Biomarkers of Cerebral Injury for Prediction of Postoperative Cognitive Dysfunction in Patients Undergoing Cardiac Surgery.

OBJECTIVES: To assess the ability of the biomarkers neuron-specific enolase (NSE), tau, neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) to predict postoperative cognitive dysfunction (POCD) at discharge in patients who underwent cardiac surgery. DESIGN: Post hoc analyses (with tests being prespecified before data analyses) from a randomized clinical trial. SETTING: Single-center study from a primary heart center in Denmark. PARTICIPANTS: Adult patients undergoing elective or subacute on-pump coronary artery bypass grafting and/or aortic valve replacement. INTERVENTIONS: Blood was collected before induction of anesthesia, after 24 hours, after 48 hours, and at discharge from the surgical ward. The International Study of Postoperative Cognitive Dysfunction test battery was applied to diagnose POCD at discharge and after three months. Linear mixed models of covariance were used to assess whether repeated measurements of biomarker levels were associated with POCD. Receiver operating characteristic (ROC) curves were applied to assess the predictive value of each biomarker measurement for POCD. MEASUREMENTS AND MAIN RESULTS: A total of 168 patients had biomarkers measured at baseline, and 47 (28%) fulfilled the POCD criteria at discharge. Patients with POCD at discharge had significantly higher levels of tau (p = 0.02) and GFAP (p = 0.01) from baseline to discharge. The biomarker measurements achieving the highest area under the ROC curve for prediction of POCD at discharge were NFL measured at discharge (AUC, 0.64; 95% confidence interval [CI], 0.54-0.73), GFAP measured 48 hours after induction (AUC, 0.64; 95% CI, 0.55-0.73), and GFAP measured at discharge (AUC, 0.64; 95% CI, 0.54-0.74), corresponding to a moderate predictive ability. CONCLUSIONS: Postoperative serum levels of tau and GFAP were significantly elevated in cardiac surgery patients with POCD at discharge, however, the biomarkers achieved only modest predictive abilities for POCD at discharge. Postoperative levels of NSE were not associated with POCD at discharge.

Efficacy of a glucagon-like peptide-1 agonist and restrictive versus liberal oxygen supply in patients undergoing coronary artery bypass grafting or aortic valve replacement: study protocol for a 2-by-2 factorial designed, randomised clinical trial.

INTRODUCTION: Coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) are associated with risk of death, as well as brain, heart and kidney injury. Glucagon-like peptide-1 (GLP-1) analogues are approved for treatment of type 2 diabetes, and GLP-1 analogues have been suggested to have potential organ-protective and anti-inflammatory effects. During cardiopulmonary bypass (CPB), consensus on the optimal fraction of oxygen is lacking. The objective of this study is to determine the efficacy of the GLP-1-analogue exenatide versus placebo and restrictive oxygenation (50% fractional inspired oxygen, FiO2) versus liberal oxygenation (100% FiO2) in patients undergoing open heart surgery. METHODS AND ANALYSIS: A randomised, placebo-controlled, double blind (for the exenatide intervention)/single blind (for the oxygenation strategy), 2×2 factorial designed single-centre trial on adult patients undergoing elective or subacute CABG and/or surgical AVR. Patients will be randomised in a 1:1 and 1:1 ratio to a 6-hour and 15 min infusion of 17.4 µg of exenatide or placebo during CPB and to a FiO2 of 50% or 100% during and after weaning from CPB. Patients will be followed until 12 months after inclusion of the last participant. The primary composite endpoint consists of time to first event of death, renal failure requiring renal replacement therapy, hospitalisation for stroke or heart failure. In addition, the trial will include predefined sub-studies applying more advanced measures of cardiac- and pulmonary dysfunction, renal dysfunction and cerebral dysfunction. The trial is event driven and aims at 323 primary endpoints with a projected inclusion of 1400 patients. ETHICS AND DISSEMINATION: Eligible patients will provide informed, written consent prior to randomisation. The trial is approved by the local ethics committee and is conducted in accordance with Danish legislation and the Declaration of Helsinki. The results will be presented in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02673931.

Lack of Association Between Gaseous Microembolisms Assessed by a Single Detection Device and Cerebral Complications in Cardiac Surgery Patients.

OBJECTIVE: To assess the association between total volume and number of gaseous microemboli (GME) in the cardiopulmonary bypass (CPB) circuit and the occurrence of new postoperative cerebral infarctions and postoperative cognitive dysfunction (POCD) in patients undergoing cardiac surgery. DESIGN: Predefined subanalyses of the randomized controlled Perfusion Pressure Cerebral Infarcts (PPCI) trial. SETTING: Primary heart center in a university hospital. PARTICIPANTS: A total of 143 adult patients undergoing cardiac surgery with CPB. INTERVENTIONS: Patients were allocated 1:1 to a low-target mean arterial pressure (MAP) of 40 to 50 mmHg or a high-target MAP of 70 to 80 mmHg during CPB with a fixed pump flow of 2.4 liters per minute per square meter body surface area plus 10% to 20%. MEASUREMENTS AND MAIN RESULTS: The total volume and number of GME in the CPB circuit were assessed by the Bubble Counter Clinical 200® (GAMPT GmbH). New cerebral infarcts were identified by diffusion-weighted magnetic resonance imaging (DWI) 3 to 6 days after surgery. The median number of GME per patient was 8069 (range 1,523-204,095) with a median total volume of 1.2 µL (range 0.07-48 µL). A total of 66 (46%) patients had DWI detected cerebral infarcts postoperatively, and 36 (28%) patients had POCD after 7 days. The authors found no significant association between volume or number of GME with MAP target allocation, presence of cerebral infarction, or POCD. CONCLUSIONS: The authors found no significant associations between volume or number of GME with the occurrence of cerebral infarction or cognitive dysfunction in cardiac surgery patients.

Right ventricular transverse displacement increases following cardiac surgery: possibly compensating loss in tricuspid annular plane systolic excursion (TAPSE).

Right Ventricular (RV) output mostly derives from longitudinal shortening in normal hearts. However, following even uncomplicated cardiac surgery with preserved RV function a significant and sustained decrease in longitudinal contraction has been observed. How the RV compensates and sustains output in this setting remains unsettled. The aim of this study was to evaluate the RV contraction pattern by speckle tracking echocardiography to elucidate possible compensatory mechanisms mitigating the reduced RV longitudinal contraction after cardiac surgery. Thirty patients with normal preoperative ejection fraction and no valvulopathy underwent coronary artery bypass grafting (CABG) with the use of cardiopulmonary bypass (CPB). RV dedicated speckle tracking software measuring longitudinal and transverse displacement, as well as strain, was employed on transesophageal echocardiographic (TEE) images as part of the Right Ventricular Echocardiography in cardiac SurgEry (ReVERSE) study. Data was recorded at baseline (after anesthesia induction), immediately after CPB and upon chest closure. Tricuspid Annulus Plane Systolic Excursion (TAPSE) was reduced from 2.0 [1.6-2.5 cm] to 0.8 [0.6-11 mm] from baseline to after chest closure. RV longitudinal displacement was reduced from 6.1 [3.4-8.8 mm] to 2.9 [0.4-5.4 mm] at the same time-points. RV speckle tracking revealed concomitantly that transverse displacement of the free wall increased significantly from 1.2 [0-2.7 mm] at baseline to 5.4 [3.6-7.2 mm] after chest closure. RV speckle tracking strain did not change significantly. Increased transverse displacement likely compensates for reduction in RV longitudinal contraction following cardiac surgery and maintains cardiac output. The sustained output from the right ventricle was not related to an increased contractility.

Tricuspid annular plane systolic excursion is significantly reduced during uncomplicated coronary artery bypass surgery: A prospective observational study.

OBJECTIVES: Longitudinal shortening constitutes most of the right ventricle (RV) contraction in the normal heart. However, after even uncomplicated cardiac surgery with preserved RV function a significant and sustained decrease in longitudinal contraction expressed as a reduction in tricuspid annular plane systolic excursion (TAPSE) has been observed. Why and exactly when this happens remains unsettled. The aim of this study was to evaluate the magnitude and timing of changes in TAPSE in relation to sternotomy, pericardial opening, cardiopulmonary bypass (CPB), and chest closure. METHODS: Fifty patients with normal preoperative ejection fraction and no valvulopathy, who underwent coronary artery bypass grafting with the use of CPB, were included. TAPSE was assessed using transthoracic echocardiography (TTE) at baseline and immediately after chest closure. Transesophageal echocardiography was performed at the following time points: after (1) anesthesia induction and transthoracic echocardiography; (2) sternotomy; (3) pericardiotomy; (4) completion of CPB; and (5) chest closure. RESULTS: TAPSE was significantly reduced to approximately half of its initial value in all patients (from 22 [95% confidence interval, 21-23 mm] after anesthesia induction to 9 [95% confidence interval, 8-10 mm] after chest closure). No change was seen after pericardiotomy. The most prominent reduction (30%-40%) was observed after weaning from CPB. An additional significant decrease of 13% to 16% was seen after chest closure. CONCLUSIONS: TAPSE was consistently reduced to approximately half of its initial value after uncomplicated coronary artery bypass grafting surgery. The reduction happened mainly after weaning from CPB, possibly reflecting conformational change of the RV.

Lung transplantation after ex vivo lung perfusion in two Scandinavian centres.

OBJECTIVES: We reviewed our combined clinical outcome in patients who underwent lung transplantation after ex vivo lung perfusion (EVLP) and compared it to the contemporary control group. METHODS: At 2 Scandinavian centres, lungs from brain-dead donors, not accepted for donation but with potential for improvement, were subjected to EVLP (n = 61) and were transplanted if predefined criteria were met. Transplantation outcome was compared with that of the contemporary control group consisting of patients (n = 271) who were transplanted with conventional donor lungs. RESULTS: Fifty-four recipients from the regular waiting list underwent transplantation with lungs subjected to EVLP (1 bilateral lobar, 7 single and 46 double). In the EVLP and control groups, arterial oxygen tension/inspired oxygen fraction ratio at arrival in the intensive care unit (ICU) was 30 ± 14 kPa compared to 36 ± 14 (P = 0.005); median time to extubation was 18 h (range 2-912) compared to 7 (range 0-2280) (P = 0.002); median ICU length of stay was 4 days (range 2-65) compared to 3 days (range 1-156) (P = 0.002); Percentage of expected forced expiratory volume at 1s (FEV1.0%) at 1 year was 75 ± 29 compared to 81 ± 26 (P = 0.18); and the 1-year survival rate was 87% [confidence interval (CI) 82-92%] compared to 83% (CI 81-85), respectively. Follow-up to a maximum of 5 years did not show any significant difference in survival between groups (log rank, P = 0.63). CONCLUSIONS: Patients transplanted with lungs after EVLP showed outcomes comparable to patients who received conventional organs at medium-term follow-up. Although early outcome immediately after transplantation showed worse lung function in the EVLP group, no differences were observed at a later stage, and we consider EVLP to be a safe method for increasing the number of transplantable organs.

Measures of right ventricular function after transcatheter versus surgical aortic valve replacement.

Objectives: Describe changes in measures of right ventricular (RV) function in patients treated for aortic stenosis using open-chest surgery (SAVR) or transcatheter treatment (TAVR). Methods: Patients in the Nordic Aortic Valve Intervention (NOTION) trial were randomized 1:1 to TAVR (n = 114) or SAVR (n = 106). Echocardiography was performed at baseline and 3 and 12 months post-procedure. Tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RVFAC) were used as measures of longitudinal and transverse RV contraction. Left ventricular ejection fraction (LVEF) and LV atrioventricular plane displacement (AVPD) were recorded as measures of LV function. Association to NYHA class was examined. Results: There were no differences in echocardiographic measurements between TAVR and SAVR at baseline. In the SAVR group, TAPSE was reduced after 3 months (2.4 ± 0.5 cm vs 1.6 ± 0.4 cm; P < 0.001), and 12 months (2.4 ± 0.5 cm vs 1.7 ± 0.4 cm; P < 0.001). RVFAC was reduced after 3 months (44% ± 11% vs 39% ± 10%; P = 0.001), but recovered at 12 months (43% ± 10%; P = 0.39). AVPD lateral increased during follow-up (1.4 ± 0.3 cm vs 1.6 ± 0.4 cm (P = 0.001) and 1.7 ± 0.4 cm, respectively; P < 0.001), whereas AVPD medial remained stable (baseline vs 3 months: P = 0.06 and baseline vs 12 months: P = 0.59). In the TAVR group, all echocardiographic measures remained unchanged from baseline to 12 months postoperatively. We found no association between echocardiographic changes and NYHA class. Conclusions: TAPSE and AVPD lateral differed between TAVR and SAVR at 3 and 12 months follow-up, but these findings were not related to any changes in NYHA class. These observations indicate that following SAVR, echocardiographic changes may not reflect right ventricular function, but merely a change in the physiological conditions. Clinicaltrials.gov identifier: NCT01057173.

Using clinical parameters to guide fluid therapy in high-risk thoracic surgery. A retrospective, observational study.

BACKGROUND: Despite extensive research, the debate continues as to the optimal way of guiding intraoperative and postoperative fluid therapy. In 2009 we changed our institutional guideline for perioperative fluid therapy in patients undergoing extrapleural pneumonectomy (EPP) and implemented the use of central venous oxygen saturation and intended low urine output to guide therapy in the early postoperative period. Here we evaluate the consequences of our changes. METHODS: Retrospective, observational study of 30 consecutive patients undergoing EPP; 18 who had surgery before and 12 who had surgery after the changes. Data were collected from patient files and from institutional databases. Outcome measures included: Volumes of administered fluids, fluid balances, length of stays and postoperative complications. Dichotomous variables were compared with Fisher's exact test, whereas continuous variables were compared with Student's unpaired t-test or the Wilcoxon Two-Sample Test depending on the distribution of data. RESULTS: The applied changes significantly reduced the volumes of administered fluids, both in the intraoperative (p = 0.01) and the postoperative period (p = 0.04), without increasing the incidence of postoperative complications. Mean length of stay in the intensive care unit (LOSI) was reduced from three to one day (p = 0.04) after the changes. CONCLUSION: The use of clinical parameters to balance fluid restriction and a sufficient circulation in patients undergoing EPP was associated with a reduction in mean LOSI without increasing the incidence of postoperative complications. Due to methodological limitations these results are only hypothesis generating.

First report on intraoperative vector flow imaging of the heart among patients with healthy and diseased aortic valves.

The vector velocity method Transverse Oscillation (TO) implemented on a conventional ultrasound (US) scanner (ProFocus, BK Medical, Herlev, Denmark) can provide real-time, angle-independent estimates of the cardiac blood flow. During cardiac surgery, epicardial US examination using TO was performed on (A) 3 patients with healthy aortic valve and (B) 3 patients with aortic valve stenosis. In group B, the systolic flow of the ascending aorta had higher velocities, was more aliased and chaotic. The jet narrowed to 44% of the lumen compared to 75% in group A and with a vector concentration, a measure of flow complexity, of 0.41 compared to 0.87 in group A. The two groups had similar secondary flow of the ascending aorta with an average rotation frequency of 4.8 Hz. Simultaneous measurements were obtained with spectral Doppler (SD) and a thermodilution technique (TD). The mean difference in peak systolic velocity compared to SD in group A was 22% and 45% in B, while the mean difference in volume flow compared to TD in group A was 30% and 32% in B. TO can potentially reveal new information of cardiac blood flow, and may become a valuable diagnostic tool in the evaluation of patients with cardiovascular diseases.

First Danish experience with ex vivo lung perfusion of donor lungs before transplantation.

INTRODUCTION: The number of lung transplantations is limited by a general lack of donor organs. Ex vivo lung perfusion (EVLP) is a novel method to optimise and evaluate marginal donor lungs prior to transplantation. We describe our experiences with EVLP in Denmark during the first year after its introduction. MATERIAL AND METHODS: The study was conducted by prospective registration of donor offers and lung transplantations in Denmark from 1 May 2012 to 30 April 2013. Donor lungs without any contraindications were transplanted in the traditional manner. Taken for EVLP were donor lungs that were otherwise considered transplantable, but failed to meet the usual criteria due to possible contusions or because they were from donors with sepsis or unable to pass the oxygenation test. RESULTS: In the study period, seven of 33 Danish lung transplantations were made possible due to EVLP. One patient died of non-EVLP-related causes, but all other recipients were alive with normal graft function at the end of our registration period. All lungs showed an improved PaO2/FiO2 ratio from a median 23.1 kPa (8.8-38.9) within the donor to 58.8 kPa (34.9-76.5) (FiO2 = 1.0) after EVLP, which corresponds to a 155% improved oxygenation. The median time to extubation, time in intensive care unit and the admission period were 1, 7 and 39 days, respectively. CONCLUSION: In the first year after the introduction of EVLP in Denmark, seven pairs of donor lungs that previously would have been rejected have been transplanted as a result of their improved function. EVLP seems to be a safe way to increase the use of marginal donor lungs. FUNDING: no funding was granted for the present paper. TRIAL REGISTRATION: not relevant.

Intraoperative cardiac ultrasound examination using vector flow imaging.

Conventional ultrasound (US) methods for blood velocity estimation only provide one-dimensional and angle-dependent velocity estimates; thus, the complexity of cardiac flow has been difficult to measure. To circumvent these limitations, the Transverse Oscillation (TO) vector flow method has been proposed. The vector flow method implemented on a commercial scanner provided real-time, angle-independent estimates of cardiac blood flow. Epicardiac and epiaortic, intraoperative US examinations were performed on three patients with stenosed coronary arteries scheduled for bypass surgery. Repeating cyclic beat-to-beat flow patterns were seen in the ascending aorta and pulmonary artery of each patient, but these patterns varied between patients. Early systolic retrograde flow filling the aortic sinuses was seen in the ascending aorta as well as early systolic retrograde flow in the pulmonary artery. In diastole, stable vortices in aortic sinuses of the ascending aorta created central antegrade flow. A stable vortex in the right atrium was seen during the entire heart cycle. The measurements were compared with estimates obtained intraoperatively with conventional spectral Doppler US using a transesophageal and an epiaortic approach. Mean differences in peak systole velocity of 11% and 26% were observed when TO was compared with transesophageal echocardiography and epiaortic US, respectively. In one patient, the cardiac output derived from vector velocities was compared with pulmonary artery catheter thermodilution technique and showed a difference of 16%. Vector flow provides real-time, angle-independent vector velocities of cardiac blood flow. The technique can potentially reveal new information of cardiovascular physiology and give insight into blood flow dynamics.

Percutaneous pulmonary valve replacement after different duration of free pulmonary regurgitation in a porcine model: effects on the right ventricle.

BACKGROUND: Free pulmonary regurgitation (PR) after surgical correction of Tetralogy of Fallot (ToF) with transannular patching can lead to irreversible right ventricular (RV) failure. However, the optimal timing of valve replacement is still debated. METHODS AND RESULTS: Thirty six pigs were included in the study. Twenty one pigs had a bare metal stent placed in the pulmonary annulus inducing free PR and 9 animals served as control. Six animals died prematurely due to procedural complications. The 21 animals were divided into 3 groups with differential duration of PR (1, 2, 3 months, respectively) after which PPVR was performed. After 1 month with competent valve the animals were euthanized. Cardiac magnetic resonance (CMR) and right heart catheterization were performed serially. Free PR led to severe dilation of the RV in all three groups compared to matched controls (p<0.001). Final RV volume after one month with competent pulmonary valve was modeled. Increase in RV volume from baseline to valve replacement (ΔRV) was the only predictor of RV recovery (p<0.001) and increases in ΔRV beyond 120 mL/m2 were predictive of very low probability of recovery. A total of 5 animals did not recover. CONCLUSIONS: Recovery of right ventricular function after free PR by treatment with PPVR was successful in the majority of animals. Increases in RV volume during PR were the only predictor of non-recovery after PPVR and duration of PR did not in itself predict treatment success.

Short- and long-term changes in myocardial function, morphology, edema, and infarct mass after ST-segment elevation myocardial infarction evaluated by serial magnetic resonance imaging.

BACKGROUND: Knowledge of the natural course after an ST-elevation myocardial infarction (STEMI) treated according to guidelines is limited because comprehensive serial magnetic resonance imaging (MRI) of systolic left ventricular function, edema, perfusion, and infarct size after STEMI has not been undertaken. The aim of this study was to evaluate effects of therapy for STEMI on left ventricular function and perfusion and to test the hypothesis that myocardial perfusion by MRI predicts recovery of left ventricular function. METHODS: Cine MRI, edema, first-pass perfusion, and late enhancement imaging were performed in 58 patients at day 2 and at 1 and 6 months after successful primary percutaneous coronary stent intervention for STEMI. RESULTS: Ejection fraction increased 6.3% during the first month (P < .001) and 1.9% from 1 to 6 months (P < .06), indicating a maximal recovery very early after the infarction. The systolic wall thickening in the infarct area almost doubled (P < .001), the perfusion of infarcted myocardium increased approximately 50% (P = .02), and perfusion improved in 72% of patients. Edema decreased with a mean of 2 segments (P < .001) during the first month and another 2.5 segments from 1 to 6 months (P < .001). Infarct size decreased to 1 month (P = .01) and was unchanged from 1 to 6 months (P = .5). Baseline perfusion did not predict improvement in ejection fraction (r = 0.2, P = .2) but did predict regional systolic function (P = .03). CONCLUSIONS: Left ventricular function, perfusion, and infarct mass recovered substantially after STEMI, with the main part of the change within the first month. First-pass perfusion at rest appeared to predict regional ventricular recovery.

Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial.

BACKGROUND: Phase 1 clinical trials of granulocyte-colony stimulating factor (G-CSF) treatment after myocardial infarction have indicated that G-CSF treatment is safe and may improve left ventricular function. This randomized, double-blind, placebo-controlled trial aimed to assess the efficacy of subcutaneous G-CSF injections on left ventricular function in patients with ST-elevation myocardial infarction. METHODS AND RESULTS: Seventy-eight patients (62 men; average age, 56 years) with ST-elevation myocardial infarction were included after successful primary percutaneous coronary stent intervention <12 hours after symptom onset. Patients were randomized to double-blind treatment with G-CSF (10 microg/kg of body weight) or placebo for 6 days. The primary end point was change in systolic wall thickening from baseline to 6 months determined by cardiac magnetic resonance imaging (MRI). An independent core laboratory analyzed all MRI examinations. Systolic wall thickening improved 17% in the infarct area in the G-CSF group and 17% in the placebo group (P=1.0). Comparable results were found in infarct border and noninfarcted myocardium. Left ventricular ejection fraction improved similarly in the 2 groups measured by both MRI (8.5 versus 8.0; P=0.9) and echocardiography (5.7 versus 3.7; P=0.7). The risk of severe clinical adverse events was not increased by G-CSF. In addition, in-stent late lumen loss and target vessel revascularization rate in the follow-up period were similar in the 2 groups. CONCLUSIONS: Bone marrow stem cell mobilization with subcutaneous G-CSF is safe but did not lead to further improvement in ventricular function after acute myocardial infarction compared with the recovery observed in the placebo group.