Fluid Management in Veno-Arterial Extracorporeal Membrane Oxygenation Therapy-Analysis of an Experimental Pig Model.

(1) Background: Fluid resuscitation is a necessary part of therapeutic measures to maintain sufficient hemodynamics in extracorporeal membrane oxygenation (ECMO) circulation. In a post-hoc analysis, we aimed to investigate the impact of increased volume therapy in veno-arterial ECMO circulation on renal function and organ edema in a large animal model. (2) Methods: ECMO therapy was performed in 12 female pigs (Deutsche Landrasse × Pietrain) for 10 h with subsequent euthanasia. Applicable volume, in regard to the necessary maintenance of hemodynamics, was divided into moderate and extensive volume therapy (MVT/EVT) due to the double quantity of calculated physiologic urine output for the planned study period. Respiratory and hemodynamic data were measured continuously. Additionally, renal function and organ edema were assessed by blood and tissue samples. (3) Results: Four pigs received MVT, and eight pigs received EVT. After 10 h of ECMO circulation, no major differences were seen between the groups in regard to hemodynamic and respiratory data. The relative change in creatinine after 10 h of ECMO support was significantly higher in EVT (1.3 ± 0.3 MVT vs. 1.8 ± 0.5 EVT; p = 0.033). No major differences were evident for lung, heart, liver, and kidney samples in regard to organ edema in comparison of EVT and MVT. Bowel tissue showed a higher percentage of edema in EVT compared to MVT (77 ± 2% MVT vs. 80 ± 3% EVT; p = 0.049). (4) Conclusions: The presented data suggest potential deterioration of renal function and intestinal mucosa function by an increase in tissue edema due to volume overload in ECMO therapy.

Concomitant Intra-Aortic Balloon Pumping Significantly Reduces Left Ventricular Pressure during Central Veno-Arterial Extracorporeal Membrane Oxygenation-Results from a Large Animal Model.

(1) Introduction: Simultaneous ECMO and IABP therapy is frequently used. Haemodynamic changes responsible for the success of the concomitant mechanical circulatory support system approach are rarely investigated. In a large-animal model, we analysed haemodynamic parameters before and during ECMO therapy, comparing central and peripheral ECMO circulation with and without simultaneous IABP support. (2) Methods: Thirty-three female pigs were divided into five groups: (1) SHAM, (2) (peripheral)ECMO(-)IABP, (3) (p)ECMO(+)IABP, (4) (central)ECMO(-)IABP, and (5) (c)ECMO(+)IABP. Pigs were cannulated in accordance with the group and supported with ECMO (±IABP) for 10 h. Systemic haemodynamics, cardiac index (CI), and coronary and carotid artery blood flow were determined before, directly after, and at five and ten hours on extracorporeal support. Systemic inflammation (IL-6; IL-10; TNFα; IFNγ), immune response (NETs; cf-DNA), and endothelial injury (ET-1) were also measured. (3) Results: IABP support during antegrade ECMO circulation led to a significant reduction of left ventricular pressure in comparison to retrograde flow in (p)ECMO(-)IABP and (p)ECMO(+)IABP. Blood flow in the left anterior coronary and carotid artery was not affected by extracorporeal circulation. (4) Conclusions: Concomitant central ECMO and IABP therapy leads to significant reduction of intracavitary cardiac pressure, reduces cardiac work, and might therefore contribute to improved recovery in ECMO patients.

Hyperthermia-induced doxorubicin delivery from thermosensitive liposomes via MR-HIFU in a pig model.

PURPOSE: Encapsulation of cytotoxic drugs for a localized release is an effective way to increase the therapeutic window of such agents. In this article we present the localized release of doxorubicin (DOX) from phosphatidyldiglycerol (DPPG2) based thermosensitive liposomes using MR-HIFU mediated hyperthermia in a swine model. MATERIALS AND METHODS: German landrace pigs of weights between 37.5 and 53.5 kg received a 30-min infusion of DOX containing thermosensitive liposomes (50 mg DOX/m2). The pigs' biceps femoris was treated locally in two separate target areas with mild hyperthermia using magnetic resonance guided high intensity focused ultrasound, starting 10 min and 60 min after initiation of the infusion, respectively. The pharmacokinetics and biodistribution of DOX were determined and an analysis of the treatment parameters' influence was performed. RESULTS: Compared to untreated tissue, we found a 15-fold and a 7-fold increase in DOX concentration in the muscle volumes that had undergone hyperthermia starting 10 min and 60 min after the beginning of the infusion, respectively. The pharmacokinetic analysis showed a prolonged circulation time of DOX and a correlation between the AUC of extra-liposomal DOX in the bloodstream and the amount of DOX accumulated in the target tissue. CONCLUSIONS: We have demonstrated a workflow for MR-HIFU hyperthermia drug delivery that can be adapted to a clinical setting, showing that HIFU-hyperthermia is a suitable method for local drug release of DOX using DPPG2 based thermosensitive liposomes in stationary targets. Using the developed pharmacokinetic model, an optimization of the drug quantity deposited in the target via the timing of infusion and hyperthermia should be possible.

Visualization of thermal washout due to spatiotemporally heterogenous perfusion in the application of a model-based control algorithm for MR-HIFU mediated hyperthermia.

PURPOSE: This article will report results from the in-vivo application of a previously published model-predictive control algorithm for MR-HIFU hyperthermia. The purpose of the investigation was to test the controller's in-vivo performance and behavior in the presence of heterogeneous perfusion. MATERIALS AND METHODS: Hyperthermia at 42°C was induced and maintained for up to 30 min in a circular section of a thermometry slice in the biceps femoris of German landrace pigs (n=5) using a commercial MR-HIFU system and a recently developed MPC algorithm. The heating power allocation was correlated with heat sink maps and contrast-enhanced MRI images. The temporal change in perfusion was estimated based on the power required to maintain hyperthermia. RESULTS: The controller performed well throughout the treatments with an absolute average tracking error of 0.27 ± 0.15 °C and an average difference of 1.25 ± 0.22 °C between T10 and T90. The MPC algorithm allocates additional heating power to sub-volumes with elevated heat sink effects, which are colocalized with blood vessels visible on contrast-enhanced MRI. The perfusion appeared to have increased by at least a factor of ∼1.86 on average. CONCLUSIONS: The MPC controller generates temperature distributions with a narrow spectrum of voxel temperatures inside the target ROI despite the presence of spatiotemporally heterogeneous perfusion due to the rapid thermometry feedback available with MR-HIFU and the flexible allocation of heating power. The visualization of spatiotemporally heterogeneous perfusion presents new research opportunities for the investigation of stimulated perfusion in hypoxic tumor regions.

Feasibility study of MR-guided pancreas ablation using high-intensity focused ultrasound in a healthy swine model.

Purpose: Pancreatic cancer is typically diagnosed in a late stage with limited therapeutic options. For those patients, ultrasound-guided high-intensity focused ultrasound (US-HIFU) can improve local control and alleviate pain. However, MRI-guided HIFU (MR-HIFU) has not yet been studied extensively in this context. To facilitate related research and accelerate clinical translation, we report a workflow for the in vivo HIFU ablation of the porcine pancreas under MRI guidance.Materials and methods: The pancreases of five healthy German landrace pigs (35-58 kg) were sonicated using a clinical MR-HIFU system. Acoustic access to the pancreas was supported by a specialized diet and a hydrogel compression device for bowel displacement. Organ motion was suspended using periods of apnea. The size of the resulting thermal lesions was assessed using the thermal threshold- and dose profiles, non-perfused volume, and gross examination. The effect of the compression device on beam path length was assessed using MRI imaging.Results: Eight of ten treatments resulted in clearly visible damage in the target tissue upon gross examination. Five treatments resulted in coagulative necrosis. Good agreement between the four metrics for lesion size and a clear correlation between the delivered energy dose and the resulting lesion size were found. The compression device notably shortened the intra-abdominal beam path.Conclusions: We demonstrated a workflow for HIFU treatment of the porcine pancreas in-vivo under MRI-guidance. This development bears significance for the development of MR-guided HIFU interventions on the pancreas as the pig is the preferred animal model for the translation of pre-clinical research into clinical application.

Delayed activation of PPAR-ß/δ improves long-term survival in mouse sepsis: effects on organ inflammation and coagulation.

Activation of peroxisome proliferator-activated receptor (PPAR)-ß/δ reduces tissue injury in murine endotoxemia. We hypothesized that the PPAR-ß/δ-agonist GW0742 improves long-term outcome after sepsis caused by cecal ligation and puncture (CLP). Fifty-one CD-1 female mice underwent CLP and received either vehicle (control), GW0742 (0.03 mg/kg/injection; five post-CLP i.v. injections), GSK0660 (PPAR-ß/δ-antagonist) or both and were monitored for 28 d. Another 20 CLP mice treated with GW0742 and vehicle were sacrificed 24 h post-CLP to assess coagulopathy. Compared to vehicle, survival of CLP-mice treated with GW0742 was higher by 35% at d 7 and by 50% at d 28. CLP mice treated with GW0742 had 60% higher IFN-γ but circulating monocyte chemoattractant protein-1 and chemokine ligand were lower at 48 h post-CLP. Compared to vehicle, CLP mice treated with GW0742 exhibited a 50% reduction in the circulating plasminogen activator inhibitor-1 associated with an increase in platelet number at 24 h post-CLP (but no changes occurred in anti-thrombin-III, plasminogen, fibrinogen and clotting-times). CLP mice treated with GW0742 exhibited a similar increase in most of the biochemical markers of organ injury/dysfunction (lactate dehydrogenase, alanine aminotransferase, creatine kinase, creatinine, blood urea nitrogen, and triglycerides) measured. Treatment with GW0742 consistently improved long-term survival in septic CD-1 mice by partially modulating the post-CLP systemic cytokine response and coagulation systems.

Mitochondria-Targeted Antioxidants SkQ1 and MitoTEMPO Failed to Exert a Long-Term Beneficial Effect in Murine Polymicrobial Sepsis.

Mitochondrial-derived reactive oxygen species have been deemed an important contributor in sepsis pathogenesis. We investigated whether two mitochondria-targeted antioxidants (mtAOX; SkQ1 and MitoTEMPO) improved long-term outcome, lessened inflammation, and improved organ homeostasis in polymicrobial murine sepsis. 3-month-old female CD-1 mice (n = 90) underwent cecal ligation and puncture (CLP) and received SkQ1 (5 nmol/kg), MitoTEMPO (50 nmol/kg), or vehicle 5 times post-CLP. Separately, 52 SkQ1-treated CLP mice were sacrificed at 24 h and 48 h for additional endpoints. Neither MitoTEMPO nor SkQ1 exerted any protracted survival benefit. Conversely, SkQ1 exacerbated 28-day mortality by 29%. CLP induced release of 10 circulating cytokines, increased urea, ALT, and LDH, and decreased glucose but irrespectively of treatment. Similar occurred for CLP-induced lymphopenia/neutrophilia and the NO blood release. At 48 h post-CLP, dying mice had approximately 100-fold more CFUs in the spleen than survivors, but this was not SkQ1 related. At 48 h, macrophage and granulocyte counts increased in the peritoneal lavage but irrespectively of SkQ1. Similarly, hepatic mitophagy was not altered by SkQ1 at 24 h. The absence of survival benefit of mtAOX may be due to the extended treatment and/or a relatively moderate-risk-of-death CLP cohort. Long-term effect of mtAOX in abdominal sepsis appears different to sepsis/inflammation models arising from other body compartments.