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Cytochrome P450 (CYP) 2D6 is a polymorphic enzyme expressed in the central nervous system (CNS), important in drug metabolism and with a potentially constitutive role in CNS function such as vigilance. This study aimed to analyze variability in CYP2D6 activity linked to vigilance-related adverse drug reactions (ADRs) in the CNS. A dataset of N = 2939 ADR cases of the prospective multicenter observational trial in emergency departments (EDs) (ADRED; trial registration: DRKS-ID: DRKS00008979) was analyzed. Dizziness as the most frequent reported CNS ADR symptom (12.7% of patients, n = 372) related to vigilance was chosen as the outcome. The association of dizziness with CYP2D6 activity markers was analyzed. The number of CYP2D6 substrates taken, a CYP2D6 saturation score (no, moderate, and strong saturation), a CYP2D6 saturation/inhibition score (no, weak, moderate, and strong), and composed CYP2D6 activity using a genotyped subsample ( n = 740) calculating additive effects of genotype and CYP2D6 saturation by drug exposure were used as CYP2D6 activity markers. Effects were compared to other frequent nonvigilance-related CNS ADR symptoms (syncope and headache). Secondary analyses were conducted to control for other ADR symptoms frequently associated with dizziness (syncope, nausea, and falls). The majority of all patients (64.5%, n = 1895) took at least one drug metabolized by CYP2D6. Around a third took a CNS drug (32.5%, n = 955). The chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01-1.23]. Presenting with drug-related dizziness was more likely with CYP2D6 saturation and saturation/inhibition (both OR 1.27 [1.00-1.60]). The composed CYP2D6 activity was positively associated with dizziness ( p = 0.028), while poorer activity affected patients more often with dizziness as an ADR. In contrast, nonvigilance-related ADR symptoms such as syncope and nausea were not consistently significantly associated with CYP2D6 activity markers. This study shows an association between the number of CYP2D6 substrates, the predicted CYP2D6 activity, and the occurrence of dizziness as a CNS ADR symptom. As dizziness is a vigilance-related CNS symptom, patients with low CYP2D6 activity might be more vulnerable to drug-related dizziness. This study underlines the need for understanding individual drug metabolism activity and individual risks for ADRs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Just, Dormann, Freitag, Schurig, Böhme, Steffens, Scholl, Seufferlein, Graeff, Schwab and Stingl.)

Background: Mutations in the EZH2 gene are recurrently found in patients with myeloid neoplasms and are associated with a poor prognosis. We aimed to characterize genetic and epigenetic alterations of EZH2 in 58 patients (51 with acute myeloid leukemia and 7 with myelodysplastic or myeloproliferative neoplasms) by integrating data on EZH2 mutational status, co-occurring mutations, and EZH2 copy number status with EZH2 protein expression, histone H3K27 trimethylation, and EZH2 promoter methylation., Results: EZH2 was mutated in 6/51 acute myeloid leukemia patients (12%) and 7/7 patients with other myeloid neoplasms. EZH2 mutations were not overrepresented in patients with chromosome 7q deletions or losses. In acute myeloid leukemia patients, EZH2 mutations frequently co-occurred with CEBPA (67%), ASXL1 (50%), TET2 and RAD21 mutations (33% each). In EZH2-mutated patients with myelodysplastic or myeloproliferative neoplasms, the most common co-mutations were in ASXL1 (100%), NRAS, RUNX1, and STAG2 (29% each). EZH2 mutations were associated with a significant decrease in EZH2 expression (p = 0.0002), which was similar in patients with chromosome 7 aberrations and patients with intact chromosome 7. An association between EZH2 protein expression and H3K27 trimethylation was observed in EZH2-unmutated patients (R 2  = 0.2, p = 0.01). The monoallelic state of EZH2 was not associated with EZH2 promoter hypermethylation. In multivariable analyses, EZH2 mutations were associated with a trend towards an increased risk of death (hazard ratio 2.51 [95% confidence interval 0.87-7.25], p = 0.09); similarly, low EZH2 expression was associated with elevated risk (hazard ratio 2.54 [95% confidence interval 1.07-6.04], p = 0.04)., Conclusions: Perturbations of EZH2 activity in AML/MDS occur on different, genetic and non-genetic levels. Both low EZH2 protein expression and, by trend, EZH2 gene mutations predicted inferior overall survival of AML patients receiving standard chemotherapy.

Background: Providing anesthesia for pediatric patients undergoing congenital cardiac surgery is complex and requires profound knowledge and clinical experience. Prospective studies on best anesthetic management are missing, partially due to different standards. The aim of the present study was to survey the current standard practice in anesthetic management in pediatric cardiac surgical centers in Germany., Methods: All 78 cardiac surgical centers in Germany were reviewed for a congenital cardiac surgery program. Centers with an active program for congenital cardiac surgery were interviewed to participate in the present online questionnaire to assess their current anesthetic practice., Results: Twenty-seven German centers running an active program for congenital heart surgery were identified, covering more than 3,000 pediatric cardiac surgeries annually. Of these centers, 96.3% (26/27) participated in our survey. Standard induction agents were etomidate in 26.9% (7/26), propofol in 19.2% (5/26), a combination of benzodiazepines and ketamine in 19.2% (5/26), and barbiturates in 11.5% (3/26). General anesthesia was preferentially maintained using volatile agents, 61.5% (16/26), with sevoflurane being the most common volatile agent within this group, 81.2% (13/16). Intraoperative first-choice/first-line inotropic drug was epinephrine, 53.8% (14/26), followed by milrinone, 23.1% (6/26), and dobutamine 15.4% (4/26). Fast-track programs performing on-table extubation depending on the type of surgical procedure were established at 61.5% (16/26) of the centers., Conclusion: This study highlights the diversity of clinical standards in pediatric cardiac anesthesia for congenital cardiac surgery in Germany.

It remains unclear how introduction of high-sensitivity troponin T testing, as opposed to conventional troponin testing, has affected the diagnosis of acute myocardial infarction (AMI) and resource utilization in unselected hospitalized patients. In this retrospective analysis, we include all consecutive cases from our center during two corresponding time frames (10/2016-04/2017 and 10/2017-04/2018) for which different troponin tests were performed: conventional troponin I (cTnI) and high-sensitivity troponin T (hs-TnT) assays. Testing was performed in 18,025 cases. The incidence of troponin levels above the 99th percentile was significantly higher in cases tested using hs-TnT. This was not associated with increased utilization of echocardiography, coronary angiography, or percutaneous coronary intervention. Although there were no changes in local standard operating procedures, study site personnel, or national coding guidelines, the number of coded AMI significantly decreased after introduction of hs-TnT. In this single-center retrospective study comprising 18,025 mixed medical and surgical cases with troponin testing, the introduction of hs-TnT was not associated with changes in resource utilization among the general cohort, but instead, led to a decrease in the international classification of diseases (ICD)-10 coded diagnosis of AMI.

Background: In Germany, emergency medical teams are staffed with physicians but evidence regarding their prehospital diagnostic accuracy remains poor., Objective: To evaluate the out-of-hospital diagnostic accuracy of physician-staffed emergency medical teams (PEMTs)., Methods: A retrospective observational cohort study involving the Emergency Medical Service Bonn, Germany, from January to December 2004 and 2014 respectively. A total of 8346 patients underwent medical treatment by PEMTs, of which 1960 adult patients (inclusion criteria: ≥18 years of age, hospital diagnosis available) were included for further analysis. Reasons for non-inclusion: death on scene, outpatient, interhospital transfer, mental illness, false alarm, no hospital medical history available. The overall diagnostic accuracy (correct or false) of PEMTs was measured after matching the prehospital diagnosis with the corresponding diagnosis of the hospital. Secondary outcome measures were incidence of common PEMT diagnoses (acute coronary syndrome (ACS), dyspnea, stroke/intracerebral bleeding), recognition rate of a given disease by PEMTs, and prehospital diagnostic accuracy in elderly patients., Results: PEMT calls increased 2-fold over a decade (2004: n = 3151 vs. 2014: n = 5195). Overall diagnostic accuracy of PEMTs increased from 87.5% in 2004 to 92.6% in the year 2014. The incidence of common PEMT diagnoses such as ACS, dyspnea or stroke/intracerebral bleeding increased 2-fold from 2004 to 2014. The recognition rate of a given disease by the PEMT varied between 2004 and 2014: an increase was observed when a stroke/intracerebral bleeding was diagnosed (2004: 67% vs. 2014: 83%; p = 0.054), a decreased rate of recognition occurred when a syncope/collapse was diagnosed (2004: 81% vs. 2014: 56%; p = 0.007) and a sepsis appears to be a rare event for EMS personnel (2004: 0% vs. 2014: 23%). Linear regression analysis revealed that the prehospital diagnostic accuracy decreases in the elderly patient., Conclusions: The overall prehospital diagnostic accuracy of PEMTs improved between the year 2004 and 2014 respectively. Our findings suggest that the incidence of common diseases (ACS, dyspnea stroke/intracerebral bleeding, sepsis) increased over a 10-year period. Diagnostic accuracy of different diseases varied but generally decreased in the elderly patient. Regular training of EMS personnel and public campaigns should be implemented to improve the diagnostic accuracy in the future.

Background: Extracorporeal membrane oxygenation procedure (ECMO) has been established in the therapy of respiratory insufficient infants with congenital diaphragmatic hernia. In congenital diaphragmatic hernia newborns, a delay in transfer to an ECMO centre is associated with a sharp increase in mortality. Predictive factors for ECMO support are urgently needed. We evaluated the routine parameters of the first blood withdrawal after birth in congenital diaphragmatic hernia infants, hypothesizing that early signs in bone marrow affecting haematology parameters for early regulation of potentially post birth hypoxia are predictive factors for ECMO support., Materials and Methods: In 44 patients born with congenital diaphragmatic hernia, differential blood cell count from the first blood withdrawal after birth was examined. Descriptive statistics included median, 95% confidence intervals, minimum and maximum differentiating ECMO/early mortality vs. no ECMO. Odds ratios with CI were calculated by binary logistic regression analysis. Best predictive markers were further checked in combination with the liver-up situation in two factorial regression models., Results: In our cohort, the survival rate was 77.3% (34/44). While 18 neonates received ECMO support, 26 experienced no ECMO during hospital stay. Odds ratio calculations showed that risk for ECMO support increases with augmenting leukocytes, erythrocytes, haemoglobin, haematocrit, mean cell volume and absolute immature granulocytes. Further, the risk advanced in line with the severity of congenital diaphragmatic hernia assessed by prenatal ultrasound., Conclusions: We conclude that these parameters are associated with disease severity in congenital diaphragmatic hernia newborns and may be considered potentially predictive biomarkers for the necessity of ECMO support.

The eligibility criteria for applying extracorporeal cardiopulmonary resuscitation (ECPR) in patients with cardiac arrest are currently unclear. For those patients with hypothermic cardiac arrest, the European Resuscitation Council (ERC) Guidelines recommend considering ECPR only for patients with potassium <8 mmol/L and a body temperature below 32°C, whereas the American Heart Association Guidelines (AHA) do not express this in a specific manner.We report the case of an urban unwitnessed out-of-hospital cardiac arrest patient found with her head immersed in water at a temperature of 23°C. The patient presented an unclear history and a dire combination of clinical and laboratory parameters (asystole, arterial blood gas: pH 6.8, potassium 8.3 mmol/L, lactate 16.0 mmol/L). Despite these poor prognostic indicators, ECPR was initiated after 95 minutes of CPR and the patient survived with a good neurological outcome.This case highlights the uncertainty in ECPR eligibility and prognostication, especially in those with hypothermia and water immersion for whom aggressive therapies may be warranted. Further data and improved strategies are required to delineate candidacy for this resource-intensive procedure better.

Background: In acute stroke patients, thrombolysis is one gold standard therapy option within the first four hours after the ischemic event. A contraindication for thrombolysis is an International Normalized Ratio (INR) value >1.7. Since time is brain, rapid and reliable INR results are fundamental. Aim was to compare INR values determined by central laboratory (CL) analyzer and Point-of-Care Testing(POCT)-device and to evaluate the quality of POCT performance in cases of potential therapeutic thrombolysis at a certified stroke unit., Methods: In 153 patients INR measurements using POCT-devices (HEMOCHRON Signature Elite®) were compared to INR measurements (BCS®XP) performed at the central laboratory. Outlier evaluation was performed regarding the critical thrombolysis cut-off., Results: Overall, we demonstrated a significant correlation (r = 0.809, p<0.0001) between both measurement methods. Mean value of the absolute difference between CL-INR and POCT-INR measurements was 0.23. In 95.4% of these cases, no differences regarding the critical cut-off (INR 1.7) were observed. POCT-INR values tended to be higher than the CL-INR values (p = 0.01). In 4.6% cases, a different value regarding thrombolysis cut-off was found. All patients were >75 years., Conclusions: POCT-INR measurements based on our POCT concept are suitable to determine INR values in critical stroke patients. Nevertheless, outlier evaluation is mandatory.

Fulfilling the requirements of point-of-care testing (POCT) training regarding proper execution of measurements and compliance with internal and external quality control specifications is a great challenge. Our aim was to compare the values of the highly critical parameter hemoglobin (Hb) determined with POCT devices and central laboratory analyzer in the highly vulnerable setting of an emergency department in a supra maximal care hospital to assess the quality of POCT performance. In 2548 patients, Hb measurements using POCT devices (POCT-Hb) were compared with Hb measurements performed at the central laboratory (Hb-ZL). Additionally, sub collectives (WHO anemia classification, patients with Hb <8 g/dl and suprageriatric patients (age >85y.) were analyzed. Overall, the correlation between POCT-Hb and Hb-ZL was highly significant (r = 0.96, p<0.001). Mean difference was -0.44g/dl. POCT-Hb values tended to be higher than Hb-ZL values (t(2547) = 36.1, p<0.001). Standard deviation of the differences was 0.62 g/dl. Only in 26 patients (1%), absolute differences >2.5g/dl occurred. McNemar´s test revealed significant differences regarding anemia diagnosis according to WHO definition for male, female and total patients (♂ p<0.001; ♀ p<0.001, total p<0.001). Hb-ZL resulted significantly more often in anemia diagnosis. In samples with Hb<8g/dl, McNemar´s test yielded no significant difference (p = 0.169). In suprageriatric patients, McNemar´s test revealed significant differences regarding anemia diagnosis according to WHO definition in male, female and total patients (♂ p<0.01; ♀ p = 0.002, total p<0.001). The difference between Hb-ZL and POCT-Hb with Hb<8g/dl was not statistically significant (<8g/dl, p = 1.000). Overall, we found a highly significant correlation between the analyzed hemoglobin concentration measurement methods, i.e. POCT devices and at the central laboratory. The results confirm the successful implementation of the presented POCT concept. Nevertheless some limitations could be identified in anemic patients stressing the importance of carefully examining clinically implausible results., Competing Interests: The authors have declared that no competing interests exist.

Severe burn injuries often require specialized treatment at a burn center. It is known that prompt admission to an intensive care unit is essential for achieving good outcome. Nevertheless, very little is known about the duration of time before a patient is admitted to a specialized center after a burn injury in Germany, and whether the situation has improved over time. We retrospectively analyzed time from burn injury to admission to the burn intensive care unit in the Cologne-Merheim Medical Center - one of Germany's specialized burn centers - over the last 25 years. Moreover, we analyzed the data based on differences according to time of injury and day of the week, as well as severity of the burn injury. There was no weekend effect with regard to transfer time; instead transfer time was particularly short on a Monday or on Sundays. Furthermore, patients with severe burn injuries of 40-89% total body surface area (TBSA) showed the least differences in transfer time. Interestingly, the youngest and the oldest patients arrived at the burn intensive care unit (BICU) the fastest. This study should help elucidate published knowledge regarding transfer time from the scene of the accident to admission to a BICU in Germany.

Background: Heparin-induced thrombocytopenia (HIT) causes thromboembolic complications which threaten life and limb. Heparin is administered to virtually every critically ill patient as a protective measure against thromboembolism. Argatroban is a promising alternative anticoagulant agent. However, a safe dose which still provides effective thromboembolic prophylaxis without major bleeding still needs to be identified., Methods: Critically ill patients (n = 42) diagnosed with HIT at a tertiary medical center intensive care unit from 2005 to 2010 were included in this retrospective analysis. Patient records were perused for preexisting history of HIT, heparin dosage before HIT, argatroban dosage, number of transfusions required, thromboembolic complications and length of ICU stay (ICU LOS). Patients were allocated to Simplified Acute Physiology Scores above and below 30 (SAPS >30, SAPS <30), respectively. For calculations, patients (n = 19) without previous history of HIT were compared to patients (n = 23) with a history of HIT before initiation of argatroban., Results: The mean initial argatroban dosage was below 0.4 mcg/kg/min regardless of SAPS score. Maintenance dosage had to be increased in patients with SAPS <30 to 0.54 ± 0.248 mcg/kg/min (p >0.05) to achieve effective anticoagulation. No thromboembolic complications were encountered. Argatroban had to be discontinued temporarily in 16 patients for a total of 57 times due to diagnostic or surgical procedures, supratherapeutic aPTT and bleeding without increasing the number of transfusions. A history of HIT was associated with a shorter ICU LOS and significantly reduced transfusion need when compared to patients with no history of HIT. Cost calculation favour argatroban due to increased transfusion needs during heparin administration and increase ICU LOS., Conclusion: Argatroban can be used at doses < 0.4 mcg/kg/min without an increase in transfusion requirements and at a reduced overall treatment cost compared to heparin.