Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: a randomized, controlled, experimental study

Introduction: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. Methods: Following 40% of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas. Results: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day. Conclusions: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.<br

Levosimendan for resuscitating the microcirculation in patients with septic shock: A randomized controlled study

__Introduction:__ The purpose of the present study was to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan as compared to an active comparator drug (i.e. dobutamine). The primary end point was a difference of ≥ 20% in the microvascular flow index of small vessels (MFIs) among groups. __Methods:__ The study was designed as a prospective, randomized, double-blind clinical trial and performed in a multidisciplinary intensive care unit. After achieving normovolemia and a mean arterial pressure of at least 65 mmHg, 40 septic shock patients were randomized to receive either levosimendan 0.2 μg·kg-1·min-1(n = 20) or an active comparator (dobutamine 5 μg·kg-1·min-1; control; n = 20) for 24 hours. Sublingual microcirculatory blood flow of small and medium vessels was assessed by sidestream dark-field imaging. Microcirculatory variables and data from right heart catheterization were obtained at baseline and 24 hours after randomization. Baseline and demographic data were compared by means of Mann-Whitney rank sum test or chi-square test, as appropriate. Microvascular and hemodynamic variables were analyzed using the Mann-Whitney rank sum test. __Results:__ Microcirculatory flow indices of small and medium vessels increased over time and were significantly higher in the levosimendan group as compared to the control group; P = .02; MFIs 2.9. The relative increase of perfused vessel density vs. baseline was significantly higher in the levosimendan group than in the control group. In addition, the heterogeneity index decreased only in the levosimendan group. There was no statistically significant correlation between systemic and microcirculatory flow variables within each group. __Conclusions:__ Compared to a standard dose of 5 μg·kg-1·min-1of dobutamine, levosimendan at 0.2 μg·kg-1·min-1improved sublingual microcirculatory blood flow in patients with septic shock, as reflected by changes in microcirculatory flow indices of small and medium vessels.Trial registration: NCT00800306

FSP1 is a glutathione-independent ferroptosis suppressor

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been believed to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants5,6. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis7 is critical to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene11, confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q10 (CoQ10)): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ10 using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1–CoQ10–NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis

In-hospital emergency care in the Federal Republic of Germany. Asite survey of hospitals in the German Resuscitation Registry

Jansen G, Kappelhoff N, Borgstedt R, Rehberg S, Seewald S, Scholz SS. Innerklinische Notfallversorgung in der Bundesrepublik Deutschland. Eine Standortbefragung der Kliniken des Deutschen Reanimationsregisters. Der Anaesthesist. 2021.BACKGROUND: In contrast to prehospital care there is alack of specifications for the organization and equipment of medical emergency teams for in-hospital emergency care.; OBJECTIVE: Evaluation of the organization, team composition, training, equipment and tasks of medical emergency teams in the Federal Republic of Germany.; MATERIAL AND METHODS: Evaluation of aweb-based survey of all hospitals participating in the German Resuscitation Register between February and March2020. The participants were asked about team composition; emergency equipment; type, content and scope of special training or further training as well as other additional tasks in the everyday clinical routine when participating in the medical emergency team. Hospitals with ≤or >600beds were compared.; RESULTS: Atotal of21 (>600beds: 10, 48%; ≤600beds: 11, 52%) hospitals participated in the survey. Team composition requirements were present at 76% (n =16; ≤600beds: 8, 72% vs. >600beds: 8, 80%), training requirements for medical emergency teams at 38% (n =16; ≤600beds: 4, 36% vs. >600beds: 4, 40%) of hospitals, with afocus on cardiac life support (n =6, 28%; ≤600beds: 3, 27% vs. >600beds: 3, 30%) and airway management (n =4, 19%; ≤600beds: 3, 27% vs. >600beds: 1, 10%). A12-lead electrocardiogram (n =7, 33%; ≤600beds: 1, 9% vs. >600beds: 6, 60%; p =0.02), video laryngoscope (n =7, 33%; ≤600beds: 2, 18% vs. >600beds: 5, 50%), ventilator without (n =7, 33%; ≤600beds: 2, 18% vs. >600beds: 5, 50%) or with the possibility of non-invasive ventilation was part of the standard equipment in n =4, 19% (≤600beds: 1, 9% vs. >600beds: 3, 30%). A total of 85% (n =18; ≤600beds: 10, 100% vs. >600beds 8, 72%), had additional tasks in the daily clinical routine. While clinics with >600beds staffed medical emergency teams 100% of the time from the intensive care units, in clinics ≤600beds medical emergency teams were deployed significantly more often in the emergency department (n =5, 45%) and in the normal wards (n =5, 45%, p =0.03).; CONCLUSION: Training and equipment of medical emergency teams in the Federal Republic of Germany is heterogeneous. They should at least meet the standards commonly used in prehospital emergency medicine and include the availability of aportable 12-lead electrocardiogram, a ventilator with the possibility of noninvasive ventilation and a video laryngoscope. Regardless of the size of the hospital, continuous availability of all members of the medical emergency teams should be ensured. © 2021. The Author(s).Hintergrund Im Gegensatz zur Präklinik fehlen für die innerklinische Notfallversorgung Vorgaben zu Organisation und Ausrüstung von innerklinischen Notfallteams (MET). Ziel der Arbeit Evaluation der Organisation, Qualifikation, Ausrüstung sowie Zusatzaufgaben von MET in der Bundesrepublik Deutschland. Material und Methoden Auswertung einer webbasierten Umfrage von Februar bis März 2020 aller am Deutschen Reanimationsregister teilnehmenden Krankenhäuser. Gefragt wurde nach Teamzusammensetzung, Ausrüstung, Qualifikation sowie Zusatzaufgaben im klinischen Alltag. Verglichen wurden Krankenhäuser mit ≤600 vs. >600 Betten. Ergebnisse Insgesamt nahmen 21 (>600: 10 [48 %]; ≤600: 11 [52 %]) Krankenhäuser an der Umfrage teil. Vorgaben zur Teamzusammensetzung gab es bei 76 % (n = 16; ≤600: 8 [72 %] vs. >600: 8 [80 %]). Ausbildungsvoraussetzungen für das MET bestanden an 38 % (n = 16; ≤600: 4 [36 %] vs. >600: 4 [40 %]) der Kliniken. Ein 12-Kanal-Elektrokardiogramm (12-Kanal-EKG) (7 [33 %]; ≤600: 1 [9 %] vs. >600: 6 [60 %]; p = 0,02), Videolaryngoskop (7 [33 %]; ≤600: 2 [18 %] vs. >600: 5 [50 %]) und Beatmungsgerät ohne (7 [33 %]; ≤600: 2 [18 %] vs. >600: 5 [50 %]) bzw. mit Möglichkeit zur nichtinvasiven Beatmung (NIV) gehörte in n = 4 [19 %] (≤600: 1 [9 %] vs. >600: 3 [30 %]) zur Standardausrüstung. Zusätzliche Aufgaben im Klinikalltag hatten 85 % (n = 18; ≤600: 10 (100 %) vs. >600 8 (72 %); ≤600: Notaufnahm/Normalstation jeweils 5 (45 %) vs. >600: Intensivstation 10 (100 %), p = 0,03). Diskussion Die Ausbildung und Ausrüstung von MET ist heterogen. Sie sollte mindestens den in der präklinischen Notfallmedizin gängigen Standards entsprechen und die Vorhaltung eines portablen 12-Kanal-EKG, NIV-fähigen Beatmungsgerätes und Videolaryngoskops umfassen. Unabhängig von der Krankenausgröße sollte eine kontinuierliche Abkömmlichkeit der MET gewährleistet sein

Impact of COVID-19-adapted guidelines using different airway management strategies on resuscitation quality in out-of-hospital-cardiac-arrest – a randomised manikin study

Abstract Background Although airway management for paramedics has moved away from endotracheal intubation towards extraglottic airway devices in recent years, in the context of COVID-19, endotracheal intubation has seen a revival. Endotracheal intubation has been recommended again under the assumption that it provides better protection against aerosol liberation and infection risk for care providers than extraglottic airway devices accepting an increase in no-flow time and possibly worsen patient outcomes. Methods In this manikin study paramedics performed advanced cardiac life support with non-shockable (Non-VF) and shockable rhythms (VF) in four settings: ERC guidelines 2021 (control), COVID-19-guidelines using videolaryngoscopic intubation (COVID-19-intubation), laryngeal mask (COVID-19-Laryngeal-Mask) or a modified laryngeal mask modified with a shower cap (COVID-19-showercap) to reduce aerosol liberation simulated by a fog machine. Primary endpoint was no-flow-time, secondary endpoints included data on airway management as well as the participants‘ subjective assessment of aerosol release using a Likert-scale (0 = no release–10 = maximum release) were collected and statistically compared. Continuous Data was presented as mean ± standard deviation. Interval-scaled Data were presented as median and Q1 and Q3. Results A total of 120 resuscitation scenarios were completed. Compared to control (Non-VF:11 ± 3 s, VF:12 ± 3 s) application of COVID-19-adapted guidelines lead to prolonged no-flow times in all groups (COVID-19-Intubation: Non-VF:17 ± 11 s, VF:19 ± 5 s;p ≤ 0.001; COVID-19-laryngeal-mask: VF:15 ± 5 s,p ≤ 0.01; COVID-19-showercap: VF:15 ± 3 s,p ≤ 0.01). Compared to COVID-19-Intubation, the use of the laryngeal mask and its modification with a showercap both led to a reduction of no-flow-time(COVID-19-laryngeal-mask: Non-VF:p = 0.002;VF:p ≤ 0.001; COVID-19-Showercap: Non-VF:p ≤ 0.001;VF:p = 0.002) due to a reduced duration of intubation (COVID-19-Intubation: Non-VF:40 ± 19 s;VF:33 ± 17 s; both p ≤ 0.01 vs. control, COVID-19-Laryngeal-Mask (Non-VF:15 ± 7 s;VF:13 ± 5 s;p > 0.05) and COVID-19-Shower-cap (Non-VF:15 ± 5 s;VF:17 ± 5 s;p > 0.05). The participants rated aerosol liberation lowest in COVID-19-intubation (median:0;Q1:0,Q3:2;p < 0.001vs.COVID-19-laryngeal-mask and COVID-19-showercap) compared to COVID-19-shower-cap (median:3;Q1:1,Q3:3 p < 0.001vs.COVID-19-laryngeal-mask) or COVID-19-laryngeal-mask (median:9;Q1:6,Q3:8). Conclusions COVID-19-adapted guidelines using videolaryngoscopic intubation lead to a prolongation of no-flow time. The use of a modified laryngeal mask with a shower cap seems to be a suitable compromise combining minimal impact on no-flowtime and reduced aerosol exposure for the involved providers

Comparison of first-line and second-line terlipressin versus sole norepinephrine in fulminant ovine septic shock

The Surviving Sepsis Guidelines suggest the use of vasopressin in case of catecholamine-refractory septic shock. Terlipressin (TP) as a V1-selective AVP analogue is a potential alternative, though data regarding the first-line administration in septic shock are scarce. The present study explored and compared the effects of first-line vs. second-line infusion of TP or sole norepinephrine regarding organ function, fluid and norepinephrine requirements and survival in fulminant ovine septic shock. Peritoneal sepsis was induced in 23 ewes after laparotomy and faecal withdrawal from the caecum. After onset of shock, causal and supportive sepsis therapy (antibiotics, peritoneal lavage, fluids and open-label norepinephrine) was performed in all animals. Concurrently, animals were randomized to receive 0.9% sodium chloride (control group) or TP (2 µg∙kg−1∙h−1, first-line group) after shock onset. In the second-line TP group, TP (2 µg∙kg−1∙h−1) was started once norepinephrine requirements exceeded 0.5 µg∙kg−1∙min−1. No significant differences were found between groups regarding survival, haemodynamics as well as fluid- and catecholamine-requirements. Kidney function and electron microscopic kidney injury were comparable between groups. In the present model of fulminant ovine septic shock, first-line TP infusion had no significant effect on fluid and norepinephrine requirements or organ dysfunction as compared to second-line TP infusion or placebo

Continuation of chronic antiplatelet therapy is not associated with increased need for transfusions: a cohort study in critically ill septic patients

Fuchs C, Scheer CS, Wauschkuhn S, et al. Continuation of chronic antiplatelet therapy is not associated with increased need for transfusions: a cohort study in critically ill septic patients. BMC Anesthesiology . 2024;24(1): 146.BACKGROUND: The decision to maintain or halt antiplatelet medication in septic patients admitted to intensive care units presents a clinical dilemma. This is due to the necessity to balance the benefits of preventing thromboembolic incidents and leveraging anti-inflammatory properties against the increased risk of bleeding.; METHODS: This study involves a secondary analysis of data from a prospective cohort study focusing on patients diagnosed with severe sepsis or septic shock. We evaluated the outcomes of 203 patients, examining mortality rates and the requirement for transfusion. The cohort was divided into two groups: those whose antiplatelet therapy was sustained (n=114) and those in whom it was discontinued (n=89). To account for potential biases such as indication for antiplatelet therapy, propensity score matching was employed.; RESULTS: Therapy continuation did not significantly alter transfusion requirements (discontinued vs. continued in matched samples: red blood cell concentrates 51.7% vs. 68.3%, p=0.09; platelet concentrates 21.7% vs. 18.3%, p=0.82; fresh frozen plasma concentrates 38.3% vs. 33.3%, p=0.7). 90-day survival was higher within the continued group (30.0% vs. 70.0%; p0.05).; CONCLUSIONS: The findings suggest that continuing antiplatelet therapy in septic patients admitted to intensive care units could be associated with a significant survival benefit without substantially increasing the need for transfusion. These results highlight the importance of a nuanced approach to managing antiplatelet medication in the context of severe sepsis and septic shock. © 2024. The Author(s)