Lower extremity extracorporeal distal revascularization (LEEDR) as a novel approach to limb salvage following prolonged ischemia

Abstract

Acute limb ischemia necessitates prompt revascularization to preserve viability and minimize systemic ischemia–reperfusion injury. Delays in care increase morbidity and mortality, underscoring the need for nonsurgical temporizing methods. Lower Extremity Extracorporeal Distal Revascularization (LEEDR) is a percutaneous technique that delivers oxygenated blood from the contralateral femoral artery to the ischemic limb via a retrograde tibial cannula. This study aimed to evaluate LEEDR compared to prolonged untreated warm ischemia. Anesthetized Yorkshire swine (40–60 kg) underwent hindlimb ischemia via endovascular balloon occlusion of the left external iliac and middle sacral arteries and were randomized to control (n = 6; 9 h ischemia) or LEEDR (n = 6; 1-h ischemia plus 8 h extracorporeal support). Revascularization was achieved by balloon deflation, followed by 48 h of observation. The primary outcome was survival; secondary outcomes included gait function, compartment pressure, and biochemical markers of ischemia–reperfusion injury. Survival was significantly higher in the LEEDR group (83% vs. 0%; p = .001). LEEDR animals demonstrated improved gait function (5.8 ± 0.34 vs. 2.5 ± 0.7; p < .001), lower compartment pressures (9.9 ± 1.7 vs. 28.5 ± 4.2 mm Hg; p < .001), and reduced serum potassium (4.57 ± 0.22 vs. 5.14 ± 0.54 mmol/L; p < .001) and lactate concentrations (1.4 ± 0.55 vs. 2.5 ± 1.6 mmol/L; p < .001) during reperfusion and recovery. LEEDR effectively mitigated the consequences of 9 h of warm ischemia in a swine model, improving survival, preserving limb function, and preventing compartment syndrome. This percutaneous technique may serve as a viable temporizing strategy in patients with delayed access to definitive revascularization.

Introduction

Acute limb ischemia (ALI) refers to a sudden reduction or cessation of arterial blood flow to an extremity, constituting a surgical emergency. Etiologies include traumatic, embolic, and thrombotic events. Without prompt intervention, ALI may result in irreversible tissue injury, loss of function, or amputation^1–4. Timely revascularization is therefore critical to optimize limb salvage.

Conventional doctrine suggests that an extremity viability begins to decline significantly after approximately 6 h of ischemia⁵; however, more recent data challenge this assumption. A contemporary military analysis demonstrated a 10% decrease in limb salvage for each hour of delay to revascularization⁶. In practice, timely intervention may be impeded by geography, inter-hospital transfer, or systemic health care limitations. For patients facing delays, there is a need for temporizing strategies that could potentially be delivered by trained providers in prehospital or resource-limited settings. Early reperfusion may reduce warm ischemic time, mitigate ischemia–reperfusion (I/R) injury, and improve salvage rates⁷.

Lower Extremity Extracorporeal Distal Revascularization (LEEDR) is a percutaneous technique that diverts oxygenated blood from the contralateral femoral artery and delivers it retrogradely via a tibial artery cannula. This enables temporary perfusion distal to a proximal arterial occlusion, such as a common femoral artery embolus.

LEEDR has been validated in a porcine model of 6-h hindlimb ischemia^8,9; however, because swine exhibit greater tolerance to warm ischemia than humans, the prior 6 h occlusion study failed to produce clinically meaningful injury endpoints. Therefore, we extended the ischemia duration to 9 h to better model irreversible ischemic insult and evaluate LEEDR’s efficacy under conditions simulating delayed care. The objective of this animal study was to evaluate LEEDR in a swine model of extended hindlimb ischemia using survival and functional performance as primary outcomes.

Methods

Study overview

All animal procedures were approved by the Mayo Clinic Institutional Animal Care and Use Committee and conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 8023, revised 1978), complied with the ARRIVE guidelines, and adhered to the U.S. Animal Welfare Act and associated regulations. The study used female Yorkshire swine (40–60 kg) to facilitate urinary drainage during prolonged anesthesia. Animals were randomized into 2 experimental groups: control (9 h of uninterrupted warm ischemia) and LEEDR (1 h of ischemia followed by 8 h of extracorporeal reperfusion). The protocol consisted of 4 sequential phases: instrumentation, ischemia, reperfusion, and recovery (Fig. 1).

Fig. 1.

Schematic overview of the experimental protocol, including instrumentation, ischaemia, extracorporeal support (LEEDR), revascularisation, and recovery phases.

Animal preparation

Animals were sedated, intubated, and maintained under general anesthesia with intravenous propofol. They were mechanically ventilated with standard settings to maintain normocapnia.

Vascular access was achieved under ultrasound guidance via bilateral carotid arteries, right external jugular vein, right femoral artery, and left posterior tibial artery using 5–7 Fr sheaths. The right femoral artery served as donor for the LEEDR circuit. Fluid boluses, medications, and maintenance infusions were administered via ear veins and the external jugular vein.

An angiogram was performed of the left lower extremity to ensure proper placement and patency of the posterior tibial (PT) artery sheath. Under fluoroscopic guidance, the left carotid artery was upsized to a 12 Fr DrySeal Flex Introducer sheath (Gore, Flagstaff, AZ) over a 260 cm, 0.035-inch Glidewire Advantage (Terumo, Tokyo, Japan). At this time, 10,000 units of unfractionated heparin were administered. Activated clotting time (ACT) was measured every 30 min, and additional heparin was administered as needed to maintain an ACT of 250–350 s.

A 5 Fr pigtail catheter (AngioDynamics, Latham, NY) was inserted into the 12 Fr DrySeal sheath to the infrarenal aorta, and angiography was performed with a power injector to appreciate the anatomy of the terminal aortic trifurcation. A baseline CT angiogram was then obtained to confirm catheter placement, evaluate perfusion symmetry, and identify any preexisting vascular abnormalities that could influence the study using a 16-slice OmniTom (Neurologica Corp, Danvers, MA) with an arterial contrast injection delivered via the aortic pigtail at 2 mL/s for 40 s. Follow-up imaging was used to detect post-reperfusion thrombotic or hemorrhagic complications and assess changes over time.”

Ischemia

To achieve hindlimb ischemia, two 260-cm, 0.035-inch Glidewire Advantage wires were inserted through the DrySeal sheath and advanced into the left external iliac artery (EIA) and middle sacral artery (MSA). A 6 Fr, 135-cm, 8 × 40 mm Mustang balloon (Boston Scientific, Marlborough, MA) and a 5 Fr, 135-cm, 6 × 20 mm Mustang balloon were advanced into the EIA and MSA, respectively.

Balloons were inflated under fluoroscopy using an Endoflator (Boston Scientific) until occlusion was confirmed by repeat angiography. Once ischemia was confirmed, animals were enrolled into either the control or LEEDR group (Fig. 2).

Fig. 2.

Representative digital subtraction angiography (DSA) images: (A) baseline angiogram of the lower extremity; (B) complete balloon occlusion of the external iliac artery (EIA) and middle sacral artery (MSA); (C) confirmation of posterior tibial artery access post-occlusion.

Control group

Total endovascular occlusion of the left lower extremity was maintained for 9 h without any intervention. Maintenance fluids were set between 50–100 mL/h to maintain a mean arterial pressure (MAP) > 65 mm Hg. Glucose was corrected with D50 administration as needed.

LEEDR group

Animals underwent 1 h of ischemia followed by 8 h of LEEDR. The initial hour of ischemia was selected to simulate the minimal realistic time required to recognize ALI, obtain access, and initiate LEEDR in a controlled setting.

The LEEDR system consisted of a custom-built circuit fabricated from 3/16-inch Tygon tubing, connected to a pump capable of delivering flow rates between 100 and 1000 mL/min. The system was primed with heparinized saline, connected to the inflow artery (right femoral) and outflow artery (left posterior tibial), and carefully de-aired. A combination of a nonclinicalgrade roller pump (Cole Palmer, Vernon Hills, IL) and a clinical-grade centrifugal pump (Amplifi Vascular, Chesterfield, MO) was used in the LEEDR circuit.

The extracorporeal circuit was connected from a 7 Fr sheath in the right femoral artery to a 5 Fr sheath in the left posterior tibial artery. Sheath sizes were selected based on vessel diameter, with the femoral artery accommodating a larger-caliber sheath for higher flow.

Flow was increased in 50 mL/min increments from 50 to 200 mL/min every 2–5 min after observing for signs of bleeding or extravasation. The rate of 200 mL/min was determined based on prior LEEDR studies, where flow rates were increased until femoral vein flow returned to > 70% of baseline⁹.

Reperfusion

Nine hours after occlusion, the left lower extremity was revascularized by deflating the left EIA and MSA balloons. In the LEEDR group, the LEEDR circuit was disconnected just prior to balloon deflation. Heparin was discontinued, and animals were observed for 4 h with continuous physiologic monitoring and serial arterial blood gas analysis every 15–30 min. Normal saline was provided via the right external jugular vein as needed to maintain MAP > 65 mm Hg.

Protamine sulfate was administered until ACT was 150 s or less. All sheaths were removed, and manual pressure was applied. The animal was placed on its right side, and a compartment pressure monitor (MY01, Montreal, Canada) was prepared and inserted using sterile technique into the haunch.

Survival

Following 4 h of reperfusion, provided the animals had achieved normalized blood gas values, sedation and ventilatory support were weaned. Animals were extubated when they were breathing spontaneously with a tidal volume > 200 mL, moving spontaneously, and able to protect their airway. After successful extubation and recovery, animals were returned to their kennel and allowed to eat, drink, and mobilize ad libitum.

At 48 h, surviving animals underwent anesthesia and intubation. End-of-study blood samples and CT imaging were obtained. The animals were euthanized, and biopsies were collected for histologic analysis.

Humane endpoints were defined a priori in accordance with IACUC protocol. Criteria included ≥ 2 of the following despite maximal supportive care: sustained mean arterial pressure  < 50 mmHg, persistent severe hypoxaemia (SpO₂ < 85% on ARDSNet ventilation and recruitment maneuvers), refractory hyperkalaemia (> 7.0 mmol/L), or loss of spontaneous respiration. Euthanasia was performed only when the attending veterinarian determined the animal was irrecoverable.

Data collection

Baseline animal weight and sex were recorded. Procedural data included vascular access details and any complications. Physiologic parameters (heart rate, blood pressure, oxygen saturation) were monitored continuously. Arterial and venous blood gases were analyzed using a Nova Prime analyzer (Nova Biomedical, Waltham, MA, USA). Plasma samples were collected at baseline, reperfusion, and study completion, then centrifuged and stored at – 80 °C. Compartment pressure (mm Hg) was monitored continuously postoperatively, with data retrieved via Bluetooth.

Imaging analysis

All animals underwent digital subtraction angiography (DSA) to evaluate the anatomical configuration of lower extremity blood vessels and the positioning of balloon catheters at baseline. Following balloon inflation and deflation, DSA was used to confirm successful occlusion and reperfusion, respectively. Computed tomography (CT) was obtained at reperfusion and at the end of the study to assess for thrombotic and hemorrhagic complications. Images were analyzed using commercially available DICOM software (Purview, Annapolis, MD, USA). A qualitative analysis was performed by an attending vascular surgeon focusing on evidence of complications and symmetry of perfusion.

Histologic analysis

End-of-study tissue samples were obtained from bilateral lower limb muscles, nerves, tibial arteries, and lungs. Specimens were fixed in 10% neutral buffered formalin, paraffinembedded, and sectioned at 5 µm. Sections were stained with hematoxylin and eosin (H&E) and evaluated by a board-certified veterinary pathologist. Histologic analysis assessed inflammation (polymorphonuclear cells, lymphocytes, plasma cells, macrophages, giant cells), infection, foreign material, necrosis, and vascular and tissue injury (eg, ulceration, edema, thrombosis, mineralization). Scoring was based on a semiquantitative scale (0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe) assessing necrosis, inflammation, edema, and vascular injury. This grading approach is adapted from prior large-animal ischemia models and reviewed by a boardcertified veterinary pathologist for internal consistency.

Primary and secondary endpoints

The primary endpoint was mortality following reperfusion. Secondary endpoints included compartment syndrome following revascularization, limb function, biochemical measures of I/R injury (pH, potassium, lactate, and cytokine profile), histologic evidence of muscle and nerve ischemic injury, and evidence of hemolysis. Hemolysis analysis was conducted to evaluate the effect of the extracorporeal pump on red blood cells. Between-group comparisons of secondary outcomes were performed using data from matched timepoints available in both groups. Compartment syndrome (CS) was chosen as a clinically relevant endpoint and was measured objectively using a compartment pressure monitor as described above. CS was defined as an anterior compartment pressure > 30 mm Hg, and persistent elevated pressures in conjunction with clinical signs (e.g., loss of limb function, pallor) were used to support the diagnosis. Limb function was measured using a validated score for quadrupeds, known as the Tarlov score¹⁰. The Tarlov score is a grading system ranging from 0 (no voluntary movement) to 6 (normal ambulation).

Statistical analysis

Statistical analysis was performed using Stata v17.0 (StataCorp, College Station, TX, USA) and GraphPad Prism v8.0 (GraphPad Software, San Diego, CA, USA). Statistical significance was defined a priori as p < 0.05. Data were compared between LEEDR and control groups across study phases (baseline, ischemia, reperfusion, recovery). Continuous variables were analyzed using Student’s t test, and ordinal data with the Mann–Whitney U test. Results are presented as mean ± standard deviation (SD) or median and interquartile range (IQR), as appropriate. GraphPad Prism was used to generate figures.

Results

Study groups

Twelve animals were enrolled (n = 6 per group). All procedures were technically successful. Baseline characteristics, including weight, were comparable (LEEDR 45.7 ± 6.1 kg vs. control 42.4 ± 2.9 kg; p = 0.15). No access-related complications or anesthesia-related mortalities occurred.

Mortality

Survival time was significantly longer in LEEDR animals compared to controls (44.5 ± 8.6 vs. 8.8 ± 6.9 h; log-rank p = 0.001; Fig. 3). All animals in the LEEDR group survived the entire reperfusion period; all control animals expired within 24 h.

Fig. 3.

Kaplan–Meier survival curve comparing LEEDR and control groups following revascularisation.

Compartment syndrome

Compartment pressure was markedly higher in the control group compared to the LEEDR group, with mean values of 28 ± 4 vs. 9 ± 2 mmHg, respectively (p < 0.001). No LEEDR animals developed compartment syndrome during reperfusion compared to 100% (6/6) of control animals. Control animals developed compartment syndrome (CS) starting at 1-h post-reperfusion with most animals experiencing unrelenting compartment syndrome until the animal expired or was euthanized (Fig. 4).

Fig. 4.

(A) Maximum compartment pressures observed during the reperfusion period in LEEDR and control animals. (B) Proportion of animals developing compartment syndrome postreperfusion in each group.

Limb function scores

Tarlov scores demonstrated significantly better motor function in the LEEDR group (median 6.0 [IQR 5.5–6.0]) vs. controls (2.5 [IQR 2.0–3.0]; p < 0.001). All LEEDR animals recovered full limb function within 24 h, with 50% achieving this within 12 h. Control animals exhibited persistent paralysis prior to death (Fig. 5).

Fig. 5.

Highest recorded modified Tarlov gait score in LEEDR and control animals during the recovery period (median and interquartile range).

Biochemical markers

Serum potassium was significantly lower in the LEEDR group across all time points (mean 4.57 ± 0.22 mmol/L) compared to the control group (5.14 ± 0.54 mmol/L; p < 0.001). In the control group, potassium peaked during the reperfusion phase (5.70 ± 0.40 mmol/L), although this temporal increase did not reach statistical significance (p = 0.050). Potassium levels in the LEEDR group did not show significant changes over time (p = 0.56) (Fig. 6A, B). Lactate concentrations were also lower in LEEDR animals relative to controls (1.4 ± 0.55 vs. 2.5 ± 1.6 mmol/L; p < 0.001). Both groups exhibited significant changes in lactate levels over time (p < 0.001). In LEEDR animals, lactate peaked after 1 h of occlusion (2.18 ± 0.55 mmol/L) and declined during reperfusion (1.37 ± 0.77 mmol/L). In contrast, control animals exhibited rising lactate throughout ischemia (1.76 ± 0.67 mmol/L), peaking during reperfusion (2.81 ± 1.72 mmol/L; Fig. 6C, D).

Fig. 6.

Serum potassium (A) and lactate (B) concentrations during ischaemia and reperfusion phases in LEEDR and control groups. Error bars denote standard deviation.

Histologic analysis

Histologic analysis showed no necrosis in muscle or nerve tissue in both the control and LEEDR groups (Fig. 7). In addition to limb tissue, lung specimens were analyzed to assess systemic ischemia–reperfusion injury. Control animals demonstrated histologic signs of pulmonary congestion and interstitial edema, consistent with early acute lung injury.

Fig. 7.

Haematoxylin and eosin-stained histological sections at 40× magnification, showing no pathological changes: (A–C) muscle, nerve, and artery from the occluded limb of a LEEDR animal; (D–F) muscle, nerve, and artery from the occluded limb of a control animal.

Hemolysis analysis

Hemolysis was assessed using plasma free hemoglobin and haptoglobin concentrations. No significant differences were observed between groups at any time point. Haptoglobin levels were comparable at baseline (LEEDR 70 ± 20 mg/dL vs. control 70 ± 10 mg/dL; p = 0.88) and prior to reperfusion (LEEDR 80 ± 30 mg/dL vs. control 80 ± 20 mg/dL; p > 0.99). Free hemoglobin concentrations were modestly higher in controls at baseline (130 ± 50 µg/mL vs. 90 ± 40 µg/mL; p > 0.9⁹) and pre-reperfusion (140 ± 50 µg/mL vs. 90 ± 40 µg/mL; p = 0.27), but these differences did not reach statistical significance.

Imaging analysis

Digital subtraction angiography (DSA) confirmed successful balloon placement, arterial occlusion, and reperfusion in all animals. Computed tomography scans demonstrated no evidence of thrombotic or hemorrhagic complications, such as abrupt contrast cut-off or hematoma formation. Subjective asymmetry in contrast distribution within the affected limb was observed in several animals during extracorporeal perfusion, but this resolved fully by the end of the study period.

Discussion

This study demonstrates that LEEDR was associated with prolonged survival and preserved limb function following extended warm ischemia in an animal model. LEEDR-treated animals demonstrate improved survival, improved gait function, and reduced biochemical markers of I/R injury compared to controls. These results build on prior work validating LEEDR in 6-h ischemia and now support its efficacy in a more clinically relevant, prolonged ischemic window⁸, while being able to objectively quantify functional outcomes for an extended period of 48 h. While long-term outcomes are still needed to demonstrate durability and the full clinical potential of LEEDR, this study offers significant insights into the use of LEEDR as a temporizing strategy for patients with prolonged ischemic time.

The timeframe of warm ischemic time is critical due to the increasing risk of cellular injury and loss of limb viability as warm ischemia persists. Prompt revascularization improves the chances of limb salvage as it minimizes the extent of tissue damage and reduces the risk of I/R injury^11–13. Although restoring blood flow is essential for tissue survival, it paradoxically exacerbates injury through I/R injury^13–15. Reoxygenation increases reactive oxygen species (ROS), causing oxidative stress, inflammation, and further cellular damage^16–18. This inflammatory response can escalate to systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF)^14,19,20.

This has been seen in the control group, where ARDS developed frequently despite adherence to ARDSNet ventilation protocols and provision of intensive critical care throughout the experiment²¹. End-of-study lung biopsies revealed histologic evidence of pulmonary congestion in control animals, consistent with acute lung injury, likely contributing to the increased mortality observed in the control group, as demonstrated by Kaplan–Meier survival analysis.

Tissue hypoxia in controls was reflected by significantly higher lactate levels than in LEEDR-treated animals. Both groups exhibited an initial rise in lactate during the ischemic phase; however, lactate levels in the LEEDR group returned to near baseline following initiation of extracorporeal perfusion. In contrast, control animals demonstrated peak lactatemia during reperfusion. Similarly, potassium concentrations peaked during reperfusion in controls, consistent with advanced cellular dysfunction. LEEDR mitigated these metabolic derangements, as evidenced by significantly lower lactate and potassium levels throughout the protocol.

Control animals died significantly earlier, limiting the window for necrosis to develop, whereas LEEDR animals were euthanized at 48 h, allowing for more complete histologic assessment. Humane endpoints were defined a priori in accordance with IACUC protocol. Criteria included ≥ 2 of the following despite maximal supportive care: sustained mean arterial pressure < 50 mmHg, persistent severe hypoxaemia (SpO₂ < 85% on ARDSNet ventilation and recruitment maneuvers), refractory hyperkalaemia (> 7.0 mmol/L), or loss of spontaneous respiration. Euthanasia was performed only when the attending veterinarian determined the animal was irrecoverable.

The absence of necrosis in the LEEDR group underscores the technique’s ability to preserve tissue integrity and mitigate ischemic injury. Importantly, survival bias is introduced, as no control animals survived to the endpoint when LEEDR histology was obtained. Although control tissue samples did not show overt necrosis, significantly elevated compartment pressures and persistent compartment syndrome were observed in all control animals. In contrast, LEEDR animals demonstrated preserved perfusion and no evidence of compartment syndrome, with rapid functional recovery indicative of muscle and nerve preservation. All animals regained normal ambulation within 24 h, and half achieved the maximum modified Tarlov score within 12 h.

Imaging demonstrated no thrombosis or hemorrhage. The use of systemic heparinization in this model was necessary to maintain circuit patency and prevent catheter-associated thrombosis. While this is common practice in human endovascular procedures, it may limit translation in settings where anticoagulation is contraindicated or delayed. Future work should evaluate alternative anticoagulation strategies or device coatings to enable safer deployment of LEEDR in trauma or coagulopathic patients. Transient perfusion asymmetry was observed, which may be related to a resolving ischemic vasospasm. Regrettably, the perfusion was not characterized further because the imaging protocol was insufficiently standardized, and there were technical issues with the scans that limited quantitative assessment.

Adjuncts for temporary perfusion in extremities have historically focused on temporary intravascular shunts (TIVS)^22,23. TIVS was first introduced in the Vietnam War, and their use was well described during conflicts in Iraq and Afghanistan^22–24. While capable of restoring flow, TIVS require vascular expertise and operating room access²². The need for rapid restoration of lower extremity perfusion has been evident, especially in settings with scarce resources. A few studies have described the successful use of extracorporeal shunts; however, controlled studies quantifying survival and functional recovery after prolonged warm ischemia are lacking. Animal models remain critical to evaluate efficacy and mechanism prior to broader clinical application^25–27.

The LEEDR technique has evolved since its initial description⁸. In this study, we implemented a fully endovascular approach to extracorporeal reperfusion using contralateral percutaneous femoral access and ipsilateral percutaneous posterior tibial artery cannulation. Posterior tibial access was typically performed at the start of the procedure, prior to occlusion; however, in later cases, access was established post-occlusion to better simulate real-world conditions. Cannulation of the posterior tibial artery in swine was consistently feasible, and human anatomy is generally more favorable for this approach. If the posterior tibial artery is unsuitable in clinical practice, the dorsalis pedis artery may serve as an alternative site. This technique may be applicable to clinical settings where vascular expertise and endovascular equipment are available. While current implementation requires catheterization of both femoral and distal tibial arteries, skills typically within the domain of vascular specialists, the study supports future development of simplified protocols or training paradigms that could extend the technique’s use to broader settings.

Translating these findings to clinical practice requires careful consideration of ischemic tolerance in humans. Data from military combat casualties show that the probability of limb salvage decreases by approximately 10% for every additional hour of ischemia, with the highest salvage rates achieved when revascularization is performed within 1 h⁶. In scenarios where definitive revascularization cannot be achieved promptly, early initiation of LEEDR within this timeframe may help preserve viability and function, although further translational work is required to validate this approach in human patients²⁸.

Several limitations of this study should be acknowledged. While the swine model provides anatomical and physiological similarities to humans, it does not fully replicate the complexity of human limb ischemia and systemic responses. At present, LEEDR requires endovascular access to distal tibial arteries, which may not be reliably achievable by nonvascular personnel. Cannulation of these vessels, even with ultrasound, is technically demanding, particularly in ischemic limbs or patients with peripheral arterial disease. As such, widespread clinical implementation will depend on future simplification of technique, miniaturization of equipment, and formalized training programs. The swine model is known to be more resilient to ischemic insult than humans, which necessitated a 9-h occlusion period to replicate the degree of tissue and systemic injury typically seen in human ALI after shorter delays⁸. However, even after 9 h of occlusion, histology did not reveal frank tissue necrosis in controls, despite gross pallor, motor deficits, and compartment syndrome. The small sample size (n = 6 per group) may limit generalizability and increase outcome variability. Furthermore, the 48-h follow-up period may not capture delayed complications or longer-term functional recovery. Future studies with larger cohorts, extended observation, and clinical translation will be necessary to validate and contextualize these findings.

Conclusions

LEEDR enabled distal perfusion of an ischemic limb via contralateral arterial inflow, without the need for advanced surgical techniques. In this porcine model, LEEDR resulted in improved survival, rapid return of limb function, and complete avoidance of compartment syndrome. All control animals developed compartment syndrome and succumbed within 48 h, whereas LEEDR-treated animals maintained physiologic stability and ambulation. These findings support LEEDR as a feasible preclinical strategy that warrants further investigation for its potential to improve outcomes and bridge patients to definitive revascularization when delays are unavoidable.

Abbreviations

ALI

Acute limb ischemia

LEEDR

Lower extremity extracorporeal distal revascularization

I/R

Ischemia–reperfusion

MAP

Mean arterial pressure

ACT

Activated clotting time

CT

Computed tomography

DSA

Digital subtraction angiography

TIVS

Temporary intravascular shunt

ARDS

Acute respiratory distress syndrome

SIRS

Systemic inflammatory response syndrome

MOF

Multiple organ failure

Author contributions

R.N.T. and G.J. contributed equally to this work and share first authorship. Together, they conceived and conducted the experiments, collected and analyzed the data, and co-wrote the manuscript. S.W. assisted with data collection and histologic evaluation. D.P.S., P.F.W., and J.J.M. provided supervision, technical guidance, and secured funding. All authors critically revised the manuscript and approved the final version.

Funding

This study was financially supported by the Department of Defense (Grant No. HU00011920072). Additional support was provided by the German Research Foundation (DFG) under the Walter-Benjamin Programme (Grant No. WI 6261/2-1).

Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Competing interests

The authors declare no competing interests.