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. Author manuscript; available in PMC: 2023 Mar 1.
Published in final edited form as: Plast Reconstr Surg. 2022 Mar 1;149(3):629–637. doi: 10.1097/PRS.0000000000008829

The Influence of Topical Vasodilator-Induced Pharmacological Delay on Cutaneous Flap Viability and Vascular Remodeling

Zi Jun Wu 1, Mohamed M Ibrahim 2, Amanda R Sergesketter 2, Ryan M Schweller 3, Brett T Phillips 2, Bruce Klitzman 2,3
PMCID: PMC9102222  NIHMSID: NIHMS1748641  PMID: 35041631

Abstract

BACKGROUND:

Surgical delay is a well-described technique to improve survival of random and pedicled cutaneous flaps. The aim of this study was to test the topical agents minoxidil and Iloprost as agents of pharmacological delay to induce vascular remodeling and decrease overall flap necrosis as an alternative to surgical delay.

METHODS:

Seven groups were studied (n=8 in each group), including the following: vehicle, Iloprost, or minoxidil pre-treatment only; vehicle, Iloprost, or minoxidil pre- and post-treatment; a standard surgical delay group as a positive control. Surgical flaps (caudally-based modified McFarlane myocutaneous skin flaps) were elevated after 14 days of pre-treatment, re-inset isotopically and observed at various time points until postoperative day 7. Gross viability, histology, doppler blood flow, perfusion imaging, tissue oxygenation measurement and vascular casting were performed for analysis.

RESULTS:

Pharmacologic delay with preoperative application of topical minoxidil or Iloprost was found to have comparable flap viability when compared to surgical delay. Significantly increased viability in all treatment groups was observed when compared with vehicle. Continued postoperative treatment with topical agents had no effect on flap viability. The mechanism of improved flap viability was inducible increases in flap blood volume and perfusion rather than the acute vasodilatory effects of the topical agents or decreased flap hypoxia.

CONCLUSION:

Preoperative topical application of the vasodilators minoxidil or Iloprost improved flap viability comparably to surgical delay. Non-invasive pharmacological delay may reduce postoperative complications without the need for an additional operation.

Keywords: pharmacologic delay, surgical delay, vascular remodeling, minoxidil, Iloprost, flap viability, choke vessel

INTRODUCTION

After pedicled and free flap reconstruction, post-operative complication rates exceed 25%, most commonly including infection, necrosis, and wound dehiscence 1,2. Owing to these complications, vascular surgical delay has emerged as a technique that involves partial elevation to invoke local ischemia of a target tissue through multiple incisions that disrupt the vascular network and induce remodeling. Remodeling mechanisms include alterations in sympathetic tone, structural vasodilation, reorientation of choke vessels, and changes in tissue metabolism 3–9. The delay procedure causes hypoxia-induced increase in flap blood flow, inducing chronic changes in vascular architecture. Overall, delay procedures have been shown to induce vascular changes and improve flap perfusion 10,11 with associated reductions in complication rates for pedicled flaps 12. Despite these benefits, surgical delay requires an additional operation, a longer hospital course and increased costs 13–15. Thus, investigation into an effective non-surgical alternative to achieve the delay phenomenon is warranted.

Prior investigations attempting to replicate the delay phenomenon using non-surgical methods including sympatholytics, direct vasodilators, and eiconsanoid pathway modulators, have yielded mixed results 16–23. However, pharmacologic delay with vasodilators, including topical minoxidil, an FDA-approved topical vasodilator in the treatment of androgenic alopecia, have been shown to effectively reduce flap necrosis 24. Iloprost, a stable prostacyclin I2 analogue, is another topical vasoactive agent shown in several studies to enhance skin flap survival as a topical and injectable agent 18,20–22. However, Iloprost has never been studied as a method of preoperative pharmacologic delay.

The aim of this study was to determine whether pharmacological delay with minoxidil and Iloprost could achieve an improvement in flap viability comparable to surgical delay. Secondarily, we aimed to elucidate mechanisms of improved flap viability and establish an effective experimental protocol to improve flap viability.

MATERIALS AND METHODS

Animals

Male Sprague-Dawley type rats (Charles Rivers Labs, Raleigh, NC), weighing 250–300gm were used in the study (n=8 per group), with all animal procedures and housing performed under protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Duke University. Rats were anesthetized using 2% isoflurane in oxygen, 2L/min.

Treatment Groups and Pre-Surgical Treatments

The experimental time course is illustrated in Figure 1. On experimental day 0 (D0), the dorsum of all rats was shaved, the flap outline was drawn, and intradermal oxygen sensors were implanted. We designed a modified caudally-based MacFarlane-type random flap 25. On D0, the flap site was outlined (3×9cm) using a marker; the base of the flap was at the level of the iliac crest 25. Three intradermal sensors were implanted at the apex, middle and base of the planned flap on D0. Three additional sensors were implanted as controls approximately 1cm lateral to the planned flap at corresponding cranial-caudal locations on the dorsum on D0.

Figure 1.

Figure 1.

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Methodology and experimental time course.

Between experimental days 1 and 14 (D1-D14), topical treatment cream (vehicle, Iloprost, or minoxidil) was applied to the entirety of the proposed flap outline after shaving excess fur once per day. Topical vehicle cream was composed of 1:1 DMSO mixed with polyethylene glycol and was administered only pre-surgery [vehicle (−)POT] or before and after flap surgery [vehicle (+)POT]. Topical Iloprost (Tocris Bioscience, Bristol, United Kingdom) was administered at a concentration of 40μg/mL and applied only pre-surgery [Iloprost (−)POT] or both pre- and post-surgery [Iloprost (+)POT]. Topical minoxidil (5%) (Spectrum Chemicals, Gardena, CA) was also administered pre-surgery [minoxidil (−)POT] or either pre- and post-surgery [minoxidil (+)POT]. Finally, in the surgical delay group, the dorsal skin flap was excised on three sides but not undermined on D1, followed by 2 weeks of monitoring. Tissue oxygen tension was assessed using six metalloporphyrin-based oxygen sensors (PROFUSA, Inc, South San Francisco, CA) 26. Prior to flap elevation, baseline blood flow and TOT were measured for each cohort.

Surgical Flap Elevation

Myocutaneous skin flaps measuring 3 × 9 cm were elevated, undermined, and re-sutured in anatomic position on the day after D14 (POD0). Various measurements described below were acquired on POD0, POD3, and POD7. After measurements on POD7, rats were euthanized and underwent a vascular casting procedure described below.

Gross Flap Viability

Gross flap viability was assessed with computer planimetric analysis on POD0, POD3, and POD7. Viable and necrotic flap areas were identified by a treatment-blind observer and quantified using ImageJ software 27.

Tissue Oxygen Tension Measurement

Inspired O2 was modulated from 100% to 12% and the tissue oxygen tension (TOT; mmHg) measured for 330 seconds after change and analyzed for both treated/flap skin and adjacent untreated skin on D0, D14, POD0, POD3, and POD7. This measurement used the above described intradermal tissue oxygen sensors.

Blood Flow Measurement

Laser Doppler flowmetry (LaserFlo BPM2 Blood Perfusion Monitor; Vasamedics; Little Canada, MN) quantified blood flow in the apex, middle and base regions of the flap and the corresponding control regions on D0, D14, POD0, POD3, and POD7.

Sodium Fluorescein Analysis

Sodium fluorescein dye (100mg/ml in saline, then filter sterilized) was injected intraperitoneally (1ml/Kg body weight). After 20 minutes, imaging was performed using an IVIS imaging system (PerkinElmer, Akron, OH). Data were gathered and analyzed on POD0, POD3, and POD7. 28

Vascular Casting

A mixture of 20mL Batson’s monomer solution, 20mL of methylmethacrylate, 3mL of catalyst and 5 drops of promoter was prepared. After retroperitoneal dissection, the aorta was irrigated with 200 μL of 1% bupivicane to prevent vasospasm and ligated immediately distal to the infrarenal vessels. An aortotomy was created using a 20g needle. A catheter made of PE-25 tubing (BD Intramedic™, Sparks, MD) was inserted into the aortotomy and perfused with saline mixed with 10units/mL heparinized and 0.05% lidocaine until a left 2nd lumbar vein transection yielded clear fluid, assuming the entire blood volume had been replaced. The casting mixture was then infused into the cannula at 100–200mmHg with the purpose of filling the vessels supplying the dorsal superficial tissues. The carcass rested for one hour for preliminary polymerization of the intravascular cast, then was eviscerated and suspended in a 50°C water overnight for complete polymerization. The next day, dorsal flap skin was harvested and placed in 40% w/v potassium hydroxide in deionized H2O. Samples were then left in a 37°C incubator for tissue digestion. The KOH was replaced every 2–3 days until complete digestion of all tissue had occurred, as subsequently confirmed by light microscopy.

Vascular Cast Imaging

Casts were imaged using an Olympus-FV1000 microscope with a tunable femtosecond pulsed titanium:sapphire laser (Chameleon, Coherent, Santa Clara, CA) set to 800 nm and a 25×0.9 numerical aperture water immersion objective (XLPL25XWMP, Olympus, Inc., Waltham, MA). Emission spectra were collected from 380 to 560 nm with 10μm steps. For each cast, four non-adjacent z-stack series of images were collected. Z-stacks were converted to 3D-volumes and measured using Imaris (Bitplane, Zurich, Switzerland) software.

Tissue Collection

Skin samples were taken from six areas corresponding to the approximate location of previous measurements using an 8mm punch biopsy. These samples were placed in liquid nitrogen and stored in −80°C freezer. Skin samples were cryosectioned into 12-μm-thick sections using a cryotome (Thermo Fisher Scientific, Kalamazoo, MI).

Data Analysis

Statistical analyses were done using the JMP Pro 12 software package (SAS, Cary, NC). Values were considered statistically significant at P<0.05. Gross planimetric analysis was done on POD3 and POD7. Viability data, fluorescein-based perfusion and vascular cast percent volume vascularity were analyzed using one-way ANOVA with post-hoc Tukey-Kramer HSD tests for all pairs and using Student’s t-tests with unequal variances. Laser Doppler blood flow and TOTs measurements were analyzed using Kruskal-Wallis tests with post-hoc Wilcoxon with Bonferroni correction.

RESULTS

Gross Planimetric Analysis

We compared flap viability on POD3 and POD7 between rats pre-treated with topical vasodilators and surgical delay using gross planimetric analysis, See Figure, Supplemental Digital Content 1. When comparing POD3 percent necrosis (mean ± SD), pre-treatment with topical minoxidil (16.8±5.1%) and topical Iloprost (15.1±11.3%) led to significantly improved flap viability compared to vehicle (39.1±9.1%; both p<0.001), Figure 2. Similarly, on POD7, both topical agents led to significant improvements in flap viability compared to controls (minoxidil: 18.7±7.9%; Iloprost: 22.0±3.9% vs. Vehicle: p<0.001), Figure 2. There was no significant difference in flap viability between pre-treatment with topical minoxidil and surgical delay groups on POD3 (p=0.234) or POD7 (p=0.089). While pre-treatment with topical Iloprost led to improved flap viability compared to surgical delay on POD3 (p=0.02), there was no significant difference between Iloprost pre-treatment and surgical delay on POD7 (p=0.10). Regarding timing of administration, there was no difference in reduction in percent flap necrosis between groups receiving minoxidil pre-treatment alone versus both pre- and post-treatment after flap elevation (POD3: p=0.88; POD7: p=0.57). Similarly, while pre-treatment with Iloprost led to a higher reduction in flap necrosis compared to combined pre- and post-treatment on POD3 (p<0.001), this difference was no longer significant at POD7 (p=0.126). Thus, for both minoxidil and Iloprost, continued treatment after flap elevation did not significantly improve flap viability, Figure 2.

Figure 2.

Figure 2.

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Percent flap necrosis on POD3 (A, top) and POD7 (B, top) between all treatment groups. Comparison of flap necrosis between pre-treatment alone versus combined pre- and post-treatment on POD3 (A, bottom) and POD7 (B, bottom). (***) indicates p<0.001.

Fluorescein Dye Angiography

On POD0, flap perfusion was higher compared to vehicle in surgical delay (p<0.001) and minoxidil (p=0.002) cohorts. However, there was no significant difference between POD0 between Iloprost and vehicle (p=0.20). On POD7, while perfusion was higher than vehicle in the surgical delay cohort (p<0.001), there was no difference between minoxidil (p=0.98) and Iloprost (p=0.12) cohorts, Figure 3.

Figure 3.

Figure 3.

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Flap perfusion after injection of sodium fluorescein dye on POD0 (left) and POD7 (right) between treatment groups. (**) indicates p<0.01, (***) indicates p<0.001.

Laser Doppler Flowmetry

Vasodilator-treated skin had significantly higher blood flow than adjacent non-treated skin preoperatively, (***) indicates p<0.001; (*) indicates p<0.05, See Figure, Supplemental Digital Content 2.

Tissue Oxygen Tension (TOT)

There was no significant difference in preoperative TOT between treated and untreated skin for both minoxidil and Iloprost (both p>0.05). On POD0, flap apex TOT was significantly lower than adjacent untreated skin for all groups (p<0.05). However, surgical delay-treated mid-flap TOT was not significantly different than adjacent untreated skin, while all other groups’ mid-flap TOTs were significantly lower than adjacent untreated skin. (See Figure, Supplemental Digital Content 3, which shows A) Comparison of tissue oxygen tension on D0 and D14 in the tip, middle, and flap base compared to adjacent untreated skin. B) Comparison of POD0 tissue oxygen tension in the flap tip, middle, and base for minoxidil and Iloprost pre-treatment and surgical delay cohorts. (*) indicates significance at p<0.05).

Vascular Cast Vascularity using Percent Volume

Compared to pre-treatment with vehicle, pre-treatment with minoxidil (p<0.001) and surgical delay (p=0.002) led to increased percent vascular volume. There was no significant difference in percent vascular volume between pre-treatment with Iloprost and vehicle (p=0.11). Combined pre- and post-treatment with both minoxidil and Iloprost led to significantly higher percent vascular volume compared to post-treatment with vehicle, Figure 4, 5.

Figure 4.

Figure 4.

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Vascular casting images taken for A) vehicle, B) Minoxidil, C) Surgical delay, and D) Iloprost cohorts.

Figure 5.

Figure 5.

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POD7 percent volume vascularity between treatment groups. (**) indicates significance at p<0.01 and (***) indicates significance at p<0.001.

DISCUSSION

In this study, we demonstrate that pharmacological delay with two weeks of preoperative treatment with topical vasodilators minoxidil and Iloprost improves flap viability to a similar degree as surgical delay. Flaps pre-treated with both pharmacological and surgical delay had improved flap viability in the postoperative period compared to flaps pre-treated with vehicle. Of note, there was negligible additional benefit associated with continuing treatment after surgical flap elevation. The mechanism of improved flap viability seen in pharmacological delay involves vascular remodeling as seen in corrosion casting exhibiting increases in microvessel density and blood volume, resulting in increased distal flap perfusion as evidenced by fluorescein perfusion and blood flow measurements. Collectively, this experimental evidence strongly supports that pharmacological delay can act as an alternative to surgical delay to reduce cutaneous flap necrosis without the need for additional surgery. Pharmacological delay induces vascular remodeling that adapts tissue to hypoxia, a treatment strategy with the potential to improve clinical outcomes in reconstructive surgery.

Despite prior studies investigating various mechanisms of pharmacologic delay, whether the delay phenomenon can be effectively recapitulated pharmacologically remains contested 29–31. Existing literature on pharmacologic delay contains inconsistent methodologies, including differing drug classes, drug mechanisms of action, animal species, flap types, and timing of treatment. Regarding vasodilatory pharmacologic delay agents, prior studies have examined the effect of preoperative minoxidil on flap viability. One recent study showed topical minoxidil improved flap viability compared to no treatment, but was not similar to the effects of surgical delay 24. However, this experiment only provided seven days of preoperative therapy compared to a surgical delay procedure that occurred two weeks before flap elevation. Our experimental design provided the same two-week interval of topical treatment and surgical delay, and we demonstrate similar improvements in flap viability with both approaches. Furthermore, we better elucidate the optimal timing of administration by showing that continuing treatment into postoperative period does not improve flap viability.

Our study provides further insight into the mechanism of pharmacologic delay with vasodilatory agents. Since the half-life of minoxidil is 3–4 hours and Iloprost is 13 minutes18,32 and these treatments were only administered once per day, the increased blood flow seen is not due to the residual effect of vasodilator but rather an induced chronic change. While many studies have demonstrated that surgical delay causes the preexisting flap vasculature caliber increase and reorientation along the axis of the incisions 5,25,33,34, the lasting effects of pharmacologic delay on remodeling flap vasculature outside of initial vasodilation have not been studied. However, we theorize that chronically increased blood flow from any mechanism (vasoactive topical treatments in our experiment) eventually induce structural microvasculature changes that persist despite removal of the inciting stimulus. In our study, corrosive casting demonstrated significantly increased blood volume after application of both vasodilatory agents. In turn, we hypothesize that this remodeled vasculature more readily accommodates ischemia by increasing perfusion. It is important to note that topical pharmacologic pretreatment never induces ischemia since no vessels are ever disrupted. While many previous publications insist that “nonlethal ischemia” is critical for the efficacy of the surgical delay phenomenon 7,25,33, this is clearly not the mechanism in pharmacological delay.

We also found that tissue oxygen tension does not account for improved flap viability seen in surgical delay and topical vasodilator pretreated skin. Jonsson et al. reported that the delay procedure reduced tissue oxygen when compared to adjacent untouched skin, but that tissue oxygen recovered 14 days afterwards 35. Similarly, in our study, while post-operative tissue oxygen tensions were reduced in the distal flap, there were no differences in tissue oxygen tensions between treatment groups. These findings further emphasize that the improved flap viability found with surgical and pharmacological delay is not due to reduced decreases in tissue oxygen tension that are inevitable with flap surgery, but rather is due to improved ischemic tolerance from surgically or pharmacologically inducible microvascular structural changes that result in improved tissue perfusion. Our data show both surgical and pharmacological delay result in vascular remodeling and measurable increased blood volume through our vascular casting data. Our data also show that there is associated increased blood flow/perfusion to the flap apex through our fluorescein perfusion and flowmetry data. Therefore, although oxygen tension is reduced secondary to the progressive extraction of oxygen from blood running from flap base/pedicle to apex as shown by our oxygen sensor measurements, the flap remains viable from increased perfusion despite the hypoxemic perfusate.

Ultimately, we aim for this study to highlight potential pharmacologic delay agents with the potential for easy clinical translation in reconstructive surgery. Both minoxidil and Iloprost are commercially available and widely used pharmacologic agents with manageable side effect profiles. Topical minoxidil is currently used as a treatment for androgenic alopecia, and its side effect profile is most often limited to hair growth and irritation or contact dermatitis at the application site.36 Furthermore, the side effect profile after topical application of Iloprost is most often limited to erythema, with systemic symptoms such as headache and inhibition of platelet function observed only after application to large surface areas of skin, a scenario not applicable to our proposed use as a topical agent prior to flap surgery.37 Thus, considered in the context of these acceptable side effect profiles, the improvements in flap viability achieved with both topical minoxidil and Iloprost in our study support the clinical translation of both of these agents of pharmacologic delay in flap surgery. By better elucidating the efficacy, mechanism of action, and timing of administration of topical minoxidil and Iloprost, this study provides the foundation for future clinical trials investigating these agents in large animals and eventual clinical translation. Pharmacological delay induced by short-term topical treatment in patients before myocutaneous flap surgery has the potential to improve flap and patient outcomes by achieving a comparable improvement in flap perfusion and reduction in post-operative necrosis without the added morbidity, extra surgery, and healthcare time and expenditures associated with formal surgical delay.

Our study is not without limitations. The dose-response relationship in these topically administered agents was not investigated. Although Iloprost has also been shown to have beneficial rheological and cytoprotective actions when administered intravascularly,38,39 our study focused solely on the vasodilatory properties and did not assess how these rheological and cytoprotective actions contributed to improved flap perfusion. Our experimental design only allowed analysis of necrosis up to POD7 and did not show long-term wound healing results. Although we used eight rats in each of the seven groups, it is possible that the addition of additional rats may provide more statistical power to our results. Vascular casting was quantified by a single study investigator who was unblinded to the study group. Additional limitations to gross analysis involve postsurgical wound dehiscence, autophagy and inter-reader interpretation of what is considered viable and unviable skin.

CONCLUSION

In our study, we report that preoperative treatment with topical minoxidil and Iloprost can improve flap viability in rats to a similar degree as surgical delay without the additional morbidity, extra surgery, and healthcare time and costs associated with surgical delay procedures. We elucidate the mechanism of this approach by showing that pharmacological delay induces vascular remodeling, increased flap blood volume and increased flap perfusion and theorize that these changes maintain flap viability despite tissue hypoxia from hypoxemic perfusate. These findings challenge theories that maintain tissue hypoxia is necessary for the surgical delay phenomenon. Rather, we believe that treatment-induced adaptations in flap blood volume and perfusion preserve flap viability despite inevitable flap apex hypoxemia and tissue hypoxia. We also demonstrate the optimal timing of administration by showing that continuing postoperative vasodilator treatment does not appear to confer continued measurable improvements in flap viability. Additional studies particularly in large animals are needed both to test modified formulations with penetrants for improved transdermal delivery and to test the efficacy of these agents.

Supplementary Material

Supplemental Digital Content 1

Figure, Supplemental Digital Content 1. Gross comparison of flap necrosis between Vehicle and pre-treatment with Iloprost, minoxidil, and surgical delay on POD0, POD3, and POD7

Supplemental Digital Content 2

Figure, Supplemental Digital Content 2. Comparison of laser doppler blood flow in (left) Minoxidil and (right) Iloprost-treated versus adjacent untreated skin on POD0 prior to surgery. (***) indicates p<0.001; (*) indicates p<0.05.

Supplemental Digital Content 3

Figure, Supplemental Digital Content 3. A) Comparison of tissue oxygen tension on D0 and D14 in the tip, middle, and flap base compared to adjacent untreated skin. B) Comparison of POD0 tissue oxygen tension in the flap tip, middle, and base for minoxidil and Iloprost pre-treatment and surgical delay cohorts. (*) indicates significance at p<0.05.

Sources of Support:

This work was supported by pilot grant #310323 from the Plastic Surgery Foundation to Mohamed Ibrahim, the Robert R. Jones Fund, and the National Institutes of Health F32HL120650. This work was presented in part at the Plastic Surgery Research Councils, 2014 (New York) and 2015 (Seattle). Profusa, Inc. (South San Francisco, CA) provided the oxygen sensors.

List of Abbreviations:

(−)POT

Groups not receiving topical postoperative treatment (only preoperative treatment).

(+)POT

Groups receiving both preoperative and postoperative topical treatment.

D0

Experimental day zero, when all rats are initially shaved, the area of a future flap was marked on the dorsum, intradermal oxygen sensors were implanted, and various initial measurements were taken. No treatments were started on D0.

D1

Experimental day one, when all rats begin either a topical treatment or undergo a surgical delay procedure.

D14

Experimental day 14, when all preoperative treatments ended. This is one day before full flap elevation and undermining.

POD0

Postoperative day zero, when rats undergo flap elevation and undermining. After this day, some groups continued to receive daily postoperative treatments.

POD3

Postoperative day three, when multiple measurements are taken.

POD7

Postoperative day seven, when multiple measurements are taken, rats are euthanized and undergo a vascular casting procedure in addition to having dorsal skin samples taken for histological studies.

TOT

Tissue oxygen tension.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Digital Content 1

Figure, Supplemental Digital Content 1. Gross comparison of flap necrosis between Vehicle and pre-treatment with Iloprost, minoxidil, and surgical delay on POD0, POD3, and POD7

NIHMS1748641-supplement-Supplemental_Digital_Content_1.pdf (1.4MB, pdf)
Supplemental Digital Content 2

Figure, Supplemental Digital Content 2. Comparison of laser doppler blood flow in (left) Minoxidil and (right) Iloprost-treated versus adjacent untreated skin on POD0 prior to surgery. (***) indicates p<0.001; (*) indicates p<0.05.

NIHMS1748641-supplement-Supplemental_Digital_Content_2.pdf (1.4MB, pdf)
Supplemental Digital Content 3

Figure, Supplemental Digital Content 3. A) Comparison of tissue oxygen tension on D0 and D14 in the tip, middle, and flap base compared to adjacent untreated skin. B) Comparison of POD0 tissue oxygen tension in the flap tip, middle, and base for minoxidil and Iloprost pre-treatment and surgical delay cohorts. (*) indicates significance at p<0.05.

NIHMS1748641-supplement-Supplemental_Digital_Content_3.pdf (149.1KB, pdf)

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