Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist

<p>Abstract</p> <p>Background</p> <p>The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia.</p> <p>Methods</p> <p>First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion.</p> <p>Results</p> <p>Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours.</p> <p>Conclusions</p> <p>Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.</p

Conductance Catheter Measurement and Effect of Different Anesthetics in a Rat Model of Postresuscitation Myocardial Dysfunction

We demonstrate the usefulness of left ventricular pressure-volume (PV) loops generated by the use of conductance catheter measurements and investigate the influence of the type of general anesthesia on postresuscitation myocardial dysfunction in a rat model of cardiac arrest (CA) and subsequent cardiopulmonary resuscitation. A total of 42 Wistar-Han rats were randomized to receive general anesthesia with sevoflurane and resuscitation after CA, general anesthesia with pentobarbital intraperitoneally and resuscitation after CA, or general anesthesia with pentobarbital without CA (sham group). Myocardial function, assessed by analysis of PV loops, was measured continuously and in real-time by using a PV-conductance catheter. Rats were monitored for 3 h after restoration of spontaneous circulation (ROSC). The use of PV-conductance catheters supported objective and reliable evaluation of myocardial function and proved feasible in this rat model of CA. End-diastolic volume increased in rats anesthetized with pentobarbital after ROSC (before CA, 237 +/- 45 mu A; after ROSC, 402 +/- 64 mu L). Preload-adjusted maximal power before CA was the same in all groups but decreased in both resuscitated groups. The decrease was less pronounced in rats anesthetized with sevoflurane compared with pentobarbital (11.8 +/- 4.9 mW/mu L-2 compared with 4.8 +/- 1.9 mW/mu L-2 at 3 h after ROSC). This finding indicates that the type of general anesthesia influences postresuscitation myocardial dysfunction in this rat model of experimentally induced CA and cardiopulmonary resuscitation. Rats that were anesthetized with sevoflurane exhibited less postresuscitation myocardial dysfunction than did those anesthetized with pentobarbital

Fazilitierte Hypothermie durch Dopamin- und Serotonin-Agonisten nach Herz-Kreislauf-Stillstand im Rattenmodell

Hintergrund: Die therapeutische Hypothermie reduziert Mortalität wie Morbidität nach Herz-Kreislauf-Stillstand. Dopamin-D2- und Serotonin-5-HT1A-Agonisten senken die Körpertemperatur durch Verstellung des Sollwerts. Die vorliegende Arbeit untersucht die Wirkung des D2-Agonisten Quinpirol und des 5-HT1A-Agonisten 8-OH-DPAT auf die Körpertemperatur und den zerebralen Schaden von Ratten nach Herz-Kreislauf-Stillstand. Methoden: Männliche Wistar-Han-Ratten wurden einem 6-minütigen Herz-Kreislauf-Stillstand durch Kammerflimmern ausgesetzt. Nach Wiederherstellung eines Spontankreislaufs wurden 1 mg Quinpirol, 1 mg 8-OH-DPAT oder Placebo subkutan verabreicht. Die Körpertemperatur wurde für 48 Stunden kontinuierlich aufgezeichnet. Eine zusätzliche Gruppe von Tieren wurde nach der Reanimation streng normotherm gehalten. Die Tiere wurden vor dem Herz-Kreislauf-Stillstand sowie nach 1, 3 und 7 Tagen mittels Tape-Removal-Test neurologisch untersucht. Nach 7 Tagen wurden histologische Schnitte des hippokampalen CA-1-Sektors angefertigt und in Nissl- und TUNEL-Färbung ausgewertet. Ergebnisse: Nach Herz-Kreislauf-Stillstand fand sich bei allen Tieren eine spontane Hypothermieneigung. Die Einleitung der Hypothermie wurde durch Quinpirol wie auch durch 8-OH-DPAT beschleunigt. Die „Gesamtdosis“ der Hypothermie, ausgedrückt durch die Fläche unter der Kurve, unterschied sich nicht zwischen den Gruppen. Alle Tiere zeigten einen neurologischen Schaden im Tape-Removal-Test, der sich im Verlauf wieder zurückbildete; die Ergebnisse der Normothermie-Gruppe blieben nach 7 Tagen tendenziell schlechter als die der Gruppen mit Hypothermie. Es gab keine klaren Unterschiede in der Histologie nach 7 Tagen. Schlussfolgerung: Quinpirol und 8-OH-DPAT führten beide zu einer schnelleren Einleitung der Hypothermie nach Herz-Kreislauf-Stillstand. Das Outcome unterschied sich jedoch nicht von dem nach spontaner Hypothermie, wahrscheinlich weil die „Gesamtdosis“ der Hypothermi

Success rates and endotracheal tube insertion times of experienced emergency physicians using five video laryngoscopes: a randomised trial in a simulated trapped car accident victim

Context No randomised controlled trial has yet compared different video laryngoscopes in respect of the success rates and the time taken to achieve endotracheal intubation in trapped car accident victims. Objective The aim of the present study was to evaluate whether five video laryngoscopes facilitate tracheal intubation more quickly or more securely than conventional laryngoscopy. Design Prospective, controlled, randomised crossover trial. Setting An airway manikin was placed on the driver's seat of a compact car. Access was possible only through the opened driver's door. Participants Twenty-five experienced anaesthetists. Intervention Tracheal intubation in a simulated trapped patient using video laryngoscopes in a typical out-of-hospital setting. Main outcome measures Times to achievement of a view of the glottis, tracheal intubation, cuff inflation, first ventilation and tracheal tube position were compared using a standard Macintosh laryngoscope or Glidescope Ranger, Storz C-MAC, Ambu-Pentax AWS, Airtraq and McGrath Series 5 video laryngoscopes in a randomised order. Wilcoxon signed-rank test and McNemar test were used for statistical analysis. A P value of less than 0.05 was considered statistically significant. Results Twenty-five anaesthetists (35.1 +/- 7.3 years; 16 male, nine female) with an intubation experience of 374 +/- 96 intubations per year and an experience of 9.1 +/- 7.3 years participated. Glottic view, tracheal intubation, cuff inflation and first ventilation were achieved most rapidly with the Macintosh laryngoscope, although the Airtraq and Pentax AWS video laryngoscopes were not significantly slower. Times were significantly longer when the Glidescope Ranger, McGrath Series 5 or Storz C-MAC video laryngoscopes were used (P<0.05), failure to place the endotracheal tube correctly was significantly commoner with the McGrath Series 5 than with the Macintosh (P=0.031). Conclusion When attempting to intubate a trapped car accident victim, video laryngoscopes provide a better view of the glottis, but some delay tracheal intubation significantly. The devices with a tube guide (Airtraq and Ambu Pentax AWS) enable tracheal intubation to be achieved significantly faster and with a lower failure rate than devices without a tube guide. No video laryngoscope outperformed direct laryngoscopy with a Macintosh laryngoscope in this simulation study. Trial registration Clinicaltrials.gov NCT01182740. Eur J Anaesthesiol 2011;28:849-85

Dynamic relative regional strain visualized by electrical impedance tomography in patients suffering from COVID-19

Respiratory failure due to SARS-CoV-2 may progress rapidly. During the course of COVID-19, patients develop an increased respiratory drive, which may induce high mechanical strain a known risk factor for Patient Self-Inflicted Lung Injury (P-SILI). We developed a novel Electrical Impedance Tomography-based approach to visualize the Dynamic Relative Regional Strain (DRRS) in SARS-CoV-2 positive patients and compared these findings with measurements in lung healthy volunteers. DRRS was defined as the ratio of tidal impedance changes and end-expiratory lung impedance within each pixel of the lung region. DRRS values of the ten patients were considerably higher than those of the ten healthy volunteers. On repeated examination, patterns, magnitude and frequency distribution of DRRS were reproducible and in line with the clinical course of the patients. Lung ultrasound scores correlated with the number of pixels showing DRRS values above the derived threshold. Using Electrical Impedance Tomography we were able to generate, for the first time, images of DRRS which might indicate P-SILI in patients suffering from COVID-19.Trial Registration This observational study was registered 06.04.2020 in German Clinical Trials Register (DRKS00021276)

Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p

In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For all analyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P < .0001) and OS (P < .0001) in arm A, whereas no statistically significant effect on PFS (P = .28) or OS (P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at the International Standard Randomised Controlled Trial Number Register as IS-RCTN64455289. (Blood. 2012;119(4): 940-948