Coagulation management in extracorporeal membrane oxygenation patients

Sustav za izvantjelesnu membransku oksigenaciju (ECMO, eng. Extracorporeal membrane oxygenation) primjenjuje se u medicini već više od pola stoljeća. Njegova uloga je održavanje izmjene plinova i cirkulacije krvi do oporavka pluća i/ili srca. Metoda izvantjelesnog krvotoka originalno je zamišljena kao kardiopulmonalna premosnica (CPB, eng. Cardiopulmonary bypass), uređaj koji omogućuje perfuziju organa za vrijeme operativnih zahvata na srcu. Uz nekoliko izmjena u tehnologiji, sustav se prilagodio korištenju u dužim vremenskim periodima u jedinicama za intenzivno liječenje (JIL). U početku je metoda najviše uspjeha postizala u liječenju novorođenčadi sa zatajenjem dišnog sustava koji bi uz pomoć ECMO-a premostili period do oporavka. U odrasloj se populaciji značajniji porast korištenja bilježi tek nedavno u pandemijama H1N1 gripe 2009. godine i trenutno aktualnoj SARS-CoV-2. Bez obzira na dugu povijest u primjeni i brojne napretke, izvantjelesna oksigenacija krvi je i dalje vrlo složen postupak s čestim komplikacijama, stoga se njeno korištenje razmatra samo kada je procijenjeni mortalitet pacijenta uz primjenu konvencionalne terapije veći od 50 %, a smatra se da je svakako indicirana kada je on veći od 80 %. Među vodećim uzrocima neželjenih ishoda ECMO-a prevladavaju upravo koagulacijski poremećaji. Naime, krv postaje hiperkoagulabilna u kontaktu s bionekompatibilnim membranama ECMO-a jer se gubi normalna antikoagulantna aktivnost endotela čija je funkcija održavanje krvi u tekućem stanju u fiziološkim uvjetima. Trenutno je najveći izazov postići ravnotežu između i zadovoljavajućeg stupnja antikoaguliranosti kako bi se izbjegli česti neželjeni ishodi krvarenja iz nativne cirkulacije i tromboze u izvantjelesnoj. Oblaganje dodirne površine raznim tvarima kako bi ona što više nalikovala djelovanju endotela i primjena antikoagulantne terapije uz praćenje laboratorijskim pretragama, pokušaji su prevencije komplikacija uzrokovanih poremećajima zgrušavanja, no još uvijek ne postoji zadovoljavajuće rješenje.Extracorporeal oxygenation has been used in medicine for almost seven decades. It is suitable as a bridging method which allows normal blood oxygenation and circulation while the heart and lungs heal. ECMO originates from the cardiopulmonary bypass, a machine used in cardiothoracic surgery, which allows adequate perfusion of organs while the heart is stopped and operated on. At first, it was somewhat difficult to adapt the procedure for use in longer time frames outside of the operating theatre. However, extracorporeal oxygenation proved to be extremely useful in treating newborns with respiratory distress. The use of ECMO in adult medicine experienced a lot more setbacks in the beginning and has only recently been widely adopted. Its beneficial effect has been mostly used as a bridging method in the treatment of severe acute respiratory distress syndrome caused by the H1N1 influenza virus and SARS-CoV-2. Extracorporeal oxygenation, despite its many advances in technology, still causes many complications. Due to the high complication rate, ECMO should be used only as salvage therapy for patients with extremely poor prognosis. It should be considered when the patient’s predicted mortality while treated with conservative therapy is greater than 50 %. Extracorporeal oxygenation is indicated if the predicted mortality reaches 80 %. Complications are most often caused by the coagulation disorders. Hemostasis is affected by the interaction of blood with artificial surfaces which makes it hypercoagulable. On the other hand, endothelium has many anticoagulant properties. The imbalance of these effects usually leads to severe hemorrhage from the native circulation or thromboembolic events in the ECMO circuit. Patients undergoing ECMO have to be closely monitored and treated with anticoagulants to prevent complications. However, the adequate solution has not yet been discovered

BPC 157 Therapy and the Permanent Occlusion of the Superior Sagittal Sinus in Rat: Vascular Recruitment

We show the complex syndrome of the occluded superior sagittal sinus, brain swelling and lesions and multiple peripheral organs lesions in rat. Recovery goes centrally and peripherally, with the stable gastric pentadecapeptide BPC 157, which alleviated peripheral vascular occlusion disturbances, rapidly activating alternative bypassing pathways. Assessments were gross recording, venography, ECG, pressure, microscopy, biochemistry. The increased pressure in the superior sagittal sinus, portal and caval hypertension, aortal hypotension, arterial and venous thrombosis, severe brain swelling and lesions (cortex (cerebral, cerebellar), hypothalamus/thalamus, hippocampus), particular veins (azygos, superior mesenteric, inferior caval) dysfunction, heart dysfunction, lung congestion as acute respiratory distress syndrome, kidney disturbances, liver failure, and hemorrhagic lesions in gastrointestinal tract were all assessed. Rats received BPC 157 medication (10 µg/kg, 10 ng/kg) intraperitoneally, intragastrically, or topically to the swollen brain at 1 min ligation-time, or at 15 min, 24 h and 48 h ligation-time. BPC 157 therapy rapidly attenuates the brain swelling, rapidly eliminates the increased pressure in the ligated superior sagittal sinus and the severe portal and caval hypertension and aortal hypotension, and rapidly recruits collateral vessels, centrally ((para)sagittal venous collateral circulation) and peripherally (left superior caval vein azygos vein-inferior caval vein). In conclusion, as shown by all assessments, BPC 157 acts against the permanent occlusion of the superior sagittal sinus and syndrome (i.e., brain, heart, lung, liver, kidney, gastrointestinal lesions, thrombosis), given at 1 min, 15 min, 24 h or 48 h ligation-time. BPC 157 therapy rapidly overwhelms the permanent occlusion of the superior sagittal sinus in rat

Robert’s Intragastric Alcohol-Induced Gastric Lesion Model as an Escalated General Peripheral and Central Syndrome, Counteracted by the Stable Gastric Pentadecapeptide BPC 157

We redefined Robert’s prototypical cytoprotection model, namely the intragastric administration of 96% alcohol in order to generate a general peripheral and central syndrome similar to that which occurs when major central or peripheral veins are occluded in animal models. With this redefinition, we used Robert’s model to examine the cytoprotective effects of the stable gastric pentadecapeptide BPC 157. The intragastric administration of alcohol induced gastric lesions, intracranial (superior sagittal sinus) hypertension, severe brain swelling and lesions, portal and vena caval hypertension, aortal hypotension, severe thrombosis, inferior vena cava and superior mesenteric vein congestion, azygos vein failure (as a failed collateral pathway), electrocardiogram disturbances, and heart, lung, liver and kidney lesions. The use of BPC 157 therapy (10 µg/kg or 10 ng/kg given intraperitoneally 1 min after alcohol) counteracted these deficits rapidly. Specifically, BPC 157 reversed brain swelling and superior mesenteric vein and inferior vena caval congestion, and helped the azygos vein to recover, which improved the collateral blood flow pathway. Microscopically, BPC 157 counteracted brain (i.e., intracerebral hemorrhage with degenerative changes of cerebral and cerebellar neurons), heart (acute subendocardial infarct), lung (parenchymal hemorrhage), liver (congestion), kidney (congestion) and gastrointestinal (epithelium loss, hemorrhagic gastritis) lesions. In addition, this may have taken place along with the activation of specific molecular pathways. In conclusion, these findings clarify and extend the theory of cytoprotection, offer an approach to its practical application, and establish BPC 157 as a prospective cytoprotective treatment