Dijagnostički i prognostički značaj angiopoietina 2 i solubilnog receptora za krajnje glikozilirane produkte (sRAGE) u adultnom akutnom respiratornom distres sindromu
Diagnostic and prognostic value of angiopoietin 2 and soluble form of the receptor for advanced glycation end-products (sRAGE) in adult form of acute respiratory distress syndrome
Докторанд
Radanović, BojanaМентор
Uvelin, ArsenЧланови комисије
Jovanović, GordanaDrašković, Biljana
Tatić, Milanka
Pajtić, Vesna
Palibrk, Ivan
Метаподаци
Приказ свих података о дисертацијиСажетак
Akutni respiratorni distres sindrom (ARDS) se karakteriše hipoksemičnom respiratornom insuficijencijom koja se javlja unutar sedam dana od izlaganja predisponirajućem faktoru sa obostranim infiltratima na rendgenskom snimku pluća ili kompjuterizovanoj tomografiji, a koji se ne mogu objasniti postojanjem efuzija, atelektaza ili čvorića. ARDS ima veliki uticaj na globalno zdravlje širom sveta i on je glavni uzrok respiratorne insuficijencije sa visokom stopom morbiditeta i mortaliteta kod kritično obolelih pacijenata. Invazivna protektivna mehanička ventilacija pluća je glavni terapijski oslonac ARDS-a. ARDS može biti prouzrokovan različitim etiološkim faktorima, ali samo adekvatan tretman istih je važan u poboljšanju ishoda lečenja. Cilj: Identifikacija, dijagnostički i prognostički značaj angiopoietina 2 i solubilnog receptora za krajnje glikozilirane produkte (sRAGE) u adultnom respiratornom distres sindromu, a u odnosu na težinu kliničke slike ARDS-a i krajnji ishod lečenja. Metodolo...gija: Ispitivanje je sprovedeno kao prospektivna studija koja je obuhvatala 69 ispitanika sa ARDS-om i 27 ispitanika bez dijagnoze ARDS-a je činilo kontrolnu grupu. Ispitanici su bili hospitalizovani na Odeljenju intenzivnog lečenja II Klinike za anesteziju, intenzivnu terapiju i terapiju bola Kliničkog centra Vojvodine, Odeljenju intenzivne nege Instituta za plućne bolesti Sremska Kamenica, kao i na Klinici za infektivne bolesti Kliničkog centra Vojvodine u periodu od 2017. do 2019. godine. Klinički uzorak činile su osobe kod kojih je postavljena dijagnoza akutnog respiratornog distres sindroma u skladu sa kriterijumima Berlinske definicije iz 2012. godine. Iz medicinske dokumentacije, za svakog ispitanika uključenog u istraživanje su uzeti u razmatranje i analizu sledeći parametri u toku prvih 24 časa od momenta prijema na prethodno navedena odeljenja: demografske i opšte karakteristike ispitanika od značaja za istraživanje, numerički pokazatelji procene težine bolesti ispitanika (APACHE II i SOFA skor), vitalni parametri za prva 24 časa (arterijski pritisak, srčana frekvenca, transkutana saturacija arterijske krvi, 24- časovni urin i telesna temperatura), gasne analize arterijske krvi (pH, parcijalni pritisak kiseonika- PaO2, parcijalni pritisak ugljen dioksida- PaCO2, zasićenost krvi kiseonikom- SpO2, odnos parcijalnog pritiska kiseonika u arterijskoj krvi i inspiratorne frakcije kiseonika (PaO2/FiO2), parametri mehaničke ventilacije pluća. U roku 24 časa od trenutka postavljanja dijagnoze ARDS-a, iz uzoraka krvi ispitanika, izvršene su predviđene laboratorijske analize. Zdravstveno stanje bolesnika je praćeno tokom 28 dana od trenutka uključivanja u studiju i nakon tog perioda je evidentiran ishod lečenja u smislu preživljavanja ili smrtnog ishoda. Statistička analiza je izvršena pomoću statističkog paketa IBM SPSS 20 Statistics. Podaci su predstavljeni tabelarno i grafički, a statistička značajnost određivana je na nivou 95% (p< 0,05) ( razlika statističkih parametara značajna) i 99% (p<0,01) ( razlika statističkih parametara visoko značajna). Izmerene koncentracije biomarkera ANG2 su statistički značajno više kod ispitanika sa ARDS-om u odnosu na kontrolnu grupu. Vrednosti sRAGE su takođe više kod ARDS ispitanika u odnosu na kontrolnu grupu, ali ova razlika nije bila statistički značajna. U odnosu na težinu ARDS-a, nije uočena statistički značajna razlika u izmerenim koncentracijama ANG2 biomarkera između teške i umereno teške forme bolesti. Takođe, nema statistički značajne razlike u vrednostima ANG2 među preminulim ARDS ispitanicima teške i umereno teške forma. Vrednosti sRAGE su statistički značajno više u umerenoj formi ARDS-a u odnosu na tešku. Kod ARDS ispitanika verifikuje se statistički značajna viša stopa mortaliteta u odnosu na kontrolnu grupu. Preminuli ARDS ispitanici imaju statistički značajno više izmerene vrednosti biomarkera ANG2. Vrednosti biomarkera sRAGE su više kod preminulih ARDS ispitanika, ali ova razlika nije statistički značajna. Ispitanici sa ARDS-om imaju statistički značajno više vrednosti APACHE II i SOFA skora u odnosu na kontrolnu grupu. Srednja vrednost APACHE II skora su bile više kod teške forme ARDS-a. Ova razlika nije statistički značajna. Srednja vrednost SOFA skora je bila više u umerenoj formi ARDS-a. Ova razlika nije statistički značajna. Preminuli ARDS ispitanici imaju statistički značajno više vrednosti za oba skora, APACHE II i SOFA. Nije utvrđena statistički značajna razlika u stopi mortaliteta ARDS ispitanika u odnosu na etiološki faktor i težinu ARDS-a. Istraživanje nije pokazalo značajnu korelaciju između ANG2 i APACHE II skora kod ARDS ispitanika. Utvrđena je pozitivna korelacija između ANG2 i SOFA skora koja je statistički visoko značajna. Više vrednosti ANG2 su pratile i viši SOFA skor i obrnuto. Utvrđena je pozitivna statistički značajna korelacija između sRAGE i APACHE II skora. Više vrednosti skora pratile su i više vrednosti sRAGE. Istraživanje nije pokazalo značajnu korelaciju između sRAGE i SOFA skora. Vrednosti biomarkera ANG2 i sRAGE su bile više kod indirektog ARDS-a u odnosu na direktni. Ova razlika nije bila statistički značajna. Analizom ROC krive za biomarkere ANG2 i sRAGE utvrđeno je da ANG2 može biti marker za smrtni ishod, dok sRAGE nije pokazao značaj na ishod ARDS-a. Zaključak: Značaj ispitivanja biomarkera ARDS-a ogleda se u njihovoj višestrukoj ulozi, a pre svega u olakšavanju postavljanja dijagnoze, predikcije i prognoze ARDS-a. Pravovremeno postavljanje dijagnoze utiče kako na klinički tok lečenja, tako i na procenu i izbor adekvatnih terapijskih mera lečenja, odnosno ishod lečenja. Ispitivanje biomarkera doprinosi i boljem razumevanju patofiziologije i molekularne osnove ovog oboljenja. Identifikacija biomarkera doprinela bi značaju shvatanja kompleksnih patoloških puteva, a koji doprinose brojnim oštećenjima i disfunkcijama na nivou epitela i endotela. Upravo ovo razlikovanje oštećenja, nekroze i apoptoze ćelija epitela, odnosno endotela, menja u značajnoj meri terapijsku strategiju, gde se pored adekvatne ventilatorne podrške sprovode i druge suportativne mere lečenja, a što sve zavisi od uzroka ARDS-a. Obzirom da se dijagozna ARDS-a postavlja na bazi kliničkih parametara, dinamika promene vrednosti biomarkera mogla bi ukazati na različite faze ovog oboljenja, ali i imati uticaj na razlikovanje uzroka ARDS-a, obzirom na potvrđenu heterogenost ovog oboljenja, što bi nadalje doprinelo selektiranju ovih pacijenata.
The acute respiratory distresssyndrome (ARDS) is characterized by hypoxemic respiratory failure occuring less than seven days from a predisposing clinical insult, with bilateral opacities on chest radiograph or computed tomography not fully explained by effusion, atelectasis or nodules. ARDS have a high impact on global health across the world and it is a major cause of acute respiratory failure with high morbidity and mortality in critically ill patients. Invasive mechanical ventilation with lung protective strategies is the mainstay of ARDS treatment. ARDS can be caused by various aetiologies and adequate treatment of the responsible cause is crucial to improve the outcome. The objective of the research: Identification of the diagnostic and prognostic significance of angiopoietin 2 and the solube forms of the receptor for advanced glycation end-products (sRAGE) in adult respiratory distress syndrome in relation to the severity of the clinical picture of ARDS and the ultimate outcome ...of treatment. Methodology: The study was conducted as a prospective study that included 69 patients with ARDS and 27 patients with no ARDS were control group. The subjects were hospitalized at the Intensive Care Unit II of the Clinic for Anesthesia, Intensive Care and Pain Therapy of the Clinical Center of Vojvodina, the Intensive Care Unit of the Institute for Pulmonary Diseases of Sremska Kamenica, as well as at the Clinic for Infectious Diseases of he Clinical Center of Vojvodina from 2017 to 2019. years. The clinical sample consisted of individuals diagnosed with acute respiratory distress syndrome in accordance with the 2012. Berlin definition criteria. From the medical records, the following parameters were considered and analyzed for each respondent within the first 24 hours of admission to the aforementioned departments: demographic and deneral characteristics of respondents of importance for the study, numerical indicators of assessment of severity of respondents'diseases (APACHE II and SOFA score), vital parameters for the first 24 hours (arterialpressure, heart rate, transcutaneous arterial blood saturation, 24 hours urine and body temperature), arterial blood gas analysis (pH, partial pressure of oxygen-PaO2, partial pressure of carbon dioxide-PaCO2, blood saturation oxygen-SpO2, ratio of partial pressure of oxygen in arterial blood and inspiratory oxygen fraction (PaO2 / FiO2), mechanical ventilation steamers. Within 24 hours of the diagnosis of ARDS, laboratory analyzes were performed from the blood samples of the subjects. Patients' health status was monitored for 28 days from the time they were included in the study and treatment outcome in terms of survival or death was recorded after that period. Statistical analysis was performed using the IBM SPSS 20 statistics statistical package. Data are presented in tables and graphs, and statistical significance was determined at 95% (p <0.05) (difference of statistical parameters significant) and 99% (p <0.01) (difference of statistical parameters highly significant). Results: The measured concentrations of the ANG2 biomarker were statistically significantly higher in subjects with ARDS compared to the control group. sRAGE values were also higher in ARDS subjects compared to the control group, but this difference was not statistically significant.In relation to the severity of ARDS, no statistically significant difference was observed in the measured concentrations of ANG2 biomarkers between severe and moderately severe forms of the disease. There is also no statistically significant difference in ANG2 values among deceased ARDS subjects of severe and moderate form. The values of sRAGE are statistically significantly higher in the moderate form of ARDS compared to the severe one. A statistically significant higher mortality rate is verified in ARDS subjects compared to the control group. Deceased ARDS patients have statistically significantly higher measured values of the biomarker ANG2. The values of the sRAGE biomarker are higher in the deceased ARDS subjects, but this difference is not statistically significant. Subjects with ARDS had statistically significantly higher values of APACHE II and SOFA scores compared to the control group. Mean APACHE II scores were higher in severe ARDS. This difference is not statistically significant. The mean value of SOFA scores was more in the moderate form of ARDS. This difference is not statistically significant. Deceased ARDS subjects have statistically significantly higher values for both scores, APACHE II and SOFA. There was no statistically significant difference in the mortality rate of ARDS subjects in relation to the etiological factor and severity of ARDS. The study did not show a significant correlation between the ANG2 and APACHE II scores in ARDS subjects. A positive correlation was found between the ANG2 and SOFA scores, which is statistically highly significant. Higher ANG2 values were followed by higher SOFA scores and vice versa. A positive statistically significant correlation was found between the sRAGE and APACHE II scores. Higher values of score were followed by higher values of sRAGE. The study did not show a significant correlation between sRAGE and SOFA scores. The values of the biomarkers ANG2 and sRAGE were higher in indirect ARDS compared to direct. This difference was not statistically significant. Analysis of the ROC curve for the biomarkers ANG2 and sRAGE revealed that ANG2 may be a marker for death, while sRAGE showed no significance on the outcome of ARDS. Conclusion: The importance of examining ARDS biomarkers is reflected in their multiple roles, and above all in facilitating the diagnosis, prediction and prognosis of ARDS. Timely diagnosis influences both the clinical course of treatment and the assessment and selection of adequate therapeutic treatment measures, that is, the outcome of treatment. Biomarker testing also contributes to a better understanding of the pathophysiology and molecular basis of this disease. Identification of biomarkers would contribute to the importance of understanding complex pathological pathways that contribute to numerous damage and dysfunctions at the epithelium and endothelium levels. It is this distinction between damage, necrosis, and apoptosis of epithelial cells, or endothelium cells, that significantly changes the therapeutic strategy, where, in addition to adequate ventilatory support, other supportive treatment measures are implemented, all of which depend on the cause of ARDS. Since the diagnosis of ARDS is made on the basis of clinical parameters, the dynamics of biomarker change could indicate different stages of this disease, but also have the potential to differentiate the causes of ARDS, given the confirmed heterogeneity of this disease, which would further contribute to the selection of these patients