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.

Implementation of quality management in early stages of research and development projects at a university.

The ultimate objective of university research and development projects is usually to create knowledge, but also to successfully transfer results to industry for subsequent marketing. We hypothesized that the university technology transfer requires efficient measures to improve this important step. Besides good scientific practice, foresighted and industry-specific adapted documentation of research processes in terms of a quality management system might improve the technology transfer. In order to bridge the gap between research institute and cooperating industry, a model project has been accompanied by a project specific amount of quality management. However, such a system had to remain manageable and must not constrain the researchers' creativity. Moreover, topics and research team are strongly interdisciplinary, which entails difficulties regarding communication because of different perspectives and terminology. In parallel to the technical work of the model project, an adaptable quality management system with a quality manual, defined procedures, and forms and documents accompanying the research, development and validation was implemented. After process acquisition and analysis the appropriate amount of management for the model project was identified by a self-developed rating system considering project characteristics like size, innovation, stakeholders, interdisciplinarity, etc. Employees were trained according to their needs. The management was supported and the technical documentation was optimized. Finally, the quality management system has been transferred successfully to further projects.

A novel approach in extracorporeal circulation: individual, integrated, and interactive heart-lung assist (I3-Assist).

Extracorporeal life support (ECLS) is a well-established technique for the treatment of different cardiac and pulmonary diseases, e.g., congenital heart disease and acute respiratory distress syndrome. Additionally, severely ill patients who cannot be weaned from the heart-lung machine directly after surgery have to be put on ECLS for further therapy. Although both systems include identical components, a seamless transition is not possible yet. The adaption of the circuit to the patients' size and demand is limited owing to the components available. The project I³-Assist aims at a novel concept for extracorporeal circulation. To better match the patient's therapeutic demand of support, an individual number of one-size oxygenators and heat exchangers will be combined. A seamless transition between cardiopulmonary bypass and ECLS will be possible as well as the exchange of components during therapy to enhance circuit maintenance throughout long-term support. Until today, a novel oxygenator and heat exchanger along with a simplified manufacturing protocol have been established. The first layouts of the unit to allow the spill- and bubble-free connection and disconnection of modules as well as improved cannulas and a rotational pump are investigated using computational fluid dynamics. Tests were performed according to current guidelines in vitro and in vivo. The test results show the feasibility and potential of the concept.

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.

Semi-fluorinated alkanes as carriers for drug targeting in acute respiratory failure.

Partial liquid ventilation (PLV) with perfluorocarbons may cause pulmonary recruitment in acute lung injury (ALI). Semi-fluorinated alkanes (SFAs) provide biochemical properties similar to perfluorocarbons. Additionally, SFAs are characterized by increased lipophilicity. Therefore, SFA-PLV may be considered for deposition of certain therapeutic drugs into atelectatic lung areas. In this experimental study SFA-PLV was evaluated to demonstrate feasibility, pulmonary recruitment, and efficacy of drug deposition. Feasibility of SFA-PLV was determined in pigs with and without experimental ALI. Animals were randomized to PLV with SFAs up to a cumulative amount of 30 mL x kg⁻¹ or to conventional mechanical ventilation. Pulmonary recruitment effects were determined by analyzing ventilation-perfusion distributions. Efficacy of intrapulmonary drug deposition was evaluated in further experiments by measuring drug serum concentrations in the course of PLV with SFA-dissolved α-tocopherol and ibuprofen. Increasing SFA doses caused progressive reduction of intrapulmonary shunt in animals with ALI, indicating pulmonary recruitment. PLV with SFA-dissolved α-tocopherol had no effect on serum levels of α-tocopherol, whereas PLV with SFA-dissolved ibuprofen caused a rapid increase of serum levels of ibuprofen. The authors conclude that SFA-PLV is feasible and causes pulmonary recruitment in ALI. Effectiveness of drug deposition in the lung obviously depends on the partitioning drugs out of the SFA phase into blood.

Effects of preserved spontaneous breathing activity during mechanical ventilation in experimental intra-abdominal hypertension.

PURPOSE: Ventilation problems are common in critically ill patients with intra-abdominal hypertension. The aim of this study was to investigate the effects of preserved spontaneous breathing during mechanical ventilation on hemodynamics, gas exchange, respiratory function and lung injury in experimental intra-abdominal hypertension. METHODS: Twenty anesthetized pigs were intubated and ventilated for 24 h with biphasic positive airway pressure without (BIPAP(PC)) or with additional, unsynchronized spontaneous breathing (BIPAP(SB)). In 12 animals, intra-abdominal pressure was increased to 30 mmHg for two 9 h periods followed by a 3 h pressure relief each. Eight animals served as controls and were ventilated for 24 h. Hemodynamics, gas exchange and respiratory mechanics were measured and lung injury was determined histologically. RESULTS: Intra-abdominal hypertension caused significant impairment of hemodynamics and respiratory mechanics in both modes. In the presence of intra-abdominal hypertension, BIPAP(SB) did not demonstrate superior respiratory mechanics and cardiovascular stability as compared to BIPAP(PC). Although the decrease of dynamic compliance and the increase of airway pressures were mitigated, BIPAP(SB) failed to lower pulmonary vascular resistance and caused increased dead space ventilation (p = 0.007). Blood pressures and cardiac output increased in BIPAP(SB), caused by an increase in heart rate (p < 0.001), but not in stroke volume (p = 0.06). BIPAP(SB) was associated with an increased breathing effort, decreased transpulmonary pressure during inspiration and lower lobe diffuse alveolar damage (p = 0.002). CONCLUSIONS: In the presence of severe intra-abdominal hypertension, the addition of unsupported spontaneous breaths to BIPAP did not improve hemodynamic and respiratory function and caused greater histopathologic damage to the lungs.

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.

Effects of partial ventilatory support modalities on respiratory function in severe hypoxemic lung injury.

OBJECTIVE: The early phase of acute respiratory distress syndrome (ARDS) is characterized by impaired respiratory mechanics, ventilation-perfusion mismatch, and severe hypoxemia. Partial ventilatory support can effectively unload the respiratory workload and improve pulmonary gas exchange with less hemodynamic compromise. The partial ventilatory support mode most indicated in early phases of ARDS has not been determined. This study compares the effects of assisted ventilatory techniques on breathing pattern, gas exchange, hemodynamic function, and respiratory effort with those of controlled mechanical ventilation in similarly sedated subjects. DESIGN: Prospectively randomized crossover animal study. SETTING: Animal research laboratory. SUBJECTS: Eleven anesthetized and mechanically ventilated pigs. INTERVENTIONS: Acute lung injury was induced by lung lavage. Pressure-controlled ventilation (PCV), pressure-controlled assisted ventilation (P-ACV), bilevel positive airway pressure (BIPAP), and pressure support ventilation (PSV) with equal airway pressures and sedation were applied in random order. MEASUREMENTS AND MAIN RESULTS: Gas exchange, respiratory effort, and hemodynamic function were measured, and ventilation-perfusion distributions were calculated by multiple inert-gas-elimination techniques. The results revealed that partial ventilatory support was superior to PCV in maintaining adequate oxygenation and hemodynamic function with reduced sedation. The effects of P-ACV, BIPAP, and PSV were comparable with respect to gas exchange and hemodynamic function, except for a more pronounced reduction in shunt during BIPAP. P-ACV and PSV were superior to BIPAP to reduce respiratory drive and work of breathing. PSV affected the pattern of breathing and deadspace to a greater degree than did P-ACV. CONCLUSIONS: In acute lung injury, P-ACV preserves oxygenation and hemodynamic function with less respiratory effort compared with BIPAP and reduces the need for sedation compared with PCV.

Ventilation with biphasic positive airway pressure in experimental lung injury. Influence of transpulmonary pressure on gas exchange and haemodynamics.

OBJECTIVE: We investigated whether improvement in ventilation perfusion (.V(A)/.Q) distribution during mechanical ventilation using biphasic positive airway pressure (BIPAP) with spontaneous breathing may be attributed to an effectively increased transpulmonary pressure (P(TP)) and can also be achieved by increasing P(TP) during controlled ventilation. DESIGN: In 12 pigs with saline lavage-induced lung injury we compared the effects of BIPAP to pressure-controlled ventilation with equal airway pressure (PCV(AW)) or equal transpulmonary pressure (PCV(TP)) on V(A)/.Q distribution assessed by the multiple inert gas elimination technique (MIGET). SETTING: Animal laboratory study. MEASUREMENTS AND RESULTS: Intrapulmonary shunt was 33+/-11% during BIPAP, 36+/-10% during PCV(AW) and 33+/-15% during PCV(TP) ( p= n.s.). BIPAP resulted in higher PaO(2) than PCV(AW) (188+/-83 versus 147+/-82 mmHg, p < 0.05), but not than PCV(TP) (187+/-139 mmHg). Oxygen delivery was significantly higher during BIPAP (530+/-109 ml/min) versus 374+/-113 ml/min during PCV(AW) and 353+/-93 ml/min during PCV(TP) ( p < 0.005). Tidal volume with PCV(TP) increased to 11.9+/-2.3 ml/kg, compared to 8.5+/-0.8 with BIPAP and 7.6+/-1.4 with PCV(AW) ( p <0.001) and cardiac output decreased to 3.5+/-0.6 l/min (BIPAP 4.9+/-0.8 and PCV(AW) 3.9+/-0.8, p<0.006). CONCLUSIONS: In experimental lung injury, BIPAP with preserved spontaneous breathing was effective in increasing regional P(TP), since pressure-controlled ventilation with the same P(TP) resulted in similar gas exchange effects. However, PCV(TP) caused increased airway pressures and tidal volumes, whereby, with BIPAP, less depression of oxygen delivery and cardiac output were observed. BIPAP could be useful in maintaining pulmonary gas exchange and slightly improving oxygenation without interfering with circulation as strongly as PCV does.

Ventilation-perfusion distribution related to different inspiratory flow patterns in experimental lung injury.

UNLABELLED: In acute lung injury (ALI), controlled mechanical ventilation with decelerating inspiratory flow (.V(dec)) has been suggested to improve oxygenation when compared with constant flow (.V(con)) by improving the distribution of ventilation and perfusion (.V(A)/.Q). We performed the present study to test this hypothesis in an animal model of ALI. Furthermore, the effects of combined decelerating and constant flow (Vdot;(deco)) were evaluated. Thus, 18 pigs with experimental ALI were randomized to receive mechanical ventilation with either .V(con), .V(dec) or a fixed combination of both flow wave forms (.V(deco)) at the same tidal volume and positive end-expiratory pressure level for 6 h. Hemodynamics, gas exchange, and .V(A)/.Q distribution were determined. The results revealed an improvement of oxygenation resulting from a decrease of pulmonary shunt within each group (P < 0.05). However, blood flow to lung areas with a normal .V(A)/.Q distribution increased only during ventilation with .V(con) (P < 0.05). Accordingly, PaO(2) was higher with .V(con) than with .V(dec) and .V(deco) (P < 0.05). We conclude that contrary to the hypothesis, .V(con)provides a more favorable .V(A)/.Q distribution, and hence better oxygenation, when compared with .V(dec) and .V(deco) in this model of ALI. IMPLICATIONS: In acute lung injury, mechanical ventilation with decelerating flow has been suggested to improve ventilation-perfusion distribution when compared with constant flow. We tested this hypothesis in an animal model. Contrary to the hypothesis, we found a more favorable ventilation-perfusion distribution during constant flow when compared with decelerating flow.

High-frequency oscillatory ventilation in experimental lung injury: effects on gas exchange.

OBJECTIVE: To compare ventilation-perfusion (V(A)/Q) distributions during improvement of oxygenation caused by high-frequency oscillatory ventilation (HFOV) and pressure-controlled mechanical ventilation with high PEEP levels (CMV) in experimental acute lung injury (ALI). DESIGN: Prospective, controlled animal study. SETTING: Animal research facility of a university hospital. INTERVENTIONS: Twelve pigs with oleic acid-induced ALI were randomised to HFOV ( n=6) or to CMV ( n=6) with a PEEP of 15 mbar for 1 h. The mean airway pressure was adjusted in both groups to achieve comparable improvements in arterial oxygen partial pressure (PaO(2)) and to avoid clinically relevant impairments of cardiac output, as assured by adequate mixed venous oxygen saturation and lactate levels. V(A)/Q distributions were determined by the multiple inert gas elimination technique (MIGET). MEASUREMENTS AND RESULTS: Arterial oxygen partial pressure improved during CMV with a mean airway pressure of 20 mbar ( p<0.05) whereas HFOV revealed comparable improvements with a mean airway pressure of 40 mbar ( p<0.05). Shunt decreased and blood flow to normal V(A)/Q areas increased due to CMV and HFOV ( p<0.05). The perfusion of low V(A)/Q areas remained unchanged. Statistical analysis did not reveal differences of PaO(2), shunt or blood flow to low V(A)/Q areas between the groups. CONCLUSIONS: In this model of acute lung injury CMV and HFOV improved gas exchange due to similar changes in V(A)/Q distribution. However, mean airway pressure had to be adjusted twofold higher during HFOV then during CMV to achieve comparable improvements in gas exchange.

Pressure support compared with controlled mechanical ventilation in experimental lung injury.

UNLABELLED: It has been suggested that, in acute lung injury (ALI), spontaneous breathing activity may increase oxygenation because of an improvement of ventilation-perfusion distribution. Pressure support ventilation (PSV) is one of the assisted spontaneous breathing modes often used in critical care medicine. We sought to determine the prolonged effects of PSV on gas exchange in experimental ALI. We hypothesized that PSV may increase oxygenation because of an improvement in ventilation-perfusion distribution. Thus, ALI was induced in 20 pigs by using repetitive lung lavage. Thereafter, the animals were randomized to receive either PSV with a pressure level set to achieve a tidal volume >4 mL/kg and a respiratory rate <40 min(-1) (n = 10) or controlled mechanical ventilation (CMV) with a tidal volume of 10 mL/kg and a respiratory rate of 20 min(-1) (n = 10). Positive end-expiratory pressure was set at 10 cm H(2)O in both groups. Blood gas analyses and determination of ventilation-perfusion (.V(A)/.Q) distribution were performed at the onset of ALI and after 2, 4, 8, and 12 h. The main result was an improvement of oxygenation because of a decrease of pulmonary shunt and an increase of areas with normal .V(A)/.Q ratios during PSV (P < 0.005). However, during CMV, a more pronounced reduction of shunt was observed compared with PSV (P < 0.005). We conclude that, in this model of ALI, PSV improves gas exchange because of a reduction of .V(A)/.Q inequality. However, improvements in .V(A)/.Q distribution may be more effective with CMV than with PSV. IMPLICATIONS: Assisted spontaneous breathing may have beneficial effects on gas exchange in acute lung injury. We tested this hypothesis for pressure support ventilation in an animal model of acute lung injury. Our results demonstrate that pressure support does not necessarily provide better gas exchange than controlled mechanical ventilation.