Mikroverenkierto ja hemoreologia kriittisesti sairailla potilailla

The study was a prospective observational and methodological study performed among thirty-six critically-ill patients and twenty-six healthy controls subjects in 2008-2012 in two Finnish intensive care units. In critically-ill patients the blood flow among the microcirculation becomes disturbed, which predisposes the patients to multiple organ failure and death. The endothelial glycocalyx layer, which is formed on the vascular surface of endothelial cells is implicated in microcirculatory events in animal studies, but the data among critically-ill patients is scarce and based on laboratory samples only. The viscosity of plasma determines shearing forces of blood, and thus, the shear induced excretion of nitric oxide by the endothelial cells, i.e. mechanosensing. In animal models, increased plasma viscosity is associated with increased microvascular flow. Futhermore, the technology of microvascular and glycocalyx research in humans is under development. The evidence of molecular mechanisms and causal relation between endothelial glycocalyx damage and microcvascular disturbance in critically-ill patients is lacking. The feasibility and reliability of a standardized technical quality analysis for video images obtained from human sublingual microcirculation was tested in the first part of the study. By analysis of a novel previously unvalidated set of technical criteria by two independent investigators, only 31% of the analyzed 240 video images qualified techically for further use in clinical studies. In the second part of the study, a semi-automatic computer algorithm was created and validated for the measurement of glycocalyx layer thickness. Use of the semi-automatic algorithm in microcirculatory video images obtained from human oral cavity diminished the coefficient of variation of measured glycocalyx layer thickness from 7.2% - 9.8% in manual measurements to 4.3% - 5.8% in the semi-automatic measurements. Two separate hypothesis were tested in the third and fourth parts of the study. A hypothesis that activation of vascular adhesion protein-1, a novel adhesion epitope and enzyme, coincides with shedding of the glycocalyx in sepsis, was supported. The second hypothesis, that the shedding of the endothelial glycocalyx layer in sepsis leads to increased plasma viscosity, was rejected. Contrary to the study hypothesis the viscosity of plasma in patients with sepsis was not increased, but was lower than controls values for four days. Ex vivo it was evident that the type of fluid therapy administered during the course of early treatment among critically-ill patients determines plasma viscosity and, thus, the shearing properies of blood in the microcirculation.Väitöskirjatyössä tutkittiin tehohoitoa vaativien potilaiden mikroverenkiertoa ja verenvirtausominaisuuksia. Menetelmiä tarkastelevassa osiossa tarkasteltiin elimistön pienimpien verisuonten tutkimuksessa käytettävän videomikroskopiamenetelmän virhelähteitä sekä kehitettiin uusi tietokonepohjaiseen kuvankäsittelyyn perustuva mittausalgoritmi verisuonen sisäkettokerroksen soluja verhoavan pinnan sokeripitoisista molekyyleistä koostuvan hunnun (t.s. endoteelin glykokalyksin) mittaukseen videokuvasta. Tutkimuksen kliinisen osion kysymyksenasetteluna oli havainnoida esiintyykö kahdellakymmenellä bakteerien aiheuttamaa verenmyrkytystä sairastavalla potilaalla kohonneita endoteelin glykokalyksin vaurion merkkiaineita syndekaani-1:tä (SDC-1) ja hyaluronaania (HA) samanaikaisesti yleistyneen tulehdusreaktion merkkiaineiden myeloperoksidaasin (MPO) ja vascular adhesion protein-1 (VAP-1) kanssa 24 tunnin kuluessa tehohoitoon saapumisesta sekä kolme vuorokautta myöhemmin, verrattaessa kahteenkymmeneen terveeseen verrokkiin. Toisena kysymyksenasetteluna samoilta tutkimushenkilöiltä otetuista verinäytteistä määritettiin suurikokoisten molekyylien pitoisuuksia veren sitkaisuutta, t.s. viskositeettia. Erillisessä elimistön ulkopuolisessa laboratoriotyössä mallinnettiin lisäksi vereen lisättyjen keittosuolan ja suurikokoisten molekyylien (hydroksietyylitärkkelys ja hyaluronaani) sekä samanaikaisesti tapahtuvan veren luonnollisten proteiinien laimenemisen vaikutusta veren sitkaisuuteen. Väitöskirjatyössä tutkittiin tehohoitoa vaativien potilaiden mikroverenkiertoa ja verenvirtausominaisuuksia. Menetelmiä tarkastelevassa osiossa tarkasteltiin elimistön pienimpien verisuonten tutkimuksessa käytettävän videomikroskopiamenetelmän virhelähteitä sekä kehitettiin uusi tietokonepohjaiseen kuvankäsittelyyn perustuva mittausalgoritmi verisuonen sisäkettokerroksen soluja verhoavan pinnan sokeripitoisista molekyyleistä koostuvan hunnun (t.s. endoteelin glykokalyksin) mittaukseen videokuvasta. Tutkimuksen kliinisen osion kysymyksenasetteluna oli havainnoida esiintyykö kahdellakymmenellä bakteerien aiheuttamaa verenmyrkytystä sairastavalla potilaalla kohonneita endoteelin glykokalyksin vaurion merkkiaineita (syndekaani-1:tä ja hyaluronaania) samanaikaisesti yleistyneen tulehdusreaktion merkkiaineiden ( myeloperoksidaasin ja vascular adhesion protein-1:n) kanssa 24 tunnin kuluessa tehohoitoon saapumisesta sekä kolme vuorokautta myöhemmin, verrattaessa kahteenkymmeneen terveeseen verrokkiin. Toisena kysymyksenasetteluna samoilta tutkimushenkilöiltä otetuista verinäytteistä määritettiin suurikokoisten molekyylien pitoisuuksia veren sitkaisuutta, t.s. viskositeettia. Erillisessä elimistön ulkopuolisessa laboratoriotyössä mallinnettiin lisäksi vereen lisättyjen keittosuolan ja suurikokoisten molekyylien (hydroksietyylitärkkelys ja hyaluronaani) sekä samanaikaisesti tapahtuvan veren luonnollisten proteiinien laimenemisen vaikutusta veren sitkaisuuteen. Verrokeilta ja tehohoitoa vaativilta potilailta kerättiin 240 videoleikettä. Videomikroskooppimenetelmän virhelähteiden tunnistamisen perusteella systemaattinen kuvan laadun analysointi ja tieteellinen raportointi on mahdollista. Tutkitussa 240 videoleikkeen aineistossa korkealaatuisen videomateriaalin osuus oli ainoastaan 31%. Tutkimuksessa kehitetyn puoliautomaattisen mittausalgoritmin käyttö pienensi mitatun endoteelin glykokalyksikerroksen paksuuden vaihteluvakiota (4.3% - 5.8%) verrattuna tutkijan käsin, mutta tietokoneavusteisesti, suorittamaan mittaamiseen (7.2% - 9.8%). Kliinisessä osiossa bakteerien aiheuttamaa verenmyrkytystä sairastavilta potilailta mitattiin samanaikaisesti merkittävästi kohonneita endoteelin glykokalyksikerroksen vaurion ja yleistyneen tulehdusreaktion merkkinaineita. Veren suurikokoisten proteiinimolekyyylien pitoisuudet ja veren sitkaisuus oli merkittävästi vähäisempiä kuin verrokeilla. Elimistön ulkopuolisen mallintamisen perusteella potilaille tehohoidossa annettu nestehoito vaikuttaa suuresti veren sitkaisuuteen ja kliinisessä tutkimusosiossa havaittuihin veren sitkaisuuden mittausarvoihin

Recirculation in single lumen cannula venovenous extracorporeal membrane oxygenation: A non-randomized bi-centric trial

Background: Recirculation is a common problem in venovenous (VV) extracorporeal membrane oxygenation (ECMO). The aims of this study were to compare recirculation fraction (Rf) between femoro-jugular and jugulo-femoral VV ECMO configurations, to identify risk factors for recirculation and to assess the impact on hemolysis. Methods: Patients in the medical intensive care unit (ICU) at the University Medical Center Regensburg, Germany receiving VV ECMO with femoro-jugular, and jugulo-femoral configuration at the ECMO Center Karolinska, Sweden, were included in this non-randomized prospective study. Total ECMO flow (QEC), recirculated flow (QREC), and recirculation fraction Rf = QREC/QEC were determined using ultrasound dilution technology. Effective ECMO flow (QEFF) was defined as QEFF = QEC * (1–Rf). Demographics, cannula specifics, and markers of hemolysis were assessed. Survival was evaluated at discharge from ICU. Results: Thirty-seven patients with femoro-jugular configuration underwent 595 single-point measurements and 18 patients with jugulo-femoral configuration 231 measurements. Rf was lower with femoro-jugular compared to jugulo-femoral configuration [5 (0, 11) vs. 19 (13, 28) %, respectively (p 8 vs. ≤ 8%. Explorative data on survival showed comparable results in the femoro-jugular and the jugulo-femoral group (81 vs. 72%, p = 0.455). Conclusion: VV ECMO with femoro-jugular configuration caused less recirculation. Further risk factors for higher Rf were shorter distance between the two cannula tips, higher ECMO flow, and lower heart rate. Rf did not affect hemolysis

Serial S100B Sampling Detects Intracranial Lesion Development in Patients on Extracorporeal Membrane Oxygenation

Introduction: Intracranial lesion development is a recognized complication in adults treated with extracorporeal membrane oxygenation (ECMO) and is associated with increased mortality. As neurological assessment during ECMO treatment remains challenging, protein biomarkers of cerebral injury could provide an opportunity to detect intracranial lesion development at an early stage. The aim of this study was to determine if serially sampled S100B could be used to detect intracranial lesion development during ECMO treatment.Methods: We conducted an observational cohort study of all patients treated with ECMO at ECMO Center Karolinska (Karolinska University Hospital, Stockholm, Sweden) between January and August 2018, excluding patients who did not undergo a computerized tomography scan (CT) during treatment. S100B was prospectively collected at hospital admission and then once daily. The primary end-point was any type of CT verified intracranial lesion. Receiver operating characteristics (ROC) curves and Cox proportional hazards models were employed.Results: Twenty-nine patients were included, of which 15 (52%) developed an intracranial lesion and exhibited higher levels of S100B overall. S100B had a robust association with intracranial lesion development, especially during the first 200 hours following admission. The best area-under-curve (AUC) to predict intracranial lesion development was 40 and 140 hours following ECMO initiation, were a S100B level of 0.69μg/L had an AUC of 0.81 (0.628-0.997). S100B levels were markedly increased following the development of intracranial hemorrhage.Conclusions: Serial serum S100B samples in ECMO patients were both significantly elevated and had an increasing trajectory in patients developing intracranial lesions. Larger prospective trials are warranted to validate these findings and to ascertain their clinical utility

Plasma hyaluronan, hyaluronidase activity and endogenous hyaluronidase inhibition in sepsis : an experimental and clinical cohort study

Background: Plasma hyaluronan concentrations are increased during sepsis but underlying mechanisms leading to high plasma hyaluronan concentration are poorly understood. In this study we evaluate the roles of plasma hyaluronan, effective plasma hyaluronidase (HYAL) activity and its endogenous plasma inhibition in clinical and experimental sepsis. We specifically hypothesized that plasma HYAL acts as endothelial glycocalyx shedding enzyme, sheddase. Methods: Plasma hyaluronan, effective HYAL activity and HYAL inhibition were measured in healthy volunteers (n = 20), in patients with septic shock (n = 17, day 1 and day 4), in patients with acute pancreatitis (n = 7, day 1 and day 4) and in anesthetized and mechanically ventilated pigs (n = 16). Sixteen pigs were allocated (unblinded, open label) into three groups: Sepsis-1 with infusion of live Escherichia coli (E. coli) 1 x 10(8) CFU/h of 12 h (n = 5), Sepsis-2 with infusion of E. coli 1 x 10(8) CFU/h of 6 h followed by 1 x 10(9) CFU/h of the remaining 6 h (n = 5) or Control with no E. coli infusion (n = 6). Results: In experimental E. coli porcine sepsis and in time controls, plasma hyaluronan increases with concomitant decrease in effective plasma HYAL activity and increase of endogenous HYAL inhibition. Plasma hyaluronan increased in patients with septic shock but not in acute pancreatitis. Effective plasma HYAL was lower in septic shock and acute pancreatitis as compared to healthy volunteers, while plasma HYAL inhibition was only increased in septic shock. Conclusion: Elevated plasma hyaluronan levels coincided with a concomitant decrease in effective plasma HYAL activity and increase of endogenous plasma HYAL inhibition both in experimental and clinical sepsis. In acute pancreatitis, effective plasma HYAL activity was decreased which was not associated with increased plasma hyaluronan concentrations or endogenous HYAL inhibition. The results suggest that plasma HYAL does not act as sheddase in sepsis or pancreatitis.Peer reviewe

Table_2_Incidence, Outcome, and Predictors of Intracranial Hemorrhage in Adult Patients on Extracorporeal Membrane Oxygenation: A Systematic and Narrative Review.DOC

<p>Background: Intracranial hemorrhage (ICH) is a common complication in adults treated with extracorporeal membrane oxygenation (ECMO).</p><p>Objectives: The aim of this study was to conduct a systematic review of the literature on the incidence, outcome and predictors of ECMO-associated ICH in adult patients, supplemented by a narrative review of its pathophysiology, management and future perspectives.</p><p>Methods: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and www.clinicaltrials.gov were systematically searched. Studies that reported incidence, outcome or predictors of ECMO-associated ICH in adults (≥18 years) were eligible for inclusion.</p><p>Results: Twenty five articles were included in the systematic review. The incidence of ECMO-associated ICH varied between 1.8 and 21 %. Mortality rates in ICH-cohorts varied between 32 and 100 %, with a relative risk of mortality of 1.27–4.43 compared to non-ICH cohorts. An increased risk of ICH was associated with ECMO-duration, antithrombotic therapy, altered intrinsic coagulation, renal failure, need of blood products, rapid hypercapnia at ECMO initiation, and even pre-ECMO morbidity.</p><p>Conclusions: ICH is a common complication in adults treated with ECMO and associated with increased mortality. Treating an ICH during ECMO represents a balance between pro- and anticoagulatory demands. Neurosurgical treatment is associated with severe morbidity, but has been successful in selected cases. Future studies should aim at investigating the validity and feasibility of non-invasive monitoring in early detection of ECMO-associated ICH.</p

Table_3_Incidence, Outcome, and Predictors of Intracranial Hemorrhage in Adult Patients on Extracorporeal Membrane Oxygenation: A Systematic and Narrative Review.DOC

<p>Background: Intracranial hemorrhage (ICH) is a common complication in adults treated with extracorporeal membrane oxygenation (ECMO).</p><p>Objectives: The aim of this study was to conduct a systematic review of the literature on the incidence, outcome and predictors of ECMO-associated ICH in adult patients, supplemented by a narrative review of its pathophysiology, management and future perspectives.</p><p>Methods: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and www.clinicaltrials.gov were systematically searched. Studies that reported incidence, outcome or predictors of ECMO-associated ICH in adults (≥18 years) were eligible for inclusion.</p><p>Results: Twenty five articles were included in the systematic review. The incidence of ECMO-associated ICH varied between 1.8 and 21 %. Mortality rates in ICH-cohorts varied between 32 and 100 %, with a relative risk of mortality of 1.27–4.43 compared to non-ICH cohorts. An increased risk of ICH was associated with ECMO-duration, antithrombotic therapy, altered intrinsic coagulation, renal failure, need of blood products, rapid hypercapnia at ECMO initiation, and even pre-ECMO morbidity.</p><p>Conclusions: ICH is a common complication in adults treated with ECMO and associated with increased mortality. Treating an ICH during ECMO represents a balance between pro- and anticoagulatory demands. Neurosurgical treatment is associated with severe morbidity, but has been successful in selected cases. Future studies should aim at investigating the validity and feasibility of non-invasive monitoring in early detection of ECMO-associated ICH.</p

Table_1_Incidence, Outcome, and Predictors of Intracranial Hemorrhage in Adult Patients on Extracorporeal Membrane Oxygenation: A Systematic and Narrative Review.DOCX

<p>Background: Intracranial hemorrhage (ICH) is a common complication in adults treated with extracorporeal membrane oxygenation (ECMO).</p><p>Objectives: The aim of this study was to conduct a systematic review of the literature on the incidence, outcome and predictors of ECMO-associated ICH in adult patients, supplemented by a narrative review of its pathophysiology, management and future perspectives.</p><p>Methods: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and www.clinicaltrials.gov were systematically searched. Studies that reported incidence, outcome or predictors of ECMO-associated ICH in adults (≥18 years) were eligible for inclusion.</p><p>Results: Twenty five articles were included in the systematic review. The incidence of ECMO-associated ICH varied between 1.8 and 21 %. Mortality rates in ICH-cohorts varied between 32 and 100 %, with a relative risk of mortality of 1.27–4.43 compared to non-ICH cohorts. An increased risk of ICH was associated with ECMO-duration, antithrombotic therapy, altered intrinsic coagulation, renal failure, need of blood products, rapid hypercapnia at ECMO initiation, and even pre-ECMO morbidity.</p><p>Conclusions: ICH is a common complication in adults treated with ECMO and associated with increased mortality. Treating an ICH during ECMO represents a balance between pro- and anticoagulatory demands. Neurosurgical treatment is associated with severe morbidity, but has been successful in selected cases. Future studies should aim at investigating the validity and feasibility of non-invasive monitoring in early detection of ECMO-associated ICH.</p

Data_Sheet_1_Recirculation in single lumen cannula venovenous extracorporeal membrane oxygenation: A non-randomized bi-centric trial.pdf

BackgroundRecirculation is a common problem in venovenous (VV) extracorporeal membrane oxygenation (ECMO). The aims of this study were to compare recirculation fraction (Rf) between femoro-jugular and jugulo-femoral VV ECMO configurations, to identify risk factors for recirculation and to assess the impact on hemolysis.MethodsPatients in the medical intensive care unit (ICU) at the University Medical Center Regensburg, Germany receiving VV ECMO with femoro-jugular, and jugulo-femoral configuration at the ECMO Center Karolinska, Sweden, were included in this non-randomized prospective study. Total ECMO flow (QEC), recirculated flow (QREC), and recirculation fraction Rf = QREC/QEC were determined using ultrasound dilution technology. Effective ECMO flow (QEFF) was defined as QEFF = QEC * (1–Rf). Demographics, cannula specifics, and markers of hemolysis were assessed. Survival was evaluated at discharge from ICU.ResultsThirty-seven patients with femoro-jugular configuration underwent 595 single-point measurements and 18 patients with jugulo-femoral configuration 231 measurements. Rf was lower with femoro-jugular compared to jugulo-femoral configuration [5 (0, 11) vs. 19 (13, 28) %, respectively (p EFF [2.80 (2.21, 3.39) vs. 2.79 (2.39, 3.08) L/min (p = 0.225)] despite lower QEC with femoro-jugular configuration compared to jugulo-femoral [3.01 (2.40, 3.70) vs. 3.57 (3.05, 4.06) L/min, respectively (p 8 vs. ≤ 8%. Explorative data on survival showed comparable results in the femoro-jugular and the jugulo-femoral group (81 vs. 72%, p = 0.455).ConclusionVV ECMO with femoro-jugular configuration caused less recirculation. Further risk factors for higher Rf were shorter distance between the two cannula tips, higher ECMO flow, and lower heart rate. Rf did not affect hemolysis.</p