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Abstract Juvenile crossbred pigs are widely used for acute and chronic animal testing due to their anatomical and physiological resemblance to humans. They are particularly prevalent in preclinical cardiovascular research, including studies investigating extracorporeal resuscitation and mechanical circulatory support devices. However, the availability of comprehensive laboratory reference values is limited. In a single-center study at the University Medical Center Freiburg, Germany, the hematologic and biochemical laboratory values of anesthetized healthy juvenile German crossbred farm pigs were determined. Blood samples were collected at the beginning of surgical procedures, either arterially or venously. Females and males were compared, and correlation with body weight was assessed. In total, 268 animals (weight 57.8 ± 12.4 kg) were included, thereof 180 castrated males (55.2 ± 7.7 kg) and 79 females (63.6 ± 18.3 kg). There were significant differences between males and females in 11 of 45 parameters and a moderate correlation between body weight and creatinine (R = 0.41, p

Abstract Background Cardiopulmonary resuscitation is a crucial skill for emergency medical services. As high-risk-low-frequency events pose an immense mental load to providers, concepts of crew resource management, non-technical skills and the science of human errors are intended to prepare healthcare providers for high-pressure situations. However, medical errors occur, and organizations and institutions face the challenge of providing a blame-free error culture to achieve continuous improvement by avoiding similar errors in the future. In this case, we report a critical medical error during an anaphylaxis-associated cardiac arrest, its handling and the unexpected yet favourable outcome for the patient. Case presentation During an out-of-hospital cardiac arrest due to chemotherapy-induced anaphylaxis, a patient received a 10-fold dose of epinephrine due to shortcomings in communication and standardization via a central venous port catheter. The patient converted from a non-shockable rhythm into a pulseless ventricular tachycardia and subsequently into ventricular fibrillation. The patient was cardioverted and defibrillated and had a return of spontaneous circulation with profound hypotension only 6 min after the administration of 10 mg epinephrine. The patient survived without any residues or neurological impairment. Conclusions This case demonstrates the potential deleterious effects of shortcomings in communication and deviation from standard protocols, especially in emergencies. Here, precise instructions, closed-loop communication and unambiguous labelling of syringes would probably have avoided the epinephrine overdose central to this case. Interestingly, this serious error may have saved the patient’s life, as it led to the development of a shockable rhythm. Furthermore, as the patient was still in profound hypotension after administering 10 mg of epinephrine, this high dose might have counteracted the severe vasoplegic state in anaphylaxis-associated cardiac arrest. Lastly, as the patient was receiving care for advanced malignancy, the likelihood of termination of resuscitation in the initial non-shockable cardiac arrest was significant and possibly averted by the medication error.

Background Germany has one of the oldest social security systems in the world. Population coverage has subsequently increased, reaching coverage of approximately 90% of the population in the statutory health insurance (SHI) system today. Before this background, Germany has been pioneering the integration of digital therapeutics (DTx) into its SHI system by the introduction of the Digital Healthcare Law (Digitale-Versorgung-Gesetz, DVG) in 2019. Thereby, patients became eligible for digital health applications (Digitale Gesundheitsanwendungen, DiGA), which are available upon prescription by qualified healthcare professionals. Challenge As conventional healthcare delivery often lacks direct outcome measures as and is mostly still reimbursed on a fee-for-service basis, DiGA offer the opportunity to continuously provide individual outcome and performance data. They are, therefore, well-suited for a performance-based payment framework. While the DVG introduced the option for performance-based reimbursement components in 2019 already, the ongoing debate about the value of DiGA and to what extent they can contribute to the healthcare system has now been reflected in a 2023 health policy bill by the German Federal Ministry of Health, which aims to introduce a mandatory performance-based reimbursement component for DiGA. Proposal In this light, we propose a framework for performance-based reimbursement of DiGA, involving an intervention-specific, performance-linked reimbursement framework with shared accountability between manufacturers and payers. The approach aims to align the often contradicting interests of the involved stakeholders to incentivize the delivery of high-value digital health care. Yet, the proposal also acknowledges the need for further research to establish a robust foundation for implementing such a framework.

Background: Since 2021, international guidelines for cardiopulmonary resuscitation recommend the implementation of so-called “life-saving systems”. These systems include smartphone alerting systems (SAS), which enable dispatch centres to alert first responders via smartphone applications, who are in proximity of a suspected out-of-hospital cardiac arrest (OHCA). However, the effect of SAS on survival remains unknown. Aim: The aim is to assess the rate of survival to hospital discharge in adult patients with OHCA not witnessed by emergency medical services (EMS): before and after SAS implementation. Design: Multicentre, prospective, observational, intention-to-treat, pre–post design clinical trial. Population: Adults (aged ≥ 18 years), OHCA not witnessed by EMS, no traumatic cause for cardiac arrest, cardiopulmonary resuscitation initiated or continued by EMS. Setting: Dispatch-centre-based. Outcomes: Primary: survival to hospital discharge. Secondary: time to first compression, rate of basic life support measures before EMS arrival, rate of patients with shockable rhythm at EMS arrival, Cerebral Performance Category at hospital discharge, and duration of hospital stay. Sample size: Assuming an absolute difference in survival rates to hospital discharge of 4% in the two groups (11% before implementation of the SAS versus 15% after) and 80% power, and a type 1 error rate of 0.05, the required sample size is N = 1,109 patients per group (at least N = 2,218 evaluated patients in total). Conclusions: The HEROES trial will investigate the effects of a SAS on the survival rate after OHCA. Trial registration: German Clinical Trials Register (DRKS, ID: DRKS00032920)

IntroductionThe application of extracorporeal circulation (ECC) systems is known to be associated with several implications regarding hemolysis, inflammation, and coagulation. In the last years, systems with pulsatile blood flow are increasingly used with the intention to improve hemodynamics in reperfusion. However, their implications on the aforementioned aspects remain largely unknown. To investigate the effects of pulsatility, this ex-vivo study was initiated.MethodsTest circuits (primed with human whole blood) were set up in accordance with the recommendations of international standards for in-vitro evaluation of new components and systems of ECC. Diagonal pumps were either set up with non-pulsatile (n = 5, NPG) or pulsatile (n = 5, PG) pump settings and evaluated for 6 h. All analyses were conducted with human whole blood. Blood samples were repeatedly drawn from the test circuits and analyzed regarding free hemoglobin, interleukin 8 (IL-8), platelet aggregation and acquired von Willebrand syndrome (AVWS).ResultsAfter 1 h of circulation, a significant coagulation impairment (impaired platelet function and AVWS) was observed in both groups. After 6 h of circulation, increased IL-8 concentrations were measured in both groups (NPG: 0.05 ± 0.03 pg./mL, PG: 0.03 ± 0.01 pg./mL, p = 0.48). Pulsatile pump flow resulted in significantly increased hemolysis after 6 h of circulation (NPG: 37.3 ± 12.4 mg/100 L; PG: 59.6 ± 14.5 mg/100 L; p

Abstract Background The city of Freiburg has been among the most affected regions by the COVID-19 pandemic in Germany. In out of hospital cardiac arrest (OHCA) care, all parts of the rescue system were exposed to profound infrastructural changes. We aimed to provide a comprehensive overview of these changes in the resuscitation landscape in the Freiburg region. Methods Utstein-style quantitative data on OHCA with CPR initiated, occurring in the first pandemic wave between February 27th, 2020 and April 30th, 2020 were compared to the same time periods between 2016 and 2019. Additionally, qualitative changes in the entire rescue system were analyzed and described. Results Incidence of OHCA with attempted CPR did not significantly increase during the pandemic period (11.1/100.000 inhabitants/63 days vs 10.4/100.000 inhabitants/63 days, p = 1.000). In witnessed cases, bystander-CPR decreased significantly from 57.7% (30/52) to 25% (4/16) (p = 0.043). A severe pre-existing condition (PEC) was documented more often, 66.7% (16/24) vs 38.2% (39/102) there were longer emergency medical services (EMS) response times, more resuscitation attempts terminated on scene, 62.5% (15/24) vs. 34.3% (35/102) and less patients transported to hospital (p = 0.019). Public basic life support courses, an app-based first-responder alarm system, Kids Save Lives activities and a prehospital extracorporeal CPR (eCPR) service were paused during the peak of the pandemic. Conclusion In our region, bystander CPR in witnessed OHCA cases as well as the number of patients transported to hospital significantly decreased during the first pandemic wave. Several important parts of the resuscitation landscape were paused. The COVID-19 pandemic impedes OHCA care, which leads to additional casualties. Countermeasures should be taken.

Abstract Background Only a small number of patients survive an out-of-hospital cardiac arrest (CA) and can be discharged from hospital alive with a large percentage of these patients retaining neurological impairments. In recent years, extracorporeal cardiopulmonary resuscitation (ECPR) has emerged as a beneficial strategy to optimize cardiac arrest treatment. However, ECPR is still associated with various complications. To reduce these problems, a profound understanding of the underlying mechanisms is required. This study aims to investigate the effects of CA, conventional cardiopulmonary resuscitation (CPR) and ECPR using a whole-body reperfusion protocol (controlled and automated reperfusion of the whole body—CARL) on the serum proteome profiles in a pig model of refractory CA. Methods N = 7 pigs underwent 5 min of untreated CA followed by 30 min CPR and 120 min perfusion with CARL. Blood samples for proteomic analysis were drawn at baseline, after CPR and at the end of the CARL period. Following albumin-depletion, proteomic analysis was performed using liquid chromatography–tandem mass spectrometry. Results N = 21 serum samples were measured resulting in the identification and quantification of 308–360 proteins per sample and 388 unique proteins in total. The three serum proteome profiles at the investigated time points clustered individually and segregated almost completely when considering a 90% confidence interval. Differential expression analysis showed significant abundance changes in 27 proteins between baseline and after CPR and in 9 proteins after CARL compared to CPR. Significant findings were further validated through a co-abundance cluster analysis corroborating the observed abundance changes. Conclusions The presented data highlight the impact of systemic ischemia and reperfusion on the entire serum proteome during resuscitation with a special focus on changes regarding haemolysis, coagulation, inflammation, and cell-death processes. Generally, the observed changes contribute to post-ischemic complications. Better understanding of the underlying mechanisms during CA and resuscitation may help to limit these complications and improve therapeutic options.

BackgroundThe Heartmate 3 (HM 3) is a left ventricular assist device featuring less shear stress, milder acquired von Willebrand syndrome, and fewer bleeding incidences than its predecessor the Heartmate II (HM II). The novel surface coating of the HM 3 suggests less contact activation of plasmatic coagulation. We hypothesized that patients with HM 3 exhibit fewer aberrations in their thrombin potential than patients with HM II. We compared these results with the thrombin potential of patients with heart transplantation (HTX).MethodsThrombin generation in plasma samples of patients with HM II (n = 16), HM 3 (n = 20), and HTX (n = 13) was analyzed 3 days after implantation/transplantation and after long-term support (3–24 months) with HM II (n = 16) or HM 3 (n = 12) using calibrated automated thrombography. Heparin in postoperative samples was antagonized with polybrene.ResultsThree days postoperatively HM II patients exhibited a lower endogenous thrombin potential (ETP) than HM 3 and HTX patients (HM II: 947 ± 291 nM*min; HM 3: 1231 ± 176 nM*min; HTX: 1376 ± 162 nM*min, p

Controlled reperfusion by monitoring the blood pressure, blood flow, and specific blood parameters during extracorporeal reperfusion after cardiac arrest has the potential to limit ischemia–reperfusion injury. The intracellular calcium overload as part of the ischemia–reperfusion injury provides the possibility for the injury to be counteracted by the early suppression of serum calcium with the aim of improving survival and the neurological outcome. We investigated the effects of prolonged serum calcium suppression via sodium citrate during extracorporeal resuscitation using the CARL protocol (CARL—controlled automated reperfusion of the whole body) compared to a single-dose approach in a porcine model after prolonged cardiac arrest. A control group (N = 10) was resuscitated after a 20 min cardiac arrest, initially lowering the intravascular calcium with the help of a single dose of sodium citrate as part of the priming solution. Animals in the intervention group (N = 13) received additional sodium citrate for the first 15 min of reperfusion. In the control group, 9/10 (90.0%) animals survived until day 7 and 7/13 (53.8%) survived in the intervention group (p = 0.09). A favorable neurological outcome on day 7 after the cardiac arrest was observed in all the surviving animals using a species-specific neurological deficit score. The coronary perfusion pressure was significantly lower with a tendency towards more cardiac arrhythmias in the intervention group. In conclusion, a prolonged reduction in serum calcium levels over the first 15 min of reperfusion after prolonged cardiac arrest tended to be unfavorable regarding survival and hemodynamic variables compared to a single-dose approach in this animal model.

Critically ill COVID-19 patients suffer from thromboembolic as well as bleeding events. Endothelial dysfunction, spiking of von Willebrand factor (vWF), and excessive cytokine signaling result in coagulopathy associated with substantial activation of plasmatic clotting factors. Thrombocytopenia secondary to extensive platelet activation is a frequent finding, but abnormal platelet dysfunction may also exist in patients with normal platelet counts. In this study, we performed analyses of platelet function and of von Willebrand factor in critically ill COVID-19 patients (n = 13). Platelet aggregometry was performed using ADP, collagen, epinephrin, and ristocetin. VWF and fibrinogen binding of platelets and CD62 and CD63 expression after thrombin stimulation were analyzed via flow cytometry. In addition, VWF antigen (VWF:Ag), collagen binding capacity (VWF:CB), and multimer analysis were performed next to routine coagulation parameters. All patients exhibited reduced platelet aggregation and decreased CD62 and CD63 expression. VWF binding of platelets was reduced in 12/13 patients. VWF:CB/VWF:Ag ratios were pathologically decreased in 2/13 patients and elevated in 2/13 patients. Critically ill COVID-19 patients exhibit platelet secretion defects independent of thrombocytopenia. Platelet exhaustion and VWF dysfunction may result in impaired primary hemostasis and should be considered when treating coagulopathy in these patients.

Introduction: Ischemia and reperfusion are crucial in determining the outcome after cardiac arrest and can be influenced by extracorporeal cardiopulmonary resuscitation (ECPR). The effect of ECPR on the availability and level of oxygen in mitochondria remains unknown. The aim of this study was to find out if skin mitochondrial partial oxygen pressure (mitoPO2) measurements in cardiac arrest and ECPR are feasible and to investigate its course.Materials and Methods: We performed a feasibility test to determine if skin mitoPO2 measurements in a pig are possible. Next, we aimed to measure skin mitoPO2 in 10 experimental pigs. Measurements were performed using a cellular oxygen metabolism measurement monitor (COMET), at baseline, during cardiac arrest, and during ECPR using the controlled integrated resuscitation device (CIRD).Results: The feasibility test showed continuous mitoPO2 values. Nine experimental pigs could be measured. Measurements in six experimental pigs succeeded. Our results showed a delay until the initial spike of mitoPO2 after ECPR initiation in all six experimental tests. In two experiments (33%) mitoPO2 remained present after the initial spike. A correlation of mitoPO2 with mean arterial pressure (MAP) and arterial partial oxygen pressure measured by CIRD (CIRD-PaO2) seemed not present. One of the experimental pigs survived.Conclusions: This experimental pilot study shows that continuous measurements of skin mitoPO2 in pigs treated with ECPR are feasible. The delay in initial mitoPO2 and discrepancy of mitoPO2 and MAP in our small sample study could point to the possible value of additional measurements besides MAP to monitor the quality of tissue perfusion during cardiac arrest and ECPR.