Validation of RESP and PRESERVE score for ARDS patients with pumpless extracorporeal lung assist (pECLA).

BACKGROUND: RESP score and PRESERVE score have been validated for veno-venous Extracorporeal Membrane Oxygenation in severe ARDS to assume individual mortality risk. ARDS patients with low-flow Extracorporeal Carbon Dioxide Removal, especially pumpless Extracorporeal Lung Assist, have also a high mortality rate, but there are no validated specific or general outcome scores. This retrospective study tested whether these established specific risk scores can be validated for pumpless Extracorporeal Lung Assist in ARDS patients in comparison to a general organ dysfunction score, the SOFA score. METHODS: In a retrospective single center cohort study we calculated and evaluated RESP, PRESERVE, and SOFA score for 73 ARDS patients with pumpless Extracorporeal Lung Assist treated between 2002 and 2016 using the XENIOS iLA Membrane Ventilator. Six patients had a mild, 40 a moderate and 27 a severe ARDS according to the Berlin criteria. Demographic data and hospital mortality as well as ventilator settings, hemodynamic parameters, and blood gas measurement before and during extracorporeal therapy were recorded. RESULTS: Pumpless Extracorporeal Lung Assist of mechanical ventilated ARDS patients resulted in an optimized lung protective ventilation, significant reduction of PaCO2, and compensation of acidosis. Scoring showed a mean score of alive versus deceased patients of 3 ± 1 versus - 1 ± 1 for RESP (p < 0.01), 3 ± 0 versus 6 ± 0 for PRESERVE (p < 0.05) and 8 ± 1 versus 10 ± 1 for SOFA (p < 0.05). Using receiver operating characteristic curves, area under the curve (AUC) was 0.78 (95% confidence interval (CI) 0.67-0.89, p < 0.01) for RESP score, 0.80 (95% CI 0.70-0.90, p < 0.0001) for PRESERVE score and 0.66 (95% CI 0.53-0.79, p < 0.05) for SOFA score. CONCLUSIONS: RESP and PRESERVE scores were superior to SOFA, as non-specific critical care score. Although scores were developed for veno-venous ECMO, we could validate RESP and PRESERVE score for pumpless Extracorporeal Lung Assist. In conclusion, RESP and PRESERVE score are suitable to estimate mortality risk of ARDS patients with an arterio-venous pumpless Extracorporeal Carbon Dioxide Removal.

Interleukin-6 Serum Levels Correlate With Severity of Burn Injury but Not With Gender.

Gender-specific differences in the outcome of patients with burn injury have been recognized in the past with female patients being at a higher risk of mortality. We hypothesized that early post-burn interleukin-6 (IL-6) cytokine levels may contribute to the different gender-specific outcome. We retrospectively examined 94 burned patients who were treated in the Burn Intensive Care Unit at the University Hospital Aachen. Age, gender, presence of inhalation injury, depth, TBSA, and clinical outcome were documented. Serum samples for IL-6 analysis were collected within 24 hours posttrauma. The relationship between IL-6 levels, gender, survival, and abbreviated burn severity index score was investigated. Male patients (64.9%; n = 61) presented a higher median TBSA (26%) than female patients (20%). The mortality rate of male patients (27.9%; n = 17) and female patients (21.2%; n = 7) was similar. Deceased patients had significant higher TBSA (P = 0.0005) and IL-6 levels (P = 0.0007) than burn survivors. A moderate correlation between IL-6 levels and abbreviated burn severity index score was observed (r = 0.554; P < 0.0001). While TBSA showed a significant influence on IL-6 levels (P = 0.0003), gender did not (P = 0.7395) and inhalation injury indicated a minor influence (P = 0.0780). Only TBSA and age presented a significant influence on mortality (P = 0.0028 and P = 0.0031, respectively). All patients with burn trauma were characterized by elevated IL-6 levels with higher TBSA values resulting in more pronounced levels. Deceased patients had higher initial IL-6 serum levels reflecting higher TBSA and severity. In contrast to other defined trauma mechanisms, gender had no significant influence on postburn IL-6 serum levels and mortality in our patient population.

Characterization of adipose tissue macrophages and adipose-derived stem cells in critical wounds.

BACKGROUND: Subcutaneous adipose tissue is a rich source of adipose tissue macrophages and adipose-derived stem cells which both play a key role in wound repair. While macrophages can be divided into the classically-activated M1 and the alternatively-activated M2 phenotype, ASCs are characterized by the expression of specific stem cell markers. METHODS: In the present study, we have investigated the expression of common macrophage polarization and stem cell markers in acutely inflamed adipose tissue. Subcutaneous adipose tissue adjacent to acutely inflamed wounds of 20 patients and 20 healthy subjects were harvested and underwent qPCR and flow cytometry analysis. RESULTS: Expression levels of the M1-specific markers CD80, iNOS, and IL-1b were significantly elevated in inflammatory adipose tissue when compared to healthy adipose tissue, whereas the M2-specific markers CD163 and TGF-ß were decreased. By flow cytometry, a significant shift of adipose tissue macrophage populations towards the M1 phenotype was confirmed. Furthermore, a decrease in the mesenchymal stem cell markers CD29, CD34, and CD105 was observed whereas CD73 and CD90 remained unchanged. DISCUSSION: This is the first report describing the predominance of M1 adipose tissue macrophages and the reduction of stem cell marker expression in acutely inflamed, non-healing wounds.

Plasma adrenomedullin in critically ill patients with sepsis after major surgery: A pilot study.

PURPOSE: Adrenomedullin is released by different tissues in hypoxia, oxidative stress, and inflammation and is found in general and medical patients and, recently, in sepsis patients in emergency departments. The aim of this study was to evaluate biologically active adrenomedullin that mirrors directly the active peptide levels in plasma of surgical intensive care unit (ICU) patients with sepsis. MATERIALS AND METHODS: In this single-center observational pilot trial, 42 ICU patients with sepsis and 14 patients after major surgery were included after sepsis diagnosis or ICU admission. RESULTS: Patients (66% male) were 70 (median) (interquartile range [IQR], 61-77]) years old and had a body mass index of 26.2 (24.2-29.4) kg/m2. The ICU and hospital length of stay was 8 (1-22) and 17 (8-21) days, respectively. Eight patients had sepsis, 19 developed severe sepsis, and 15 suffered from septic shock. Adrenomedullin increased with severity (sepsis: 25.8 pg/mL [IQR 20.3-40.2], severe sepsis: 84.2 pg/mL [IQR 42.7-118.5], septic shock: 119.7 pg/mL [IQR 83.8-172.6]; P<.0001). Higher adrenomedullin was associated with poor 90-day outcomes (P=.019) and more frequent vasopressor use (P=.001). CONCLUSIONS: This is the first study investigating adrenomedullin in patients with sepsis following major surgery. Higher adrenomedullin on admission is associated with increased vasopressor need and mortality after 90 days. Thus, adrenomedullin may be a useful additional parameter in surgical patients with sepsis.

Kinetics of ventilation-induced changes in diaphragmatic metabolism by bilateral phrenic pacing in a piglet model.

Perioperative necessity of deep sedation is inevitably associated with diaphragmatic inactivation. This study investigated 1) the feasibility of a new phrenic nerve stimulation method allowing early diaphragmatic activation even in deep sedation and, 2) metabolic changes within the diaphragm during mechanical ventilation compared to artificial activity. 12 piglets were separated into 2 groups. One group was mechanically ventilated for 12 hrs (CMV) and in the second group both phrenic nerves were stimulated via pacer wires inserted near the phrenic nerves to mimic spontaneous breathing (STIM). Lactate, pyruvate and glucose levels were measured continuously using microdialysis. Oxygen delivery and blood gases were measured during both conditions. Diaphragmatic stimulation generated sufficient tidal volumes in all STIM animals. Diaphragm lactate release increased in CMV transiently whereas in STIM lactate dropped during this same time point (2.6 vs. 0.9 mmol L-1 after 5:20 hrs; p < 0.001). CMV increased diaphragmatic pyruvate (40 vs. 146 µmol L-1 after 5:20 hrs between CMV and STIM; p < 0.0001), but not the lactate/pyruvate ratio. Diaphragmatic stimulation via regular electrodes is feasible to generate sufficient ventilation, even in deep sedation. Mechanical ventilation alters the metabolic state of the diaphragm, which might be one pathophysiologic origin of ventilator-induced diaphragmatic dysfunction. Occurrence of hypoxia was unlikely.

Automatic Control of Veno-Venous Extracorporeal Lung Assist.

Veno-venous extracorporeal lung assist (ECLA) can provide sufficient gas exchange even in most severe cases of acute respiratory distress syndrome. Commercially available systems are manually controlled, although an automatically controlled ECLA could allow individualized and continuous adaption to clinical requirements. Therefore, we developed a demonstrator with an integrated control algorithm to keep continuously measured peripheral oxygen saturation and partial pressure of carbon dioxide constant by automatically adjusting extracorporeal blood and gas flow. The "SmartECLA" system was tested in six animal experiments with increasing pulmonary hypoventilation and hypoxic inspiratory gas mixture to simulate progressive acute respiratory failure. During a cumulative evaluation time of 32 h for all experiments, automatic ECLA control resulted in a peripheral oxygen saturation ≥90% for 98% of the time with the lowest value of 82% for 15 s. Partial pressure of venous carbon dioxide was between 40 and 49 mm Hg for 97% of the time with no value <35 mm Hg or >49 mm Hg. With decreasing inspiratory oxygen concentration, extracorporeal oxygen uptake increased from 68 ± 25 to 154 ± 34 mL/min (P < 0.05), and reducing respiratory rate resulted in increasing extracorporeal carbon dioxide elimination from 71 ± 37 to 92 ± 37 mL/min (P < 0.05). The "SmartECLA" demonstrator allowed reliable automatic control of the extracorporeal circuit. Proof of concept could be demonstrated for this novel automatically controlled veno-venous ECLA circuit.

Twelve Hours In Vitro Biocompatibility Testing of Membrane Oxygenators.

In vitro test systems for extracorporeal membrane oxygenation (mock loop) represent an interesting alternative to complex and expensive in vivo test systems to analyze the pathomechanisms leading to insufficient biocompatibility. Data on mock loop systems are limited, and operation times are constricted to a maximum duration of 6 hr. This study aims at a 12 hr operation time and frequent monitoring of markers for insufficient biocompatibility in two experimental settings. Porcine blood circulated in a mock loop without any modifications, or the circuit was operated with a CO2-enhanced gas (5% CO2/21% O2/74% N2) in combination with a nutrient solution (phosphate-adenine-glucose-guanosine-saline-mannitol). Coagulation parameters changed over time without differences between the two groups. In the unmodified test setting, a pH increase was detected after 1 hr, followed by significantly increased levels of free hemoglobin as a marker for hemolysis and elevated numbers of activated platelets, which correlate with detected von Willebrand factor, microparticles, and interleukin-ß. Proinflammatory cytokine levels were significantly increased after 12 hr. In contrast, these parameters remained constant in the modified test setting providing proof of a stable operating in vitro mock loop system with an extended/prolonged operation time.

A miniaturized extracorporeal membrane oxygenator with integrated rotary blood pump: preclinical in vivo testing.

Extracorporeal membrane oxygenation can achieve sufficient gas exchange in severe acute respiratory distress syndrome. A highly integrated extracorporeal membrane oxygenator (HEXMO) was developed to reduce filling volume and simplify management. Six female pigs were connected to venovenous HEXMO with a total priming volume of 125 ml for 4 hours during hypoxemia induced by a hypoxic inspired gas mixture. Animals were anticoagulated with intravenous heparin. Gas exchange, hemodynamics, hemolysis, and coagulation activation were examined. One device failed at the magnetic motor coupling of the integrated diagonal pump. In the remaining five experiments, the oxygenation increased significantly (arterial oxygen saturation [SaO2] from 79 ± 5% before HEXMO to 92% ± 11% after 4 hours) facilitated by a mean oxygen transfer of 66 ± 29 ml/dl through the oxygenator. The CO2 elimination by the HEXMO reduced arterial PaCO2 only marginal. Extracorporeal blood flow was maintained at 32% ± 6% of cardiac output. Hemodynamic instability or hemolysis was not observed. The plasmatic coagulation was only mildly activated without significant platelet consumption. The HEXMO prototype provided sufficient gas exchange to prevent hypoxemia. This proof of concept study supports further development and design modifications to increase performance and to reduce coagulation activation for potential long-term application.

Hemocompatibility of a miniaturized extracorporeal membrane oxygenation and a pumpless interventional lung assist in experimental lung injury.

Extracorporeal membrane oxygenation (ECMO) is used for most severe acute respiratory distress syndrome cases in specialized centers. Hemocompatibility of devices depends on the size and modification of blood contacting surfaces as well as blood flow rates. An interventional lung assist using arteriovenous perfusion of a low-resistance oxygenator without a blood pump (Novalung, Hechingen, Germany) or a miniaturized ECMO with reduced filling volume and a diagonal blood pump (Deltastream, Medos AG, Stolberg, Germany) could optimize hemocompatibility. The aim of the study was to compare hemocompatibility with conventional ECMO. Female pigs were connected to extracorporeal circulation for 24 h after lavage induced lung injury (eight per group). Activation of coagulation and immune system as well as blood cell damage was measured. A P value <0.05 was considered significant. Plasmatic coagulation was slightly activated in all groups demonstrated by increased thrombin-anti-thrombin III-complex. No clinical signs of bleeding or thromboembolism occurred. Thrombelastography revealed decreased clotting capacities after miniaturized ECMO, probably due to significantly reduced platelet count. These resulted in reduced dosage of intravenous heparin. Scanning electron microscopy of oxygenator fibers showed significantly increased binding and shape change of platelets after interventional lung assist. In all groups, hemolysis remained negligible, indicated by low plasma hemoglobin concentration. Interleukin 8 and tumor necrosis factor-alpha concentration as well as leukocyte count remained unchanged. Both devices demonstrated adequate hemocompatibility for safe clinical application, although a missing blood pump did not increase hemocompatibility. Further studies seem necessary to analyze the influence of different blood pumps on platelet drop systematically.

Mechanism of complement activation during extracorporeal blood-biomaterial interaction: effects of heparin coated and uncoated surfaces.

In vitro studies with miniaturized rotating circuits and heparinized human blood, as well as long-term extracorporeal membrane oxygenation with either heparin coated (HBS) or uncoated surfaces connected to adult sheep, were performed comparing the impact on complement activation in blood and on surfaces. Analysis of surface bound complement proteins revealed significantly reduced binding of activated C3 and C5b-9 to HBS in vitro, compared with uncoated surfaces, which was probably due to more HBS bound complement inhibitors (C1-Inhibitor, factor H) being present. This was reflected by significantly reduced activation of the alternative pathway (C3bBbP) and terminal complex (SC5b-9) by HBS but slightly increased levels of classic pathway complex (C1rs-C1-inhibitor). These results were confirmed during in vivo study by analysis of hemolytic complement function, activation specific C3 derived split products, and surface bound complement proteins. Increased binding of complement regulators to HBS appears to effectively reduce complement activation by biomaterials, leading to improved long-term biocompatibility.