EP3870249A1

EP3870249A1 - Device having an artificial gills system and use therof for supporting a newborn

Info

Publication number: EP3870249A1
Application number: EP19804634.4A
Authority: EP
Inventors: Michael Tchirikov
Original assignee: Individual
Current assignee: Individual
Priority date: 2018-10-25
Filing date: 2019-10-25
Publication date: 2021-09-01
Also published as: JP2022509400A; CN113226399A; WO2020084125A1; US20210308350A1; DE102018126634A1

Abstract

The present invention relates to a device and a method for supporting a human being, preferably a newborn, in particular an extremely premature infant between the 21/0 and 28/0 week of pregnancy (SSW), comprising at least one through-flow system (21), comprising a number of fluid-permeable elements (22) and connecting elements (26, 28) for the connection to an umbilical arterial catheter (30) and an umbilical venous catheter (32) of the newborn and a through-flow lumen (20) for passing modified amniotic fluid enriched with oxygen or a oxygen-containing gas mixture through the fluid-permeable elements (22), and at least one connection (12) for introducing the modified amniotic fluid enriched with oxygen or an oxygen-containing gas mixture into the through-flow system (21), wherein the through-flow system (21) is configured in such a way that the amniotic fluid modified with oxygen or an oxygen-containing gas mixture is guided through the fluid-permeable elements (22) of the through-flow system (21) while the foetal blood is passed along the outer side of the fluid-permeable elements (22), but directed past the through-flow lumen, whereby a gas exchange occurs.

Description

DEVICE WITH ARTIFICIAL GEM SYSTEM AND YOUR

USE FOR THE LIFE OF A NEWBORN

Description:

TECHNICAL AREA

The present invention relates to a device and a method for the life support of a person, preferably a newborn, in particular an extremely premature baby, between the 21/0 and 28/0 week of pregnancy (SSW).

STATE OF THE ART

The births of children under the 24th week of pregnancy (SSW) with a weight of less than 500 g who show no sign of life are considered "late abortion" and are not statistically recorded as births. A late abortion affects several million children in developed countries worldwide. Compared to fully born babies, premature babies have a significantly higher risk of developing health complications immediately after birth or during life. The earlier a baby is born, the underdeveloped its organs and the higher the risk of health problems. Of all extremely premature babies (i.e. under the 28/0 SSW), 40% die within the first five years (WAO report "Born to soon", 201 1). Furthermore, 91% of premature babies die in the 23rd week of pregnancy and 67% in the 24th week of pregnancy (Stoll et al. JAMA 2015). Extremely premature babies rarely survive without serious long-term consequences (Chen F. et al. Arch Dis Chld Fetal Noanatal 2016; 101: 377-83). These include cerebral palsy, sensory and motor disabilities, learning and

Behavioral disorders and often lung problems. Only 6% of all premature babies in the 22nd week of pregnancy survive until they are discharged from the hospital, with 95 to 96% of them showing marked physical and / or mental damage (Stoll et al. JAMA 2015). At 22

The surviving premature babies suffer from retinopathy with a severity of greater than 3 (relative blindness) in 89% of cases. In the 23rd week of pregnancy, 42% are affected. Only a percentage of less than 20% of premature babies survive until discharge from the hospital without developing necrotizing enterocolitis, sepsis, meningitis, bronchiopulmonary hypoplasia and / or pronounced cerebral hemorrhage in premature babies under the 24th week of pregnancy (Stoll et al. JAMA 2015). A similar picture with sometimes drastically poor survival rates is also provided by a recent study in newborns between the 22nd and 24th week of pregnancy (Noelle Younge et al., Survival and Neurodevelopmental Outcomes among Periviable Infants, The New England Journal of Medicine, February 16, 2017, volume 376, no.7). The lung is one of the most recently developed organs in fetuses. This means that in the event of extreme premature birth, the immature insufficient lungs can lead to short-term and / or long-term health problems or death of the premature baby. The development of bronchopulmonary dysplasia is 72% in extremely premature babies <25/0 week of pregnancy (Noelle Younge et al., Survival and Neurodevelopmental Outcomes among Periviable Infants, The New England Journal of Medicine, February 16, 2017 vol. 376 no. 7). Pneumothorax often occurs when ventilating extremely immature lungs. The immature inadequate lungs are in most cases unable to provide normal, permanent oxygen supply to the placenta, which leads to hypoxic brain damage and / or pronounced brain hemorrhage.

To counteract this problem, methods and therapies with artificial lungs are being developed to increase the survival rate of extremely premature babies and avoid late effects.

In human fetuses, the placenta takes over the oxygen supply. Other important placental functions are, for example, a transplacental active and / or passive

Transport of amino acids, fatty acids, micro-elements, vitamins, water, electrolytes, growth factors, hormones, cytokines and other regulating substances (NO etc.). Some substances such as amino acids, hormones, NO are also synthesized in the placenta itself. The fetal metabolites such as bilirubin or C0 ₂ are disposed of via the placenta. The maternal kidneys and lungs then take on the disposal function.

The arterial blood is transported to the uterus through the uterine vessels. The spiral arteries bring the blood over the basal plate of the placenta into the placental intervillous space. There is a 0 ₂ / C0 ₂ exchange between the maternal blood and the fetal blood. The fetal placental blood is located in the fetal capillaries of the placental villi and is separated from the maternal blood by a thin layer of tissue syncytium and cytotrophoblast.

The 0 ₂ - binding curve of fetal hemoglobin is steeper in laboratory conditions than that of maternal blood. Due to the low physiological fetal pH value, the Hb affinity is very similar to the adult Hb affinity under normal conditions. The

Oxygen binding curve is shifted to the right by the lowering of the pH. The

Hemoglobin releases the oxygen in the fetal tissue more easily due to the lowering of the pH. The C0 ₂ - and H ^{+ influence} on the 0 ₂ affinity of hemoglobin is also referred to as the Bohr effect. Dissociation of carbonic acid is promoted the less the fetal

Hemoglobin is loaded with 0 ₂ (Haldane effect). The normal fetal

Hemoglobin concentration increases from 10-12 g / dl in the 17th / 18th SSW on 14-15 g / dl at

Delivery date.

Systems and artificial uteruses are known to increase the life functions of a premature baby.

WO 2018/171905 A1 describes an artificial uterine system for the life support of newborns, especially of extremely premature babies between the 21/0 and 28/0

Week of pregnancy, with an oxygenator and / or a fumigation device for oxygenation of the newborn or premature baby.

The US 2014/0255253 A1 describes an artificial uterus, which with a

Oxygen supply device for the premature baby is equipped. The device comprises a gas permeable membrane and a vascular network over which, for example

Liquids with nutrients can be supplied. Oxygen is supplied via an oxygenator via the umbilical cord using a umbilical catheter

(Umbilical cord catheter) comprising a venous catheter and an arterial catheter. A gas mixture containing 40% oxygen in nitrogen was administered via this catheter system.

Another possibility of oxygenating a premature baby is described in WO 2014/145494 A1, in which the circulatory system of the premature baby is coupled to an extracorporeal membrane, which is part of an oxygen supply system. One variant provides that the oxygenator enriches the fetal blood with oxygen.

WO 2016/154319 A1 describes an artificial placenta in which microfluidic channels are provided which are arranged between a membrane in such a way that liquid can be transported through the membrane in order to supply the fetus with nutrients, for example. The regulation of the gas exchange by the pressure, amniotic fluid velocity along the membranes is not described. Furthermore, cell layers are of at least two

Different cell types are provided, which adhere to the two sides of the membrane. The first cell type is, for example, primary human placental villous

Endothelial cells, while the second cell type includes choriocarcinoma cells.

Such membranes are also part of US 4,556,489 A, in which a device for

Mass transfer through a membrane is disclosed, which is particularly suitable for use as Blood oxygenator is suitable.

Extracorporeal membrane oxygenation (ECMO) is often performed to replace lung function. With the ECL system (extracorporal life support) there is also one

Hemodynamic relief of the heart is possible because it supports the circulatory system. The blood is transported from the patient's venous system by means of a pump and, after passage through the oxygenator, is returned to the arterial system. The

Oxygen supply to the organism is made up of the ECMO / ECLS flow and the patient's remaining circulatory function. The connection with the

extracorporeal circulation is usually done through cannulas. The systems require blood heparinization to avoid thrombosis in the artificial system. The other problem is the destruction of erythrocytes with consequences of fetal anemia and an increase in the bilirubin concentration.

The placenta systems described in the prior art are inadequate in many respects since they are unsuitable for the treatment of extremely premature babies.

Partridge et al. (An extra-uterine system to physiologically support the extreme premature lamb. Nature Communications. 2017; 8: 15112) describe the use of an oxygenator (Quadrox-ID Pediatric oxygenator (Maquet Quadrox-ID Pediatric Oxygenator: Maquet

Cardiopulmonary AG, Rastatt, Germany) and Quadrox Neonatal Oxygenator (Maquet Quadrox-I Neonatal and Pediatric Oxygenator: Maquet Cardiopulmonary AG) in a fetal sheep model in the 2nd-3rd Trimester. The oxygenator is connected to the umbilical cord vessels via catheters. Out of a total of 33 fetuses, only 3 survived for several weeks without complications. Sepsis, heart failure and bleeding were among the most complications. In order to stabilize the fetal blood gases in the areas Pa0 ₂ 20-30 mm Hg and Pa C0 ₂ 35-45 mmHg and to avoid excessive oxygen saturation, the oxygen concentration of the medical air had to be reduced from 21% to 11-14%. Oxidative stress, as an imbalance between free radicals and antioxidant defense mechanisms, is one of the main factors in the poor outcome of pregnancy (Sultana et al. 2017 Am J Reprod Immunol. 2017 May; 77 (5)). Side effects may include hemolysis and embolism when using such oxygenators. You can also use a

Post-perfusion syndrome or organ damage may occur.

The modern oxygenators also need their own integrated system for the

Warming of blood. Air bubbles are a known problem with oxygenators, which is why ventilation systems are often provided. This is another problem requires that the membranes of the oxygenator on the side of the 0 ₂ or gas mixture inflow are dry, which significantly increases the risk of thrombi in the blood.

The alveolar space of the human lungs is coated with surfactant. The surfactant mainly consists of phospholipids and is synthesized by type II pneumocytes and secreted into the alveoli in order to avoid surface tension. The alveolar epithelial cells and the endothelial cells lie between the capillary blood and the air. There is no direct contact between the blood and the air.

When there is air contact, the coagulation system is activated. The activated (blood) clotting time (ACT) of the fetuses is increased to 150-180 s when using an oxygenator with heparin (10-400 UPS / h) in order to avoid thrombosis of the ECMO / ECL system .

Youngle et al. (New Engl J Med 2017) describes the rate of pronounced cerebral hemorrhage in extremely premature babies of 29%. Additional heparin infusions would significantly worsen this complication in human fetuses and premature babies. The development of fetal anemia when using an oxygenator was also documented (Partridge et al. 2017).

In summary, existing uterine systems and oxygenators are still inadequate, especially when it comes to efficient oxygenation for extremely premature babies. A system that would not require blood heparinization would be desirable

Avoid thrombosis, erythrocyte destruction, or fetal anemia.

PRESENTATION OF THE INVENTION

Against this background, it is an object of the present invention to provide an improved

to provide an artificial system which is suitable for the life support of a newborn, in particular an extremely premature baby between the 21/0 and 28/0 week of pregnancy, and which

Avoids or at least reduces disadvantages of the EZMO / ECL system in order to improve the neonatal income.

This object is achieved by a device and an ex vivo method with the features of the following claims. Preferred design variants can be found in the subclaims.

The crux of the invention device is an artificial flow system, which consists of a number there are fluid-permeable elements, for example stacked or lamellar membranes or micropore material (eg tubes), which enables an efficient 0 ₂ - / C0 ₂ exchange in fetal blood, similar to a gill system in fish. It is envisaged that the oxygen dissolved in oxygenated amniotic fluid or present in an artificial uterine space via the invention

Flow system to which fetal blood is delivered. The fetal blood is branched from the blood vessels of the umbilical cord. In contrast to known systems, the

system according to the invention an oxygenation of the amniotic fluid and not the fetal blood. The oxygenated amniotic fluid flows through the

fluid-permeable elements while the blood is passed on the outside. This leads to gas exchange, similar to the gills in fish.

Instead of the modified amniotic fluid, a plasma replacement solution can also be used.

The flow system is preferably arranged in a container (i.e. housing or lumen) in which the fetus is also located. This container serves as an artificial one

Uterus. In an alternative variant, the flow system is located outside the artificial uterus in a separate housing. In a further variant, a container or housing can be dispensed with completely, i.e. the flow system itself is not integrated in any container.

The membranes or the micropore material of the flow systems can be connected to one another either in series or in parallel in the direction of flow. The flow system is constructed like a gill system, i.e. it includes one with the oxygenated amniotic fluid

flowed through lumen and a flow lumen through which blood is passed.

The gill-like flow system enables efficient gas, electrolyte exchange and toxin and waste product disposal, e.g. of bilirubin, ammonia, nitrogen. Osmoregulation via ion transport is also possible.

The present invention is based on the idea that the fetus develops in the amniotic fluid. A gas exchange takes place between the fetal blood and the modified amniotic fluid enriched with oxygen or an oxygen-containing gas mixture via the ultra-thin fetal skin, the mucous membranes and the fetal intestine of the fetus. The gas mixture preferably comprises oxygen (0 ₂ ), carbon dioxide (C0 ₂ ) and / or nitrogen (N ₂ ) _. Some living beings use a gill system for breathing, ie fish, crustaceans and molluscs, which Supply the organism with oxygen. The gills take over next to the

respiratory function still other functions, such as nitrogen excretion, osmoregulation and food intake. For example, Nitrogen excreted through the gills in the form of ammonia. The lipid-soluble pollutants, which are increasingly in higher

Accumulations in sea and fresh water can also be excreted through the gills.

The flow system according to the invention comprises a number of fluid-permeable elements which work according to the gill principle. The fluid-permeable elements can have a lamella-like, comb-like, leaf-like, tuft-like or tree-like structure, so that the largest possible surface for gas exchange (0 ₂ / C0 ₂ ) can arise. The 0 ₂ exchange to the fetal blood preferably takes place via the countercurrent principle, which is greatly improved compared to conventional problem solutions. The modified amniotic fluid enriched with oxygen or the oxygen-containing gas mixture is passed through the fluid-permeable elements of the flow system, while the fetal blood is glided past the outside of the fluid-permeable elements.

Furthermore, the C0 ₂ solubility in liquid (eg amniotic fluid) is in the

The gill structure according to the invention is approximately 24 times higher than that of oxygen, the passive diffusion in the tissue being mainly dependent on the diameter of the respective gas molecule. For example, oxygen defines 0 ₂ with a molecular weight of 32 faster than C0 ₂ with a molecular weight of 44. As a result, marine animals such as fish are able to extract up to 90% of the available oxygen from the water with their gill system.

In one embodiment variant, the device according to the invention initially comprises a closed container which serves to hold the fetus and the flow system. When the device is used, the fetus is in modified amniotic fluid and is supplied with oxygen or the oxygen-containing gas mixture and other vital substances via its umbilical cord. There is at least one inside the container

Flow system arranged, preferably two or more flow systems that can run independently or in parallel. Each flow system consists of a larger number of fluid-permeable elements, for example of> 5, preferably> 10 fluid-permeable elements, preferably> 50 fluid-permeable elements. These can consist, for example, of membranes, tubes or micropore material.

For connection to the two umbilical arteries and the umbilical vein of a premature baby Connecting elements are provided, which over the blood vessels of the umbilical cord

Connect the arterial and venous catheters to the flow system. This can be a single catheter with several lumens or several separate catheters. The flow system further comprises one or more flow lumens which are used for

Feed modified amniotic fluid through.

Modified (or artificial) amniotic fluid is amniotic fluid that has been adapted to the fetus and in which one or more components have been added or omitted. The components are, for example, electrolytes such as NaCl or KCl, or drugs, nutrients or medical devices.

Depending on the design variant, amniotic fluid is guided from the outside in the longitudinal direction through the fluid-permeable elements of the flow system. In one variant, with

Oxygenated amniotic fluid (oxygenated amniotic fluid) through the

fluid-permeable elements. Conversely, in a further variant, the fetal blood could be passed through the fluid-permeable elements. The amniotic fluid flows around the fluid-permeable elements from the outside, i.e. the membranes or capillaries. The umbilical cord blood vessels are fixed using a fixation system, for example a stent. At least one connection is provided on the container for introducing amniotic fluid and / or respiratory gas (oxygen, oxygen gas mixture or carbogen) in order to conduct modified amniotic fluid and / or respiratory gas into or to the flow system.

The gill-like design of the at least one flow system also enables the function of a dialysis system to dispose of substances. In the method according to the invention, there is preferably an exchange of electrolytes, a disposal of toxins and waste products, in particular bilirubin, ammonia, nitrogen, and osmoregulation via the flow system.

In a further variant, the modified amniotic fluid for the gill system is provided and used separately from the amniotic fluid of the artificial uterine system in order to adjust the blood parameters of the fetus and / or the fetal treatment via the

Gill system. The modified amniotic fluid provided in a separate container is preferably optionally mixed with drugs, heparin, vitamins, proteins, growth factors and / or hormones. It is particularly preferred that the

Gas exchange and / or drug administration and / or electrolyte administration and / or

Micro-element administration and / or a toxin and waste product disposal, for example of bilirubin, ammonia, nitrogen, and / or plasma osmoregulation via the separate Amniotic fluid system takes place. Alternatively, a supply via the artificial uterine system is also possible.

In a further variant, the artificial gill system is located outside the artificial uterine system in order to reduce the noise pollution of the fetus. This can be within another container or housing. In a preferred one

Embodiment, on the other hand, provides that the flow system manages entirely without a container, i.e. it is located outside the artificial uterus and is not itself enclosed by a housing.

The device according to the invention is constructed like an artificial uterine system, so that the fetus develops in the modified amniotic fluid in the interior of the container. The

Exchange between the fetal blood and the modified amniotic fluid takes place via the ultra-thin skin, the mucous membranes and the intestine of the fetus. The fetal oxygen requirement in fetuses is about 5 ml / min / kg (Campbell et al., J. Physiol 1966; 182: 439-464). In the human fetus in the 22nd to 25th week of pregnancy with a fetal weight of 300 to 500 g, the oxygen requirement is around 2 to 4 ml / min. One ml of oxygen weighs around 1.34 mg. With an oxygen content in amniotic fluid of 7 to 50 mg / l, the fetal

Oxygen requirements, depending on the intrauterine pressure, number and design of the fluid-permeable elements of the flow system (e.g. membrane strength) are almost completely covered with a water perfusion of 0.2 to 5 l / min.

The fluid-permeable elements preferably comprise membranes, membranes with

Micropores (polymethylpentene; PNP material) or membranes with micropores. However, other fluid-permeable elements are also covered by the invention

Work gill principle and have gas-permeable channels for 0 ₂ and C0 ₂ . Furthermore, other fluid-permeable elements can be used in the flow-through system, which provide transport channels or micropores for the detoxification function or for the normalization of electrolytes (for example CI and Na ⁺ ).

The flow system is connected to the child's vascular system via the connecting elements (ie via the child's umbilical cord), preferably via a port system. The fumigated amniotic fluid (eg provided as 0 ₂ or 0 ₂ / C0 ₂ or 0 ₂ / C0 ₂ and nitrogen mixture) is arranged in a first embodiment directly above the stack

pumped fluid permeable elements. For this purpose, a pressurized container with amniotic fluid is preferably present. Alternatively, a pump can also be used, which is the amniotic fluid enriched with oxygen or the oxygen-containing gas mixture passed through the fluid permeable elements. In a further variant, the oxygen supply can also take place directly by gassing the interior of the container with oxygen or an oxygen-containing gas mixture. Appropriate connections for the supply of breathing gas are available for this. This allows the individual proportions for the oxygenation of the fetus to be set precisely, in particular the ratio of amniotic fluid / gas,

Amniotic fluid / oxygen. These ratios can range from 0.1 / 10 to 9.9 / 10. The

Gas exchange is determined by the speed of the flow through the system

amniotic fluid flowing through, the fluid volume, the direction / opposite direction, the frequency (oscillation 0-1000 Hz), the 0 ₂ supply and / or gas mixture supply and / or regulated by a pressure change in the flow system. This preferably includes

Flow system a pressure valve, which at the umbilical cord outlet of the

Flow system is integrated. This is preferably a pressure flap that can be mechanically adjusted in advance. The flap can be opened and closed mechanically and / or digitally. The countercurrent principle facilitates the 0 ₂ uptake from the amniotic fluid into the fetal blood, similar to a natural gill system.

In a further embodiment variant, the fetal blood flows directly through the fluid-permeable elements, preferably via tubes or a membrane system, where gas exchange takes place. The modified amniotic fluid (with or without oxygen) or an amniotic fluid / gas mixture (ratio amniotic fluid / gas from 0.1 / 10 to 9.9 / 10) is by the

fluid-permeable elements bypassed and accelerated in the flow rate, preferably by a tapering diameter of tubes. The water pressure in the system on the fluid-permeable elements (e.g. membranes) can be increased via the pressure valve. The pressure can be increased periodically or kept at a constant level. The pressure in the flow system can also be controlled by gassing the amniotic fluid. The modified amniotic fluid in the flow system is preferably oscillated via the pressure valve or via a feed device, preferably at a frequency of 0-1000 Hz.

It is conceivable e.g. also that the flow system (i.e. the gill system) is used independently of the artificial uterine system, for example to replace or supplement the lung function in children or adults.

Depending on the variant, the modified amniotic fluid can also be replaced by other solutions or liquids, for example blood, plasma, nutritional solutions, salt solutions (NaCI), plasma substitute solutions, sea water, etc.). The flow system according to the invention preferably works on the principle of acceleration, in which the amniotic fluid (or a other liquid) is accelerated with a pump, which makes the oxygen / C0 ₂ exchange more efficient.

In a preferred variant, the flow system of the invention

Device additionally an additional absorber to dispose of substances such as cytokines, toxins, ammonia, bilirubin, myoglobin, creatinine, inflammatory substances or degradation products from the fetal blood. The cytokines are, for example, IL-6, IL-8, IL-10, TNA-alfa, IFN. The modified amniotic fluid is preferably preheated to a temperature between 37 ° and 39 ° C. by means of a heating device. Preferably, the interior of the container (corresponding to an artificial uterus) is also kept at a temperature between 37 ° and 39 ° C. A thermoregulator can be used to temporarily cool down to a temperature of up to around 34 ° C to reduce organ damage after asphyxia. The flow system preferably further comprises a measuring device for

Measurement of the oxygen saturation in the amniotic fluid of the artificial uterine system.

The composition of the modified amniotic fluid is also crucial for successful life support and further development of the premature baby. At a

Inadequate amniotic fluid there is a risk of fetal internal

Organs, umbilical cord, amnion, skin, eyes or mucous membranes irreversible damage

suffer.

The amniotic fluid used according to the invention therefore includes a preferred one

Embodiment a nutrient composition, the concentrations of which with the

physiological situation in the fetus at the respective gestational age. As a result, the concentration of fatty acids, vitamins, microelements, growth factors, hormones, electrolytes, cytokines and other regulatory substances is constantly checked, adjusted and substituted if necessary. The space preferably comprises the artificial one

Uterus of the uterine system according to the invention modified amniotic fluid, which has the composition of US 9,072,755B2.

Other trace elements, such as Boron, chromium, iron, fluorine, iodine, cobalt, lithium, manganese, molybdenum, nickel, silicon, vanadium, amino acids, growth factors, vitamins and

Hormones can supplement the modified amniotic fluid. The amniotic fluid is preferably preheated to a temperature between 37 and 39 ° C. before being introduced into the artificial uterus, and gassed with oxygen or an oxygen-containing gas mixture at the same time.

The fetal 0 ₂ saturation becomes 60-90% in the artificial after the umbilical cord Uterine system held in the fumigated amniotic fluid by the flow system.

The present invention further relates to an ex vivo method for the maintenance of life of a person, preferably a newborn, in particular an extremely premature baby between the 21/0 and 28/0 week of gestation, in order to maintain his life functions. The features previously described for the device also apply analogously to the method. The procedure is applicable to children and adults. In the method, amniotic fluid or a plasma replacement solution enriched with oxygen or oxygen-containing gas mixture is supplied to a container in which there is at least one flow system, which consists of a number of fluid-permeable elements and connecting elements for connection to the catheters for the umbilical arteries and umbilical vein People (e.g.

Premature babies) and a flow lumen for the passage of modified amniotic fluid or the plasma replacement solution through the fluid-permeable elements, as well as at least one connection for introducing modified oxygenated amniotic fluid, plasma replacement solution and / or respiratory gas into the flow system. Either the amniotic fluid or plasma replacement solution or the blood through the

fluid-permeable elements. A pressure between 5 mbar and 5 bar is preferably maintained in the flow system.

The premature baby is preferably a fetus born before the 28th week of pregnancy. However, the uterine system according to the invention and the ex vivo method also work in children who have a limited life expectancy due to lung insufficiency, for example due to congenital defects or due to functions that have not yet been developed, as can be ascertained, for example, in neonates with hypoplasia of the lungs. With the aid of the device or the method according to the invention, permanent treatment of lung insufficiency and also damage to respiratory tract or lungs, which are caused, for example, by burns, are possible.

In a preferred embodiment it is provided that monitoring and

Regulation of the vital functions of the newborn (in particular the physiological fetal parameters) takes place via a computer network using artificial intelligence, with which it is also possible to carry out a data exchange via the Internet. Also the

Remote regulation of the system via a network using artificial intelligence is possible. Data on the vital functions such as concentrations of C0 ₂ or 0 ₂ , saturation, blood flow volume, blood values, amino acids, coagulation status, fatty acids, glucose, growth factors, the CRP and other inflammation parameters such as IL-6, pro-calcitonin, metalloproteinases and other cytokines are to be transmitted via the computer network monitored and continuously analyzed will. Bacterial colonization is also monitored and analyzed. The analysis is intended to provide information about the child's acute state of health as well as to enable a constantly more precise risk forecast. Chips send them practically permanently

corresponding values to an evaluation unit. The complete analysis of the data can be done via a control center for each individual uterine system. The parents can, as needed or desired, e.g. via a smartphone, can be integrated into fetal video monitoring or vital signs monitoring. This type of parent integration also enables audio and / or video based communication, which enables interaction between the parent and the child. This is particularly important because the mother often suffers from fear of loss or failure. An audio and / or video based interaction between mother and fetus, e.g. via a smart phone, is among other things advantageous to avoid depression of the mother. Can be transferred e.g. the voice of the parents, breathing, heartbeats, but also bowel sounds, which are part of a natural environment.

A variant provides that, for example, increased heartbeats of the child, after filtering out the device noises, are transmitted to the mother in real time via a communication device (e.g. smartphone). In return, noises from the mother and / or the father (e.g. heartbeat, voice, breathing noises, possibly bowel noises) can be emitted acoustically into the uterine system in real time ("live") or via a continuous loop.

According to the invention, devices are provided which enable high-frequency data acquisition and analysis. The analysis includes in particular the use of density prediction methods, a corresponding risk forecast and the implementation of regime switching models.

For example, a Markov-Switching GARCH specification according to Haas et al. (2004), but with additional consideration of delayed cross correlation between the

Blood value series and the effect of exogenous interventions in which the system or method according to the invention are used to assign their different behavior patterns with a certain probability (Haas M, Mittnik S, Paolella MS 2004; Hastie et al. 2008). A precise estimate of the parameters and probabilities can e.g. via EM algorithms.

High observation cycles of certain patterns in the regime assignment, especially before the appearance of a pathological condition, could mean an enormous gain in information for the understanding of a disease. For this pattern recognition, the use of an artificial neural network could be checked to determine the probability of an entry Assess medication need. Therefore, in a preferred variant, a continuous analysis and assessment of the neonatal outcome to correct the therapy and adjust the setting of the flow system should take place.

In a preferred embodiment, the device according to the invention comprises a

Communication system with which a transmission of audio signals between the

Fetus in the artificial uterine system and the mother or father is possible.

The device is preferably equipped with an audio system with which one

Communication between the fetus in the artificial uterine system and the mother or father is possible. In this way, for example, the language,

Transmitting sounds or sounds from the outside into the interior of the uterine system.

Digital filters do not allow natural noises (e.g. fumigation noises,

Digitally filter out noises from machines, devices, etc.). Furthermore, too

acoustic heart actions of the fetus are recorded and, if necessary, digitally amplified in order to transmit this information via a network, for example to a smartphone of the mother and / or the father.

In a further developed variant, the device according to the invention comprises more than one flow system, preferably two or more flow systems, which are either connected in parallel or in series. This makes it possible to run several systems in parallel or independently of one another. This is important, for example, when changing the oxygenator. If necessary, the existing redundancy can also be used to replace a defective system with a functioning system in order to ensure, for example, the 0 ₂ gassing, an increase in pressure in the flow system or an increase in the amniotic fluid flow and thus to maintain the physiological functions of the child. These functions should also be networked so that the systems can be monitored and, if necessary, controlled worldwide via a network. The recording, recording and transmission of the vital data of the fetus and other information, such as audio information, are preferably transmitted via an encrypted network. The vital functions should be regulated via control software and a control integrated in the uterine system (e.g. for gas exchange, amniotic fluid supply, the supply of fetal blood). The control takes over here

in particular the control of the flow rate, the enrichment of 0 ₂ in the amniotic fluid and / or the concentration of breathing gas in the interior of the container etc.

Several flow systems also have the advantage that the risk of contamination is reduced and the possibility of medication being administered via the amniotic fluid of the artificial gill system is also possible. In addition, an indirect electrolyte, osmolarity, plasma Regulation of the fetus is possible by adapting the formula of the modified amniotic fluid for the flow system as an artificial gill system.

The invention has significant advantages over conventional oxygenators. The inventor of the present invention has found that those described in the prior art

Devices and methods alone are inadequate since the use of an oxygenator in an artificial extrauterine system is associated with a high level of heparin substitution. A very high incidence of intracranial hemorrhage in extreme

Preterm infants are still an unsolved problem in pediatrics (see Younge et al., New Eng J Med 2017 Paper). High-dose heparin substitution significantly increases the risk and extent of cerebral haemorrhage in children. In addition, the common oxygenators deliver too much 0 ₂ with a very strong reduction of C0 ₂ , which is not physiological for the fetal situation and is associated with complications. The fetal blood gases were stabilized by an additional complicated new mixture of gases used in the oxygenators (0 ₂ , C0 ₂ and N ₂ ). The function of the oxygenator often leads to complications, such as an increased risk of thrombosis, destruction of erythrocytes, anemia and hyperbilirubinemia.

Furthermore, in the sense of the invention it is additionally or alternatively possible to convert known oxygenators to "moist" gassing (for example via modified amniotic fluid, plasma substitute solutions, electrolyte solutions etc.) instead of a 0 ₂ gassing.

Replacing the gas mixture with perfusion with a 0 ₂ enriched modified amniotic fluid reduces the risk of thrombosis and heparin, contributes to the physiological stabilization of the fetal blood gases and increases the duration of the workability of the

Flow system.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is explained in more detail in the following drawings. It shows

Fig. 1 shows a first embodiment of the device in which modified oxygenated

Amniotic fluid flows through membranes of the flow system (gill system),

Fig. 2 shows another embodiment in which the fetal blood through the flow system

flows,

3 shows a variant of an artificial uterine system, 4 shows a further variant with two flow systems,

Fig. 5 shows a variant with a second amniotic fluid system for supplying the fetus

Medication,

Fig. 6 shows the structure of an embodiment of the artificial gill system.

WAYS OF CARRYING OUT THE INVENTION

In Fig. 1, the device according to the invention and its individual components are shown. The device comprises a container 10 in which a flow system 21 is arranged. Modified amniotic fluid (preferably preheated) is introduced into the flow system 21 via a line 14 via a connecting piece 18 via a pump system via a connection 12. The amniotic fluid can be oxygenated via an oxygen line 16. Nevertheless, it is also provided that the artificial space inside the container can be gassed with medical breathing air via its own gas connection. The flow system 21 itself consists of a number of more than 20 fluid-permeable elements, which are 0 ₂ - and C0 ₂ - permeable. These are preferably lamellar ones

Membranes or a number of tubes with integrated micropores for the

Gas exchange. The catheter connector for umbilical vein catheter 32 and the two

Umbilical artery catheter 30.1; 30.2 to the umbilical cord 36 of the fetus takes place over

Connecting elements 26, 28 and at the other end via a port system 34. The internal pressure of the gill system can be regulated at a frequency of 0-1000 Hz, preferably 10-80 Hz, via a pressure valve 24. Fetal blood is conducted according to the countercurrent principle via appropriate flow lumens 20 around the membrane of the flow system 21.

This results in an efficient oxygen exchange of the dissolved in the amniotic fluid

Oxygen and fetal blood. By increasing the flow rate, the efficiency of the 0 ₂ / C0 ₂ exchange can be increased considerably. The pressure in the flow system is preferably maintained between 5 mbar and 5 bar. Accesses for oxygen or a gas mixture are provided. Furthermore, a gas mixture of 0 ₂ , C0 ₂ and N ₂ can also be applied. Alternatively or additionally, the carbogen gas mixture or from 0 _{2 can} also be applied directly to the amniotic fluid.

Via the pressure valve 24, the amount of amniotic fluid, the speed and the pressure in the flow system 21 are regulated in addition to the amniotic fluid pump (not shown). The pressure valve 24 can be controlled mechanically or digitally. Via a measuring lead can be taken for a measuring device (not shown), for example to determine the oxygen saturation in the blood before and after oxygenation.

FIG. 2 shows a further variant in which the fluid-permeable elements 22 of the

Flow system 21 are flowed through directly by the fetal blood. In this variant, the modified amniotic fluid flows around the fluid-permeable elements 22, i.e. the capillaries or membranes.

3 shows a variant of the device according to the invention as a vital system. The container 10 comprises a flow-through system 21. A connection 12 is used to supply modified amniotic fluid, which is preferably provided in a preheated reservoir 42. For this purpose, the storage container 42 is preferably equipped with a thermostat and a pump. A preheating temperature of 37 ° to 39 ° C. in the reservoir 42 for the modified amniotic fluid of the gill system is preferred

sought. The amniotic fluid can be oxygenated directly from an oxygen container 40. As an alternative or in addition, direct gassing of the artificial space of the container 10 and / or of the flow system 21 with oxygen can take place. Appropriate sensors 48 make it possible to monitor vital functions and to forward them via a network. Furthermore, the recording and playing of noises and sounds are possible via an audio device 43. Data are transmitted to corresponding servers 44 via a network 41 and ultimately analyzed using an analysis device 46. The entire system can also be regulated in the same way.

In Fig. 4, a system is shown analogously, which is constructed similarly to the variant of Fig. 3. Here, the gassing is carried out with a gas mixture of 0 ₂ , C0 ₂ , N ₂ provided in container 40.1, 40.2, 40.3. The addition of CO ₂ can be useful, for example, for the relaxation of vessels. According to the invention, two flow systems 21 are provided. However, as with the other variants, the data can also be exchanged via a smartphone 50, ie important vital functions, audio files or other information from and to the artificial

Uterine systems can be replaced directly by the mother / father or another person who monitors the uterine system.

5 shows a further developed system in which an additional container 60 with modified amniotic fluid is provided in addition to the storage container 42 filled with modified modified amniotic fluid. The fetus is supplied with the substances via the flow system 21, i.e. about artificial enriched with the substances

Amniotic fluid, which is provided by the reservoir 42. This is a supply fetus with medication, including heparin, vitamins, proteins, growth factors and / or hormones. By supplying the fetus with modified amniotic fluid that is supplied through the artificial gill system, for example, the neonatal care can be ensured or prophylactic or therapeutic treatment can be carried out. For example, blood parameters of the fetus can be set individually.

Water-soluble substances which dissolve in the modified amniotic fluid are preferably used. The system has the advantage of preventing the premature baby from being overwashed, since it prevents an increase in volume due to the absorption of too much fluid. Furthermore, decompensation occurring in other systems or treatment methods is prevented, because at least some of the active ingredients and nutrients can be absorbed via the gill system in order to avoid unnecessary volume loading of the fetus. In the embodiment variant, it is therefore provided that the modified

Amniotic fluid of the gill system reservoir 42 is separate from the amniotic fluid of the uterine system in the container 60. For example, the administration of heparin or other antithrombotic medication can be locally via the artificial gill system

(Flow system 21) so as to have an antithrombotic effect. Systemic heparin contamination of the fetus is avoided.

In this variant, it is further provided that the flow system 21 in one

external housing 52 is arranged as an external gill system. Via a port system

51 becomes the umbilical cord 36 of the fetus with the external artificial gill system

connected. For optimal oxygen supply, the temperature of the modified

Amniotic fluid in the reservoir 42 can be cooled down to up to 4 ° C

Increase oxygenation of the amniotic fluid several times. Temperatures in one

A range from 4 ° C to room temperature (approx. 21 ° C) is preferred. However, too

Temperatures up to 39 ° C possible. The application of the flow system

21 with modified amniotic fluid from the reservoir 42 is regulated via a valve 53.

In a further variant (not shown), a thermostat is used

equipped reservoir 42 with modified amniotic fluid dispensed with. At this

The variant is the function of the one equipped with a thermostat and a pump

Storage container 42 integrated in a housing 52. The housing 52 can accordingly

include a pump and a thermostat.

6, a finished device is constructed in accordance with the specifications of the invention.

Claims

Claims:

1 . Device for the life support of a newborn, in particular an extremely premature baby between the 21/0 and 28/0 week of pregnancy (SSW), comprising at least one flow system (21), comprising a number of fluid-permeable

Elements (22) and connecting elements (26, 28) for connection to

Umbilical artery catheter (30) and umbilical vein catheter (32) of the newborn and a

Flow lumens (20) for the passage of modified amniotic fluid enriched with oxygen or an oxygen-containing gas mixture through the fluid-permeable elements (22), and at least one connection (12) for the introduction of oxygen or

Modified amniotic fluid enriched with oxygen in the gas mixture

Flow system (21), wherein the flow system (21) is configured so that the amniotic fluid modified with oxygen or an oxygen-containing gas mixture is passed through the fluid-permeable elements (22) of the flow system (21), while the fetal blood on the outside of the fluid-permeable elements (22) is passed through the flow lumen (20), whereby a gas exchange takes place.

2. Device according to claim 1, characterized in that the flow system (21) is arranged in a container (10).

3. Device according to claim 1, characterized in that an oscillation and a pressure change of the modified amniotic fluid in the flow system (21) via a pressure valve (24) or via a feed device, preferably with a frequency of 0-1000 Hz.

4. Device according to one of claims 1 to 3, characterized in that the fluid-permeable elements (22) of the flow system (21) are arranged or constructed like a gill.

5. The device according to claim 4, characterized in that the fluid permeable

Elements (22) have a lamellar, comb-like, leaf-like, tuft-like or tree-like structure.

6. Device according to one of claims 1 to 5, characterized in that the

The arrangement of the fluid-permeable elements (22) and the flow-through lumen (20) are designed such that the modified amniotic fluid enriched with oxygen or an oxygen-containing gas mixture flows through the fluid-permeable elements (22).

7. Device according to one of claims 1 to 6, characterized in that the fluid-permeable elements (22) are a plurality of membranes, tubes or micropore material arranged one behind the other.

8. Device according to one of claims 1 to 7, characterized in that for

Disposal of cytokines, toxins, ammonia, bilirubin, myoglobin, creatinine,

an additional absorber is provided for inflammatory substances or breakdown products from the fetal blood.

9. Device according to one of claims 1 to 8, characterized in that devices are provided via which the vital functions of the newborn are monitored or the physiological fetal parameters are regulated via a network using artificial intelligence.

10. Device according to one of claims 1 to 9, characterized in that a housing (52) is equipped with a pump and a thermostat.

1 1. Device according to one of claims 1 to 10, characterized in that a pump for introducing the modified amniotic fluid is arranged on the flow system (21).

12. The device according to one of claims 1 to 1 1, characterized in that a storage container (42) is provided, via which additional drugs, nutrients or medical products are introduced into the flow system (21).

13. Device according to one of claims 1 to 12, characterized in that it comprises two or more flow systems (21).

14. Device according to one of claims 1 to 13, characterized in that it comprises a communication system with which an interaction between the fetus and the mother or the father takes place by a transmission of audio and / or video signals, in particular for transmission the parental voice, breathing, heartbeat or bowel sounds.

15. Ex vivo method for the maintenance of life of a person, in particular an extremely premature baby between the 21/0 and 28/0 week of pregnancy (SSW), in which modified amniotic fluid or a plasma replacement solution initially with oxygen or a Enriched oxygen-containing gas mixture and the amniotic fluid or the plasma replacement solution so enriched is fed to a flow system, which consists of a number of fluid-permeable elements and connecting elements for connection to the arteries and veins of humans and a flow lumen for the passage of the modified

Amniotic fluid through the fluid-permeable elements, and at least one connection for introducing the modified amniotic fluid enriched with oxygen or the oxygen-containing gas mixture into the flow system, the modified amniotic fluid enriched with oxygen through the fluid-permeable elements of the

Flow system is directed, while the blood on the outside of the fluid-permeable elements is passed over the flow lumen, whereby a gas exchange takes place.

16. The method according to claim 15, characterized in that a digital

Real time connection exists between the fetus and the parent at which the fetus

Sounds of the mother and / or the father, preferably the voice, breathing,

Heartbeats and possibly bowel sounds.

17. The method according to any one of claims 15 to 16, characterized in that a

Electrolyte exchange, a disposal of toxins and waste products, in particular from

Bilirubin, ammonia, nitrogen and osmoregulation are carried out via the flow system.

18. The method according to any one of claims 15 to 17, characterized in that, alternatively or additionally, a moist fumigation takes place via modified amniotic fluid, plasma replacement solutions, electrolyte solutions.

19. The method according to any one of claims 15 to 18, characterized in that the

Gas exchange in the flow system through the speed of the through the

Flow system of amniotic fluid flowing through, the volume of fluid that

Direction / opposite direction, the frequency (oscillation 0 - 1000 Hz), the 0 ₂ supply

and / or gas mixture supply and / or by a pressure change in the

Flow system is regulated.

20. The method according to any one of claims 15 to 19, characterized in that the

Amniotic fluid is preheated to a temperature between 37 and 39 ° C before being introduced into the at least one flow system and is simultaneously gassed with oxygen or the oxygen-containing gas mixture.

21st Method according to one of claims 15 to 20, characterized in that in the Flow system a pressure between 5 mbar and 5 bar is maintained.

22. The method according to any one of claims 15 to 21, characterized in that additional drugs, nutrients or medical products are introduced into the flow system.

23. The method according to any one of claims 15 to 22, characterized in that the flow system is arranged either inside or outside a container.