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.

[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.

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.

The Benefit of Benzodiazepine Reduction: Improving Sedation in Surgical Intensive Care.

AIMS: Sedation, as it is often required in critical care, is associated with immobilization, prolonged ventilation, and increased morbidity. Most sedation protocols are based on benzodiazepines. The presented study analyzes the benefit of benzodiazepine-free sedation. METHODS: In 2008, 134 patients were treated according to a protocol using benzodiazepine and propofol (Group 1). In 2009, we introduced a new sedation strategy based on sufentanil, nonsteroidal anti-inflammatory drugs, neuroleptics, and antidepressants, which was applied in 140 consecutive patients (Group 2). Depth of sedation, duration of mechanical ventilation, duration of Intensive Care Unit, and hospital stay were analyzed. RESULTS: Group 1 had both a longer duration of deep sedation (18.7 ± 2.5 days vs. 12.6 ± 1.85 days, P = 0.031) and a longer duration of controlled ventilation (311, 35 ± 32.69 vs. 143, 96 ± 20.76 h, P < 0.0001) than Group 2. Ventilator days were more frequent in Group 1 (653, 66 ± 98.37 h vs. 478, 89 ± 68.92 h, P = 0.128). CONCLUSIONS: The benzodiazepine-free sedation protocol has been shown to significantly reduce depth of sedation and controlled ventilation. Additional evidence is needed to ascertain reduction of ventilator days which would not only be of benefit for the patient but also for the hospital Management.

[The perioperative myocardial infarction - an interdisciplinary task]. / Der perioperative Myokardinfarkt - Eine interdisziplinäre Aufgabe.

Cardiovascular complications, particularly perioperative myocardial infarction (PMI), are major contributors to mortaliyt after noncardiac surgery. PMI often occurs unnoticed without symptoms or ECG changes. Despite ist silent presentation, PMI is associated with increased mortality. The combination of high associated mortality and diagnostic challenges mandates increased awareness of PMI. Perioperative myocardial infarction may result from plaque rupture (PMI type I) or be caused by a myocardial supply-demand imbalance of oxygen without plaque rupture (PMI type II). Most PMIs occur within the first 3 days after surgery, highlighting the need for clinical monitoring in order to allow fast diagnosis and initiation of appropriate therapy. Measurement of cardiac troponin and 12-lead ECG are the diagnostic cornerstone. Therapy of PMI represents a challenge for physicians and requires a collaboration of surgeons, anesthesiologists and cardiologists.

TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes.

TASK-1 channels have emerged as promising drug targets against atrial fibrillation, the most common arrhythmia in the elderly. While TASK-3, the closest relative of TASK-1, was previously not described in cardiac tissue, we found a very prominent expression of TASK-3 in right human auricles. Immunocytochemistry experiments of human right auricular cardiomyocytes showed that TASK-3 is primarily localized at the plasma membrane. Single-channel recordings of right human auricles in the cell-attached mode, using divalent-cation-free solutions, revealed a TASK-1-like channel with a single-channel conductance of about 30pS. While homomeric TASK-3 channels were not found, we observed an intermediate single-channel conductance of about 55pS, possibly reflecting the heteromeric channel formed by TASK-1 and TASK-3. Subsequent experiments with TASK-1/TASK-3 tandem channels or with co-expressed TASK-1 and TASK-3 channels in HEK293 cells or Xenopus oocytes, supported that the 55pS channels observed in right auricles have electrophysiological characteristics of TASK-1/TASK-3 heteromers. In addition, co-expression experiments and single-channel recordings suggest that heteromeric TASK-1/TASK-3 channels have a predominant surface expression and a reduced affinity for TASK-1 blockers. In summary, the evidence for heteromeric TASK-1/TASK-3 channel complexes together with an altered pharmacologic response to TASK-1 blockers in vitro is likely to have further impact for studies isolating ITASK-1 from cardiomyocytes and for the development of drugs specifically targeting TASK-1 in atrial fibrillation treatment.

The role of acid-sensitive two-pore domain potassium channels in cardiac electrophysiology: focus on arrhythmias.

The current kinetics of two-pore domain potassium (K2P) channels resemble those of the steady-state K(+) currents being active during the plateau phase of cardiac action potentials. Recent studies support that K2P channels contribute to these cardiac currents and thereby influence action potential duration in the heart. Ten of the 15 K2P channels present in the human genome are sensitive to variations of the extracellular and/or intracellular pH value. This review focuses on a set of K2P channels which are inhibited by extracellular protons, including the subgroup of tandem of P domains in a weak inward-rectifying K(+) (TWIK)-related acid-sensitive potassium (TASK) and TWIK-related alkaline-activated K(+) (TALK) channels. The role of TWIK-1 in the heart is also discussed since, after successful expression, an extracellular pH dependence, similar to that of TASK-1, was described as a hallmark of TWIK-1. The expression profile in cardiac tissue of different species and the functional data in the heart are summarized. The distinct role of the different acid-sensitive K2P channels in cardiac electrophysiology, inherited forms of arrhythmias and pharmacology, and their role as drug targets is currently emerging and is the subject of this review.

Kv1.5 blockers preferentially inhibit TASK-1 channels: TASK-1 as a target against atrial fibrillation and obstructive sleep apnea?

Atrial fibrillation and obstructive sleep apnea are responsible for significant morbidity and mortality in the industrialized world. There is a high medical need for novel drugs against both diseases, and here, Kv1.5 channels have emerged as promising drug targets. In humans, TASK-1 has an atrium-specific expression and TASK-1 is also abundantly expressed in the hypoglossal motor nucleus. We asked whether known Kv1.5 channel blockers, effective against atrial fibrillation and/or obstructive sleep apnea, modulate TASK-1 channels. Therefore, we tested Kv1.5 blockers with different chemical structures for their TASK-1 affinity, utilizing two-electrode voltage clamp (TEVC) recordings in Xenopus oocytes. Despite the low structural conservation of Kv1.5 and TASK-1 channels, we found all Kv1.5 blockers analyzed to be even more effective on TASK-1 than on Kv1.5. For instance, the half-maximal inhibitory concentration (IC50) values of AVE0118 and AVE1231 (A293) were 10- and 43-fold lower on TASK-1. Also for MSD-D, ICAGEN-4, S20951 (A1899), and S9947, the IC50 values were 1.4- to 70-fold lower than for Kv1.5. To describe this phenomenon on a molecular level, we used in silico models and identified unexpected structural similarities between the two drug binding sites. Kv1.5 blockers, like AVE0118 and AVE1231, which are promising drugs against atrial fibrillation or obstructive sleep apnea, are in fact potent TASK-1 blockers. Accordingly, block of TASK-1 channels by these compounds might contribute to the clinical effectiveness of these drugs. The higher affinity of these blockers for TASK-1 channels suggests that TASK-1 might be an unrecognized molecular target of Kv1.5 blockers effective in atrial fibrillation or obstructive sleep apnea.

Diagnosis and management for urosepsis.

Urosepsis is defined as sepsis caused by a urogenital tract infection. Urosepsis in adults comprises approximately 25% of all sepsis cases, and is in most cases due to complicated urinary tract infections. The urinary tract is the infection site of severe sepsis or septic shock in approximately 10-30% of cases. Severe sepsis and septic shock is a critical situation, with a reported mortality rate nowadays still ranging from 30% to 40%. Urosepsis is mainly a result of obstructed uropathy of the upper urinary tract, with ureterolithiasis being the most common cause. The complex pathogenesis of sepsis is initiated when pathogen or damage-associated molecular patterns recognized by pattern recognition receptors of the host innate immune system generate pro-inflammatory cytokines. A transition from the innate to the adaptive immune system follows until a T(H2) anti-inflammatory response takes over, leading to immunosuppression. Treatment of urosepsis comprises four major aspects: (i) early diagnosis; (ii) early goal-directed therapy including optimal pharmacodynamic exposure to antimicrobials both in the plasma and in the urinary tract; (iii) identification and control of the complicating factor in the urinary tract; and (iv) specific sepsis therapy. Early adequate tissue oxygenation, adequate initial antibiotic therapy, and rapid identification and control of the septic focus in the urinary tract are critical steps in the successful management of a patient with urosepsis, which includes early imaging, and an optimal interdisciplinary approach encompassing emergency unit, urological and intensive-care medicine specialists.

Outcome in patients with long-term treatment in a surgical intensive care unit.

BACKGROUND: This study aimed to evaluate the outcome of patients with abdominal, thoracic or vascular operations and long-term intensive care unit (ICU) treatment. PATIENTS AND METHODS: The present retrospective observational cohort study was performed at the authors' surgical ICU at the Marburg University Medical Centre. All patients who stayed at the ICU longer than 48 h and underwent visceral, thoracic or vascular surgery between January 2005 and December 2006 were retrospectively analysed. Patients with an ICU stay of 20 or more days were defined as the long-term study group. Clinical variables were tested for prognostic value. RESULTS: In 2 years, 852 patients were treated at the intensive care unit. Follow-up was available in 502 patients, with 219 patients treated for two and more days and a median of 16.4 days. Sixty-seven long-term patients were compared to 152 (69.4 %) patients treated between 2 and 20 days. Overall survival after 12 months was 50.2 % (110/219), while 65.8 % (144/219) were discharged from ICU. Older age, longer treatment at the ICU and increased simplified acute physiology score (SAPS) at admission were associated with decreased 12-month survival, while no statistical differences were observed for the underlying and malignant disease by univariate analysis. The risk of death was 29, 56 and 61 % for patients treated 2-4, 5-19 and ≥20 days at the ICU. Decreased survival of patients treated for 5-19 and ≥20 days were confirmed by logrank test (p = 0.001). CONCLUSIONS: Patients with long-term ICU stay showed decreased survival than patients who are treated less than 5 days but similar survival as patients which stayed between 5 and 19 days. Malignant disease is not associated with an unfavourable 12-month survival while older age, higher SAPS index at discharge and longer stay at ICU are. Long-term ICU survivors have no increased risk to succumb after discharge from ICU.

[Case report - Tako-Tsubo Syndrom]. / Kasuistik - Tako-Tsubo-Syndrom nach Allgemeinanästhesie.

A 69-year-old woman reported that underwent endonasal frontal sinus surgery under general anesthesia. In her medical history the patient reports a multiple occurrence of angina pectoris attacks, especially in stressful situations. Coronary heart disease has so far been excluded. At preoperative presentation of this patient was in good general and nutritional state. Intraoperative hypotension had to be treated with norepinephrine. In the recovery room, the patient developed angina pectoris symptoms and the ECG showed T negativity. The patient was admitted on an ICU. Coronary angiography showed left ventricular apical ballooning with a transient akinesia typical of the left ventricle, as is seen in a Tako-Tsubo syndrome. The symptoms are similar to acute coronary artery disease, but without stenosis of coronary arteries. Physical or emotional stress is known to trigger Tako-Tsubo Syndrome, but the exact etiology or pathophysiology remains somewhat unclear.

Pumpless Extracorporeal Hemadsorption Technique (pEHAT): A Proof-of-Concept Animal Study.

Background: Extracorporeal hemadsorption eliminates proinflammatory mediators in critically ill patients with hyperinflammation. The use of a pumpless extracorporeal hemadsorption technique allows its early usage prior to organ failure and the need for an additional medical device. In our animal model, we investigated the feasibility of pumpless extracorporeal hemadsorption over a wide range of mean arterial pressures (MAP). Methods: An arteriovenous shunt between the femoral artery and femoral vein was established in eight pigs. The hemadsorption devices were inserted into the shunt circulation; four pigs received CytoSorb® and four Oxiris® hemadsorbers. Extracorporeal blood flow was measured in a range between mean arterial pressures of 45-85 mmHg. Mean arterial pressures were preset using intravenous infusions of noradrenaline, urapidil, or increased sedatives. Results: Extracorporeal blood flows remained well above the minimum flows recommended by the manufacturers throughout all MAP steps for both devices. Linear regression resulted in CytoSorb® blood flow [mL/min] = 4.226 × MAP [mmHg] - 3.496 (R-square 0.8133) and Oxiris® blood flow [mL/min] = 3.267 × MAP [mmHg] + 57.63 (R-square 0.8708), respectively. Conclusion: Arteriovenous pumpless extracorporeal hemadsorption resulted in sufficient blood flows through both the CytoSorb® and Oxiris® devices over a wide range of mean arterial blood pressures and is likely an intriguing therapeutic option in the early phase of septic shock or hyperinflammatory syndromes.

TASK-1 channels may modulate action potential duration of human atrial cardiomyocytes.

BACKGROUND/AIMS: Atrial fibrillation is the most common arrhythmia in the elderly, and potassium channels with atrium-specific expression have been discussed as targets to treat atrial fibrillation. Our aim was to characterize TASK-1 channels in human heart and to functionally describe the role of the atrial whole cell current I(TASK-1). METHODS AND RESULTS: Using quantitative PCR, we show that TASK-1 is predominantly expressed in the atria, auricles and atrio-ventricular node of the human heart. Single channel recordings show the functional expression of TASK-1 in right human auricles. In addition, we describe for the first time the whole cell current carried by TASK-1 channels (I(TASK-1)) in human atrial tissue. We show that I(TASK-1) contributes to the sustained outward current I(Ksus) and that I(TASK-1) is a major component of the background conductance in human atrial cardiomyocytes. Using patch clamp recordings and mathematical modeling of action potentials, we demonstrate that modulation of I(TASK-1) can alter human atrial action potential duration. CONCLUSION: Due to the lack of ventricular expression and the ability to alter human atrial action potential duration, TASK-1 might be a drug target for the treatment of atrial fibrillation.

[Fungal infections in the intensive care unit]. / Krankenhaushygiene - Pilzinfektionen auf der Intensivstation.

Invasive infections through to sepsis caused by fungi in intensive care units have increased markedly in the past few years. In the mean time almost every tenth case of sepsis in the intensive care unit is the result of an invasive fungal infection. Not only hemato-oncological or organ-transplanted patients are affected but increasingly also those patients who have been under intensive care for a considerable time and who exhibit particular risk factors. The lethality among the afflicted patients is high. The diagnosis of fungal infections is still difficult; unambiguous, highly sensitive and specific test procedures are still lacking. The decision for therapy must often be made empirically and as early as possible. In the past few years newly developed antimycotic agents have opened up new options for therapy.

The janus-kinase inhibitor ruxolitinib in SARS-CoV-2 induced acute respiratory distress syndrome (ARDS).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 (coronavirus disease 2019), which is associated with high morbidity and mortality, especially in elder patients. Acute respiratory distress syndrome (ARDS) is a life-threatening complication of COVID-19 and has been linked with severe hyperinflammation. Dexamethasone has emerged as standard of care for COVID-19 associated respiratory failure. In a non-randomized prospective phase II multi-center study, we asked whether targeted inhibition of Janus kinase-mediated cytokine signaling using ruxolitinib is feasible and efficacious in SARS-CoV-2- induced ARDS with hyperinflammation. Sixteen SARS-CoV-2 infected patients requiring invasive mechanical ventilation for ARDS were treated with ruxolitinib in addition to standard treatment. Ruxolitinib treatment was well tolerated and 13 patients survived at least the first 28 days on treatment, which was the primary endpoint of the trial. Immediate start of ruxolitinib after deterioration was associated with improved outcome, as was a lymphocyte-to-neutrophils ratio above 0.07. Together, treatment with the janus-kinase inhibitor ruxolitinib is feasible and might be efficacious in COVID-19 induced ARDS patients requiring invasive mechanical ventilation. The trial has been registered under EudraCT-No.: 2020-001732-10 and NCT04359290.

[ECMO and ARDS-therapy - an update]. / Die ECMO in der ARDS-Therapie - Ein Update.

The "Acute Respiratory Distress Syndrome" (ARDS) is a life threatening disease and is associated with a high mortality, mainly due to multi-organ failure. Invasive mechanical ventilation can worsen multi-organ failure which must be avoided. A tidal volume of 6 ml/kg bodyweight should be the aim. Extracorporeal lung assist devices like ECMO or iLA can contribute to lung-protective mechanical ventilation.

Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children. Currently, there is no RSV vaccine or universally accessible antiviral treatment available. Addressing the urgent need for new antiviral agents, we have investigated the capacity of a non-coding single-stranded oligonucleotide (ssON) to inhibit RSV infection. By utilizing a GFP-expressing RSV, we demonstrate that the ssON significantly reduced the proportion of RSV infected A549 cells (lung epithelial cells). Furthermore, we show that ssON's antiviral activity was length dependent and that both RNA and DNA of this class of oligonucleotides have antiviral activity. We reveal that ssON inhibited RSV infection by competing with the virus for binding to the cellular receptor nucleolin in vitro. Additionally, using a recombinant RSV that expresses luciferase we show that ssON effectively blocked RSV infection in mice. Treatment with ssON in vivo resulted in the upregulation of RSV-induced interferon stimulated genes (ISGs) such as Stat1, Stat2, Cxcl10, and Ccl2. This study highlights the possibility of using oligonucleotides as therapeutic agents against RSV infection. We demonstrate that the mechanism of action of ssON is the inhibition of viral entry in vitro, likely through the binding of the receptor, nucleolin and that ssON treatment against RSV infection in vivo additionally results in the upregulation of ISGs.

COVID-19 Induced Acute Respiratory Distress Syndrome-A Multicenter Observational Study.

Background: Proportions of patients dying from the coronavirus disease-19 (COVID-19) vary between different countries. We report the characteristics; clinical course and outcome of patients requiring intensive care due to COVID-19 induced acute respiratory distress syndrome (ARDS). Methods: This is a retrospective, observational multicentre study in five German secondary or tertiary care hospitals. All patients consecutively admitted to the intensive care unit (ICU) in any of the participating hospitals between March 12 and May 4, 2020 with a COVID-19 induced ARDS were included. Results: A total of 106 ICU patients were treated for COVID-19 induced ARDS, whereas severe ARDS was present in the majority of cases. Survival of ICU treatment was 65.0%. Median duration of ICU treatment was 11 days; median duration of mechanical ventilation was 9 days. The majority of ICU treated patients (75.5%) did not receive any antiviral or anti-inflammatory therapies. Venovenous (vv) ECMO was utilized in 16.3%. ICU triage with population-level decision making was not necessary at any time. Univariate analysis associated older age, diabetes mellitus or a higher SOFA score on admission with non-survival during ICU stay. Conclusions: A high level of care adhering to standard ARDS treatments lead to a good outcome in critically ill COVID-19 patients.