, injury severity, and amount of blood transfused during resuscitation, there was a decreased incidence of MOF over the study period. Of the patients who developed MOF, there was a decrease in disease severity and duration as measured by the maximum daily MOF score and the MOF free days. Although the overall mortality rate remained constant, the MOF-specific mortality decreased. CONCLUSIONS: The incidence, severity, and attendant mortality of postinjury MOF decreased over the last 12 years despite an increased MOF risk. Improvements in MOF outcomes can be attributed to improvements in trauma and critical care and are associated with decreased use of blood transfusion during resuscitation.     

Relative production of tumour necrosis factor alpha and interleukin 10 in adult respiratory distress syndrome

BACKGROUND: The adult respiratory distress syndrome (ARDS) may be regarded as an example of an uncontrolled or excessive inflammatory response in which tumour necrosis factor alpha (TNF-alpha) has been proposed to play a central role. Interleukin 10 (IL-10) has been identified as an important regulator of this response. The potential role for IL-10 in this context was investigated by measuring the relative production of IL-10 and TNF-alpha protein in the plasma, bronchoalveolar lavage (BAL) fluid, and alveolar macrophage culture supernatants of patients with, or at risk of developing, ARDS. METHODS: Twenty six patients were studied from three groups at risk of or with ARDS: sepsis (n = 12), multiple trauma (n = 8), and perforated bowel (n = 6). Ten patients had ARDS. Bronchoalveolar lavage and venepuncture were performed within 24 hours of arrival on the intensive therapy unit or of diagnosis of ARDS. IL-10 and TNF-alpha protein were detected in the plasma, BAL fluid, and alveolar macrophage supernatants by sandwich enzyme linked immunoabsorbent assays. RESULTS: The median IL-10 concentrations in the plasma and BAL fluid of patients with ARDS were significantly lower than the concentrations detectable in the plasma (median difference-17.5, 95% CI -52.4 to 1.31, p < 0.05) and BAL fluid of at risk patients (median difference -32.1, 95% CI -47.5 to 2.3, p < 0.05). There was a tendency towards enhanced concentrations of TNF- alpha detectable in the alveolar macrophage supernatants and the BAL fluid of patients with ARDS compared with at risk patients, although this did not reach statistical significance. No difference was observed in the plasma concentrations of TNF-alpha between the two groups. The ratios of TNF-alpha to IL-10 protein in the BAL fluid of patients with ARDS and at risk patients were 3.52 and 0.85, respectively (median difference 1.44, 95% CI 0.07 to 5.01, p < 0.01). There was no difference in alveolar macrophage production of IL-10 between the two groups. CONCLUSIONS: This study highlights the potential importance of the pro-inflammatory versus the anti-inflammatory imbalance in ARDS which may be reflected by the ratio of IL-10 and TNF-alpha in the lung.


     

Relationship between sleep complaints and proinflammatory cytokines in haemodialysis patients

BACKGROUND: Sleep complaints are common in end-stage renal disease. We aimed to investigate the relationship between sleep-related complaints and inflammatory cytokines in haemodialysis (HD) patients, and also the effects of HD on sleep patterns and cytokine levels. METHODS: Predialysis serum interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) levels in nine patients with sleep complaints were compared with those of nine patients without sleep complaints and nine healthy controls. Patients with sleep complaints underwent polysomnography the night after HD and the following night. RESULTS: Patients with sleep complaints had significantly higher predialysis IL-1beta levels compared with those without and healthy controls (P=0.004 and P=0.000, respectively). They also had higher predialysis IL-6 and TNF-alpha levels than those without sleep complaints; however, the difference was not significant. Patients without sleep complaints had higher mean IL-6 and TNF-alpha and similar mean IL-1beta levels compared with healthy controls (P=0.001, P=0.024, P=0.26, respectively). Obstructive sleep apnoea syndrome (OSAS) was found in six out of nine (66%) patients with sleep complaints. Sleep architecture and cytokine levels did not differ between the two nights. The mean serum IL-1beta, IL-6 and TNF-alpha levels did not differ in the pre- and post-polysomnographic samples. There was no correlation between IL-1beta, IL-6 or TNF-alpha levels and the apnoea-hypopnoea index. CONCLUSIONS: Proinflammatory cytokines, IL-1beta in particular, might be associated with sleep complaints in HD patients. OSAS is not uncommon in HD patients with sleep-related complaints and sleep architecture does not appear to be effected by the HD procedure itself.