Development and evaluation of a variable, miniaturized oxygenator for various test methods.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) became an accepted therapy for the treatment of severe acute respiratory distress syndrome and chronic obstructive pulmonary disease. However, ECMO systems are still prone to thrombus formation and decrease of gas exchange over time. Therefore, it is necessary to conduct qualified studies to identify parameters for optimization of ECMO systems, and especially the oxygenator. However, commercially marketed oxygenators are not always appropriate and available for certain research use cases. Therefore, we aimed to design an oxygenator, which is suitable for various test conditions such as blood tests, numerical simulation, and membrane studies, and can be modified in membrane area size and manufactured in laboratory. METHODS: Main design criteria are a homogeneous blood flow without stagnation zones, low pressure drop, manufacturability in the lab, size variability with one set of housing parts and cost-efficiency. Our newly designed oxygenator was tested comparatively regarding blood cell damage, gas transfer performance and pressure drop to prove the validity of the design in accordance with a commercial device. RESULTS: No statistically significant difference between the tested oxygenators was detected and our new oxygenator demonstrated sufficient hemocompatibility. Furthermore, our variable oxygenator has proven that it can be easily manufactured in the laboratory, allows to use various membrane fiber configurations and can be reopened easily and non-destructively for analysis after use, and the original geometry is available for numerical simulations. CONCLUSION: Therefore, we consider this newly developed device as a valuable tool for basic experimental and numerical research on the optimization of oxygenators.

[Treatment of thermal injuries in adults : Update of the S2k guidelines from 1 February 2021]. / Behandlung thermischer Verletzungen des Erwachsenen : Update der S2k-Leitlinie vom 01.02.2021.

The current S2k guidelines on treatment of thermal injuries in adults are summarized in this article from the perspective of anesthesiology, emergency medicine and intensive care medicine. The guidelines were prepared under the auspices of the German Society for Burn Medicine with the participation of other professional societies and interest groups and were published last year in revised form by the AWMF.

Effects of Pulsatile Blood Flow on Oxygenator Performance.

Extracorporeal membrane oxygenation (ECMO) is mainly used for the therapy of acute respiratory distress syndrome and chronic obstructive lung disease. In the last years, the development of these systems underwent huge steps in optimization, but there are still problems with thrombus formation, clogging, and thus insufficient gas exchange. One idea of ECMO optimization is a pulsatile blood flow through the oxygenator, but this is still a controversy discussion. Analyzing available publications, it was not possible to identify a general statement about the effect of pulsatile blood flow on the gas exchange performance. The variety of parameters and circuit components have such a high influence on the outcome that a direct comparison of the studies is difficult. For this reason, we performed a structured study to evaluate the effects of pulsatile blood flow on the gas exchange performance of oxygenator. In in vitro tests according to DIN EN ISO 7199, we tested a small oxygenator (0.25 m2 exchange surface, polymethylpentene fibers, 33 mL priming volume) with constant and pulsatile blood flow in comparison. Therefore, we varied the mean blood flow from 250 to 1200 mL/min, the amplitude of 0, 20, and 50%, and the frequency of 30, 60, and 90 bpm. The results demonstrate that the gas transfer for pulsatile and constant blood flow was similar (oxygen: 36-64 mLO2 /LBlood ; carbon dioxide 35-80 mLCO2 /LBlood ) for the same mean blood flow ranges. Over all, the results and analyses showed a statistically nonsignificant difference between pulsatile and nonpulsatile flow. Consequently, we conclude that the implementation of pulsatile blood flow has only a small to no effect on the gas exchange performance in an oxygenator. As the results were obtained using an oxygenator with a coiled fiber bundle, the test must be verified for a stacked fiber oxygenator.

D-dopachrome tautomerase in adipose tissue inflammation and wound repair.

D-dopachrome tautomerase (D-DT/MIF-2) is a member of the macrophage migration inhibitory factor (MIF) cytokine superfamily, and a close structural homolog of MIF. MIF and D-DT have been reported to be involved in obesity, but there is little known about the regulation of D-DT in adipose tissue inflammation and wound healing. Subcutaneous adipose tissue was collected from 54 healthy donors and 28 donors with acutely inflamed wounds undergoing wound debridement. In addition, epididymal fat pads of mice were injected with lipopolysaccharide to study receptor expression and cell migration in vivo. D-DT protein levels and mRNA expression were significantly decreased in subcutaneous adipose tissue adjacent to acutely inflamed wounds. D-DT improved fibroblast viability and increased proliferation in vitro. While D-DT alone did not have a significant effect on in vitro fibroblast wound healing, simultaneous addition of neutralizing MIF antibody resulted in a significant improvement of fibroblast wound healing. Interestingly, expression of the MIF and D-DT receptor CD74 was down-regulated while the MIF receptors CXCR2 and CXCR4 were up-regulated primarily on macrophages indicating that the MIF-CXCR2/4 axis may promote recruitment of inflammatory cells into adipose tissue. Our results describe a reciprocal role of D-DT to MIF in inflamed adipose tissue, and indicate that D-DT may be beneficial in wound repair by improving fibroblast survival and proliferation.

[Not Available]. / Kasuistik - 44-jähriger Patient mit Fieber und Hautrötung in der Notaufnahme.

Skin and soft tissue infections may progress rapidly and take a fatal ending unless not treated in time. A 44-year old male patient without any pre-existing conditions got hospitalized with a bursitis ofthe right olecranon and unspecific general symptoms. Within a short period of time he became critically ill due this seemingly harmless infection. We describe our approach leading to the right diagnoses and the treatment of this unexpected progress.

Tissue oxygen saturation as an early indicator of delayed lactate clearance after cardiac surgery: a prospective observational study.

BACKGROUND: In this observational study near infrared spectroscopy (NIRS) was evaluated as a non-invasive monitor of impaired tissue oxygenation (StO2) after cardiac surgery. StO2, cardiac output, mixed venous oxygen saturation and mean arterial pressure were compared with lactate clearance as established measure for sufficient tissue perfusion and oxygen metabolism. METHODS: Forty patients after cardiac surgery (24 aortocoronary bypass grafting, 5 heart valve, 3 ascending aorta and 8 combined procedures) were monitored until postoperative day 1 with NIRS of the thenar muscle (InSpectra™ StO2-monitor, Hutchinson Technology), a pulmonary-artery catheter and intermittent blood gas analyses for the assessment of lactate clearance. RESULTS: StO2 was reduced 4 h after surgery (75 ± 6 %), but recovered at day 1 (84 ± 5 %), while lactate concentration remained increased. Using uni- and multivariate regression analysis, minimum StO2 (r = 0.46, p <0.01) and cardiac index (r = 0.40, p <0.05) correlated with lactate clearance at day 1, while minimum mixed venous saturation and mean arterial pressure did not. In a receiver-operating characteristics (ROC) analysis, minimum StO2 (with a threshold of 75 %) predicted a lactate clearance <10 % at day 1 with an area under the ROC-curve of 0.83, a sensitivity of 78 % and a specificity of 88 %. In the subgroup with StO2 <75 %, troponin and creatine kinase MB were significantly increased at day 1. CONCLUSIONS: StO2 below 75 % in the first hours after surgery was a better early indicator of persistent impaired lactate clearance at day 1 than cardiac index, mixed venous oxygen saturation or mean arterial pressure.

The Ventilatory Ratio as a Predictor of Successful Weaning from a Veno-Venous Extracorporeal Membrane Oxygenator.

Background: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a critical intervention for patients with severe lung failure, especially acute respiratory distress syndrome (ARDS). The weaning process from ECMO relies largely on expert opinion due to a lack of evidence-based guidelines. The ventilatory ratio (VR), which correlates with dead space and mortality in ARDS, is calculated as [minute ventilation (mL/min) x arterial pCO2 (mmHg)]/[predicted body weight × 100 × 37.5]. Objectives: The aim of this study was to determine whether the VR alone can serve as a reliable predictor of safe or unsafe liberation from VV-ECMO in critically ill patients. Methods: A multicenter retrospective analysis was conducted, involving ARDS patients undergoing VV-ECMO weaning at Massachusetts General Hospital (January 2016 - December 2020) and at the University Hospital Aachen (January 2012-December 2021). Safe liberation was defined as no need for ECMO recannulation within 48 h after decannulation. Clinical parameters were obtained for both centers at the same time point: 30 min after the start of the SGOT (sweep gas off trial). Results: Of the patients studied, 83.3% (70/84) were successfully weaned from VV-ECMO. The VR emerged as a significant predictor of unsafe liberation (OR per unit increase: 0.38; CI: 0.17-0.81; p = 0.01). Patients who could not be safely liberated had longer ICU and hospital stays, with a trend towards higher mortality (38% vs. 13%; p = 0.05). Conclusions: The VR may be a valuable predictor for safe liberation from VV-ECMO in ARDS patients, with higher VR values associated with an elevated risk of unsuccessful weaning and adverse clinical outcomes.

Hardware-in-the-loop simulation of vascular cannula interaction.

Traditionally, the functional development, testing and verification of higher level automation, control and safety functions in extracorporeal circulations systems relies very much on the conduction of animal experiments. This especially applies to functions requiring interaction with the patients physiology. Besides ethical aspects, animal experiments have the disadvantage of higher complexity, limited reproducibility and certain pathological conditions can only be represented with difficulty. An alternative to this can be Hardware-in-the-loop (HIL) simulators.In this paper we present a HIL solution to simulate the hydraulic interaction between the cannula and the connected blood vessel. We derive a hydraulic model for an elastic vessel with particular emphasis on negative transmural pressure. In this case the resistance is mainly determined by collapse phenomena. The next section describes the design of an universal resistance actuator that can simulate vascular resistances in the expected range. Combined in the HIL simulator, the simulation model then generates the setpoint for the actuator while simultaneously receiving the resulting internal states of the hydraulic interface. This creates a truly interactive HIL simulator where the device under test interacts in the same way as with a physiological system.

Inflow from a Cardiopulmonary Assist System to the Pulmonary Artery and Its Implications for Local Hemodynamics-a Computational Fluid Dynamics Study.

When returning blood to the pulmonary artery (PA), the inflow jet interferes with local hemodynamics. We investigated the consequences for several connection scenarios using transient computational fluid dynamics simulations. The PA was derived from CT data. Three aspects were varied: graft flow rate, anastomosis location, and inflow jet path length from anastomosis site to impingement on the PA wall. Lateral anastomosis locations caused abnormal flow distribution between the left and right PA. The central location provided near-physiological distribution but induced higher wall shear stress (WSS). All effects were most pronounced at high graft flows. A central location is beneficial regarding flow distribution, but the resulting high WSS might promote detachment of local thromboembolisms or influence the autonomic nervous innervation. Lateral locations, depending on jet path length, result in lower WSS at the cost of an unfavorable flow distribution that could promote pulmonary vasculature changes. Case-specific decisions and further research are necessary.

Treatment of children with hyperbaric oxygenation (HBOT): a Europe-wide survey.

BACKGROUND: Hyperbaric oxygenation therapy (HBOT) is used as emergency treatment for decompression sickness, gas embolism, carbon monoxide intoxication, and necrotizing fasciitis. There is low evidence and little clinical knowledge about the treatment of children with HBOT. METHODS: We sent an internet-based questionnaire to HBO centers in Europe to gain information about their experience with children and HBOT. RESULTS: Out of all HBO-centers who participated in the questionnaire 90% treat children analogue to adults about indication and HBOT protocol. Most treated children had life-threatening indications or the risk of organ loss. The reported rate of side effects was: 6.8% anxiety, 2.4% barotrauma, 0.9% seizure, 0.2% retinopathy and no case of pulmonary barotrauma or oxygen toxicity. CONCLUSIONS: HBO therapy for children is present in European HBO centers. The rate of severe side effects is as low to the rates in adults; apart from this, oxygen-related seizures and anxiety are more frequent. A special focus seems necessary on the psychological management of the children, because anxiety is common depending on the age of the children. Especially for smaller children, an adequate psychological support seems essential. Prospective observational or controlled studies in children seem necessary to create relevant clinical evidence for HBOT and to observe the rate of side-effects.

Effects of hypercapnia versus normocapnia during general anesthesia on outcomes: a systematic review and meta-analysis.

BACKGROUND: The effect of mild changes in CO2 levels to organ perfusion and tissue inflammation are well known, whereas an influence of hypercapnia under general anesthesia on adverse events as nausea and vomiting, or length of hospital stay is barely examined. The goal of our meta-analysis was to identify possibly positive effects of hypercapnia versus normocapnia in general anesthesia in adult patients. METHODS: We conducted a systematic review of parallel-arm randomised controlled trials comparing hypercapnia versus normocapnia in adult patients undergoing general anesthesia. In July 2018 and September 2019 we searched "CENTRAL‿, "MEDLINE‿, and "Embase‿, checked reference lists of all included studies and relevant systematic reviews for additional references to trials. Two review authors independently assessed trials for inclusion, extracted data, and completed a "Risk of bias‿ assessment for all included studies. RESULTS: Our search identified 297 records after abstract screening 30 full-text papers remained for further examination. Ten publications met our inclusion criteria and were used for narrative description of this systematic review. Three studies were eligible for the meta-analysis normocapnia versus hypercapnia with the outcomes: time to extubation and adverse events. On average, time to extubation was significantly reduced in the hypercapnia group with a mean difference 3.78 (95% CI 0.85 to 6.71). No difference was found regarding adverse events. CONCLUSIONS: The findings of our study do not enable us to produce evidence of a positive influence of increased CO2 partial pressure levels during general anesthesia. A well-planned, adequately powered randomized controlled trial would be desirable in the future.

In Vitro and In Vivo Feasibility Study for a Portable VV-ECMO and ECCO2R System.

Extracorporeal membrane oxygenation (ECMO) is an established rescue therapy for patients with chronic respiratory failure waiting for lung transplantation (LTx). The therapy inherent immobilization may result in fatigue, consecutive deteriorated prognosis, and even lost eligibility for transplantation. We conducted a feasibility study on a novel system designed for the deployment of a portable ECMO device, enabling the physical exercise of awake patients prior to LTx. The system comprises a novel oxygenator with a directly connected blood pump, a double-lumen cannula, gas blender and supply, as well as control and energy management. In vitro experiments included tests regarding performance, efficiency, and blood damage. A reduced system was tested in vivo for feasibility using a novel large animal model. Six anesthetized pigs were first positioned in supine position, followed by a 45° angle, simulating an upright position of the patients. We monitored performance and vital parameters. All in vitro experiments showed good performance for the respective subsystems and the integrated system. The acute in vivo trials of 8 h duration confirmed the results. The novel portable ECMO-system enables adequate oxygenation and decarboxylation sufficient for, e.g., the physical exercise of designated LTx-recipients. These results are promising and suggest further preclinical studies on safety and efficacy to facilitate translation into clinical application.

Extracorporeal Hyperoxygenation Therapy (EHT) for Carbon Monoxide Poisoning: In-Vitro Proof of Principle.

Carbon monoxide (CO) poisoning is the leading cause of poisoning-related deaths globally. The currently available therapy options are normobaric oxygen (NBO) and hyperbaric oxygen (HBO). While NBO lacks in efficacy, HBO is not available in all areas and countries. We present a novel method, extracorporeal hyperoxygenation therapy (EHT), for the treatment of CO poisoning that eliminates the CO by treating blood extracorporeally at elevated oxygen partial pressure. In this study, we proof the principle of the method in vitro using procine blood: Firstly, we investigated the difference in the CO elimination of a hollow fibre membrane oxygenator and a specifically designed batch oxygenator based on the bubble oxygenator principle at elevated pressures (1, 3 bar). Secondly, the batch oxygenator was redesigned and tested for a broader range of pressures (1, 3, 5, 7 bar) and temperatures (23, 30, 37 °C). So far, the shortest measured carboxyhemoglobin half-life in the blood was 21.32 min. In conclusion, EHT has the potential to provide an easily available and effective method for the treatment of CO poisoning.

[Improvement in burn wound care: summary of the AWMF guideline for the treatment of thermal injuries in adults]. / Optimierung der chirurgischen Behandlung Brandverletzter: Auszüge aus der fachübergreifenden S2k-Leitlinie "Behandlung thermischer Verletzungen des Erwachsenen".

INTRODUCTION: More than half a million patients suffer from minor burns in Germany per year. In 2018, almost 2000 patients needed intensive care for their burn injuries. Despite high standards of burn care, mortality remains high. Burn injuries may lead to long-term sequelae. In order to provide up-to-date burn care, guidelines are available online with public access. METHODS AND RESULTS: This overview presents a summary of the German AWMF guideline for the treatment of thermal injuries in adults (https://www.awmf.org/leitlinien/detail/ll/044-001.html). Experts of eleven different medical organisations and specialties have contributed to this S2k guideline with their expertise. The focus of the article is on acute burn wound assessment, the indication for specialised care in burn centres, the management of the burn wound at the trauma scene and in hospitals as well as scar management and rehabilitation. CONCLUSION: This overview reports on the consensus-based treatment of acute burn wounds in adults in Germany. The article is intended to guide doctors and professional caretakers to perform state-of-the-art burn care. The current guideline aims to improve burn outcome.

[Assisted circulation: an overview from a clinical perspective]. / Assistierte Zirkulation: ein Uberblick aus klinischer Sicht.

A higher grade cardiac failure is associated with poor prognosis. In addition to medical conservative treatment and traditional cardiac surgery, in the past years different forms of an assisted circulation evolved. Short-term devices serve to bridge an acute life-threatening situation. The chosen system is dependent on the anticipated clinical course. It is possible to fall back on slightly assisting techniques up to a complete takeover of the cardiac pump function. In the case of severe cardiac failure, the question for transplantation has to be addressed because transplantation is the treatment of choice to date. For an assisted circulation in cases of chronic congestive failure, devices of different generations are available. First generation pulsatile systems are used for assistance of the left ventricle and results have been shown to be superior to medical therapy (REMATCH). With second generation continuous-flow systems, results regarding infections, thromboembolism and also quality of life appear to be further improved. Contact-free centrifugal pumps as third generation systems are in clinical evaluation. So-called "total artificial hearts" are successfully used for bridge-to-transplantation. Taken together, a graded safe treatment of cardiac failure is available today. In the near future, it could be possible to reach results similar to those of cardiac transplantation.

[Automatic control and safety concepts for extracorporeal lung support]. / Regelungs- und Sicherheitskonzepte für extrakorporale Systeme zur Lungenunterstützung.

In some cases of severe acute respiratory distress syndrome, hypoxemia occurs despite optimized conservative therapy; however, extracorporeal membrane oxygenation (ECMO) can assure sufficient gas exchange. To increase safety and reliability of devices, the oxygenator design was optimized integrating new plasma-resistant composite membranes and new blood pumps are used with longer durability and reduced blood cell damage. Another approach is the use of an arterio-venous pumpless extracorporeal lung assist (pECLA) using an oxygenator with reduced pressure drop to simplify management and to avoid pump-related complications. First attempts were made to integrate basic control and safety concepts in ECMO circuits, but this does not seem to be sufficient to overcome the specific problems of ECMO (long-term use and limited supervision of the intensive care unit). The integration of sophisticated automated control and safety concepts in combination with revised ECMO circuits could allow a more reliable application of ECMO of the intensive care unit without continuous observation by a perfusionist. Easier intra- and interhospital transfer of patients with running ECMO would be another advantage.

Septic porcine blood does not further activate coagulation during in vitro membrane oxygenation.

Objectives: For patients with a severe acute respiratory distress syndrome (ARDS), extracorporeal membrane oxygenation (ECMO) represents a life-saving measure. Frequently, patients with severe ARDS also show signs of severe sepsis. As blood contact with the membrane oxygenator surface leads to adverse effects due to insufficient biocompatibility partly caused by activation of platelets, coagulation factors and leucocytes, we hypothesized that these adverse effects would be amplified if septic blood in a preactivated state came into contact with the membrane oxygenator. Methods: In a previously established in vitro 12-h ECMO test system (mock loop), we used septic or healthy domestic pig blood to analyse coagulation and inflammatory parameters. Sepsis was induced by a caecal ligation and puncture model in pigs. Results: At the beginning of the mock loop experiments, the septic blood showed significantly increased thrombin-antithrombin complexes (76.9 vs 27.7 µg/l), D-dimers (1.2 vs 0.3 mg/l) and fibrinogen concentration (1.8 vs 1.5 g/l), as well as elevated extrinsic coagulation activity (shorter EXTEM-CT: 44.2 vs 57 s) and higher lactate (3.4 vs 1.5 mmol/l) and cytokine levels (interleukin-6: 827 vs 31 pg/ml) when compared with the blood from healthy animals. Despite the preactivated status of the septic blood, no further increase of coagulation activity, inflammatory response or increased oxygenator resistance was observed in comparison to the control experiments. Conclusion: Septic porcine blood was not further activated due to the contact with an oxygenator, and no increased clot formation or biocompatibility problems were observed.

Physiological closed-loop control of mechanical ventilation and extracorporeal membrane oxygenation.

A new concept is presented for cooperative automation of mechanical ventilation and extracorporeal membrane oxygenation (ECMO) therapy for treatment of acute respiratory distress syndrome (ARDS). While mechanical ventilation is continuously optimized to promote lung protection, extracorporeal gas transfer rates are simultaneously adjusted to control oxygen supply and carbon dioxide removal using a robust patient-in-the-loop control system. In addition, the cooperative therapy management uses higher-level algorithms to adjust both therapeutic approaches. The controller synthesis is derived based on the introduced objectives, the experimental setup and the uncertain models. Finally, the autonomous ARDS therapy system capabilities are demonstrated and discussed based on in vivo data from animal experiments.

Decentralized safety concept for closed-loop controlled intensive care.

This paper presents a decentralized safety concept for networked intensive care setups, for which a decentralized network of sensors and actuators is realized by embedded microcontroller nodes. It is evaluated for up to eleven medical devices in a setup for automated acute respiratory distress syndrome (ARDS) therapy. In this contribution we highlight a blood pump supervision as exemplary safety measure, which allows a reliable bubble detection in an extracorporeal blood circulation. The approach is validated with data of animal experiments including 35 bubbles with a size between 0.05 and 0.3 ml. All 18 bubbles with a size down to 0.15 ml are successfully detected. By using hidden Markov models (HMMs) as statistical method the number of necessary sensors can be reduced by two pressure sensors.

Blood lead levels in scuba divers: a pilot study.

INTRODUCTION: Lead is a toxic element which is known to accumulate in the body. Nevertheless, it is very widely used as a diving weight. METHODS: Blood samples were taken from 20 recreational scuba divers to assess blood lead concentrations. RESULTS: The last dive before blood sampling was an average of 4.8 weeks previously (range 1-18 weeks). All the samples were within the normal background range, the highest lead concentration being 44.8 µg∙L⁻¹ with an average concentration of 26.5 µg∙L⁻¹ (range 11.7-44.8 µg∙L⁻¹). CONCLUSIONS: The results show no elevated blood lead concentrations in this group of divers compared to background levels. However, owing to the small number of divers studied and the variable, often long interval between the last dive and blood sampling, the results cannot be generalized.