[Pathophysiology of Acute Respiratory Distress Syndrome]. / Pathophysiologie des akuten Lungenversagens (ARDS).

Acute respiratory distress syndrome (ARDS) is a common condition in intensive care medicine. Various intra- and extrapulmonal causes may trigger an epithelial and endothelial permeability increase, which leads to impaired gas exchange due to fluid overload of the alveoli and transmigration of leukocytes. This results in hypoxemia and hypercapnia, as well as deleterious consequences for the macro- and microcirculation with the risk of multi-organ failure and high mortality. This review summarizes ARDS pathophysiology and clinical consequences.

High-dose methylprednisolone pulse therapy during refractory COVID-19 acute respiratory distress syndrome: a retrospective observational study.

BACKGROUND: Current COVID-19 guidelines recommend the early use of systemic corticoids for COVID-19 acute respiratory distress syndrome (ARDS). It remains unknown if high-dose methylprednisolone pulse therapy (MPT) ameliorates refractory COVID-19 ARDS after many days of mechanical ventilation or rapid deterioration with or without extracorporeal membrane oxygenation (ECMO). METHODS: This is a retrospective observational study. Consecutive patients with COVID-19 ARDS treated with a parenteral high-dose methylprednisolone pulse therapy at the intensive care units (ICU) of two University Hospitals between January 1st 2021 and November 30st 2022 were included. Clinical data collection was at ICU admission, start of MPT, 3-, 10- and 14-days post MPT. RESULTS: Thirty-seven patients (mean age 55 ± 12 years) were included in the study. MPT started at a mean of 17 ± 12 days after mechanical ventilation. Nineteen patients (54%) received ECMO support when commencing MPT. Mean paO2/FiO2 significantly improved 3- (p = 0.034) and 10 days (p = 0.0313) post MPT. The same applied to the necessary FiO2 10 days after MPT (p = 0.0240). There were no serious infectious complications. Twenty-four patients (65%) survived to ICU discharge, including 13 out of 20 (65%) needing ECMO support. CONCLUSIONS: Late administration of high-dose MPT in a critical subset of refractory COVID-19 ARDS patients improved respiratory function and was associated with a higher-than-expected survival of 65%. These data suggest that high-dose MPT may be a viable salvage therapy in refractory COVID-19 ARDS.

Omega-6 sparing effects of parenteral lipid emulsions-an updated systematic review and meta-analysis on clinical outcomes in critically ill patients.

BACKGROUND: Parenteral lipid emulsions in critical care are traditionally based on soybean oil (SO) and rich in pro-inflammatory omega-6 fatty acids (FAs). Parenteral nutrition (PN) strategies with the aim of reducing omega-6 FAs may potentially decrease the morbidity and mortality in critically ill patients. METHODS: A systematic search of MEDLINE, EMBASE, CINAHL and CENTRAL was conducted to identify all randomized controlled trials in critically ill patients published from inception to June 2021, which investigated clinical omega-6 sparing effects. Two independent reviewers extracted bias risk, treatment details, patient characteristics and clinical outcomes. Random effect meta-analysis was performed. RESULTS: 1054 studies were identified in our electronic search, 136 trials were assessed for eligibility and 26 trials with 1733 critically ill patients were included. The median methodologic score was 9 out of 14 points (95% confidence interval [CI] 7, 10). Omega-6 FA sparing PN in comparison with traditional lipid emulsions did not decrease overall mortality (20 studies; risk ratio [RR] 0.91; 95% CI 0.76, 1.10; p = 0.34) but hospital length of stay was substantially reduced (6 studies; weighted mean difference [WMD] - 6.88; 95% CI - 11.27, - 2.49; p = 0.002). Among the different lipid emulsions, fish oil (FO) containing PN reduced the length of intensive care (8 studies; WMD - 3.53; 95% CI - 6.16, - 0.90; p = 0.009) and rate of infectious complications (4 studies; RR 0.65; 95% CI 0.44, 0.95; p = 0.03). When FO was administered as a stand-alone medication outside PN, potential mortality benefits were observed compared to standard care. CONCLUSION: Overall, these findings highlight distinctive omega-6 sparing effects attributed to PN. Among the different lipid emulsions, FO in combination with PN or as a stand-alone treatment may have the greatest clinical impact. Trial registration PROSPERO international prospective database of systematic reviews (CRD42021259238).

Key characteristics impacting survival of COVID-19 extracorporeal membrane oxygenation.

BACKGROUND: Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. METHODS: 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. RESULTS: Most patients were between 50 and 70 years of age. PaO2/FiO2 ratio prior to ECMO was 72 mmHg (IQR: 58-99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41-0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28-1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. CONCLUSIONS: Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival. TRIAL REGISTRATION: Registered in the German Clinical Trials Register (study ID: DRKS00022964, retrospectively registered, September 7th 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022964 .

[Measurement of Anti-SARS CoV-2 Antibodies following Vaccination: Valuable Monitoring or Irrelevant Tool?] / Antikörperbestimmung nach SARS-CoV-2-Impfung: Sinnvolles Monitoring oder bedeutungslos?

Vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) provides effective protection against infection or severe coronavirus disease 2019 (COVID-19). Moreover, it is regarded as the single most important measure to end the pandemic. Individual vaccination effectiveness is often judged via measurement of anti-SARS-CoV-2 antibodies. However, considering the complexity of the humoral and cellular immune response the question arises whether the relation of anti-SARS-CoV-2 antibody titers and COVID-19 vaccine effectiveness is a myth or a fact? The current article aims to answer this question and provide a short review of the immunological mechanisms of SARS-CoV-2 vaccination. Recommendations for clinical practice are given based on the current evidence and known problems of anti-SARS-CoV-2 antibody measurements after vaccination.

Point of care diagnostic of hypercoagulability and platelet function in COVID-19 induced acute respiratory distress syndrome: a retrospective observational study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) associated coagulopathy (CAC) leads to thromboembolic events in a high number of critically ill COVID-19 patients. However, specific diagnostic or therapeutic algorithms for CAC have not been established. In the current study, we analyzed coagulation abnormalities with point-of-care testing (POCT) and their relation to hemostatic complications in patients suffering from COVID-19 induced Acute Respiratory Distress Syndrome (ARDS). Our hypothesis was that specific diagnostic patterns can be identified in patients with COVID-19 induced ARDS at risk of thromboembolic complications utilizing POCT. METHODS: This is a single-center, retrospective observational study. Longitudinal data from 247 rotational thromboelastometries (Rotem®) and 165 impedance aggregometries (Multiplate®) were analysed in 18 patients consecutively admitted to the ICU with a COVID-19 induced ARDS between March 12th to June 30th, 2020. RESULTS: Median age was 61 years (IQR: 51-69). Median PaO2/FiO2 on admission was 122 mmHg (IQR: 87-189), indicating moderate to severe ARDS. Any form of hemostatic complication occurred in 78 % of the patients with deep vein/arm thrombosis in 39 %, pulmonary embolism in 22 %, and major bleeding in 17 %. In Rotem® elevated A10 and maximum clot firmness (MCF) indicated higher clot strength. The delta between EXTEM A10 minus FIBTEM A10 (ΔA10) > 30 mm, depicting the sole platelet-part of clot firmness, was associated with a higher risk of thromboembolic events (OD: 3.7; 95 %CI 1.3-10.3; p = 0.02). Multiplate® aggregometry showed hypoactive platelet function. There was no correlation between single Rotem® and Multiplate® parameters at intensive care unit (ICU) admission and thromboembolic or bleeding complications. CONCLUSIONS: Rotem® and Multiplate® results indicate hypercoagulability and hypoactive platelet dysfunction in COVID-19 induced ARDS but were all in all poorly related to hemostatic complications..

Pulmonary Hemodynamics and Ventilation in Patients With COVID-19-Related Respiratory Failure and ARDS.

BACKGROUND: It has been suggested that COVID-19-associated severe respiratory failure (CARDS) might differ from usual acute respiratory distress syndrome (ARDS) due to failing autoregulation of pulmonary vessels and higher shunt. We sought to investigate pulmonary hemodynamics and ventilation properties in patients with CARDS compared to patients with ARDS of pulmonary origin. METHODS: This was a retrospective analysis of prospectively collected data from consecutive adults with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 patients treated in our ICU in 04/2020 and a comparison of the data to matched controls with ARDS due to respiratory infections treated in our ICU from 01/2014 to 08/2019 for whom pulmonary artery catheter data were available. RESULTS: CARDS patients (n = 10) had ventilation characteristics similar to those of ARDS (n = 10) patients. Nevertheless, mechanical power applied by ventilation was significantly higher in CARDS patients (23.4 ± 8.9 J/min) than in ARDS (15.9 ± 4.3 J/min; P < 0.05). COVID-19 patients had similar pulmonary artery pressure but significantly lower pulmonary vascular resistance, as cardiac output was higher in CARDS vs. ARDS patients (P < 0.05). Shunt fraction and dead space were similar in CARDS compared to ARDS (P > 0.05) and were correlated with hypoxemia in both groups. The arteriovenous pCO2 difference (▵pCO2) was elevated (CARDS 5.5 ± 2.8 mmHg vs. ARDS 4.7 ± 1.1 mmHg; P > 0.05), as was the P(v-a)CO2/C(a-v)O2 ratio (CARDS mean 2.2 ± 1.5 vs. ARDS 1.7 ± 0.8; P > 0.05). CONCLUSIONS: Respiratory failure in COVID-19 patients seems to differ only slightly from ARDS regarding ventilation characteristics and pulmonary hemodynamics. Our data indicate microcirculatory dysfunction. More data need to be collected to assure these findings and gain more pathophysiological insights into COVID-19 and respiratory failure.

Effects of inhaled nitric oxide in COVID-19-induced ARDS - Is it worthwhile?

BACKGROUND: Changes in pulmonary hemodynamics and ventilation/perfusion were proposed as hallmarks of Coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). Inhaled nitric oxide (iNO) may overcome these issues and improve arterial oxygenation. METHODS: We retrospectively analyzed arterial oxygenation and pulmonary vasoreactivity in seven COVID-19 ARDS patients receiving 20 ppm iNO for 15-30 minutes. RESULTS: The inhalation of NO significantly improved oxygenation. All patients with severe ARDS had higher partial pressures of oxygen and reduced pulmonary vascular resistance. Significant changes in pulmonary shunting were not observed. CONCLUSION: Overall, iNO could provide immediate help and delay respiratory deterioration in COVID-19-induced moderate to severe ARDS.

Pumpless Extracorporeal Hemadsorption Technique: A New Method for Early Cytokine Elimination?

In recent years, extracorporeal hemadsorption (HA) techniques capable of adsorbing pro- and anti-inflammatory cytokines are increasingly used in various clinical situations. The therapeutic benefit of cytokine elimination likely depends on timing. Although treatment seems to be most effective when started within the first 24 h, therapy is often delayed as it must be combined with another extracorporeal circuit. Thus, using a pumpless extracorporeal HA technique might be a valuable option in order to expedite the commencement of cytokine elimination in critically ill patients.

COVID-19 Pulmonary Failure and Extracorporeal Membrane Oxygenation: First Experience from Three European Extracorporeal Membrane Oxygenation Centers.

On April 17, 2020, a coronavirus disease 2019 (COVID-19) webinar was held by selected international experts in the field of intensive care and specialized respiratory ECMO centers from Germany, Italy, Spain, and the United Kingdom, which was hosted by the German Heart Centre Berlin/Charité. The experts shared their experience about the treatment of 42 patients with severe acute respiratory failure requiring venovenous extracorporeal membrane oxygenation (VV-ECMO). Patients were predominantly male (male-to-female ratio: 3:1), with a mean age of 51 years (range: 25-73 years). VV-ECMO support was indicated in 30% of the ventilated COVID-19 patients. The mean time requiring mechanical ventilation was 16.5 days, with a mean duration of ECMO support of 10.6 days. At the time of the webinar, a total of 17 patients had already been decannulated from ECMO, whereas six died with multiorgan failure. 18 patients remained on ECMO, with their final outcomes unknown at the time of the webinar. Hospital mortality was 25.6% (as of April 17, 2020). In this respect, VV-ECMO, provided by expert centers, is a recognized and validated mode of advanced life-support during the recent COVID-19 pandemic with good outcomes.

Mitochondria and Pharmacologic Cardiac Conditioning-At the Heart of Ischemic Injury.

Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning.

[Extracorporeal cardiopulmonary resuscitation (eCPR) for out-of-hospital cardiac arrest (OHCA) : Retrospective analysis of a load and go strategy under the aspect of golden hour of eCPR]. / Extrakorporale kardiopulmonale Reanimation (eCPR) bei prähospitalem Herz-Kreislauf-Stillstand (OHCA) : Retrospektive Analyse einer "Load-and-go"-Strategie unter dem Aspekt "golden hour of eCPR".

BACKGROUND: Survival rates after an out-of-hospital cardiac arrest (OHCA) remain low. Extracorporeal cardiopulmonary resuscitation (eCPR) has been introduced as an attempt to increase survival in selected patients and observational studies have shown promising results. Nevertheless, inclusion criteria and timing of eCPR remain undefined. OBJECTIVE: The current study analyzed a load and go strategy with respect to the golden hour of eCPR as a cut-off time for survival and favorable neurological outcome. MATERIAL AND METHODS: This retrospective cohort study included 32 patients who underwent eCPR treatment due to an OHCA between January 2017 and September 2019. Routinely taken patient demographic data (age, BMI, sex) were analyzed. The main focus was set on processing times in the preclinical and clinical setting. Time intervals including OHCA until ambulance arrival, time on scene, transportation times and door to eCPR were extracted from emergency medical service (EMS) and resuscitation protocols. Low-flow times, survival and neurological outcome were analyzed. RESULTS: The use of eCPR in OHCA was associated with survival to hospital discharge in 28% and a good neurological outcome in 19% of the cases. Both groups (survivor and nonsurvivor) did not differ in patient demographics except for age. Survivors were significantly younger (47 (30-60) vs. 59 (50-68) years, p = 0.035). Processing times as well as low-flow times were not significantly different (OHCA-eCPR survivor 64 (50-87) vs. non-survivor 74 (51-85) min; p-value 0.64); however, median low-flow times were outside the golden hour of eCPR (69 (52-86)). CONCLUSION: Despite low-flow times of more than 60 min, eCPR was associated with survival in 28% after OHCA. Hence, exceeding the golden hour of eCPR cannot act as a definitive exclusion criterion for eCPR.

[Anesthesiology Seminar in Times of COVID-19: a Hybrid Model evolving from Digital and Virtual Lessons]. / Anästhesiologische Lehre in Zeiten von Corona ­ von der Präsenzlehre zum Hybridmodell.

On March 14, 2020, the first Bavaria-wide exit restriction was imposed and university teaching in its familiar form was drastically restricted. For intensive care physicians and anesthetists, there was a special area of tension in many places due to the extraordinary demand for the treatment of critically ill patients and the restructuring and maintenance of teaching. We report on the realignment of the anesthesia seminar in an online flipped classroom and the development towards a hybrid model. As such, an adequate transfer of knowledge could take place under difficult conditions and at the same time the teaching concept could be further developed.

Targeted temperature management in patients undergoing extracorporeal life support after out-of-hospital cardiac arrest: an EURO-ELSO 2018 annual conference survey.

Targeted temperature management and extracorporeal life support, particularly extracorporeal membrane oxygenation in patients undergoing cardiopulmonary resuscitation, represent outcome-enhancing strategies for patients following in- and out-of-hospital cardiac arrest. Although targeted temperature management with hypothermia between 32°C and 34°C and extracorporeal cardiopulmonary resuscitation bear separate potentials to improve outcome after out-of-hospital cardiac arrest, each is associated with bleeding risk and risk of infection. Whether the combination imposes excessive risk on patients is, however, unknown.

Controlled Hypercapnia Enhances Cerebral Blood Flow and Brain Tissue Oxygenation After Aneurysmal Subarachnoid Hemorrhage: Results of a Phase 1 Study.

BACKGROUND: This study investigated if cerebral blood flow (CBF) regulation by changes of the arterial partial pressure of carbon dioxide (PaCO2) can be used therapeutically to increase CBF and improve neurological outcome after subarachnoid hemorrhage (SAH). METHODS: In 12 mechanically ventilated poor-grade SAH-patients, a daily trial intervention was performed between day 4 and 14. During this intervention, PaCO2 was decreased to 30 mmHg and then gradually increased to 40, 50, and 60 mmHg in 15-min intervals by modifications of the respiratory minute volume. CBF and brain tissue oxygen saturation (StiO2) were the primary and secondary endpoints. Intracranial pressure was controlled by an external ventricular drainage. RESULTS: CBF reproducibly decreased during hyperventilation and increased to a maximum of 141 ± 53 % of baseline during hypercapnia (PaCO2 60 mmHg) on all days between day 4 and 14 after SAH. Similarly, StiO2 increased during hypercapnia. CBF remained elevated within the first hour after resetting ventilation to baseline parameters and no rebound effect was observed within this time-span. PaCO2-reactivities of CBF and StiO2 were highest between 30 and 50 mmHg and slightly decreased at higher levels. CONCLUSION: CBF and StiO2 reproducibly increased by controlled hypercapnia of up to 60 mmHg even during the period of the maximum expected vasospasm. The absence of a rebound effect within the first hour after hypercapnia indicates that an improvement of the protocol is possible. The intervention may yield a therapeutic potential to prevent ischemic deficits after aneurysmal SAH.

[Cardiac support and replacement therapies]. / Organersatzverfahren - Kreislaufunterstützung und -ersatz.

Circulatory support represents an integral part within the treatment of the critically ill patient. Sophisticated pharmacologic regimens help to maintain systemic perfusion pressure by increasing vascular tone as well as mediating positive inotropic effects. Besides the administration of catecholamines and phosphodiesterase-III-inhibitors, in particular the administration of levosimendan represents a promising alternative during low-cardiac-output. Nevertheless, sufficient evidence demonstrating a survival benefit for any pharmacologic regimen is nonexistent. In case pharmacological measures do not suffice mechanical cardiopulmonary support (MCS) may be used. MCS may be used during cardiopulmonary resuscitation or a "low-cardiac-output-syndrome" as bridging towards decision, recovery or long-term support. Venoarterial extracorporeal membrane oxygenation (vaECMO) may take over cardiopulmonary function and may improve survival as well as neurological outcome after cardiogenic shock or cardiopulmonary resuscitation.

[Respiratory and extracorporeal lung support]. / Organersatzverfahren - Lungenersatzverfahren.

Mechanical ventilation is the most commonly used form of respiratory support to restore or maintain adequate gas exchange. However, mechanical ventilation does not provide a physiological form of breathing. Neither does it provide an optimal ventilation / perfusion ratio due to passive movement of the diagphragm favoring the non-dependent parts of the lung. Furthermore, patients are in danger of ventilator-associated/induced lung injury (VALI/VILI). Hence, lung protective ventilation is mandatory in patients with an acute respiratory distress syndrome (ARDS) and should likewise be used in the operating room. Extracorporeal pulmonary support is required in case mechanical ventilation is unable to secure sufficient gas exchange or VILI is imminent. Venovenous extracorporeal membrane oxygenation (vvECMO) acts as lung replacement therapy and may improve survival along with treatment in an ARDS-center.

Netrin-1 abrogates ischemia/reperfusion-induced cardiac mitochondrial dysfunction via nitric oxide-dependent attenuation of NOX4 activation and recoupling of NOS.

Despite an established role of mitochondrial dysfunction in cardiac ischemia/reperfusion (I/R) injury, the upstream activators have remained incompletely defined. We have recently identified an innovative role of exogenously applied netrin-1 in cardioprotection, which is mediated by increased nitric oxide (NO) bioavailability. Here, we tested the hypothesis that this "pharmacological" treatment of netrin-1 preserves mitochondrial function via novel mechanisms that are NO dependent. Freshly isolated C57BL6 mouse hearts were perfused using a Langendorff system, and subjected to a 20min global ischemia/60min reperfusion, in the presence or absence of netrin-1. I/R induced marked increases in infarct size, total superoxide and hydrogen peroxide production, activity and protein abundance of NADPH oxidase (NOX) isoform 4 (NOX4), as well as impaired mitochondrial integrity and function, all of which were attenuated by netrin-1. This protective effect of netrin-1 is attributed to cGMP, a downstream effector of NO. The protein levels of NOX1 and NOX2 were however unaffected, and infarct size from NOX1 and NOX2 knockouts was not different from wild type animals. Scavenging of NO with PTIO reversed inhibitory effects of netrin-1 on NOX4, while NO donor attenuated NOX4 protein abundance. In vivo NOX4 RNAi, or sepiapterin perfusion, resulted in recoupling of NOS, decreased infarct size, and blockade of dysfunctional mitochondrial swelling and mitochondrial superoxide production. These data demonstrate that netrin-1 induces cardioprotection through inhibition of NOX4 activity, which leads to recoupling of NOS, augmented NO bioavailability, reduction in oxidative stress, and ultimately preservation of mitochondrial function. The NO-dependent NOX4 inhibition connects with our previously established pathway of DCC/ERK1/2/eNOS/NO/DCC feed-forward mechanism, to maintain NOS in the coupling state to attenuate oxidative stress to preserve mitochondrial function. These findings may promote development of novel therapeutics for cardiac I/R injury. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".