OBJECTIVES: Cerebrospinal fluid (CSF) drainage is routinely utilized to mitigate perioperative and postoperative spinal cord ischaemia in open and endovascular thoraco-abdominal aortic aneurysm repair to prevent permanent paraplegia. Clinical decision-making in the vulnerable perioperative period, however, is still based on limited clinical and experimental data. Our aim was to investigate the isolated effect of CSF pressure elevation on spinal cord perfusion in an established large animal model. METHODS: Ten juvenile pigs with normal (native) arterial inflow (patent segmental arteries and collaterals) underwent iatrogenic CSF pressure elevation (×2, ×3, ×4 from their individual baseline pressure). Each pressure level was maintained for 30 min to mimic clinical response time. After the quadrupling of CSF pressure, the dural sac was slowly depressurized against gravity allowing CSF pressure to passively return to baseline values. Measurements were taken 30 and 60 min after normalization, and microspheres for regional blood flow analysis were injected at each time point. RESULTS: Spinal cord perfusion decreased significantly at all mid-thoracic to lumbar cord segments at the doubling of CSF pressure and declined to values <53% compared to baseline when pressure was quadrupled. Normalizing CSF pressure led to an intense hyperperfusion of up to 186% at the cervical level and 151% within the lumbar region. CONCLUSIONS: CSF pressure elevation results in a relevant impairment of spinal cord blood supply. Close perioperative and postoperative monitoring of CSF pressure is crucial for maintaining sufficient spinal cord perfusion. Radical and rapid withdrawal of CSF is followed by significant hyperperfusion in all spinal cord segments and may lead to ‘drainage-related’ iatrogenic reperfusion injury—aggravating the risk of delayed spinal cord injury—and should therefore be avoided.

Cardioplegic solutions play a major role in cardiac surgery due to the fact that they create a silent operating field and protect the myocardium against ischemia and reperfusion injury. For studies on cardioplegic solutions, it is important to compare their effects and to have a valid platform for preclinical testing of new cardioplegic solutions and their additives. Due to the strong anatomical and physiological cardiovascular similarities between pigs and humans, porcine models are suitable for investigating the effects of cardioplegic solutions. This review provides an overview of the results of the application of cardioplegic solutions in adult or pediatric pig models over the past 25 years. The advantages, disadvantages, limitations, and refinement strategies of these models are discussed.

: OBJECTIVES: Distal aortic perfusion (DaP) is a widely accepted protective adjunct facilitating early reinstitution of visceral perfusion during extended thoracic and thoraco-abdominal aortic repair. DaP has also been suggested to secure distal inflow to the paraspinal collateral network via the hypogastric arteries and thereby reduce the risk of spinal cord ischaemia. However, an increase in cerebrospinal fluid (CSF) pressure is frequently observed during thoracoabdominal aortic aneurysm repair. The aim of this study was to evaluate the effects of DaP on regional spinal cord blood flow (SCBF) during descending aortic cross-clamping and iatrogenic elevation of cerebrospinal fluid pressure.METHODS: Eight juvenile pigs underwent central cannulation for cardiopulmonary bypass according to our established experimental protocol followed by aortic cross-clamping of the descending thoracic and abdominal aorta—mimicking sequential aortic clamping—with the initiation of DaP. Thereafter, CSF pressure elevation was induced by the infusion of blood plasma until baseline CSF pressure was tripled. At each time-point, microspheres of different colours were injected allowing for regional SCBF analysis.RESULTS: DaP led to a pronounced hyperperfusion of the distal spinal cord [SCBF up to 480%, standard deviation (SD): 313%, compared to baseline]. However, DaP provided no or only limited additional flow to the upper and middle segments of the spinal cord (C1–Th7: 5% of baseline, SD: 5%; Th8–L2: 24%, SD: 39%), which was compensated by proximal flow only at C1–Th7 level. Furthermore, DaP could not counteract an experimental CSF pressure elevation, which led to a further decrease in regional SCBF most pronounced in the mid-thoracic spinal cord segment.CONCLUSIONS: Protective DaP during thoraco-abdominal aortic repair may be associated with inadequate spinal protection particularly at the mid-thoracic spinal cord level (‘watershed area’) and result in the adverse effect of a potentially dangerous hyperperfusion of the distal spinal cord segments.

Compared to other forms of drug administration, the use of Transdermal Drug Delivery Systems (TDDSs) offers significant advantages, including uniform drug release profiles that contribute to lower side effects and higher tolerability, avoidance of direct exposure to the gastrointestinal tract, better patient compliance due to their non-invasive means of application and others. Mesoporous silica membranes are of particular interest in this regard, due to their chemical stability and their tunable porous system, with adjustable pore sizes, pore volumes and surface chemistries. While this allows for fine-tuning and, thus, the development of optimized TDDSs with high loading capacities and the desired release profile of a given drug, its systemic availability also relies on skin penetration. In this paper, using a TDDS based on mesoporous silica membranes in Franz cell experiments on porcine skin, we demonstrate surprisingly substantial drug loss during skin penetration. Drug passage through porcine skin was found to be dependent on the age and pre-treatment of the skin. pH and temperature were major determinants of drug recovery rates as well, indicating drug loss in the skin by enzymatic metabolization. Regarding the TDDS, higher loading obtained by SO₃H surface modification of the mesoporous silica membranes reduced drug loss. Still, high loss rates in the skin were determined for different drugs, including anastrozole, xylazine and imiquimod. We conclude that, beyond the fine-tuned drug release profiles from the mesoporous silica membrane TDDS, remarkably high drug loss in the skin is a major issue for achieving desired skin penetration and, thus, the systemic availability of drugs. This also poses critical requirements for defining an optimal TDDS based on mesoporous silica membranes.

Minimally invasive staged segmental artery (SA) coil- and plug embolization is a new method for paraplegia prevention associated with extensive aortic procedures. Near-infrared spectroscopy of the paraspinal collateral network (cnNIRS) has emerged as a non-invasive method for spinal cord monitoring. The aim of this study was to evaluate cnNIRS to guide minimally invasive SA occlusion. In a chronic large animal experiment, 18 juvenile pigs underwent two-stage minimally invasive staged SA coil- and plug embolization for complete SA occlusion. Coil-embolization was performed either by SA main stem occlusion (characteristic of pig anatomy) or separately for the left- and right SA. Lumbar cnNIRS was recorded during and after the procedure. Neurological status was assessed up to 3 days after complete SA occlusion. Mean time from SA coil embolization to minimum cnNIRS values was 11 ± 5 min with an average decrease from 101 ± 2% to 78 ± 8% of baseline (difference: −23 ± 9, P < 0.001). Lumbar cnNIRS demonstrated significant differences between left and right when SAs were occluded separately in all cases (−7 ± 4%, 1 min after first SA occlusion; P = 0.001). Permanent paraplegia occurred in 2 (11%) and any kind of neurological deficit—temporary or permanent—in 7 animals (39%). Association between lumbar cnNIRS and neurological outcome after minimally invasive staged SA coil- and plug embolization suggests positive correlation (R = 0.5, P = 0.052). Lumbar cnNIRS independently reacts to unilateral SA occlusion. cnNIRS-guided SA occlusion is feasible and may become a useful adjunct facilitating adequate and complete vessel occlusion.

A restoration of low homoarginine (hArg) levels in obese ZSF1 rats (O-ZSF1) before (S1-ZSF1) and after (S2-ZSF1) the manifestation of heart failure with preserved ejection fraction (HFpEF) did not affect the worsening of cardiac HFpEF characteristics. Here, potential regulation of key enzymes of arginine metabolism in other organs was analyzed. Arginase 2 (ARG2) was reduced >35% in the kidney and small intestine of hArg-supplemented rats compared to O-ZSF1. Glycine amidinotransferase (GATM) was 29% upregulated in the kidneys of S1-ZSF1. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) levels were reduced >50% in the livers of O-ZSF1 but restored in S2-ZSF1 compared to healthy rats (L-ZSF1). In the skeletal muscle, iNOS was lower in O-ZSF1 and further decreased in S1-ZSF1 and S2-ZSF1 compared to L-ZSF1. iNOS levels were lower in the liver of the S2-ZSF1 group but higher in the kidneys of S1-ZSF1 compared to L-ZSF1. Supplementation with hArg in an in vivo HFpEF model resulted in the inhibition of renal ARG2 and an increase in GATM expression. This supplementation might contribute to the stabilization of intestinal iNOS and ARG2 imbalances, thereby enhancing barrier function. Additionally, it may offer protective effects in skeletal muscle by downregulating iNOS. In the conceptualization of hArg supplementation studies, the current disease progression stage as well as organ-specific enzyme regulation should be considered.