Analgesic efficacy of tramadol if coadministered with ondansetron.
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Analgesics, Opioid↗
Biomedical subjects
F Stüber
Publications and source records attributed to F Stüber.
Cardiorespiratory effects of automatic tube compensation during airway pressure release ventilation in patients with acute lung injury.
BACKGROUND: Spontaneous breaths during airway pressure release ventilation (APRV) have to overcome the resistance of the artificial airway. Automatic tube compensation provides ventilatory assistance by increasing airway pressure during inspiration and lowering airway pressure during expiration, thereby compensating for resistance of the artificial airway. The authors studied if APRV with automatic tube compensation reduces the inspiratory effort without compromising cardiovascular function, end-expiratory lung volume, and gas exchange in patients with acute lung injury. METHODS: Fourteen patients with acute lung injury were breathing spontaneously during APRV with or without automatic tube compensation in random order. Airway pressure, esophageal and abdominal pressure, and gas flow were continuously measured, and tracheal pressure was estimated. Transdiaphragmatic pressure time product was calculated. End-expiratory lung volume was determined by nitrogen washout. The validity of the tracheal pressure calculation was investigated in seven healthy ventilated pigs. RESULTS: Automatic tube compensation during APRV increased airway pressure amplitude from 7.7+/-1.9 to 11.3+/-3.1 cm H2O (mean +/- SD; P < 0.05) while decreasing trans-diaphragmatic pressure time product from 45+/-27 to 27+/-15 cm H2O x s(-1) x min(-1) (P < 0.05), whereas tracheal pressure amplitude remained essentially unchanged (10.3+/-3.5 vs. 10.1+/-3.5 cm H2O). Minute ventilation increased from 10.4+/-1.6 to 11.4+/-1.5 l/min (P < 0.001), decreasing arterial carbon dioxide tension from 52+/-9 to 47+/-6 mmHg (P < 0.05) without affecting arterial blood oxygenation or cardiovascular function. End-expiratory lung volume increased from 2,806+/-991 to 3,009+/-994 ml (P < 0.05). Analysis of tracheal pressure-time curves indicated nonideal regulation of the dynamic pressure support during automatic tube compensation as provided by a standard ventilator. CONCLUSION: In the studied patients with acute lung injury, automatic tube compensation markedly unloaded the inspiratory muscles and increased alveolar ventilation without compromising cardiorespiratory function and end-expiratory lung volume.
Adult↗
The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone.
OBJECTIVE: To investigate the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with severe sepsis by stimulating with corticotropin-releasing hormone (CRH). DESIGN: Prospective observational study in consecutive intensive care unit patients with severe sepsis. SETTING: Surgical intensive care unit and outpatient department of endocrinology in a university hospital. PATIENTS: The study included 20 patients with the diagnosis of severe sepsis; six critically ill, nonseptic patients after major surgery; ten patients with primary adrenal insufficiency; ten patients with anterior pituitary insufficiency; and ten individuals without clinical signs of HPA axis disturbance. INTERVENTIONS: CRH tests were performed with an intravenous bolus injection of 100 microg of human CRH. MEASUREMENTS AND MAIN RESULTS: We studied the functional integrity of the HPA axis in patients with severe sepsis by performing the CRH test. In addition, during the period of severe sepsis, we repeatedly measured basal plasma concentrations of adrenocorticotropin hormone (ACTH) and cortisol. The mean basal plasma cortisol concentration was decreased significantly in nonsurvivors with severe sepsis (288.8 +/- 29.1 [sem] nmol/L) compared with survivors (468.1+/- 18.6 nmol/L; p <.01). By calculating the ACTH/cortisol indices, we found no evidence for adrenal insufficiency in patients with severe sepsis. The mean ACTH/cortisol indices of nonsurvivors with severe sepsis (0.02 +/- 0.008) and survivors (0.01 +/- 0.002) were significantly lower compared with the index of patients with primary adrenal insufficiency (6.8 +/- 1.0; p <.001). In contrast, in nonsurvivors with severe sepsis, the plasma cortisol response to CRH stimulation was impaired compared with survivors: The mean basal cortisol concentration within the CRH test was 269.4 +/- 39.8 nmol/L in nonsurvivors compared with 470.8 +/- 48.4 nmol/L in survivors and increased to a peak value of 421.6 +/- 72.6 nmol/L in nonsurvivors and 680.7 +/- 43.8 nmol/L in survivors (p <.02). However, the change in plasma cortisol, expressed as mean +/- sem and calculated by subtracting the basal cortisol from the peak cortisol after CRH stimulation, was not significantly different in survivors with severe sepsis (243.5 +/- 36.1, range 111.0-524.0 nmol/L, n = 15) compared with nonsurvivors (161.0 +/- 38.9, range 42.0-245.0 nmol/L, n = 5; p >.05). CONCLUSIONS: We found lower basal plasma cortisol concentrations in nonsurvivors compared with survivors of severe sepsis. In addition, the plasma cortisol response to a single CRH stimulation was impaired in nonsurvivors compared with survivors. Reduced responses to CRH stimulation may reflect a state of endocrinologic organ dysfunction in severe sepsis.
Adolescent↗
Gene variants of the bactericidal/permeability increasing protein and lipopolysaccharide binding protein in sepsis patients: gender-specific genetic predisposition to sepsis.
OBJECTIVES: To determine whether the genotype frequencies of the five bi-allelic polymorphisms in the bactericidal/permeability increasing protein (BPI) (Lys216 --> Glu; PstI polymorphism in intron 5; silent mutation G545 --> C) and the lipopolysaccharide binding protein (LBP) (Cys98 --> Gly; Pro436 --> Leu) are associated with the incidence and lethality of sepsis. DESIGN: Case control study of patients with sepsis. SETTING: Intensive care units within university hospitals. PATIENTS: A total of 204 patients diagnosed with sepsis and 250 healthy blood donors. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Short DNA fragments containing the polymorphic sites of the LBP and BPI locus were amplified by the polymerase chain reaction or mismatched polymerase chain reaction. The individual polymorphisms were determined with the appropriate restriction enzyme digestions and subsequent agarose gel electrophoresis. The presence of LBP genotypes with the less frequent Gly98 allele was found to be associated with sepsis (p < .02) in male patients, but not in females. Patients which were homozygote for either of the rare Gly98 (n = 6) and/or Leu436 (n = 5) LBP alleles, furthermore, exclusively were nonsurvivors of sepsis. The genotype frequencies in the BPI gene did not differ between patients and control individuals. CONCLUSIONS: Our findings suggest that common polymorphisms in the gene for LBP in combination with male gender are associated with an increased risk for the development of sepsis and, furthermore, may be linked to an unfavorable outcome. These data support the important immunomodulatory role of LBP in Gram-negative sepsis and suggest that genetic testing may be helpful for the identification of patients with an unfavorable response to Gram-negative infection.
Acute-Phase Proteins↗
Effects of genomic polymorphisms on the course of sepsis: is there a concept for gene therapy?
Sepsis and its sequelae are still a major cause of morbidity and mortality on today's intensive care units. The evidence that endogenous mediators actually mediate the individual's response to infection has led to various approaches to assess the individual's contribution to the course of the disease. The role of an individual's genetic background and predisposition for the extent of inflammatory responses is determined by variabilities of genes encoding endogenous mediators that constitute the pathways of inflammation. Primary responses in inflammation are mediated by proinflammatory cytokines such as tumor necrosis factor and interleukin 1. Conversely, anti-inflammatory mediators are released and may induce a state of immunosuppression in sepsis. Pro- and anti-inflammatory responses contribute to the outcome of patients with systemic inflammation and sepsis. Therefore, all genes encoding proteins involved in the transduction of inflammatory processes are candidate genes to determine the human genetic background that is responsible for interindividual differences in systemic inflammatory responses to injury. The genetically determined capacity of cytokine production and release, heat shock protein expression, nitric oxide synthase activity, gene polymorphisms of coagulation factors or factors of the innate immune system-like defensins, and other genes involved in inflammation may contribute to a wide range of clinical manifestations of an inflammatory disease. Genomic information may be used to identify groups of patients with a high risk of developing severe sepsis and multiple organ dysfunction, and determining which patients will benefit from antimediator strategies because of their genetic determination to high cytokine release in the inflammatory response will be the subject of future trials.
Genetic Therapy↗
Prothrombin gene G20210A mutation and elevated anticardiolipin antibodies in a patient with combined portal-mesenteric vein thrombosis.
A 29-year-old man was admitted to the ICU after emergency laparotomy for portal-mesenteric vein thrombosis. Under continuous intravenous heparin therapy the portal-mesenteric shunt occluded on the first postoperative day. After thrombectomy the heparin dose was increased, and the patient remained free of symptoms (partial thromboplastin time 53 s). Two days later abdominal distension developed concomitantly with ventilatory distress due to a large retroperitoneal hematoma. The patient was mechanically ventilated and underwent the third consecutive laparotomy for the hematoma removal on the fifth day. During the surgical procedure the abdomen was packed with towels to stop multiple bleeding sites. The heparin dose was reduced, aiming for a partial thromboplastin time of 30-35 s. Initial coagulation tests revealed increased levels of anticardiolipin immunoglobulin G. After removal of the surgical towels the patient was successfully weaned from mechanical ventilation and discharged from the ICU. Two weeks later genomic testing revealed that he also had a G20210A mutation of the prothrombin gene. Both, increased levels of anticardiolipin immunoglobulin G and the G20210A mutation of the prothrombin gene predispose to thrombosis. Increased levels of anticardiolipin immunoglobulin G may also cause bleeding. Long-term anticoagulation therapy was started with a vitamin K antagonist, and 2 months later a follow-up showed that the patient had no further symptoms of portal-mesenteric vein thrombosis or bleeding. This case illustrates that the convergence of multiple risk factors, including genetic defects, must be considered in patients suffering from thrombosis in unusual sites
Adult↗
The Pstl polymorphism of the endotoxin-inducible heat-shock protein 70-2 gene does not affect messenger RNA level in human whole-blood cultures.
OBJECTIVE: To determine whether the human leukocyte antigen linked biallelic heat-shock protein 70-2 (HSP70-2) gene polymorphism is associated with variable HSP70-2 messenger RNA expression. DESIGN: Prospective observational study in consecutive healthy blood donors. SETTING: Department of Anesthesiology, laboratory for molecular biology in a university hospital. PARTICIPANTS: 24 healthy blood donors. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We studied the functional implication of the HSP70-2 (G/A) PstI gene polymorphism in 24 healthy, white blood donors with various HSP70-2 (G/A) genotypes by analyzing the endotoxin-inducible HSP70-2 mRNA expression by means of the reverse transcription-polymerase chain reaction. HSP70 expression was expressed semiquantitatively by calculating the ratio of HSP70-2 mRNA and the constitutively expressed glutaraldehyde 3-phosphate dehydrogenase mRNA. No significant differences in HSP70-2 mRNA expression after lipopolysaccharide (from Salmonella minnesota Re 595) stimulation were detected in individuals homozygous for the allele A (0.68, range 0.38-1, n = 10), in individuals homozygous for the allele G (0.79, range 0.42-1.1, n = 8), and in heterozygotes (HSP70-2 G/A; 0.52, range 0.4-0.67, n = 6; p > 0.05). CONCLUSIONS: The PstI polymorphism of the endotoxin-inducible HSP70-2 gene is not associated with variable HSP70-2 mRNA expression ex vivo. This finding is in accordance with the observation that HSP70-2 genotypes do not affect clinical outcome in human systemic inflammation.
Adult↗
The common functional C(-159)T polymorphism within the promoter region of the lipopolysaccharide receptor CD14 is not associated with sepsis development or mortality.
Sepsis is characterised by a systemic inflammatory response to bacterial products during infection, which interestingly both in humans and animal models is gender associated with a higher susceptibility of males than females. The CD14 receptor is involved in activation of cells by lipopolysaccharides released from Gram-negative bacteria and, as recently shown, also by products of Gram-positive bacteria (e.g., peptidoglycans and lipoteichoic acid). The functional relevance of a C(-159)T CD14 polymorphism recently has been shown based on correlation of the T allele to higher plasma levels of soluble CD14, and higher membrane expression on monocytes. We, therefore, now analysed this CD14 polymorphism in 204 patients with severe sepsis and 247 controls. No significant difference of allele frequencies was observed between sepsis patients and controls neither for males nor females. Mortality also was not associated with the polymorphism studied. This may suggest that other mechanisms for lipopolysaccharide recognition, such as the recently described Toll-like receptors are important for inflammatory cell activation in sepsis.
Adolescent↗
Effects of mechanical ventilation on release of cytokines into systemic circulation in patients with normal pulmonary function.
BACKGROUND: Mechanical ventilation with high tidal volumes (V(T)) in contrast to mechanical ventilation with low V(T) has been shown to increase plasma levels of proinflammatory and antiinflammatory mediators in patients with acute lung injury. The authors hypothesized that, in patients without previous lung injury, a conventional potentially injurious ventilatory strategy with high V(T) and zero end-expiratory pressure (ZEEP) will not cause a cytokine release into systemic circulation. METHODS: A total of 39 patients with American Society of Anesthesiologists physical status I-II and without signs of systemic infection scheduled for elective surgery with general anesthesia were randomized to receive mechanical ventilation with either (1) V(T) = 15 ml/kg ideal body weight on ZEEP, (2) V(T) = 6 ml/kg ideal body weight on ZEEP, or (3) V(T) = 6 ml/kg ideal body weight on positive end-expiratory pressure of 10 cm H2O. Plasma levels of proinflammatory and antiinflammatory mediators tumor necrosis factor, interleukin (IL)-6, IL-10, and IL-1 receptor antagonist were determined before and 1 h after the initiation of mechanical ventilation. RESULTS: Plasma levels of all cytokines remained low in all settings. IL-6, tumor necrosis factor, and IL-1 receptor antagonist did not change significantly after 1 h of mechanical ventilation. IL-10 was below the detection limit (10 pg/ml) in 35 of 39 patients. There were no differences between groups. CONCLUSIONS: Initiation of mechanical ventilation for 1 h in patients without previous lung injury caused no consistent changes in plasma levels of studied mediators. Mechanical ventilation with high V(T) on ZEEP did not result in higher cytokine levels compared with lung-protective ventilatory strategies. Previous lunge damage seems to be mandatory to cause an increase in plasma cytokines after 1 h of high V(T) mechanical ventilation.
Adult↗
Gender differences in sepsis: genetically determined?
In the pathogenesis of sepsis, tumor necrosis factor (TNF) release and host reaction may be genetically determined as demonstrated for TNFbeta Ncol polymorphism. Gender differences are considered as another important prognostic variable in patients with sepsis with better survival for women. The effect of sexual dimorphism on the genetic background of sepsis, however, is unknown. In a prospective study at two university hospital surgical intensive care units, (Bonn and Kiel), the role of the genomic marker TNFbeta Ncol polymorphism was evaluated with respect to gender. Two-hundred and one patients (68 women and 133 men) with severe sepsis were evaluated. A fragment of genomic DNA including the polymorphic site of the restriction enzyme Ncol was amplified by means of polymerase chain reaction. The genotype of each patient was determined after Ncol digestion of the amplified product. The genotype distribution of patients homozygous for TNFB1, heterozygous or homozygous for TNFB2 was comparable between men and women with severe sepsis. In women, no difference in survival rate was found between the different genotypes, while mortality rate was significantly increased in men homozygous for TNFB2 compared with the other genotypes (P < 0.05; P < 0.01, chi2 test). Overall, survival rate was higher for women (P < 0.05) but was not significantly different between men and women with respect to genotypes (P = 0.07 for TNFB2/B2). Poor prognosis of surgical sepsis can be determined by male gender and the genomic marker TNFbeta Ncol polymorphism which should be considered for further therapeutic interventions in sepsis.
Aged↗
Endotoxin inhibits heat shock protein 70 (HSP70) expression in peripheral blood mononuclear cells of patients with severe sepsis.
OBJECTIVE: To investigate the ex vivo endotoxin-inducible heat shock protein 70 (HSP70) expression in the peripheral blood mononuclear cells (PBMC) of patients with severe sepsis in order to assess the capacity of this potentially protective response during systemic inflammation. DESIGN: Prospective observational study in consecutive patients with severe sepsis and healthy blood donors. SETTING: Surgical intensive care unit in a university hospital. PATIENTS AND PARTICIPANTS: Eleven patients with the diagnosis of severe sepsis, one patient who had recovered from severe sepsis and 13 healthy blood donors. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We studied the inducibility of HSP70 expression in the PBMC of patients with severe sepsis and healthy blood donors ex vivo. Human whole blood was incubated with variable lipopolysaccharide (LPS from Salmonella minnesota Re 595) concentrations (0; 0.1; 10; 100 ng/ml) for different periods of time (0.5; 2; 4; 10 h). The PBMC were separated by Ficoll density gradient and then disrupted by hypotonic lysis. HSP70 was measured by means of enzyme-linked immunosorbent assay (ELISA). We found a LPS dose- and time-dependent inhibition of ex vivo HSP70 expression in the PBMC of both patients with severe sepsis and healthy individuals. However, the levels of HSP70 expression in patients were significantly lower compared to those of healthy individuals at all LPS concentrations and incubation times. On average, HSP70 expression in the PBMC of healthy controls was 2.8 (range 1.2-3.9) times higher than in patients. HSP70 expression was inducible by thermal heat shock in the PBMC of both patients and healthy individuals. CONCLUSIONS: Endotoxin inhibits HSP70 expression in PBMC ex vivo. In vivo, the suppression of HSP70 expression induced by endotoxin and high levels of proinflammatory cytokines may contribute to the cellular dysfunction of immunocompetent cells concerning antigen presentation, phagocytosis and antibody production associated with decreased resistance to infectious insults during severe sepsis.
Adult↗
Procalcitonin as a marker of severity in septic shock.
BACKGROUND/AIMS: Procalcitonin (PCT) was shown to be related to the severity of bacterial infection and is recommended as a new parameter of inflammation and infection. To evaluate the prognostic value in septic shock, PCT levels were repeatedly determined and compared with tumour necrosis factor-alpha (TNF-alpha)- and interleukin (IL)-6 bioactivity as well as with C-reactive protein (CRP) serum levels. PATIENTS: Twenty-four surgical patients with septic shock were included. Eight patients died within the study period of 14 days. METHODS: Serum levels of TNF-(WEHI 164) and IL-6 (B13-29 subclone 9) bioactivity, CRP and PCT were determined on days 1, 3, 5, 7, 10 and 14 following diagnosis of septic shock. RESULTS: Survivors and non-survivors were comparable in terms of age and severity of sepsis characterized by the APACHE II score and multiple-organ-failure score. Predominant causes of sepsis were peritonitis and necrotiszing pancreatitis. TNF levels increased in non-survivors with no significant difference to survivors. IL-6 bioactivity was increased on day 1 (P = 0.06) and remained elevated in non-survivors, in whom it was significant on day 7 (P<0.05). CRP was constantly elevated with no difference between the groups. In nonsurvivors PCT remained increased, while the course of survivors was characterized by decreased values which were significantly lower (P<0.05) at every time point compared with those patients who died. A significant correlation could be found on day 1 (P<0.05) and at the end of the observation period (P<0.01) when comparing PCT levels with the multiple-organ-failure score. CONCLUSIONS: PCT seems to be a more reliable prognostic parameter in septic shock than IL-6, while TNF and CRP did not show any difference between survivors and non-survivors. These data indicate that PCT may represent a valuable parameter not only in the diagnosis of sepsis but also in the clinical course of the disease.
APACHE↗
Relation of the bi-allelic NcoI restriction fragment length polymorphism within the tumour necrosis factor B gene to the development of mediastinitis.
During recent years the dual role of endogenous inflammatory mediators such as tumour necrosis factor (TNF) has become evident. While TNF has been recognised to possess a great detrimental potential, for example in the case of sepsis, it is on the other hand an integral component of an adequate immune response to bacterial invasion. These different properties of TNF and others seem to be dependent mainly on the quantitative extent of their formation. Some recent findings indicate that this extent may in part be determined genetically. The classification of patients according to polymorphic cytokine genes might, therefore, predict some of their reactions to septic challenges.
Alleles↗
Relation of a TNF gene polymorphism to severe sepsis in trauma patients.
OBJECTIVE: To investigate the relation of the biallelic Nco1 restriction fragment length polymorphism in the first intron of the tumor necrosis factor (TNF) beta gene with the development of severe sepsis in multiply injured patients. SUMMARY BACKGROUND DATA: The biallelic Nco1 polymorphism of the TNFbeta gene has been described to be associated with autoimmune diseases and with the mortality rate in severe sepsis. Therefore, the Nco1 polymorphism may be associated with the clinical finding that despite comparable risk factors, posttraumatic sepsis develops in some patients but not others. METHODS: The study group consisted of 110 patients with severe blunt trauma (Injury Severity Score > or = 17). Typing of each patient for the biallelic Nco1 polymorphism was performed by analyzing restriction fragments of an Nco1-digested DNA fragment obtained using polymerase chain reaction. Genotypes were then related to the occurrence of severe posttraumatic sepsis and TNFalpha serum concentrations. RESULTS: Fifty-seven patients showed an uncomplicated posttraumatic recovery, and severe sepsis developed in 53 patients. The overall allele frequency (TNFB1 0.29, TNFB2 0.71) and genotype distribution (TNFB1 homozygous 7.3%, TNFB1/TNFB2 42.7%, TNFB2 homozygous 50%) were in agreement with the distribution in healthy volunteers. Genotype distribution in patients with an uncomplicated clinical course was significantly different from that in patients with severe posttraumatic sepsis. Development of severe posttraumatic sepsis was significantly increased in patients homozygous for the allele TNFB2. In patients with severe posttraumatic sepsis, TNFalpha serum concentrations were significantly higher in TNFB2-homozygous individuals compared with heterozygous and TNFB1 -homozygous individuals. The age- and injury-matched odds ratio for the homozygous TNFB2 genotype compared with the heterozygous genotype was 5.22 (p = 0.007, 95% confidence interval 1.6 to 17.9). CONCLUSIONS: In multiply injured patients, the Nco1 polymorphism within the TNFbeta gene is associated with the development of severe posttraumatic sepsis and with increased TNFalpha serum levels when severe sepsis has occurred. This suggests a genetic determination of the individual inflammatory response after infection or tissue damage, which significantly influences susceptibility to severe nosocomial infections.
Adult↗
Impaired inducibility of heat shock protein 70 in peripheral blood lymphocytes of patients with severe sepsis.
OBJECTIVE: To determine the extent of the potentially protective heat shock protein 70 response in peripheral blood lymphocytes of patients with severe sepsis after ex vivo lipopolysaccharide stimulation. DESIGN: Entry study of consecutive patients with severe sepsis, those who were critically ill or nonseptic after major surgery, and healthy blood donors. SETTING: Surgical intensive care unit in a university hospital. PATIENTS: Ten patients with diagnoses of severe sepsis; ten critically ill, nonseptic patients after major surgery; and ten healthy blood donors. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We investigated the ex vivo endotoxin-inducible expression of heat shock protein 70 in peripheral blood lymphocytes of patients with severe sepsis by means of flow cytometry. Only negligible amounts of inducible intracellular heat shock protein 70 accumulation (<4.2% of lymphocytes) could be detected in peripheral blood lymphocytes without lipopolysaccharide stimulation. The proportion of cells accumulating heat shock protein 70 after treatment with lipopolysaccharide was distinctly lower in patients with severe sepsis (p < .05) than in critically ill, nonseptic patients after major surgery and healthy blood donors (38.3+/-3.3%, 82.2+/-4.5%, and 70.9+/-3.9%, respectively; mean +/- SEM; n = 10). Patients with clinical signs of recovery from severe sepsis showed an increase in heat shock protein 70 expression. CONCLUSIONS: Inducibility of ex vivo heat shock protein 70 was impaired in peripheral blood lymphocytes of patients with severe sepsis. The impaired expression of the potentially protective heat shock protein 70 may contribute in vivo to immune dysfunction, because intact functioning of T and B lymphocyte responses is of central importance in resisting infection in severe sepsis. Monitoring of inducible heat shock protein 70 in peripheral blood lymphocytes may contribute to the evaluation of the immune consequences of severe sepsis.
APACHE↗
Analysis of two human leukocyte antigen-linked polymorphic heat shock protein 70 genes in patients with severe sepsis.
OBJECTIVE: To determine whether the genotype and allelic frequencies of two human leukocyte antigen-linked bi-allelic 70-kilodalton heat shock protein (HSP70) gene polymorphisms are associated with susceptibility to and outcome of severe sepsis. Furthermore, we investigated a possible linkage between HSP70 gene polymorphisms and the previously reported and mortality-related tumor necrosis factor-beta (TNF-beta) NcoI gene polymorphism. DESIGN: Consecutive entry study of patients with severe sepsis. SETTING: Surgical intensive care unit in a university hospital. PATIENTS: Eighty-seven patients with a diagnosis of severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We studied two bi-allelic polymorphisms within the coding region of the constitutively expressed HSP70-HOM C/T, and the stress-inducible HSP70-2 G/A in patients with severe sepsis. The HSP70-HOM Ncol, HSP70-2 Pstl, and TNF-beta NcoI polymorphisms were identified by means of the polymerase chain reaction followed by restriction analysis of the polymerase chain reaction product. No significant differences in genotype and allelic frequencies were observed for both HSP70 gene polymorphisms between the 87 patients and the 110 healthy Caucasians serving as the control group. In addition, no differences in genotype and allelic frequencies between surviving and nonsurviving patients were detected. The allelic frequencies in the group of nonsurvivors were 0.8 for the HSP70-HOM C allele and 0.2 for the HSP70-HOM T allele vs. 0.87 and 0.13 for the survivors (p > .05). The frequency for the HSP70-2 G allele was 0.36 and 0.64 for the HSP70-2 A allele in the group of nonsurvivors vs. 0.41 and 0.59 for the survivors (p > .05). Analysis of a possible linkage between HSP70 and TNF-beta genotypes resulted in a significant association (odds ratio, 4.15; p < .01) of the HSP70-2 A/A homozygous genotype and the TNFB2/B2 homozygous genotype, which is reported to be a genomic marker for a poor prognosis in severe sepsis. CONCLUSIONS: Our data show that the bi-allelic NcoI and PstI polymorphisms within the HSP70-HOM and HSP70-2 locus, respectively, are associated with neither susceptibility to nor outcome of severe sepsis. Moreover, we found a linkage between HSP70-2 A homozygotes and the previously reported and mortality-related homozygous genotype, TNFB2/B2, in patients suffering from severe sepsis.
Case-Control Studies↗
Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis.
OBJECTIVES: To determine whether the allele frequencies and genotype distribution of an interleukin (IL)-1beta TaqI polymorphism and an interleukin-1 receptor antagonist polymorphism are associated with susceptibility to and outcome of severe sepsis. In addition, we analyze a possible linkage disequilibrium between a previously described NcoI polymorphism within the tumor necrosis factor (TNF) locus and the two IL-1 gene family polymorphisms. DESIGN: Prospective, consecutive entry study of patients with diagnosis of severe sepsis. SETTING: Intensive care unit (ICU) of a university hospital. PATIENTS: Ninety-three patients with diagnosis of severe sepsis admitted to the ICU between June 1993 and June 1996. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The polymorphic region within intron 2 of the IL-1ra gene containing variable numbers of a tandem repeat of 86 base pairs was amplified by means of the polymerase chain reaction. Alleles A1-5 are identified according to the size of the amplified DNA product. The region that contains the biallelic TaqI site within exon 5 of the IL-1beta gene was analyzed by polymerase chain reaction amplification and subsequent digestion using the TaqI restriction enzyme. A NcoI TNF-beta polymorphism was determined. The allele frequency of the allele IL-1raA2 was increased in 93 patients with severe sepsis compared with normal individuals (p < .01). No association with patients' outcome was observed. Allele frequencies or genotype distribution of the IL-1beta TaqI polymorphism did not differ between patients and controls. In addition, the allele TNFB2 of the NcoI TNF-beta polymorphism was associated with nonsurvival. Occurrence of the TNFB1 and TNFB2 alleles and genotypes was unrelated to alleles and genotypes of the two IL-1 gene family polymorphisms. CONCLUSION: In contrast to the TNF-beta NcoI polymorphism, which has been associated with patients' nonsurvival, the allele IL-1raA2 of the polymorphism within the intron 2 of IL-1ra may contribute to susceptibility to sepsis.
Case-Control Studies↗
Effect of pentoxifylline in severe sepsis: results of a randomized, double-blind, placebo-controlled study.
OBJECTIVE: To evaluate the effect of pentoxifylline on organ dysfunction, survival, and mediator response in patients with severe sepsis. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Surgical intensive care units at 2 university hospitals. PATIENTS: Fifty-one surgical patients with severe sepsis were randomized to receive pentoxifylline continuously (27 patients) or saline infusion as placebo (24 patients). INTERVENTIONS: PATIENTS received pentoxifylline (1 mg/kg of body weight per hour; maximum, 1800 mg/d) during 28 days or until they were discharged from the intensive care unit or died. MEASUREMENTS AND MAIN RESULTS: Vital signs and organ function were determined at diagnosis; daily from day 1 to 7; on days 10, 14, 17, 21, and 24; and 28 days after diagnosis of sepsis. There were no differences in characteristics of patients at diagnosis in the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (mean+/-SEM, 17+/-4 points for the pentoxifylline group and 18+/-5 points for the placebo group), the multiple organ dysfunction score (mean+/-SEM, 11.0+/-0.8 vs 11.8+/-1.0 points), tumor necrosis factor alpha and interleukin 6 bioactivity, serum endotoxin levels, or organ dysfunction. At study entrance, 23 of 27 patients in the pentoxifylline group and 21 of 24 patients in the placebo group experienced septic shock. No adverse effects of pentoxifylline treatment were observed. The 28-day mortality rate was 30% (8/27) in pentoxifylline-treated patients and 33% (8/24) in the placebo group. Hospital mortality was 41% (11/27) in the pentoxifylline group and 54% (13/24) in the placebo group. The multiple organ dysfunction score decreased in patients receiving pentoxifylline 4 days after diagnosis of sepsis compared with placebo-treated patients; a significant difference was reached on day 14 (P<.05; Student t test, Bonferoni correction). The PaO2/FIO2 (fraction of inspired oxygen) ratio was significantly improved in pentoxifylline-treated patients on days 14 and 17 (P<.05), and the pressure-adjusted heart rate was significantly improved on day 6 (P<.05) compared with the placebo group. Serum endotoxin levels, tumor necrosis factor alpha and interleukin 6 bioactivity were not different between the groups during the study. CONCLUSIONS: Continuous intravenous administration of pentoxifylline beneficially influenced cardiopulmonary dysfunction in patients with sepsis without adverse effects. Larger trials are needed to evaluate the efficacy in improving organ function in relation to the outcome for patients with severe sepsis.
APACHE↗