Kaugisheemilise eelkohastamise mõju elundikahjustusele ja atsüülkarnitiinide ainevahetusele veresoontekirurgias

Väitekirja elektrooniline versioon ei sisalda publikatsiooneKirurgiliste operatsioonidega kaasnevad terviseriskid, mis sõltuvad lisaks operatsiooni iseloomule ka inimese füsioloogiast ja tervislikust seisundist. Efektiivseid ja ohutuid võimalusi nende riskide vähendamiseks pole senini leitud. Inimorganismil on olemas kaitsemehhanismid, mis käivituvad elundit ohustava teguri, näiteks isheemia toimel. Neid organismi kaitsemehhanisme kasutakse ära kaugisheemilises eelkohastamises (KIE). KIE käigus tekitatakse lühiajaliselt jäsemes isheemia, mis käivitab kogu organismis mehhanismid, vähendamaks võimalikku sihtorgani verevarustuse puudumisest tulenevat kahjustust. Seetõttu tekivad ajutiselt verevarustuseta olnud koes (nt. ülajäsemes) signaalid, mis kanduvad ka mujale organismi ja valmistavad kaugemal asetsevad elundid, näiteks südame ja neerud, ette tulevaseks kahjustuseks. Seeläbi on võimalik organismi loomulikku kaitsemehhanismi ennetavalt aktiveerides saavutada kaitse elunditele, mis operatsiooni käigus võivad kahjustatud saada. Käesolevas doktoritöös uuriti KIE meetodit neil, kelle operatsiooniga seotud risk on suur ehk veresoontekirurgilist operatsiooni vajavatel haigetel. Vahetult enne operatsiooni teostati uuritavatel KIE protseduur, mille käigus katkestati neljal korral käe verevarustus viieks minutiks 5-minutiliste vaheaegadega. Leiti, et antud meetod ei avalda mõju arterite jäikusele, kuid vähendab operatsioonijärgselt neeru- ja südamekahjustuse markerite tõusu, mille põhjal saab järeldada, et KIE kaitseb operatsiooni ajal neere ja südant. Lisaks tuvastati, et meetod mõjutab organismis atsüülkarnitiinide ainevahetust, mis võib olla üheks kaitsvat toimet vahendavaks mehhanismiks. KIE-t peetakse ohutuks protseduuriks ja ka antud doktoritöös ei leitud protseduuril ühtegi olulist kahjulikku kõrvalmõju. Kokkuvõtvalt saab järeldada, et arvestades KIE kergesti teostatavust ning ohutust, on meetodil suur potentsiaal leida tee kliinilisse kasutusse operatsiooniga seonduvate elundikahjustuste vähendamiseksSurgical procedures have health risks that depend in addition to its nature also on physiology and health condition of the individual. Until now no effective and safe solutions have been found to undo these risks. To reduce possible damage human organism has got natural protection mechanisms, that are activated by factors endangering the system, like ischaemia. These protection mechanisms are used in remote ischaemic preconditioning (RIPC) by suspending briefly blood flow to the upper limb, activating thus the corresponding mechanisms that reduce the possible damage coming from the absence of blood supply. Yet, the blood flow will be restored before the damage occurs and the tissues being temporally left without blood supply create signals that spread elsewhere in the system and prepare other organs, like for example heart or kidneys to the possible damage. Hence it is possible to get protection for the remote organs that could suffer from the surgery by activating the natural protection mechanisms of the system in advance. This doctoral thesis has studied the RIPC methodology in individuals that suffer from high risk in connection with surgery, that is in individuals that need vascular surgery procedures. RIPC was performed to these patients directly before the surgery, by suspending blood flow to their upper limb for five minutes by five minute intervals. By using this method kidney and heart damage biomarkers, but not arterial stiffness, diminished showing that RIPC reduces the possible damage of kidneys and heart resulting from the surgery. Besides it was discovered that this method has an effect on the metabolism of acylcarnitines that could be one of the intermediating mechanisms providing protection. RIPC is considered to be a harmless procedure, and this research did not find any serious negative side effects. In conclusion, given the safety of RIPC and the easiness of the procedure, the method has great potential to find a way to clinical use to reduce organ damage associated with surgery.https://www.ester.ee/record=b538730

Effects of RIPC on the Metabolome in Patients Undergoing Vascular Surgery: A Randomized Controlled Trial

Background: remote ischemic preconditioning (RIPC) is a phenomenon in which short episodes of ischemia are applied to distant organs to prepare target organs for more prolonged ischemia and to induce protection against ischemia-reperfusion injury. This study aims to evaluate whether preoperatively performed RIPC affects the metabolome and to assess whether metabolomic changes correlate with heart and kidney injury markers after vascular surgery. Methods: a randomized sham-controlled, double-blinded trial was conducted at Tartu University Hospital. Patients undergoing elective open vascular surgery were recruited and RIPC was applied before operation. Blood was collected preoperatively and 24 h postoperatively. The metabolome was analyzed using the AbsoluteIDQ p180 Kit. Results: final analysis included 45 patients from the RIPC group and 47 from the sham group. RIPC did not significantly alter metabolites 24 h postoperatively. There was positive correlation of change in the kynurenine/tryptophan ratio with change in hs-troponin T (r = 0.570, p r = 0.552, p r = 0.534, p r = 0.504, p < 0.001) only in the RIPC group. Conclusions: preoperative RIPC did not significantly affect the metabolome 24 h after vascular surgery. The positive linear correlation of kynurenine/tryptophan ratio with heart and kidney injury markers suggests that the kynurenine–tryptophan pathway can play a role in RIPC-associated cardio- and nephroprotective effects

Remote Ischaemic Preconditioning Reduces Kidney Injury Biomarkers in Patients Undergoing Open Surgical Lower Limb Revascularisation: A Randomised Trial

Background and Aims. Perioperative kidney injury affects 12.7% of patients undergoing lower limb revascularisation surgery. Remote ischaemic preconditioning (RIPC) is a potentially protective procedure against organ damage and consists of short nonlethal episodes of ischaemia. The main objective of this substudy was to evaluate the effect of RIPC on kidney function, inflammation, and oxidative stress in patients undergoing open surgical lower limb revascularisation. Materials and Methods. This is a subgroup analysis of a randomised, sham-controlled, double-blinded, single-centre study. A RIPC or a sham procedure was performed noninvasively along with preparation for anaesthesia in patients undergoing open surgical lower limb revascularisation. The RIPC protocol consisted of 4 cycles of 5 minutes of ischaemia, with 5 minutes of reperfusion between every episode. Blood was collected for analysis preoperatively, 2, 8, and 24 hours after surgery, and urine was collected preoperatively and 24 hours after surgery. Results. Data of 56 patients were included in the analysis. Serum creatinine, cystatin C, and beta-2 microglobulin increased, and eGFR decreased across all time points significantly more in the sham group than in the RIPC group (p=0.021, p=0.021, p=0.024, and p=0.015, respectively). Comparison of two time points, baseline and 24 hours after surgery, revealed that the change in creatinine, eGFR, urea, cystatin C, and beta-2 microglobulin was significantly different between the groups (p<0.05). Conclusions. Our finding of reduced release of kidney injury biomarkers may indicate the renoprotective effect of RIPC in patients undergoing open surgical lower limb revascularisation. The trial is registered with ClinicalTrials.gov NCT02689414