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Background Impaired cerebrovascular reactivity (CVR) is one feature of post cardiac arrest encephalopathy. We studied the incidence and features of CVR by near infrared spectroscopy (NIRS) and associations with outcome and biomarkers of brain injury. Methods A post-hoc analysis of 120 comatose OHCA patients continuously monitored with NIRS and randomised to low- or high-normal oxygen, carbon dioxide and mean arterial blood pressure (MAP) targets for 48 h. The tissue oximetry index (TO x ) generated by the moving correlation coefficient between cerebral tissue oxygenation measured by NIRS and MAP was used as a dynamic index of CVR with TO x  > 0 indicating impaired reactivity and TO x  > 0.3 used to delineate the lower and upper MAP bounds for disrupted CVR. TO x was analysed in the 0–12, 12–24, 24–48 h time-periods and integrated over 0–48 h. The primary outcome was the association between TO x and six-month functional outcome dichotomised by the cerebral performance category (CPC1-2 good vs. 3–5 poor). Secondary outcomes included associations with MAP bounds for CVR and biomarkers of brain injury. Results In 108 patients with sufficient data to calculate TO x , 76 patients (70%) had impaired CVR and among these, chronic hypertension was more common (58% vs. 31%, p  = 0.002). Integrated TO x for 0–48 h was higher in patients with poor outcome than in patients with good outcome (0.89 95% CI [− 1.17 to 2.94] vs. − 2.71 95% CI [− 4.16 to − 1.26], p  = 0.05). Patients with poor outcomes had a decreased upper MAP bound of CVR over time ( p  = 0.001), including the high-normal oxygen ( p  = 0.002), carbon dioxide ( p  = 0.012) and MAP ( p  = 0.001) groups. The MAP range of maintained CVR was narrower in all time intervals and intervention groups ( p  < 0.05). NfL concentrations were higher in patients with impaired CVR compared to those with intact CVR (43 IQR [15–650] vs 20 IQR [13–199] pg/ml, p  = 0.042). Conclusion Impaired CVR over 48 h was more common in patients with chronic hypertension and associated with poor outcome. Decreased upper MAP bound and a narrower MAP range for maintained CVR were associated with poor outcome and more severe brain injury assessed with NfL. Trial registration ClinicalTrials.gov, NCT02698917 .

Background Cerebral hypoperfusion may aggravate neurological damage after cardiac arrest. Near-infrared spectroscopy (NIRS) provides information on cerebral oxygenation but its relevance during post-resuscitation care is undefined. We investigated whether cerebral oxygen saturation (rSO 2 ) measured with NIRS correlates with the serum concentration of neuron-specific enolase (NSE), a marker of neurological injury, and with clinical outcome in out-of-hospital cardiac arrest (OHCA) patients. Methods We performed a post hoc analysis of a randomised clinical trial (COMACARE, NCT02698917) comparing two different levels of carbon dioxide, oxygen and arterial pressure after resuscitation from OHCA with ventricular fibrillation as the initial rhythm. We measured rSO 2 in 118 OHCA patients with NIRS during the first 36 h of intensive care. We determined the NSE concentrations from serum samples at 48 h after cardiac arrest and assessed neurological outcome with the Cerebral Performance Category (CPC) scale at 6 months. We evaluated the association between rSO 2 and serum NSE concentrations and the association between rSO 2 and good (CPC 1–2) and poor (CPC 3–5) neurological outcome. Results The median (inter-quartile range (IQR)) NSE concentration at 48 h was 17.5 (13.4–25.0) μg/l in patients with good neurological outcome and 35.2 (22.6–95.8) μg/l in those with poor outcome, p  < 0.001. We found no significant correlation between median rSO 2 and NSE at 48 h, r s  = − 0.08, p  = 0.392. The median (IQR) rSO 2 during the first 36 h of intensive care was 70.0% (63.5–77.0%) in patients with good outcome and 71.8% (63.3–74.0%) in patients with poor outcome, p  = 0.943. There was no significant association between rSO 2 over time and neurological outcome. In a binary logistic regression model, rSO 2 was not a statistically significant predictor of good neurological outcome (odds ratio 0.99, 95% confidence interval 0.94–1.04, p  = 0.635). Conclusions We found no association between cerebral oxygenation measured with NIRS and NSE concentrations or outcome in patients resuscitated from OHCA. Trial registration ClinicalTrials.gov, NCT02698917 . Registered on 26 January 2016.

Background Rarely, the first sign of chronic thromboembolic pulmonary hypertension (CTEPH) is acute embolism, an acute-on-chronic event. These patients are challenging: they need emergent care but are not candidates for immediate definitive treatment with pulmonary endarterectomy (PEA) due to their critical condition. Case presentation We report a patient with massive acute-on-chronic pulmonary thromboembolism leading to cardiogenic shock. We decided on a staged surgical treatment strategy: emergency surgical embolectomy; brindging and stabilization with central veno-arterial extracorporeal membrane oxygenator; and delayed PEA. The patient had full recovery. Conclusions Patients with an undiagnosed CTEPH developing an acute embolism are in a very high risk of facing a complicated recovery and death. A multidisciplinary team effort is warranted. A staged surgical approach with delayed PEA after stabilization seems a reasonable option to manage these rare and complex patients.

Background In cardiac surgery with cardiopulmonary bypass (CPB), large amounts of fluids are administered. CPB priming with crystalloid solution causes marked hemodilution and fluid extravasation. Colloid solutions may reduce fluid overload because they have a better volume expansion effect than crystalloids. The European Medicines Agency does not recommend the use of hydroxyethyl starch solutions (HES) due to harmful renal effects. Albumin solution does not impair blood coagulation but the findings on kidney function are conflicting. On the other hand, albumin may reduce endothelial glycocalyx destruction and decrease platelet count during CPB. No large randomized, double-blind, clinical trials have compared albumin solution to crystalloid solution in cardiac surgery. Methods/design In this single-center, double-blind, randomized controlled trial comprising 1386 adult cardiac surgery patients, 4% albumin solution will be compared to Ringer’s acetate solution in CPB priming and volume replacement up to 3200 mL during surgery and the first 24 h of intensive care unit stay. The primary efficacy outcome is the number of patients with at least one major adverse event (MAE) during 90 postoperative days (all-cause death, acute myocardial injury, acute heart failure or low output syndrome, resternotomy, stroke, major arrhythmia, major bleeding, infection compromising post-procedural rehabilitation, acute kidney injury). Secondary outcomes are total number of MAEs, incidence of major adverse cardiac events (MACE; cardiac death, acute myocardial injury, acute heart failure, arrhythmia), amount of each type of blood product transfused (red blood cells, fresh frozen plasma, platelets), total fluid balance at the end of the intervention period, total measured blood loss, development of acute kidney injury, days alive without mechanical ventilation in 90 days, days alive outside intensive care unit at 90 days, days alive at home at 90 days, and 90-day mortality. Discussion The findings of this study will provide new evidence regarding efficacy and safety of albumin solution in adult patients undergoing cardiac surgery with CPB. Trial registration EudraCT (clinicaltrialsregister.eu) 2015–002556-27 Registered 11 Nov 2016 and ClinicalTrials.gov NCT02560519 . Registered 25 Sept 2015.

Matrix metalloproteinases (MMPs) -8 and -9 are released from neutrophils in acute inflammation and may contribute to permeability changes in burn injury. In retrospective studies on sepsis, levels of MMP-8, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) differed from those of healthy controls, and TIMP-1 showed an association with outcome. Our objective was to investigate the relationship between these proteins and disease severity and outcome in burn patients. In this prospective, observational, two-center study, we collected plasma samples from admission to day 21 post-burn, and burn blister fluid samples on admission. We compared MMP-8, -9, and TIMP-1 levels between TBSA<20% (N = 19) and TBSA>20% (N = 30) injured patients and healthy controls, and between 90-day survivors and non-survivors. MMP-8, -9, and TIMP-1 levels at 24-48 hours from injury, their maximal levels, and their time-adjusted means were compared between groups. Correlations with clinical parameters and the extent of burn were analyzed. MMP-8, -9, and TIMP-1 levels in burn blister fluids were also studied. Plasma MMP-8 and -9 were higher in patients than in healthy controls (P<0.001 and P = 0.016), but only MMP-8 differed between the TBSA<20% and TBSA>20% groups. MMP-8 and -9 were not associated with clinical severity or outcome measures. TIMP-1 differed significantly between patients and controls (P<0.001) and between TBSA<20% and TBSA>20% groups (P<0.002). TIMP-1 was associated with 90-day mortality and correlated with the extent of injury and clinical measures of disease severity. TIMP-1 may serve as a new biomarker in outcome prognostication of burn patients.

PurposeWe aimed to determine the feasibility of targeting low-normal or high-normal mean arterial pressure (MAP) after out-of-hospital cardiac arrest (OHCA) and its effect on markers of neurological injury.MethodsIn the Carbon dioxide, Oxygen and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial, we used a 23 factorial design to randomly assign patients after OHCA and resuscitation to low-normal or high-normal levels of arterial carbon dioxide tension, to normoxia or moderate hyperoxia, and to low-normal or high-normal MAP. In this paper we report the results of the low-normal (65–75 mmHg) vs. high-normal (80–100 mmHg) MAP comparison. The primary outcome was the serum concentration of neuron-specific enolase (NSE) at 48 h after cardiac arrest. The feasibility outcome was the difference in MAP between the groups. Secondary outcomes included S100B protein and cardiac troponin (TnT) concentrations, electroencephalography (EEG) findings, cerebral oxygenation and neurological outcome at 6 months after cardiac arrest.ResultsWe recruited 123 patients and included 120 in the final analysis. We found a clear separation in MAP between the groups (p < 0.001). The median (interquartile range) NSE concentration at 48 h was 20.6 µg/L (15.2–34.9 µg/L) in the low-normal MAP group and 22.0 µg/L (13.6–30.9 µg/L) in the high-normal MAP group, p = 0.522. We found no differences in the secondary outcomes.ConclusionsTargeting a specific range of MAP was feasible during post-resuscitation intensive care. However, the blood pressure level did not affect the NSE concentration at 48 h after cardiac arrest, nor any secondary outcomes.

Background The atrial appendages are a tissue reservoir for cardiac stem cells. During on-pump coronary artery bypass graft (CABG) surgery, part of the right atrial appendage can be excised upon insertion of the right atrial cannula of the heart-lung machine. In the operating room, the removed tissue can be easily cut into micrografts for transplantation. This trial aims to assess the safety and feasibility of epicardial transplantation of atrial appendage micrografts in patients undergoing CABG surgery. Methods/design Autologous cardiac micrografts are made from leftover right atrial appendage during CABG of 6 patients. Atrial appendage is mechanically processed to micrografts consisting of atrial appendage-derived cells (AADCs) and their extracellular matrix (ECM). The micrografts are epicardially transplanted in a fibrin gel and covered with a tissue-engineered ECM sheet. Parameters including echocardiography—reflecting cardiac insufficiency—are studied pre- and post-operatively as well as at 3 and 6 months of the follow-up. Cardiac functional magnetic resonance imaging is performed preoperatively and at 6-month follow-up. The primary outcome measures are patient safety in terms of hemodynamic and cardiac function over time and feasibility of therapy administration in a clinical setting. Secondary outcome measures are left ventricular wall thickness, change in the amount of myocardial scar tissue, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, New York Heart Association class, days in hospital, and changes in the quality of life. Twenty patients undergoing routine CAGB surgery will be recruited to serve as a control group. Discussion This study aims to address the surgical feasibility and patient safety of epicardially delivered atrial appendage micrografts during CABG surgery. Delivery of autologous micrografts and AADCs has potential applications for cell and cell-based gene therapies. Trial registration ClinicalTrials.gov Identifier: NCT02672163 . Date of registration: 02.02.2016

Purpose Neurofilament light (NfL) is a biomarker reflecting neurodegeneration and acute neuronal injury, and an increase is found following hypoxic brain damage. We assessed the ability of plasma NfL to predict outcome in comatose patients after out-of-hospital cardiac arrest (OHCA). We also compared plasma NfL concentrations between patients treated with two different targets of arterial carbon dioxide tension (PaCO 2 ), arterial oxygen tension (PaO 2 ), and mean arterial pressure (MAP). Methods We measured NfL concentrations in plasma obtained at intensive care unit admission and at 24, 48, and 72 h after OHCA. We assessed neurological outcome at 6 months and defined a good outcome as Cerebral Performance Category (CPC) 1–2 and poor outcome as CPC 3–5. Results Six-month outcome was good in 73/112 (65%) patients. Forty-eight hours after OHCA, the median NfL concentration was 19 (interquartile range [IQR] 11–31) pg/ml in patients with good outcome and 2343 (587–5829) pg/ml in those with poor outcome, p  < 0.001. NfL predicted poor outcome with an area under the receiver operating characteristic curve (AUROC) of 0.98 (95% confidence interval [CI] 0.97–1.00) at 24 h, 0.98 (0.97–1.00) at 48 h, and 0.98 (0.95–1.00) at 72 h. NfL concentrations were lower in the higher MAP (80–100 mmHg) group than in the lower MAP (65–75 mmHg) group at 48 h (median, 23 vs. 43 pg/ml, p  = 0.04). PaCO 2 and PaO 2 targets did not associate with NfL levels. Conclusions NfL demonstrated excellent prognostic accuracy after OHCA. Higher MAP was associated with lower NfL concentrations.

Background Fluid challenges (FCs) are one of the most commonly used therapies in critically ill patients and represent the cornerstone of hemodynamic management in intensive care units. There are clear benefits and harms from fluid therapy. Limited data on the indication, type, amount and rate of an FC in critically ill patients exist in the literature. The primary aim was to evaluate how physicians conduct FCs in terms of type, volume, and rate of given fluid; the secondary aim was to evaluate variables used to trigger an FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC. Methods This was an observational study conducted in ICUs around the world. Each participating unit entered a maximum of 20 patients with one FC. Results 2213 patients were enrolled and analyzed in the study. The median [interquartile range] amount of fluid given during an FC was 500 ml (500–1000). The median time was 24 min (40–60 min), and the median rate of FC was 1000 [500–1333] ml/h. The main indication for FC was hypotension in 1211 (59 %, CI 57–61 %). In 43 % (CI 41–45 %) of the cases no hemodynamic variable was used. Static markers of preload were used in 785 of 2213 cases (36 %, CI 34–37 %). Dynamic indices of preload responsiveness were used in 483 of 2213 cases (22 %, CI 20–24 %). No safety variable for the FC was used in 72 % (CI 70–74 %) of the cases. There was no statistically significant difference in the proportion of patients who received further fluids after the FC between those with a positive, with an uncertain or with a negatively judged response. Conclusions The current practice and evaluation of FC in critically ill patients are highly variable. Prediction of fluid responsiveness is not used routinely, safety limits are rarely used, and information from previous failed FCs is not always taken into account.

Background In circulatory shock, tissue hypoperfusion leads to adverse outcomes. We hypothesized that peripheral tissue oxygen saturation (StO 2 ), measured with near-infrared spectroscopy (NIRS), could provide a non-invasive method for assessing tissue hypoperfusion and predicting pending organ dysfunction and mortality. Methods ASSESS-SHOCK was a prospective, observational study enrolling circulatory shock patients from April 2019 to May 2023 in three intensive care units (ICU). Adult patients fulfilling the criteria for circulatory shock within 24 h of ICU admission were eligible. Patients underwent continuous 48 h StO 2 (INVOS™) monitoring of the knee region. To express the burden of tissue hypoperfusion we calculated mean StO 2 and areas below predefined StO 2 thresholds. The primary outcome, change in Sequential Organ Failure Assessment (SOFA) score, was dichotomized to improvement or non-improvement in SOFA score from enrollment to day 7 or ICU discharge. Death within 7 days was considered as SOFA non-improvement. 90-day mortality was among the secondary outcomes. Results We included 256 patients. Due to several reasons, including the COVID-19 pandemic, the patient sample was not consecutive. The median of 48-h mean StO 2 was 68.3% (interquartile range [IQR] 57.5–74.1) in SOFA-improvers (n = 171), compared to 63.5% (IQR 52.7–70.8, p  = 0.020) in non-improvers (n = 85), and 68.7% (IQR 58.2–74.5) in 90-day survivors, versus 60.9% (IQR 49.5–67.1, p  < 0.001) in non-survivors. There were no statistically significant differences in the areas below predefined StO 2 thresholds between the SOFA-improvers and non-improvers but all the areas were larger in 90-day non-survivors. The 90-day mortality was 27.0% (n = 69). In multivariable analyses 48-h mean StO 2 was associated with 90-day mortality (Odds ratio [OR] 0.97, 95% confidence interval [CI 95%] 0.94–1.00, p  = 0.047) but not with SOFA change. The association with mortality was, however, no longer significant in multivariable analyses after exclusion of the last 6 hours of StO 2 registration in the patients (n = 29) who died during the 48 h registration (OR 0.97, CI 95% 0.94–1.00, p  = 0.062). Conclusions Lower peripheral StO 2 was associated with 90-day mortality in critically ill patients with circulatory shock but not with persisting or worsening organ dysfunction. NIRS shows promise as a non-invasive monitor of tissue perfusion in circulatory shock. Trial registration : ClinicalTrials.gov Identifier: NCT03814564, registered 15 January 2019.