The Advantage of FLASH Radiotherapy Confirmed in Mini-pig and Cat-cancer Patients.

PURPOSE: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. EXPERIMENTAL DESIGN: Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called "FLASH-RT" and irradiation delivered at a conventional dose rate called "Conv-RT." A clinical, phase I, single-dose escalation trial (25-41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT. RESULTS: Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%. CONCLUSIONS: Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients.See related commentary by Harrington, p. 3.

Extraluminal biodegradable splint to treat upper airway anterior malacia: A preclinical proof of principle.

OBJECTIVE: Upper airway malacia highly complicates the treatment of benign laryngotracheal stenosis, and no ideal option is available to date. We here explore the use of extraluminal biodegradable splints in an animal model of long-segment anterior tracheomalacia (TM). We show the efficacy, as well as the tissue tolerance, of a custom-made biodegradable extraluminal device surgically inserted around the trachea. STUDY DESIGN: Preclinical animal study. METHODS: Anterior TM was induced in rabbits through an anterior neck approach by removing eight consecutive anterior tracheal rings without damaging the underlying mucosa. Malacia was corrected during the same surgery by pexy sutures, suspending the tracheal mucosa to an experimental biodegradable device. Symptoms, survival, and tissue reaction were compared to healthy and sham surgery controls. RESULTS: The model induced death by respiratory failure within minutes. Ten animals received the experimental treatment, and those who survived the perioperative period remained asymptomatic with a maximum follow-up of 221 days. Histological studies at programmed euthanasia showed complete degradation of the prosthesis, with significant remnant fibrosis around the trachea. However, the tracheal stiffness of test segments was comparatively less than that of control segments. CONCLUSION: Extraluminal biodegradable splints rescued animals with a condition otherwise incompatible with life. It was well tolerated, leaving peritracheal fibrosis that was not as stiff as normal trachea. The external tracheal stiffening was sufficient for the test animals to live through the phase of severe acute hypercollapsibility. This represents a valid option to help pediatric patients with laryngotracheal stenosis and associated cartilaginous airway malacia. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E53-E58, 2018.

Impact of synthetic elements on aortic root haemodynamics: computed fluid dynamics of aortic root reconstruction and valve reimplantation.

Objectives: The aim was to evaluate the impact of the aortic valve reimplantation (David) and of the aortic root (AoR) remodelling (Yacoub) on the AoR haemodynamics. Methods: In an experimental setup where the clinical scenario of Yacoub, ( n = 5, domestic pig) and of David ( n = 5, domestic pig) procedure was performed in each AoR, six high-fidelity (200 Hz) sonomicrometric crystals were implanted. Crystals were positioned at three commissures with their projection at the root base. In post-measurement processing 3D deformation of both AoR was determined and used for computed fluid dynamic modelling in order to evaluate pressure, velocity and shear stress profiles. Results: In David AoR: high pressure (> 150 mmHg) and low to moderate shear stress (0-30 Pa) were found from the period of isovolemic contraction to the closure of the aortic valve. At mid diastole pressure augmentation (> 120 mmHg) a low shear stress (0-10 Pa) was registered at the leaflets, three commissures, and intervalvular triangles. In Yacoub AoR: high pressure (110-130 mmHg) with moderate low shear stress (0-30 Pa) was only registered at isovolemic contraction. Conclusions: The results show that haemodynamic conditions following a David procedure have a less favourable pattern as compared to a Yacoub AoR. In David AoR, high pressure and low shear stress are present during 2/3 of the cardiac cycle, whereas in Yacoub root, these conditions are present only for a short period of isovolemic contraction.

A Model of Anterograde Oxygenated Lung Blood Flow in Acardia.

In extreme situations such as hyperacute rejection of heart transplant or major heart trauma, heart explantation and extracorporeal membrane oxygenation (ECMO) hemodynamic support might be the only means for survival. In our previous model of acardia, pulmonary artery (PA) was clamped and did not receive any anterograde blood flow. A model of anterograde PA perfusion might be necessary to avoid ischemic pulmonary damage in prolonged ECMO in acardia. The aim of this study was to describe the surgical technique and to determine the feasibility of an anterograde lung perfusion in acardia through the anastomosis of the right internal mammary artery (RIMA) to the PA. A venoarterial cardiopulmonary bypass was established in three pigs (72 ± 2.6 kg) by the transjugular insertion to the caval axis of a double-staged cannula with carotid artery return. Heart was excised and ECMO was established as previously reported. Right internal mammary artery was harvested and after measurement of its output (93.3 ± 5.8 ml/min, representing 2.17% ± 0.15% of total pump flow), it was anastomosed to PA. Right internal mammary artery anastomosis to PA is a feasible, safe, and easy to perform maneuver assuring an anterograde lung perfusion in acardia.

Aortic root haemodynamics following David procedure: numerical analysis of 3-dimensional haemodynamics.

OBJECTIVES: The aim was to determine 3-dimensional (3D) geometrical deformation of the aortic root (AoR) following the David procedure in order to evaluate local haemodynamical conditions of individual AoR elements. METHODS: In the experimental set-up, the David procedure was performed on 10 domestic pigs. Data were compared with the measurements obtained in 10 native AoRs. In each AoR, six high-resolution ultrasonometric crystals (200 Hz) were implanted, being positioned at each commissure and at the AoR base. 3D geometrical deformation of the AoR, torsion and tilt angle was determined. Computed fluid dynamics (CFD) simulation analysis was used to evaluate local pressure, flow and shear stress. RESULTS: In David AoRs, the tilt angle was maximal at a peak ejection of 25.9 ± 1.49° and minimal at the end of isovolemic contraction at 23.5 ± 0.80°. David root rotation was maximal at a peak ejection of 27.93 ± 1.54° and minimal at the end of the isovolemic contraction at 25.7 ± 1.32°. In the native AoR, the opposite was observed. Here, the tilt and rotation angle were maximal at the end of isovolemic contraction (17.25 ± 0.68° and 19.71 ± 0.73°) and decreased to its minimal values at peak ejections (14.1 ± 0.62° and 16.33 ± 0.47°). In David AoR, high pressure (>140 mmHg) combined with low-to-moderate shear stress (0-40 Pa) was found at the leaflet body from the beginning of isovolemic contraction till the opening of the aortic valve. Similar high pressure (>140 mmHg) and shear stress (0-40 Pa) were found in the period from aortic valve closure till the beginning of the isovolemic contraction. In native AoRs, high pressure (>95 mmHg) was conjoined with low-to-moderate shear stress (0-30 Pa) at the leaflets and was registered at the end of isovolemic contraction. CONCLUSIONS: The David AoR is haemodynamically less favourable when compared with the native AoR. During almost two-thirds of the time period of the cardiac cycle, AoR elements are exposed to high pressure and low shear stress. In contrast, in native AoRs, similar conditions were present only during the short period of isovolemic contraction.

Computational fluid dynamics of the right ventricular outflow tract and of the pulmonary artery: a bench model of flow dynamics.

OBJECTIVES: The reconstruction of the right ventricular outflow tract (RVOT) with valved conduits remains a challenge. The reoperation rate at 5 years can be as high as 25% and depends on age, type of conduit, conduit diameter and principal heart malformation. The aim of this study is to provide a bench model with computer fluid dynamics to analyse the haemodynamics of the RVOT, pulmonary artery, its bifurcation, and left and right pulmonary arteries that in the future may serve as a tool for analysis and prediction of outcome following RVOT reconstruction. METHODS: Pressure, flow and diameter at the RVOT, pulmonary artery, bifurcation of the pulmonary artery, and left and right pulmonary arteries were measured in five normal pigs with a mean weight of 24.6 ± 0.89 kg. Data obtained were used for a 3D computer fluid-dynamics simulation of flow conditions, focusing on the pressure, flow and shear stress profile of the pulmonary trunk to the level of the left and right pulmonary arteries. RESULTS: Three inlet steady flow profiles were obtained at 0.2, 0.29 and 0.36 m/s that correspond to the flow rates of 1.5, 2.0 and 2.5 l/min flow at the RVOT. The flow velocity profile was constant at the RVOT down to the bifurcation and decreased at the left and right pulmonary arteries. In all three inlet velocity profiles, low sheer stress and low-velocity areas were detected along the left wall of the pulmonary artery, at the pulmonary artery bifurcation and at the ostia of both pulmonary arteries. CONCLUSIONS: This computed fluid real-time model provides us with a realistic picture of fluid dynamics in the pulmonary tract area. Deep shear stress areas correspond to a turbulent flow profile that is a predictive factor for the development of vessel wall arteriosclerosis. We believe that this bench model may be a useful tool for further evaluation of RVOT pathology following surgical reconstructions.

New prototype of femoral arterial SmartCannula with anterograde and retrograde flow.

OBJECTIVES: Femoral artery cannulation is routinely used in circulatory support scenarios for cardiorespiratory support in patients with acute cardiac and/or pulmonary decompensation. During prolonged perfusion, this may cause acute ischemia of the leg and, in the worst case, even amputation. The aim of this experimental study was to test a newly designed arterial cannula allowing proximal and distal blood flow. METHODS: Veno-arterial cardiopulmonary bypass was established in three calves (67.6 ± 5.1 kg). The venous line was secured by cannulation of the external jugular vein. The arterial line of each animal was secured by cannulation of iliac arteries on both legs. On one side, we used a modified SmartCannula (SmartCannula 18Fr 130 mm) and, on the other side, a standard rectilinear BioMedicus cannula system was used, 19 Fr for retrograde and an 8 Fr BioMedicus shunt for anterograde flow toward the leg. An ultrasonic flow probe was used to quantify the perfusion of the distal leg. RESULTS: At 0.5, 1.0, 1.5, and 2.0 l/min, the anterograde leg blood flow increased steadily for each cannula, but remained higher in the self-expanding cannula. That is, the 8 F rectilinear cannula achieved a blood flow of 0.02 ± 0.01, 0.1 ± 0.04, 0.22 ± 0.09, and 0.21 ± 0.02 l/min, respectively, and the 18 F self-expanding cannula achieved 0.06 ± 0.02, 0.15 ± 0.03, 0.24 ± 0.07 and 0.36 ± 0.04 l/min. CONCLUSION: The modified self-expanding cannula exhibited superior distal arterial flow compared to the routinely used rectilinear shunt system. This has a potential to reduce ischemic events of the inferior extremity in prolonged perfusion.

Seal properties of TachoSil: in vitro hemodynamic measurements.

Fibrin glue products and collagen patches are frequently used as a sealing product, preventing surgical side bleedings. This is especially true in the field of cardiovascular surgery, where increasing numbers of patients are being operated with antiplatelet and anticoagulation therapy. The aim of this report was, in an in vitro hemodynamic setting, to examine the sealant properties of the TachoSil (Nycomed Pharma, Linz, Austria) patch. Burst pressure and normal force of 15 TachoSil sealed defects were measured. This was determined in a closed hydraulic system. Mean burst pressure load for a 5-mm defect was 69+/-11.4 mmHg; for a 7-mm defect was 63+/-16 mmHg; and, 62+/-16 mmHg for the defect with a diameter of 10 mm (P>0.05). The mean calculated normal force was as follows: 0.91+/-0.15 N for the 5 mm defect, 6.5+/-1.6 N for the 7 mm, and 8.1+/-0.75 N for the 10 mm defect. The TachoSil patch has the capability to seal small defects. However, at the larger defects the seal character was significantly reduced. These results suggest that the device may be a good alternative for hemostasis for small defects. The capacity to curtail or stop hemorrhage at the larger defects is unlikely.

Self-expanding mini-cannula for remote perfusion with pediatric scenarios.

The aim of this report is to address the benefits of the minimal invasive venous drainage in a pediatric cardio surgical scenario. Juvenile bovine experiments (67.4+/-11 kg) were performed. The right atrium was cannulated in a trans-jugular way by using the self-expandable (Smart Stat, 12/20F, 430 mm) venous cannula (Smartcannula LLC, Lausanne, Switzerland) vs. a 14F 250 mm (Polystan Lighthouse) standard pediatric venous cannula. Establishing the cardiopulmonary bypass (CPB), the blood flows were assessed for 20 mmHg, 30 mmHg and 40 mmHg of driving pressure. Venous drainage (flow in l/min) at 20 mmHg, 30 mmHg, and 40 mmHg drainage load was 0.26+/-0.1, 0.35+/-0.2 and 0.28+/-0.08 for the 14F standard vs. 1.31+/-0.22, 1.35+/-0.24 and 1.9+/-0.2 for the Smart Stat 12/20F cannula. The 43 cm self-expanding 12/20F Smartcannula outperforms the 14F standard cannula. The results described herein allow us to conclude that usage of the self-expanding Smartcannula also in the pediatric patients improves the flow and the drainage capacity, avoiding the insufficient and excessive drainage. We believe that similar results may be expected in the clinical settings.

Impact of the C2/C6 ratio of high-molecular-weight hydroxyethyl starch on pharmacokinetics and blood coagulation in pigs.

BACKGROUND: High-molecular-weight, low-substituted hydroxyethyl starch (HES) may not affect blood coagulation more than low-molecular-weight, low-substituted HES. The authors assessed in vivo the effect of a lowered C2/C6 ratio on pharmacokinetic characteristics and the impact on blood coagulation of high-molecular-weight, low-substituted HES. METHODS: A prospective, randomized, parallel study in 30 pigs compared HES 650/0.42/2.8 with HES 650/0.42/5.6. Before, during, and after infusion of 30 ml/kg body weight HES, blood samples were collected over 630 min to measure HES concentrations and plasmatic coagulation and to assess blood coagulation in whole blood by Thrombelastography (TEG; Haemoscope Corporation, Niles, IL). Pharmacokinetic parameters were estimated using a two-compartment model. RESULTS: The elimination constant was 0.009 +/- 0.001 min(-1) for HES 650/0.42/2.8 and 0.007 +/- 0.001 min(-1) for HES 650/0.42/5.6 (P < 0.001); the area under the plasma concentration-time curve was 1,374 +/- 340 min x g/l for HES 650/0.42/2.8 and 1,697 +/- 411 min x g/l for HES 650/0.42/5.6 (P = 0.026). The measured plasma HES concentrations were not different between HES 650/0.42/2.8 and HES 650/0.42/5.6. Both HES solutions equally affected blood coagulation: Thrombelastographic coagulation index decreased similarly at the end of infusion of HES 650/0.42/2.8 and at the end of infusion of HES 650/0.42/5.6 (P = 0.293). Also, activated partial thromboplastin and prothrombin times increased similarly for HES 650/0.42/2.8 and HES 650/0.42/5.6 (P = 0.831). CONCLUSION: Reducing the C2/C6 ratio in high-molecular, low-substituted HES solutions results in a slightly faster HES elimination. However, the blood coagulation compromising effect was unaffected.

(Poly)acrylonitrile-based hydrogel as a therapeutic bulking agent in urology.

Vesicoureteral reflux and urinary incontinence can be treated by endoscopic injection. Injectables such as collagen and hyaluronic acid-dextranomer are commonly used, however are not offering optimal therapeutic effect yet. In the present study a novel application for poly(acrylonitrile)-based hydrogel (Hypan), already tested in other clinical indications, has been investigated for its aptitude as an injectable bulking agent. This non-degradable, extremely hydrophilic hydrogel has the capacity of a 6-fold swelling once implanted into the body, assuring the bulking effect. Deposits of this bulking agent have been implanted into the submucosal space of the bladder of 6 minipigs and the histological reaction, as well as the physical implant behavior have been studied over a time period of 6 months. The implants have developed the desired bulking effect by the above-described hydrophilic swelling. They have been enclosed into a fine fibrous tissue capsule and provoked a very limited inflammatory reaction. This study has showed that poly(acrylonitrile)-based hydrogel implants injected into the bladder are well tolerated and, due to their defined bulking ability, feasible for the treatment of vesico-ureteral reflux and urinary incontinence. To determine the therapeutic efficiency of this treatment the implants will be studied in a vesicoureteral reflux and urinary incontinence animal model.

Effect of high- and low-molecular-weight low-substituted hydroxyethyl starch on blood coagulation during acute normovolemic hemodilution in pigs.

BACKGROUND: Hydroxyethyl starches (HES) with lower impact on blood coagulation but longer intravascular persistence are of clinical interest. The current study aimed to investigate in vivo the isolated effect of molecular weight on blood coagulation during progressive acute normovolemic hemodilution. METHODS: Twenty-four pigs were normovolemically hemodiluted up to a total exchange of 50 ml . kg . body weight of HES 650/0.42 or HES 130/0.42. Serial blood sampling was performed to measure HES plasma concentration and to assess blood coagulation. Concentration-effect relations were analyzed by linear regression, followed by the Student t test on regression parameters. RESULTS: Blood coagulation was increasingly compromised toward hypocoagulability by acute normovolemic hemodilution with both treatments (P < 0.01). Significantly greater impact on activated partial thromboplastin time (P = 0.04) and significantly stronger decrease of maximal amplitude (P = 0.04), angle alpha (P = 0.02), and coagulation index (P = 0.02) was seen after acute normovolemic hemodilution with HES 650/0.42 as compared with HES 130/0.42. Except for factor VIII (P = 0.04), no significant differences between both treatments were observed when relating antihemostatic effects to HES plasma concentrations (P > 0.05). A significantly lesser decrease of hemoglobin concentration has been found with HES 650/0.42 as compared with HES 130/0.42 (P < 0.01) in relation to HES plasma concentrations. CONCLUSION: High-molecular-weight HES (650/0.42) shows a moderately greater antihemostatic effect than low-molecular-weight HES (130/0.42) during acute normovolemic hemodilution. However, similar effects on hemostasis were observed with both treatments when observed antihemostatic effects were related to measured HES plasma concentrations. In addition, HES 650/0.42 may have a lower efficacy in immediately restoring plasma volume.