Eike Martin

Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response

While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation.

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.

Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial

BACKGROUND During cardiopulmonary resuscitation (CPR), thrombolysis can help to stabilise patients with pulmonary embolism and myocardial infarction. Moreover, thrombolysis during CPR has beneficial effects on cerebral reperfusion after cardiac arrest. We investigated this new therapeutic approach in patients in whom conventional CPR had been unsuccessful. METHODS We assessed, in a prospective study, patients undergoing CPR after out-of-hospital cardiac arrest for cardiological reasons in whom return of spontaneous circulation was not achieved within 15 min. According to the Ustein criteria, our control group consisted of patients who were assessed during 1 year. After this year patients were treated with a bolus of 5000 U of heparin and 50mg, over 2 min, of tissue-type plasminogen activator (rt-PA treated group). This intervention was repeated if return of spontaneous circulation was not achieved within the following 30 min. For controls only CPR was given. FINDINGS Overall, 90 patients were included; heparin and rt-PA were given to 40 patients. There were no bleeding complications related to the CPR procedures. Of the rt-PA group, 68% (27) had return of spontaneous circulation and 58% (23) were admitted to a cardiac intensive care unit, compared with 44% (22; p=0.026) and 30% (15; p=0.009) of the controls, respectively. At 24 h after cardiac arrest a larger proportion of the rt-PA group than of the controls was alive (35% [14] vs 22% [11], p=0.171), and 15% (six) of rt-PA-treated patients and 8% (four) of controls could be discharged from hospital. INTERPRETATION After initially unsuccessful out-of-hospital CPR, thrombolytic therapy combined with heparin is safe and might improve patient outcome. On the basis of our data a randomised controlled trial might be regarded as ethical.

Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.

Objective To identify a safe and potentially effective recombinant tissue factor pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with severe sepsis. Design Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial. Setting Thirty-eight intensive care units in the United States and Europe. Patients Two hundred and ten subjects with severe sepsis who received standard supportive care and antimicrobial therapy. Interventions Subjects received a continuous intravenous infusion of placebo or rTFPI at 0.025 or 0.05 mg/kg/hr for 4 days (96 hrs). Measurements and Main Results There were no significant imbalances in demographics, severity of illness, or source of infection in patients randomized to placebo or either dose of rTFPI. A 20% relative reduction in 28-day all-cause mortality was observed when all rTFPI-treated patients were compared with all placebo patients. An improvement in pulmonary organ dysfunction score and in a composite intensive care unit score (pulmonary, cardiovascular, and coagulation) were also noted in the rTFPI-treated patients. Logistic regression modeling indicated a substantial treatment by baseline laboratory international normalized ratio (INR) interaction effect when only treatment and INR were in the model (p = .037) and when baseline Acute Physiology and Chronic Health Evaluation (APACHE II) and log10 interleukin 6 were adjusted for (p = .026). This interaction effect indicates that higher baseline INR is associated with a more pronounced beneficial rTFPI effect. There was no increase in mortality in subjects treated with either dose of rTFPI compared with placebo. Biological activity, as detected by a statistically significant reduction in thrombin-antithrombin complexes (TATc), was noted in the all rTFPI-treated patients compared with those receiving placebo. There were no major imbalances across all treatment groups with respect to safety. The frequency of adverse events (AEs) and severe adverse events (SAEs) was similar among the treatment groups, with a slight increase in SAEs and SAEs involving bleeding in the 0.05 mg/kg/hr rTFPI group. The overall incidence of AEs involving bleeding was 28% of patients in the all placebo group and 23% of patients in the all rTFPI-treated group; a slight but statistically insignificant increase in incidence of SAEs involving bleeding was observed in the all rTFPI group (9%) as compared with the all placebo group (6%;p = .39). Conclusions Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all rTFPI group compared with all placebo. This study demonstrates that rTFPI doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe sepsis patients. Additionally, rTFPI demonstrated bioactivity, as shown by reduction in TATc complexes and interleukin-6 levels. These findings warrant further evaluation of rTFPI in an adequately powered, placebo controlled, randomized trial for the treatment of severe sepsis.

Randomised clinical trial comparing the effects of acupuncture and a newly designed placebo needle in rotator cuff tendinitis

Acupuncture has gained increasing attention in the treatment of chronic pain. The lack of a satisfying placebo method has made it impossible to show whether needling is an important part of the method or whether the improvement felt by the patient is due to the therapeutic setting and psychological phenomena. Also, the effectiveness of acupuncture has not been demonstrated sufficiently. We treated 52 sportsmen with rotator cuff tendinitis in a randomised single-blind clinical trial using a new placebo-needle as control. Patients were treated for 4 weeks. The primary endpoint of the trial was the change in the modified Constant-Murley-score from the baseline. Assessment of the treatment outcome was made by experienced orthopaedists not informed of the treatment allocation. Acupuncture with penetration of the skin was shown to be more effective than a similar therapeutic setting with placebo needling in the treatment of pain. The acupuncture-group improved 19.2 Constant-Murley-score points (SD 16.1, range from -13 to 50), the control-group improved 8.37 points (SD 14.56, range from -20 to 41), (P=0.014; C.I. 2.3;19.4). This study showed that needling is an important part of the acupuncture effect in the treatment of chronic shoulder pain in athletes. No conclusions can be derived from this study concerning the importance of choosing points and the rules of Traditional Chinese Medicine. Using the new placebo method as control for other ailments could improve the evidence of specific acupuncture effects beyond pain treatment.

Efficacy of ultrasound imaging in obstetric epidural anesthesia

STUDY OBJECTIVE To assess the clinical use of ultrasonographic localization of the epidural space, and to evaluate the clinical efficacy of ultrasound diagnostics in obstetric anesthesia. DESIGN Randomized prospective study. SETTING University Clinic of Obstetrics and Gynecology. PATIENTS 300 parturients, 85 of whom had conventional delivery and 65 who underwent cesarean section. INTERVENTIONS Patients underwent ultrasonography for the identification of the intervertebral structures. Puncture depth and angle were measured to improve the placement of the Tuohy needle. MEASUREMENTS In the ultrasound group, additional puncture data, optimized puncture point, expected puncture depth, and angle were used to optimize the puncture technique. To control for side effects, we compiled data on the number of puncture attempts and the number of necessary puncture levels, visual analog scale (VAS) scores, the rate of side effects, and the patient acceptance of the technique. MAIN RESULTS The two groups were similar regarding demographic data. Using ultrasound for structure detection, the rate of puncture attempts were significantly (p < 0.013) reduced from 2.18 +/- 1.07 to 1.35 +/- 0.61. The mean rate of necessary puncture levels was 1.30 +/- 0.55 and with ultrasound detection 1.136 +/- 0.36 (p < 0.029). Complete analgesia was achieved in 147 patients with ultrasound detection versus 138 patients in the Control group (p < 0,03). The maximum VAS pain score in the control group was 1.3 +/- 2.1 versus 0.8 +/- 1.5 in the Ultrasound group (p < 0.006). The rate of side effects were reduced significantly: 99 patients in the Control group had no side effects compared with 120 patients from the Ultrasound group who were free of side effects. Patient acceptance of the technique in the Ultrasound group was significantly higher than in the Control group. CONCLUSION The clinical use of ultrasound for epidural catheter placement may improve regional anesthesia. The use of ultrasound resulted in superior quality in all measured endpoints.

Astroglial Protein S-100 Is an Early and Sensitive Marker of Hypoxic Brain Damage and Outcome After Cardiac Arrest in Humans

Background—The results of early conventional tests do not correlate with cerebral outcome after cardiac arrest. We investigated the serum levels of astroglial protein S-100 as an early marker of brain damage and outcome after cardiac arrest. Methods and Results—In 66 patients undergoing cardiopulmonary resuscitation after nontraumatic cardiac arrest, blood samples for the evaluation of S-100 were drawn immediately after and 15, 30, 45, and 60 minutes; 2, 8, 24, 48, and 72 hours; and 7 days after initiation of cardiopulmonary resuscitation. Moreover, the serum levels of neuron-specific enolase were determined between 2 hours and 7 days. If patients survived for >48 hours, brain damage was assessed by a combination of neurological, cranial CT, and electrophysiological examinations. Overall, 343 blood samples were taken for the determination of S-100. Maximum S-100 levels within 2 hours after cardiac arrest were significantly higher in patients with documented brain damage (survivors and nonsurvivors, 3.70±0.77 &mgr;g/L) than in patients without brain damage (0.90±0.29 &mgr;g/L). Significant differences between these 2 groups were observed from 30 minutes until 7 days after cardiac arrest. In addition, the positive predictive value of the S-100 test at 24 hours for fatal outcome within 14 days was 87%, and the negative predictive value was 100% (P <0.001). With regard to neuron-specific enolase, significant differences between patients with documented brain damage and those with no brain damage were found at 24, 48, and 72 hours and 7 days. Conclusions—Astroglial protein S-100 is an early and sensitive marker of hypoxic brain damage and short-term outcome after cardiac arrest in humans.

The acute myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blockades.

Compared with bupivacaine, acute myotoxicity of ropivacaine is less severe. Thus, in this study we compared the long term myotoxic effects of both drugs in a clinically relevant setting. Femoral nerve catheters were inserted in anesthetized pigs, and either 20 mL of bupivacaine (5 mg/mL) or ropivacaine (7.5 mg/mL) was injected. Subsequently, bupivacaine (2.5 mg/mL) and ropivacaine (3.75 mg/mL) were continuously infused (8 mL/h) over 6 h. Control animals were treated with corresponding volumes of normal saline. After 7 and 28 days, respectively, muscle samples were dissected at the former injection sites, and histological patterns of muscle damage were blindly scored (0 = no damage to 3 = marked lesions/myonecrosis) and compared. No morphological tissue changes were detected in control animals. In the observed period, both local anesthetics induced morphologically identical patterns of calcific myonecrosis, formation of scar tissue, and a marked rate of fiber regeneration. However, bupivacaine’s effects were constantly more pronounced than those of ropivacaine. These data show that both drugs induce irreversible skeletal muscle damage in a clinically relevant model, and confirm the exceeding rate of myotoxicity of bupivacaine. However, the clinical impact of these long term myotoxic effects still has to be assessed.

Ultrasound imaging improves learning curves in obstetric epidural anesthesia: a preliminary study.

PurposeEpidural anesthesia may be difficult in pregnancy. We intended to evaluate the teaching possibilities of ultrasonography as a diagnostic approach to the epidural region.MethodsTwo groups of residents performed their first 60 obstetric epidurals under supervision. One proceeded in the conventional way using the loss of resistance technique (control group = CG). The other group proceeded in the same way but was supported by prepuncture ultrasound imaging, giving them information about the optimal puncture point, depth and angle (ultrasound group = UG). Success was defined as adequate epidural anesthesia requiring a maximum of three attempts, reaching a visual analogue scale score of less than I, while neither changing the anesthesia technique, nor starting at another vertebral level. In addition, intervention by the supervisor was defined as failure.ResultsIn the CG we observed asuccess rate of 60% ± 16% after the first ten attempts followed by a nearly continuous rise of the learning curve. Within the next 50 epidurals the rate of success increased to 84%. In the UG the rate of success started at 86% ± 15%. Wthin 50 epidural insertions it rose up to a level of 94%. The difference between the two groups remained significant (P < 0.001).ConclusionUsing ultrasound imaging for teaching epidural anesthesia in obstetrics we found a higher rate of success during the first 60 attempts compared to conventional teaching. We believe this shows the possible value of ultrasound imaging for teaching and learning obstetric regional anesthesia.RésuméObjectifL’anesthésie épidurale peut être difficile à réaliser pendant la grossesse. Nous avons voulu évaluer les possibilités d’apprentissage de l’échographie comme approche diagnostique de la région épidurale.MéthodeDeux groupes de résidents ont réalisé leurs 60 premières anesthésies épidurales sous supervision. Un premier groupe a procédé de manière traditionnelle selon la technique de perte de résistance (groupe témoin = GT). Lautre groupe a fait la même chose, mais bénéficiait de l’assistance de l’échographie qui donnait des informations sur les meilleurs site, profondeur et angle de ponction (groupe d’échographie = GE). La réussite était une anesthésie épidurale adéquate exigeant au plus trois essais, affichant un score de moins de I à l’échelle visuelle analogique et n’exigeant pas de modifier la technique anesthésique, ni de faire la ponction à un autre niveau vertébral. De plus, l’intervention d’un superviseur constituait un échec.RésultatsUn taux de un succès de 60% ± 16% a été noté dans le GT après les 10 premières tentatives suivies par une hausse presque continue de la courbe d’apprentissage. Pendant les 50 anesthésies suivantes, le taux est monté à 84 %. Dans le GE, le taux a été d’abord de 86 % ± 15 %, puis, pour les 50 anesthésies suivantes, il s’est élevé à 94 %. La différence intergroupe demeurait donc significative. (P < 0,001).ConclusionLutilisation de l’échographie dans l’enseignement de l’anesthésie épidurale obstétricale, comparée à la méthode traditionnelle d’enseignement, a montré un taux de succès plus élevé pendant les 60 premiers essais. Cette expérience démontre la valeur de l’échographie dans l’enseignement et l’apprentissage de l’anesthésie obstétricale régionale.

Ultrasound control for presumed difficult epidural puncture

Background: The efficacy of epidural anaesthesia depends on the accurate identification of the epidural space (ES). Abnormal anatomical conditions may make the procedure difficult or impossible. The aim of this study was to investigate whether pre‐puncture ultrasound examination of the spinal anatomy might be beneficial in expected cases of difficult epidural anaesthesia.