Amniotic fluid-derived mesenchymal stem cells reduce inflammation and improve lung function following transplantation in a porcine model.

BACKGROUND: Lung transplantation is hindered by low donor lung utilization rates. Infectious complications are reasons to decline donor grafts due to fear of post-transplant primary graft dysfunction. Mesenchymal stem cells are a promising therapy currently investigated in treating lung injury. Full-term amniotic fluid-derived lung-specific mesenchymal stem cell treatment may regenerate damaged lungs. These cells have previously demonstrated inflammatory mediation in other respiratory diseases, and we hypothesized that treatment would improve donor lung quality and postoperative outcomes. METHODS: In a transplantation model, donor pigs were stratified to either the treated or the nontreated group. Acute respiratory distress syndrome was induced in donor pigs and harvested lungs were placed on ex vivo lung perfusion (EVLP) before transplantation. Treatment consisted of 3 doses of 2 × 106 cells/kg: one during EVLP and 2 after transplantation. Donors and recipients were assessed on clinically relevant parameters and recipients were followed for 3 days before evaluation for primary graft dysfunction (PGD). RESULTS: Repeated injection of the cell treatment showed reductions in inflammation seen through lowered immune cell counts, reduced histology signs of inflammation, and decreased cytokines in the plasma and bronchoalveolar lavage fluid. Treated recipients showed improved pulmonary function, including increased PaO2/FiO2 ratios and reduced incidence of PGD. CONCLUSIONS: Repeated injection of lung-specific cell treatment during EVLP and post transplant was associated with improved function of previously damaged lungs. Cell treatment may be considered as a potential therapy to increase the number of lungs available for transplantation and the improvement of postoperative outcomes.

Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs.

There is a clinical need for conceptually new treatments that target the excessive activation of inflammatory pathways during systemic infection. Thrombin-derived C-terminal peptides (TCPs) are endogenous anti-infective immunomodulators interfering with CD14-mediated TLR-dependent immune responses. Here we describe the development of a peptide-based compound for systemic use, sHVF18, expressing the evolutionarily conserved innate structural fold of natural TCPs. Using a combination of structure- and in silico-based design, nuclear magnetic resonance spectroscopy, biophysics, mass spectrometry, cellular, and in vivo studies, we here elucidate the structure, CD14 interactions, protease stability, transcriptome profiling, and therapeutic efficacy of sHVF18. The designed peptide displays a conformationally stabilized, protease resistant active innate fold and targets the LPS-binding groove of CD14. In vivo, it shows therapeutic efficacy in experimental models of endotoxin shock in mice and pigs and increases survival in mouse models of systemic polymicrobial infection. The results provide a drug class based on Nature´s own anti-infective principles.

Integrin α10ß1-selected mesenchymal stem cells reduced hypercoagulopathy in a porcine model of acute respiratory distress syndrome.

Mesenchymal stem cells (MSCs) have been studied for their potential benefits in treating acute respiratory distress syndrome (ARDS) and have reported mild effects when trialed within human clinical trials. MSCs have been investigated in preclinical models with efficacy when administered at the time of lung injury. Human integrin α10ß1-selected adipose tissue-derived MSCs (integrin α10ß1-MSCs) have shown immunomodulatory and regenerative effects in various disease models. We hypothesized that integrin α10ß1 selected-MSCs can be used to treat a sepsis-induced ARDS in a porcine model when administering cells after established injury rather than simultaneously. This was hypothesized to reflect a clinical picture of treatment with MSCs in human ARDS. 12 pigs were randomized to the treated or placebo-controlled group prior to the induction of mild to moderate ARDS via lipopolysaccharide administration. The treated group received 5 × 106 cells/kg integrin α10ß1-selected MSCs and both groups were followed for 12 h. ARDS was confirmed with blood gases and retrospectively with histological changes. After intervention, the treated group showed decreased need for inotropic support, fewer signs of histopathological lung injury including less alveolar wall thickening and reduction of the hypercoagulative disease state. The MSC treatment was not associated with adverse events over the monitoring period. This provides new opportunities to investigate integrin α10ß1-selected MSCs as a treatment for a disease which does not yet have any definitive therapeutic options.

New insight: particle flow rate from the airways as an indicator of cardiac failure in the intensive care unit.

AIMS: Exhaled breath particles have been explored for diagnosing different lung diseases. We recently showed in an experimental model that different cardiac output results in different particle flow rate (PFR) from the airways. Given the well-known close relationship between impaired cardiac function and respiratory failure, we hypothesized that PFR in exhaled air can be used to detect cardiac failure. METHODS: PFR was analysed using a customized PExA device. Particles in the range of 0.41-4.55 µm were measured. The included patients (n = 20) underwent cardiac surgery and received mechanical ventilation as a part of routine post-operative care. Ten patients with clinical signs of pronounced post-operative haemodynamic instability and need for inotrope or mechanical support had been selected to the cardiac failure group. The control group consisted of 10 patients without signs of cardiac failure. RESULTS: The patients in cardiac failure group required inotropic support in the form of dobutamine (9/10), epinephrine (2/10), or levosimendan (4/10) or use of an intra-aortic balloon pump (4/10). There was no use of inotropes or mechanical support devices among the controls. All patients in the cardiac failure group had pre-operative left ventricular ejection fraction ≤40% compared with the control group, whose pre-operative ejection fraction was ≥50%, P < 0.001. Patients with cardiac failure had significantly longer median total time in mechanical ventilation compared with the patients in the control group: 53.5 h (IQR 6.8-116101.0 h) and 4.5 h (IQR 4.0-5.5 h), respectively, P < 0.001, and the median length of stay in the ICU, 165 h (IQR 28-192 h) and 22 h (IQR 20-23.5 h), respectively, P = 0.007. Median PFR in patients with cardiac failure was higher than PFR in those with normal cardiac function: 80.9 particles/min (interquartile range (IQR) 25.8-336.6 particles/min), vs. 15.3 particles/min (IQR 8.1-17.7 particles/min), respectively, P < 0.001. Median particle mass was 8.95 ng (IQR 1.68-41.73 ng) in the cardiac failure group and 0.75 ng (IQR 0.18-1.45 ng) in the control group, P = 0.002. CONCLUSIONS: Patients with post-operative cardiac failure following cardiac surgery exhibited an increase in exhaled particle mass and PFR compared with the control group, indicating a significant difference between those two groups. The increase in particle mass and PFR in the absence of respiratory pathologies may indicate cardiac failure. In comparison with controls, impaired cardiac function was also associated with different composition of the particles regarding their size distribution.

Monitoring lung injury with particle flow rate in LPS- and COVID-19-induced ARDS.

In severe acute respiratory distress syndrome (ARDS), extracorporeal membrane oxygenation (ECMO) is a life-prolonging treatment, especially among COVID-19 patients. Evaluation of lung injury progression is challenging with current techniques. Diagnostic imaging or invasive diagnostics are risky given the difficulties of intra-hospital transportation, contraindication of biopsies, and the potential for the spread of infections, such as in COVID-19 patients. We have recently shown that particle flow rate (PFR) from exhaled breath could be a noninvasive, early detection method for ARDS during mechanical ventilation. We hypothesized that PFR could also measure the progress of lung injury during ECMO treatment. Lipopolysaccharide (LPS) was thus used to induce ARDS in pigs under mechanical ventilation. Eight were connected to ECMO, whereas seven animals were not. In addition, six animals received sham treatment with saline. Four human patients with ECMO and ARDS were also monitored. In the pigs, as lung injury ensued, the PFR dramatically increased and a particular spike followed the establishment of ECMO in the LPS-treated animals. PFR remained elevated in all animals with no signs of lung recovery. In the human patients, in the two that recovered, PFR decreased. In the two whose lung function deteriorated while on ECMO, there was increased PFR with no sign of recovery in lung function. The present results indicate that real-time monitoring of PFR may be a new, complementary approach in the clinic for measurement of the extent of lung injury and recovery over time in ECMO patients with ARDS.

Particle flow rate from the airways as fingerprint diagnostics in mechanical ventilation in the intensive care unit: a randomised controlled study.

INTRODUCTION: Mechanical ventilation can be monitored by analysing particles in exhaled air as measured by particle flow rate (PFR). This could be a potential method of detecting ventilator-induced lung injury (VILI) before changes in conventional parameters can be detected. The aim of this study was to investigate PFR during different ventilation modes in patients without lung pathology. METHOD: A prospective study was conducted on patients on mechanical ventilation in the cardiothoracic intensive care unit (ICU). A PExA 2.0 device was connected to the expiratory limb on the ventilator for continuous measurement of PFR in 30 patients randomised to either volume-controlled ventilation (VCV) or pressure-controlled ventilation (PCV) for 30 min including a recruitment manoeuvre. PFR measurements were continued as the patients were transitioned to pressure-regulated volume control (PRVC) and then pressure support ventilation (PSV) until extubation. RESULTS: PRVC resulted in significantly lower PFR, while those on PSV had the highest PFR. The distribution of particles differed significantly between the different ventilation modes. CONCLUSIONS: Measuring PFR is safe after cardiac surgery in the ICU and may constitute a novel method of continuously monitoring the small airways in real time. A low PFR during mechanical ventilation may correlate to a gentle ventilation strategy. PFR increases as the patient transitions from controlled mechanical ventilation to autonomous breathing, which most likely occurs as recruitment by the diaphragm opens up more distal airways. Different ventilation modes resulted in unique particle patterns and could be used as a fingerprint for the different ventilation modes.

Mechanically ventilated patients exhibit decreased particle flow in exhaled breath as compared to normal breathing patients.

INTRODUCTION: In this cohort study, we evaluated whether the particles in exhaled air (PExA) device can be used in conjunction with mechanical ventilation during surgery. The PExA device consists of an optical particle counter and an impactor that collects particles in exhaled air. Our aim was to establish the feasibility of the PExA device in combination with mechanical ventilation (MV) during surgery and if collected particles could be analysed. Patients with and without nonsmall cell lung cancer (NSCLC) undergoing lung surgery were compared to normal breathing (NB) patients with NSCLC. METHODS: A total of 32 patients were included, 17 patients with NSCLC (MV-NSCLC), nine patients without NSCLC (MV-C) and six patients with NSCLC and not intubated (NB). The PEx samples were analysed for the most common phospholipids in surfactant using liquid-chromatography-mass-spectrometry (LCMS). RESULTS: MV-NSCLC and MV-C had significantly lower numbers of particles exhaled per minute (particle flow rate; PFR) compared to NB. MV-NSCLC and MV-C also had a siginificantly lower amount of phospholipids in PEx when compared to NB. MV-NSCLC had a significantly lower amount of surfactant A compared to NB. CONCLUSION: We have established the feasibility of the PExA device. Particles could be collected and analysed. We observed lower PFR from MV compared to NB. High PFR during MV may be due to more frequent opening and closing of the airways, known to be harmful to the lung. Online use of the PExA device might be used to monitor and personalise settings for mechanical ventilation to lower the risk of lung damage.

The use of mannitol in cardiopulmonary bypass prime solution-Prospective randomized double-blind clinical trial.

BACKGROUND: The optimal prime solution for the cardiopulmonary bypass (CPB) circuit in adult cardiac surgery has not yet been defined. Mannitol is widely used in the priming solution for CPB despite the fact that there is no clear consensus on the role of mannitol in cardiac surgery. The aim of this study was to investigate the effect of mannitol in the CPB prime solution. METHODS: This prospective, randomized, double-blind study included 40 patients with normal cardiac and renal functions, who underwent coronary artery bypass grafting. One group received a prime based on Ringer's acetate (n = 20), and the other a prime consisting of Ringer's acetate with 200 mL mannitol (n = 20). Changes in osmolality, acid-base status, electrolytes, and renal-related parameters were monitored. RESULTS: No significant differences were found in osmolality between the Ringer's acetate group and the mannitol group at any time. The mannitol group showed a pronounced decrease in sodium, from 138.7 ± 2.8 mmol/L at anaesthesia onset, to 133.9 ± 2.6 mmol/L after the start of CPB (P < .001). No differences were seen in the renal parameters between the groups, apart from a short-term effect of mannitol on peroperative urine production (P = .003). CONCLUSION: We observed no effects on osmolality of a prime solution containing mannitol compared to Ringer's acetate-based prime in patients with normal cardiac and renal function. The use of mannitol in the prime resulted in a short-term, significant decrease in sodium level.

Right ventricular performance after valve repair for chronic degenerative mitral regurgitation.

BACKGROUND: Our aim was to assess right ventricular (RV) performance after mitral valve repair by use of RV focused echocardiography and to evaluate the influence of elevated pulmonary artery systolic pressure (PASP) on RV recovery. METHODS: Forty consecutive patients undergoing mitral valve repair were prospectively investigated with RV focused echocardiography, including two-dimensional speckle tracking-derived longitudinal strain and measurement of N-terminal protype-B natriuretic peptide levels performed on the day before operation and 6 months postoperatively. RESULTS: The 30-day mortality was 0%. Overall survival was 97.5% ± 2.5% at 6-month follow-up, and the prevalence of postoperative RV dysfunction was 61% (n = 22). Conventional longitudinal indices of RV function decreased significantly after operation (n = 36): tricuspid annular plane systolic excursion (mean 24 ± 5 mm vs mean 15 ± 3 mm, p < 0.001), systolic peak velocity (mean 14 ± 3 cm/s vs mean 10 ± 2 cm/s, p < 0.001), isovolumic acceleration time (mean 2.5 ± 1.0 cm/s(2) vs mean 2.1 ± 0.7 cm/s(2), p = 0.022), but the RV free wall, septal, and global strain did not change significantly. Patients with preoperative PASP above 50 mm Hg showed a significant change in postoperative RV global strain compared with those whose PASP was 50 mm Hg or below (mean difference 10% ± 30% vs -17% ± 23%, p = 0.033). CONCLUSIONS: RV dysfunction was common at 6-month follow-up. Pulmonary hypertension, although reversible after operation, had a negative effect on RV function. Speckle tracking-derived RV strain may assist in the prioritization of surgical referrals to avoid biventricular impairment.

Left atrial reverse remodeling following valve surgery for chronic degenerative mitral regurgitation in patients with preoperative sinus rhythm: effects on long-term outcome.

BACKGROUND AND AIM OF STUDY: Chronic degenerative mitral regurgitation (MR) with left atrial (LA) enlargement is predictive of adverse cardiovascular events including stroke, atrial fibrillation (AF), and impaired survival. Mitral valve surgery (MVS) initiates left atrial reverse remodeling (LARR) characterized by LA volume reduction and improved function. The aim of this study was to evaluate the effects of LARR on clinical outcome in patients with and without LARR following MVS. METHODS: A retrospective study was conducted of 137 consecutive patients in sinus rhythm with degenerative severe MR undergoing isolated MVS. The left atrial volume index (LAVi) was assessed by studying pre- and postoperative echocardiograms; LARR was defined as a reduction in LAVi ≥ 15%. Clinical outcome was evaluated in relation to the absolute and relative reduction in LAVi, and the presence or absence of postoperative LARR. RESULTS: The incidence of postoperative LARR was 74% (n = 101). The overall 90-day survival was 100%. Freedom from complications and cardiac events 10 years after surgery for patients with LARR versus those without was: 92 ± 4% versus 66 ± 13% (p = 0.088) for mortality; 72 ± 1% versus 51 ± 18% (p = 0.131) for new onset of chronic AF; 72 ± 1% versus 81 ± 6% (p = 0.477) for cerebral thromboembolism; and 50 ± 10% versus 49 ± 11% (p = 0.744) for major cardiac adverse events. CONCLUSIONS: Preoperative LA enlargement due to severe degenerative MR in patients with sinus rhythm demonstrates a high potential for postoperative reverse remodeling following MVS. The absence of postoperative LARR was not associated with an increase in the risk of postoperative mortality or adverse clinical events.

Determinants of left atrial reverse remodeling after valve surgery for degenerative mitral regurgitation.

BACKGROUND AND AIM OF THE STUDY: Left atrial (LA) enlargement is a pathophysiological response to volume overload resulting from chronic mitral regurgitation (MR), is known as LA remodeling, and has been shown previously to be associated with cardioembolic events. Following mitral valve surgery (MVS), the left atrium may undergo reverse remodeling characterized by LA volume reduction. The study aim was to evaluate the incidence and determinants of postoperative left atrial reverse remodeling (LARR) following MVS. METHODS: The postoperative left atrial volume index (LAVi) was determined echocardiographically in patients with degenerative chronic MR undergoing isolated MVS (n = 110), using three different algorithms, and compared to the preoperative values. LARR was defined as a reduction in LAVi > or = 15%. RESULTS: The postoperative mean LA diameter (p < 0.001), LA area (p < 0.001), and LAVi (p < 0.001) were each decreased significantly. LARR was observed in 84 patients (76%), with a mean postoperative LAVi reduction of 29 +/- 26%. Younger patients (aged < 60 years) demonstrated a significantly greater degree of LARR (p = 0.022). A high preoperative LAVi was found to be an independent predictor of impaired reverse remodeling (OR 0.98, p = 0.002, 95% CI 0.97-0.99). CONCLUSION: Following MVS, LARR was observed in the majority of patients studied, including those with a high preoperative LAVi, but to a lesser extent. Patients with preoperative LA enlargement should be closely monitored, with a low threshold for surgical admittance, as the potential for postoperative LARR decreases with increasing preoperative LAVi.

Prognostic value of pulmonary hypertension in patients undergoing surgery for degenerative mitral valve disease with leaflet prolapse.

BACKGROUND AND AIM OF THE STUDY: The aim of this study was to evaluate the impact of pulmonary hypertension (PH) on early and late outcomes following surgery in patients with degenerative mitral regurgitation. METHODS: The study included 270 patients who had undergone isolated mitral valve surgery (MVS) for leaflet prolapse during 1998 to 2010. Pulmonary artery systolic pressure (PASP) was measured with Doppler echocardiography pre- and postoperatively. The impact of PH (PASP > 50 mmHg) on mortality and the potential for postoperative resolution of preoperatively elevated PASP was retrospectively analyzed. RESULTS: The incidence of PH was 27% (n = 74/270). Postoperative normalization, or reduction of preoperative PASP, was demonstrated in 87% of the patients with PH at a median of two months (interquartile range 1 to 19). Absent improvement or a postoperative increase in PASP was independently predicted by age (OR 1.08, 95% CI 1.02-1.14, p = 0.010). Preoperative PH resulted in a fourfold higher risk of postoperative mortality (HR 4.3, 95% CI 1.1-17.4, p = 0.039) during the first three years of follow-up. CONCLUSIONS: PH is an independent predictor of mortality during the initial three years following MVS. The majority of patients with PH demonstrated a reduction of preoperatively elevated PASP following surgery and the increased risk of mortality gradually decreased after three years. Our findings support early admission for mitral valve surgery before the occurrence of PH.