Michael Heesen

Tumor Necrosis Factor Gene Polymorphisms, Leukocyte Function, and Sepsis Susceptibility in Blunt Trauma Patients

ABSTRACT The tumor necrosis factor alpha (TNF-α) −308 G/A and TNF-β NcO1 polymorphisms have been described to be associated with an increased risk for sepsis in critically ill patients. Functional consequences associated with these polymorphisms remain unclear. We compared the genotype distribution of these TNF polymorphisms with susceptibility to severe sepsis and leukocyte function in blunt trauma patients (n = 70; mean injury severity score, 24 points [range, 4 to 57). Severe sepsis was defined according to the American College of Chest Physicians-Society of Critical Care Medicine consensus conference criteria. Genotyping for the NcO1 polymorphism (alleles TNFB1 and TNFB2) was performed by PCR and digestion of the products with NcO1, and that for the TNF-α −308 G/A polymorphism (alleles TNF1 and TNF2) was performed by real-time PCR. Leukocyte function was assessed by measurement of the production of endotoxin-induced cytokines (TNF-α, interleukin-6 [IL-6], and IL-8) in whole blood. TNF-α, IL-6, and IL-8 were determined by enzyme-linked immunosorbent assay. For the genotypes of the TNF-α −308 G/A polymorphism, differences in the frequency of development of severe sepsis were not detectable. Patients developing severe sepsis after trauma were significantly more likely to posses a homozygous genotype of the TNF-β NcO1 polymorphism. Compared with heterozygotes, the odds ratio for the TNFB2/B2 genotype for the development of severe posttraumatic sepsis was 11 (P = 0.01), and that for the TNFB1/B1 genotype was 13 (P = 0.014). TNF-α −308:TNF-β NcO1 haplotype analysis showed that the TNFB2:TNF2 haplotype is significantly negatively associated with development of severe sepsis. Patients homozygous for the TNFB1 or TNFB2 allele showed a persistently higher cytokine-producing capacity during at least 4 to 8 days after trauma than the heterozygotes. In patients homozygous for the TNF1 allele, a higher TNF-α- and IL-8-producing capacity was found only at day 1 after trauma. Although the TNF-β NcO1 polymorphism appears to be less likely to be causative for development of severe sepsis after trauma, it is thus far the only genetic marker identified which can be used as a relevant risk estimate for severe sepsis in trauma patients immediately after the injury.

Definitions of hypotension after spinal anaesthesia for caesarean section: literature search and application to parturients

Background: Spinal anaesthesia for caesarean section may cause hypotension, jeopardizing the foetus and its mother. We aimed to identify the spectrum of definitions of hypotension used in the scientific literature. In a second part, we applied these definitions to a prospective cohort in order to evaluate the effect of different definitions on the incidence of hypotension.

Vasopressors for the management of hypotension after spinal anesthesia for elective caesarean section. Systematic review and cumulative meta-analysis

Phenylephrine use has been recommended over ephedrine for the management of hypotension after spinal anesthesia for elective caesarean section. The evidence for this is rather limited because in previous trials, pH was significantly lower after ephedrine, but absolute values were still within normal range. We pooled the available data to define maternal and neonatal effects of the two vasopressors.

Lack of association between the -260 C-->T promoter polymorphism of the endotoxin receptor CD14 gene and the CD14 density of unstimulated human monocytes and soluble CD14 plasma levels.

Abstract.Objective: CD14 is a receptor for endotoxin and binds components of Gram-positive and Gram-negative bacteria. CD14-bearing monocytes respond to stimulation with the increased synthesis and release of cytokines. The recently described –260 C→T promoter polymorphism of the CD14 gene has been found to be related to a risk of myocardial infarction. This study evaluated the role of this polymorphism in the expression of monocyte and soluble CD14. Moreover, the effect of the CD14 –260 genotypes for the ex vivo TNF-α response to endotoxin was analyzed in whole blood. Patients and participants: Ninety-five healthy blood donors were studied. Measurements and results: CD14 –260 genotyping was performed by means of a real-time PCR with fluorescence labeled hybridization probes. CD14 expression on human monocytes (mCD14) was assessed by fluorescence-activated cell sorting analysis with anti-CD14 monoclonal antibodies. Plasma levels of soluble CD14 (sCD14) were measured by ELISA. The TNF-α synthesis was determined by chemiluminescence in whole blood after endotoxin stimulation. There were no differences in mCD14 density, sCD14 levels, or the tumor necrosis factor-α concentrations between individuals with the three different CD14 –260 genotypes CC, CT, and TT. Conclusions: The CD14 –260 polymorphism does not affect the CD14 expression of unstimulated circulating monocytes or soluble CD14 plasma levels.

Can the interleukin-6 response to endotoxin be predicted? studies of the influence of a promoter polymorphism of the interleukin-6 gene, gender, the density of the endotoxin receptor CD14, and inflammatory cytokines

OBJECTIVES To evaluate whether the -174 G/C promoter polymorphism of the interleukin-6 gene, gender, the monocyte density of the endotoxin receptor CD14, or the inflammatory cytokines tumor necrosis factor-alpha or interleukin-1beta influence the interleukin-6 response of whole blood to endotoxin. DESIGN Analysis of interleukin-6 release from endotoxin-stimulated human whole blood. SETTING Medical research laboratory. PATIENTS Healthy human blood donors. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The interleukin-6 -174 G/C and the tumor necrosis factor -308 G/A promoter polymorphisms were determined by real-time polymerase chain reaction assay by using specific fluorescence labeled hybridization probes. Monocyte CD14 expression was assessed by flow cytometry. After incubation of whole blood with endotoxin, plasma concentrations of interleukin-6, tumor necrosis factor-alpha, and interleukin-1beta were measured by means of chemiluminescence. The interleukin-6 concentrations were lower (p = .005) in individuals who were CG heterozygotes compared with individuals homozygous for the C or the G. The difference between C and G homozygotes was not significant (p = .67). The interleukin-6 response was enhanced in men compared with women (p = .015). There was no correlation between interleukin-6 concentrations and monocyte CD14 density. Interleukin-6 concentrations correlated with the concentrations of tumor necrosis factor-alpha (r = .59, p = .01) and interleukin-1beta (r = .47, p = .01). There was no linkage between the tumor necrosis factor -308 and the interleukin-6 -174 polymorphisms. CONCLUSIONS The interleukin-6 response to endotoxin was influenced by gender and correlated with the concentrations of more proximal cytokine tumor necrosis factor-alpha and interleukin-1beta. The interleukin-6 -174 G/C promoter polymorphism can only partly predict the interleukin-6 response of human whole blood to endotoxin stimulation, and the results were different from previous reporter gene assays that reported higher interleukin-6 concentrations for the G allele. Tumor necrosis factor -308 G homozygotes produce the lowest tumor necrosis factor concentrations. The number of tumor necrosis factor -308 G homozygotes was not higher among interleukin-6 -174 heterozygotes, and thus this cannot account for their significantly smaller interleukin-6 production.

Attentional Avoidance of Negative Experiences as Predictor of Postoperative Pain Ratings and Consumption of Analgesics: Comparison with Other Psychological Predictors

OBJECTIVE Attentional avoidance of negative stimuli and preference for positive stimuli (assessed prior to surgery) have been found to be predictive of postoperative pain. However, findings so far were mainly obtained in young patients with benign diagnoses. The aim of the present study was to test whether this relationship holds for aged patients with poorer prognosis. DESIGN Preoperatively assessed psychological predictors, including attentional measures for emotionally loaded stimuli, among others, were used to predict acute postoperative pain as indicated by rating and consumption of analgesics. PATIENTS Fifty-eight patients scheduled for surgery due to cancer (80%) with a mean age of 60.5 years participated in the study. OUTCOME MEASURES As predictors attentional biases for pain-related, social threat, and positive stimuli were assessed in a dot-probe task. Further predictors were self-reported pain vigilance, pain anxiety, pain catastrophizing, general anxiety, depression, and somatization, as well as pressure pain thresholds. As criteria of prediction, numerical scale ratings of acute postoperative pain and the amount of analgesics (patient-controlled intravenous analgesia [PCIA]) requested after surgery were used. RESULTS   Only the dot-probe task parameters provided significant explanation of acute postoperative pain. A significant 23% of variance of the PCIA use was accounted for by the dot-probe task parameters. Here, it was mainly the avoidance of social threat words which contributed to significant prediction and did not appear to be related to the other psychological predictors. Seventy-seven percent of the patients with frequent PCIA use could be classified correctly by this variable. CONCLUSIONS Attentional avoidance of emotionally negative stimuli prior to surgery proved to be a powerful predictor of acute postoperative pain reflected by the consumption of analgesics; this time in a sample of aged patients with various but mainly malign diagnoses. This measure outperformed traditional predictors like depression, anxiety, as well as pain catastrophizing, and deserves further attention.

Maternal and foetal effects of remifentanil for general anaesthesia in parturients undergoing caesarean section: a systematic review and meta-analysis

Remifentanil has been suggested for the induction of general anaesthesia for caesarean section. We aimed to define remifentanil effects on maternal stress response as well as neonatal effects.

Meta-analysis of the success of block following combined spinal-epidural vs epidural analgesia during labour.

Observational studies suggest that combined spinal‐epidural analgesia (CSE) is associated with more reliable positioning, lower epidural catheter replacement rates, and a lower incidence of unilateral block compared with epidural analgesia. However, evidence from high‐quality trials still needs to be assessed systematically. We performed a systematic review that included 10 randomised controlled trials comparing CSE and epidural analgesia in 1722 labouring women in labour. The relative risk of unilateral block was significantly reduced after CSE vs epidural analgesia (0.48, 95% CI 0.24–0.97), but significant between‐study heterogeneity was present (I2 = 69%, p = 0.01). No differences were found for rates of epidural catheter replacement, epidural top‐up, and epidural vein cannulation. On the basis of current best evidence, a consistent benefit of CSE over epidural analgesia cannot be demonstrated for the outcomes assessed in our review. A large randomised controlled trial with adequate power is required.

Insertion of an intrathecal catheter following accidental dural puncture: a meta-analysis

BACKGROUND Inserting an intrathecal catheter after accidental dural puncture in parturients to prevent postdural puncture headache is becoming increasingly popular. We aimed to identify relevant published articles investigating this intervention and subject data to a meta-analysis. METHODS A systematic literature search was performed, paralleled by a hand search of abstract publications. Studies that reported the dichotomous outcome parameters postdural puncture headache or need for an epidural blood patch were considered eligible. Risk ratios with 95% confidence intervals were calculated. RESULTS We identified nine reports investigating placement of intrathecal catheters after accidental dural puncture. The risk ratio for an epidural blood patch after intrathecal catheter insertion was 0.64 (95% CI 0.49-0.84, P=0.001). The risk ratio for postdural puncture headache was 0.82 (95% CI 0.67-1.01, P=0.06). DISCUSSION Inserting an intrathecal catheter significantly reduced the risk for an epidural blood patch; the incidence of postdural puncture headache was reduced but not significantly. Accidental dural puncture is a rare complication and therefore trials on intervention need to include a large number of patients which is time-consuming and costly. Intrathecal catheterisation is a promising approach for the prevention of postdural puncture headache and should be evaluated further. This intervention has additional benefits including a reduced risk of repeat dural puncture, rapid onset of action and use for anaesthesia.

Prophylactic tranexamic acid in parturients at low risk for post-partum haemorrhage: systematic review and meta-analysis

Tranexamic acid is effective in reducing blood loss during various types of surgery and after trauma. No compelling evidence has yet been presented for post‐partum haemorrhage. A systematic literature search of relevant databases was performed to identify trials that assessed blood loss and transfusion incidence after tranexamic acid administration for post‐partum haemorrhage. The random effects model was used for meta‐analysis. Risk ratios (RRs) and weighted mean differences (WMDs) were calculated with 95% confidence intervals (CIs). Seven trials with a low risk of bias comparing tranexamic acid vs. placebo with a total of 1760 parturients were included in our systematic review and meta‐analysis. Blood loss was significantly lower after tranexamic acid use (WMD −140.29 ml, 95% CI −189.64 to −90.93 ml; P < 0.00001). Tranexamic acid reduced the risk for blood transfusions (RR 0.34, 95% CI 0.20–0.60, P = 0.0001). The incidence of transfusions in the placebo group varied between 1.4% and 33%. When omitting the two trials with the highest incidence of transfusions, the RR was no longer significant. Additional uterotonics were necessary in the placebo groups; gastrointestinal adverse events were more common after tranexamic acid use. Only four cases of thrombosis were found, two each in the tranexamic acid and control groups. Tranexamic acid effectively reduced post‐partum blood loss; the effect on the incidence of blood transfusions requires further studies. Only few trials observed adverse events including thromboembolic complications and seizures.