H. Böhrer

Role of NFkappaB in the mortality of sepsis.

Binding activity for nuclear factor kappa B (NFkappaB) consensus probes was studied in nuclear extracts from peripheral blood mononuclear cells of 15 septic patients (10 surviving and 5 not surviving). Nonsurvivors could be distinguished from survivors by an increase in NFkappaB binding activity during the observation period (P < 0.001). The increase in NFkappaB binding activity was comparable to the APACHE-II score as a predictor of outcome. Intravenous somatic gene transfer with an expression plasmid coding for IkappaBalpha was used to investigate the role of members of the NFkappaB family in a mouse model of endotoxemia. In this model, increased NFkappaB binding activity was present after injection of LPS. Intravenous somatic gene transfer with IkappaBalpha given before LPS attenuated renal NFkappaB binding activity and increased survival. Endothelial cells and monocytes/macrophages were the major target cells for somatic gene transfer, transfected with an average transfection efficiency of 20-35%. Tissue factor, a gene under regulatory control of NFkappaB, was induced by LPS. Somatic gene transfer with a reporter plasmid containing the functional tissue factor promoter demonstrated NFkappaB-dependent stimulation by LPS. Intravenous somatic gene transfer with IkappaBalpha reduced LPS-induced renal tissue factor expression, activation of the plasmatic coagulation system (decrease of thrombin-antithrombin III complexes) and renal fibrin/fibrinogen deposition. Somatic gene transfer with an expression plasmid with tissue factor cDNA in the antisense direction (in contrast to sense or vector alone) also increased survival. Furthermore, antisense tissue factor decreased renal tissue factor expression and the activation of the plasmatic coagulation system.

Inhaled Nitric Oxide Inhibits Human Platelet Aggregation, P-Selectin Expression, and Fibrinogen Binding In Vitro and In Vivo

BACKGROUND Recent data suggest that inhaled NO can inhibit platelet aggregation. This study investigates whether inhaled NO affects the expression level and avidity of platelet membrane receptors that mediate platelet adhesion and aggregation. METHODS AND RESULTS In 30 healthy volunteers, platelet-rich plasma was incubated with an air/5% CO2 mixture containing 0, 100, 450, and 884 ppm inhaled NO. ADP- and collagen-induced platelet aggregation, the membrane expression of P-selectin, and the binding of fibrinogen to the platelet glycoprotein (GP) IIb/IIIa receptor were determined before (t0) and during the 240 minutes of incubation. In addition, eight patients suffering from severe adult respiratory distress syndrome (ARDS) were investigated before and 120 minutes after the beginning of administration of 10 ppm inhaled NO. In vitro, NO led to a dose-dependent inhibition of both ADP-induced (3+/-3% at 884 ppm versus 70+/-6% at 0 ppm after 240 minutes; P<.001) and collagen-induced (13+/-5% versus 62+/-5%; P<.01) platelet aggregation. Furthermore, P-selectin expression (36+/-7% of t0 value; P<.01) and fibrinogen binding (33+/-11%; P<.01) were inhibited. In patients with ARDS, after two who did not respond to NO inhalation with an improvement in oxygenation had been excluded, an increase in plasma cGMP, prolongation of in vitro bleeding time, and inhibition of platelet aggregation and P-selectin expression were observed, and fibrinogen binding was also inhibited (19+/-7% versus 30+/-8%; P<.05). CONCLUSIONS NO-dependent inhibition of platelet aggregation may be caused by a decrease in fibrinogen binding to the platelet GP IIb/IIIa receptor.

Mechanism of the Tumor Necrosis Factor α-mediated Induction of Endothelial Tissue Factor

This study examines the regulation of the human tissue factor (TF) promotor in vitro and in vivo. Transient transfections were performed in bovine aortic endothelial cells to investigate the role of two fundamentally different AP-1 sites and a closely located NF-κB site in the human TF promotor. The NF-κB site is functionally active, since overexpression of NF-κB(p65) resulted in induction of TF mRNA and activity. Promotor analysis showed that NF-κB induction was dependent on the integrity of the region from base pair −188 to −181. Overexpression of Jun/Fos resulted in TF induction of transcription and protein/activity. Functional studies revealed that the proximal AP-1 site, but not the distal, was inducible by Jun/Fos heterodimers. The distal AP-1 site, which has a G → A switch at position 4, was inducible by Jun homodimers. Electrophoretic mobility shift assays, using extracts of tumor necrosis factor α (TNFα)-stimulated bovine aortic endothelial cells, demonstrated TNFα-inducible binding to the proximal AP-1 site, comprising JunD/Fos heterodimers. At the distal AP-1 site, only minor induction of binding activity, characterized as proteins of the Jun and ATF family, was observed. Consistently, this site only marginally participates in TNFα induction. Functional studies with TF promotor plasmids confirmed that deletion of the proximal AP-1 or the NF-κB site decreased TNFα-mediated TF induction to a higher extend than loss of the distal AP-1 site. However, integrity of both AP-1 sites and the NF-κB site was required for optimal TNFα stimulation. The relevance of these in vitro data was confirmed in vivo in a mouse tumor model. Expression plasmids for a dominant negative Jun mutant or I-κB were packaged in liposomes. When either mutated Jun or I-κB were injected intravenously 48 h before TNFα, a reduction in TNFα-mediated TF expression in the tumor endothelial cells was observed. Simultaneously, fibrin/fibrinogen deposition decreased and free blood flow could be restored. Thus, TNFα-induced up-regulation of endothelial cell TF depends on a concerted action of members of the bZIP and NF-κB family.

Effect of patient-controlled analgesia on pulmonary complications after coronary artery bypass grafting.

OBJECTIVE To determine whether treatment with patient-controlled analgesia (PCA) alone or in combination with nonsteroidal anti-inflammatory drugs can prevent postoperative pulmonary complications after cardiac surgery, when compared with conventional nurse-controlled analgesia. DESIGN Randomized controlled trial. SETTING University Medical Center. PATIENTS A total of 120 patients undergoing elective coronary artery bypass grafting. INTERVENTIONS After extubation of the trachea, 120 patients were randomly allocated to three different methods of postoperative pain relief for 72 hrs. In group 1, patients received PCA with a bolus of 1.5 mg piritramide combined with a 10-min lockout interval. Group 2 patients were treated with a combination of PCA and administration of nonsteroidal anti-inflammatory drugs prescribed three times per day. Patients of group 3 received conventional nurse-controlled analgesia. Postoperative assessment included daily visual analog pain scoring (VAS) and chest radiographs. All chest radiographs were graded for the extent of atelectasis by a radiologist blinded as to treatment using a scale from 0 to 9 for each of the three lung fields of the right and left lungs. MEASUREMENTS AND MAIN RESULTS Chest radiograph atelectasis scores and VAS values were similar among the three groups on the first and second days. On the third day, the chest radiograph atelectasis scores of the left lower and the right middle lung field were significantly better in the groups treated with PCA alone (4.7 +/- 3.0; 0.3 +/- 1.0) and in combination with nonsteroidal anti-inflammatory drugs (3.9 +/- 1.1; 0.4 +/- 1.2) than in the control group (5.5 +/- 3.1; 0.8 +/- 1.8). Furthermore, on the third day, the VAS values for maximum pain were higher in the control group (42.6 +/- 19.7) compared with the VAS values in the two groups with PCA (32.2 +/- 17.9 and 34.5 +/- 21.0). CONCLUSIONS PCA significantly decreases postoperative pulmonary atelectasis in patients after coronary artery bypass grafting when compared with nurse-controlled analgesia. In addition, patients treated with PCA experienced a higher quality of analgesia. We therefore conclude that treatment with PCA may reduce respiratory complications after coronary artery bypass grafting.

Tussive effect of a fentanyl bolus administered through a central venous catheter

One hundred and ten male patients scheduled for coronary artery bypass grafting were allocated randomly into one of three groups. Patients in group A received fentanyl 7 μg/kg via a central venous catheter, those in group B were given fentanyl 7 μg/kg through a peripheral venous cannula, and patients in group C received sterile water via a central venous catheter. In group A, 45.9% of patients coughed after injection of fentanyl; the mean onset time from the end of fentanyl administration to the beginning of coughing was 10.6 seconds. Only one patient in group B and no patient in the control group exhibited a cough response (p < 0.0001). We hypothesise that fentanyl can evoke the pulmonary chemoreflex.

Measuring patient satisfaction with anaesthesia: perioperative questionnaire versus standardised face-to-face interview

Background: Patient satisfaction represents an essential part of quality management. Measuring the degree of patient satisfaction can be achieved with a variety of tools such as postoperative visits and patient questionnaires. The primary aim of this study was to quantify the degree of patient satisfaction with anaesthesia. A secondary aim was to compare the questionnaire technique with standardised face‐to‐face interviewing.

Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity.

Thrombomodulin (TM), recognized as an essential vessel wall cofactor of the antithrombotic mechanism, is also expressed by a wide range of tumor cells. Tumor cell lines subcloned from four patients with malignant melanoma displayed a negative correlation between TM expression and cell proliferation in vitro and in vivo. Overexpression of wild-type TM decreased cell proliferation in vitro and tumor growth in vivo. TM mutants with altered protein C activation capacity lead to a similar effect. In contrast, transfection of melanoma cells with mutant TM constructs, in which a portion of the cytoplasmic or lectin domain was deleted, abrogated the antiproliferative effect associated with overexpression of wild-type TM. Experiments performed with either peptide agonists/antagonists of the thrombin receptor, with hirudin, or with inhibitors of thrombin-TM interaction did not alter the growth inhibitory effect of TM overexpression. These data suggest that TM exerts an effect on cell proliferation independent of thrombin and the thrombin receptor, possibly related to the binding of novel ligands to determinants in the lectin domain which might trigger signal transduction pathways dependent on the cytoplasmic domain.

Bolus injection of thrombolytic agents during cardiopulmonary resuscitation for massive pulmonary embolism

Thrombolytic therapy has proved to be efficacious in the treatment of massive and fulminant pulmonary embolism (PE), but thrombolysis has been considered as contraindicated during cardiopulmonary resuscitation (CPR). This review on the administration of thrombolytic agents in patients who have suffered massive PE necessitating CPR summarises 14 anecdotal reports and three case series involving 34 patients. The case series revealed an overall initial survival rate of 55-100% following bolus administration of thrombolytic agents. In general, bleeding complications were managed conservatively. The establishment of the diagnosis may be feasible using echocardiography or bedside angiography during CPR. However, therapeutic measures should be taken without delay; the patients history and the clinical picture may thus be the only diagnostic criteria. Even where myocardial infarction is misinterpreted as PE during CPR, bolus injection of a thrombolytic agent can be an appropriate therapeutic option. An alternative may be mechanical catheter fragmentation of the thrombus with subsequent local thrombolysis. Surgery may be restricted to hospitals with ready access to extracorporeal circulation. We conclude that early administration of thrombolytic agents during PE necessitating CPR may help to reduce mortality. We favour the administration of urokinase (2- to 3,000,000-U bolus) or rt-PA.

Continuous versus intermittent cardiac output measurement in cardiac surgical patients undergoing hypothermic cardiopulmonary bypass

OBJECTIVE Continuous thermodilution cardiac output (CCO) measurement was clinically evaluated in patients who underwent coronary revascularization using hypothermic low-flow, low-pressure cardiopulmonary bypass (CPB). DESIGN Prospective study. SETTING University hospital setting. PARTICIPANTS 30 cardiac surgical patients. INTERVENTIONS CCO was correlated to standard bolus thermodilution cardiac output (ICO) obtained at end-expiration. MEASUREMENTS AND MAIN RESULTS Measurements were taken at selected time points (n = 18) before anesthesia induction, before CPB, and 5 minutes to 12 hours after CPB. A total of 540 data pairs were thus obtained. ICO ranged from 1.9 to 9.9 L/min, CCO from 1.5 to 9.9 L/min. Correlation between ICO and CCO was highly significant (r = 0.872; p < 0.01), accompanied by an excellent accuracy (bias -0.0213 L) and precision (0.59 L) before CPB and more than 45 minutes after CPB. However, during the first 45 minutes after CPB, there was no correlation (r = 0.273) between ICO and CCO, and ICO tended to be relatively high, whereas CCO measurements showed relatively low values. During the first 45 minutes after hypothermic CPB, but not during the ensuing time period, central blood temperature decreased, which may be interpreted as a lack of thermal equilibration between central and peripheral compartments. It is hypothesized that thermal instability in combination with increased respiratory variations in pulmonary artery blood temperature caused inhomogenous rewarming of different body sites and might be the main reason for the lack of correlation between ICO and CCO. CONCLUSIONS Despite an excellent correlation, accuracy, and precision between CCO and ICO before CPB and more than 45 minutes after hypothermic CPB, a lack of correlation in the early phase after CPB has been found. Further investigation is needed to elucidate the underlying cause of these findings and to clarify whether ICO or CCO or both fail to represent the real cardiac output up to 45 minutes after weaning from hypothermic CPB.

Effects of continuous (CPAP) and bi-level positive airway pressure (BiPAP) on extravascular lung water after extubation of the trachea in patients following coronary artery bypass grafting

ObjectiveTo evaluate the effects of continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) on extravascular lung water during weaning from mechanical ventilation in patients following coronary artery bypass grafting.DesignProspective, randomized clinical study.SettingIntensive care unit at a university hospital.PatientsSeventy-five patients following coronary artery bypass grafting.InterventionsAfter extubation of the trachea, patients were treated for 30 min with CPAP via face mask (n=25), with nasal BiPAP (n=25), or with oxygen administration via nasal cannula combined with routine chest physiotherapy (RCP) for 10 min (n=25).Measurements and resultsExtravascular lung water (EVLW), pulmonary blood volume index (PBVI) and cardiac index (CI) were obtained during mechanical ventilation (T1), T-piece breathing (T2), interventions (T3), spontaneous breathing 60 min (T4) and 90 min (T5) after extubation of the trachea using a combined dye-thermal dilution method. Changing from mechanical ventilation to T-piece breathing did not show any significant differences in EVLW between the three groups, but a significant increase in PBVI from 155±5 ml/m2 to 170±4 ml/m2 could be observed in all groups (p<0.05). After extubation of the trachea and treatment with BiPAP, PBVI decreased significantly to 134±6 ml/m2 (p<0.05). After treatment with CPAP or BiPAP, EVLW did not change significantly in these groups (5.5±0.3 ml/kg vs 5.0±0.4 ml/kg and 5.1±0.4 ml/kg vs 5.7±0.4 ml/kg). In the RCP-treated group, however, EVLW increased significantly from 5.8±0.3 ml/kg to 7.1±0.4 ml/kg (p<0.05). Sixty and 90 min after extubation, EVLW stayed at a significantly higher level in the RCP-treated group (7.5±0.5 ml/kg and 7.4±0.5 ml/kg) than in the CPAP-(5.6±0.3 ml/kg and 5.9±0.4 ml/kg). No significant differences in CI could be observed within the three groups during the time period from mechanical ventilation to 90 min after extubation of the trachea.ConclusionsMask CPAP and nasal BiPAP after extubation of the trachea prevent the increase in extravascular lung water during weaning from mechanical ventilation. This effect is seen for at least 1 h after the discontinuation of CPAP or BiPAP treatment. Fuether studies have to evaluate the clinical relavance of this phenomenon.