Clinical outcome observation of the embolization of orbital vascular malformation with medical glue under direct intra-operative view

Orbital vascular malformation is a mass lesion made up of blood vessels. According to the origin of the blood vessel, the lesion can be categorized as venous, arterial and arterial-venous malformation. The malformed blood vessels often encircle the normal tissue in orbit and have ill-defined borders making surgical treatment of orbital vascular malformations difficult. Because of the risk of hemorrhage during operation, the malformed blood vessel may hard to be removed completely. Accordingly, there are many post-surgical complications and a high incidence of reoccurrence. In this article we summarized the method of embolization with medical glue during the surgical treatment of orbital vascular malformation as well as the resection of lesions, and the prognosis of patients.

The surgical resection of orbital vascular malformations includes a risk of hemorrhage, many complications, and even loss of vision in severe cases. Once a malformed blood vessels rupture during surgery, it is difficult to separate lesions from normal tissue, and may result in the incomplete resection of the lesion. Unfilled malformed blood vessels are even harder to remove completely. Hence, recurrence after surgery is common. Controlling for hypotension, tilting the patients head up, hemostatsis and preparations for blood transfusion are important measures needed to prevent and treat any intraoperative bleeding previously. In this article we reported on the application of medical glue embolization under direct surgical view, which rapidly molded and solidified in the malformed vessels with clearly defined borders, making it easier to resect the malformation completely and reduced blood loss.

In the past years, there have been many reports about the treatment of blood vessel malformation using embolization and many clinically available materials [1‐6]. Medical adhesive is one such tool, which can be categorized according its application as a soft tissue glue, dental glue, bone cement or skin pressure sensitive adhesives. Soft tissue glue can be further subcategorized into bioadhesive and chemical adhesive. Fibrous protein glue, a bioadhesive, is widely used in ophthalmology, such as to glue the conjunctiva or amniotic membrane tissue together in pterygium excision and amniotic membrane transplantation [7]. The chemical adhesive α-cyanoacrylate has recently undergone rapid development, and is widely used in neurosurgery, general surgery and obstetrics and gynecological surgery [8‐10]. The main gel content we used in this study was a highly purified α-Cyanoacrylic high carbon alkyl ester which polymerized instantly when mixed with weakly nucleophilicity materials (anionic materials including water, amidogen, alcohol, mild bases, and proteins or organic amine in organisms). The liquid medical gel can became solid adhesive medium to bind damaged tissue with solidification only taking about 6~15 s. It has a strong intensity, adhesiveness, and non-flowing features as well as strong antibiosis, bacteriostat activities. This is mainly applied to the treatment of cerebral spinal fluid leakage, cranioplasty and dura mater repair in neurosurgery. Its chemical features are stable; it does not degrade nor release toxic materials, and has good biological compatibility. Animal toxicity studies have demonstrated it is non-toxic, not carcinogenic nor teratogenic, and can be degraded or excreted, without toxicity accumulation [11]. The longer the molecular chain of the ester group, the less toxic is the ester [12]. The n-octyl ester is almost non-toxic. In clinical α-cyanoacrylate has been used as portal vein embolic agent for many years. It’s long-term effect is stable and there is less toxicity or adverse effects reported [13].

In ophthalmology, medical glue has been used to treat orbital burst fractures, orbital reconstruction, and restoration of enophthalmos deformity. It has proven to have good hemostasis and inner fixation [14]. Researchers used octyl-α-cyanoacrylate to treat corneosclera lacerations in an experimental animal model(Japanese white rabbits) in order to observe the tensile strength, wound healing and its biological compatibility with superficial eye tissues. This study confirmed that the glue was capable of rapid closing wound, and generating enough tensile strength to support wound healing. Glue has good biocompatibility and caused neither toxic nor pathological changes to the cornea and sclera. The time for wound healing and the tensile strength was normal. Its application could also prevent secondary injury during stitches removal. Using laser confocal microscopy to compare glue treatment with sutured cornea samples, it has been confirmed that medical glue suppressed the growth of new vessels and had no effect on wound healing time [15].

In our preliminary experimentation we found that medical glue immediately solidified once it came in contact with blood, thus obstructing continuous injection. We then inferred that different concentration of medical glue would have a different rate of solidification, so we attempted to dilute the glue with sterile WFI before injection. Unfortunately, the diluted medical glue became cloudy. We then stopped diluting the glue and used original glue for injection as part of clinical methodological improvement. We found several matters should be attended to during the application of glue surgical resection. ① The syringe used to draw/inject medical glue needs to be dry. Changing the needle after drawing glue can avoid the blockage caused by glue residue in the needle if it contact with blood when injected. ② The velocity of injection should be properly controlled. Slowly injection would cause the glue to solidify and block the syringe needle. Conversely, quickly injection might risk of injecting into the cavernous sinus. ③ The volume of injected medical glue is relevant to the range and size of the lesion. It’s better to appropriately inject the medical glue instead of it being overused. ④ When applying glue, the change in color and rigidity of the malformed blood vessels should be monitored closely in order to avoid glue leaking from the vessels. ⑤ Using an approach with multiple injection sites better guarantees procedure efficacy and safety.

There was one case of severe complication-- CRAO perioperative period in this case series. It is difficult to distinguish CRAO that may arise from the injection of medical glue or filling of tungsten wire, and other, more insidious reasons. As this was a preliminary trail with limited understanding of the medical glue, we used medical glue combined with tungsten wire to fill the region of vascular malformation for hemostasis. However, we are now convinced of the efficacy of medical glue embolization so we have stopped using tungsten wire filling method as it introduces a foreign body to inside human body, we. Some scholars reported that using medical glue for massive cerebral arterial-venous malformation, may be complicated by the embolization of draining vein or over-perfusion syndrome due to the difficulty in controlling the concentration and injection speed [8]. This suggests that clinicians should examine the safety of the intra-orbital application of medical glue for the embolization treatment.

Scholars have found that four months after using medical glue for brain tissue hemostasis, second surgery was performed due to tumor recurrence and residual glue were present intraoperatively. This finding was different from the complete absorption of glue observed in experimental animals [16]. Other scholars found that glue can cause neuronal necrosis, nerve fiber rupture and demyelination, and lead to T lymphocytes, mast cells and macrophages infiltration. It suggests that the application of medical glue to nervous tissue or other sensitive tissues must be carefully selected [17, 18]. In our early study, most patients did not have adverse reactions although medical glue was not completely removed from deep orbital lesions. However, there were local adverse reactions in three cases of superficial lesions of eyelid skin. One such case suffered from local inflammation and a skin ulcer due to residual glue in the subcutaneous vascular malformations. This residual glue was removed and patient was cured with a second operation. Further analysis of this case suggested that medical glue embolization affected local blood supply of the skin and induced local inflammatory response as a foreign body especially in the superficial lesions. In the two other cases, although intra-operative exploration did not find glue residue, the adverse skin reactions were still present after surgery, involving the skin of both the surgical area and the surrounding non-surgical area. It is speculated that the human body has individual differences in the inflammation response to medical glue. Some people with a sensitive constitution may have a rejection reaction. With the gradually recognition of medical glue, we made several improvements to treatment. ① Before surgery, patients were informed of the advantages of using medical glue, and the possible adverse effects of local inflammatory response or even rejection caused by medical glue and these adverse effects may have individual differences. All patients gave informed consent. ② During the intra-operative injection, we ensured that the glues did not penetrate deformed blood vessels, and do not overflow from the puncture site. ③ For abnormal blood vessels with a rich blood supply, such as varicosity and arterial-venous malformations, ligation of the blood supply vessels at first during the surgery (including the draining vein and the blood supplying artery) may keep the medical glue from spreading and the embolization of other tissues. ④ In view of the existing basic research and clinical observation results, it is recommended that the medical glue be considered as a foreign body, with cautious and careful application. It should be removed as much as possible after application to avoid residue. Medical glue in the orbital apex should be evaluated the relationship between the optic nerve and/or the eyeball in order to decide whether to remove it.

In light of the above analysis we believe that it is feasible to use intra-vascular injection of medical glue for the embolization of orbital vascular malformation. However, since there is a different growth pattern of deformed blood vessels (isolated or diffuse), a different growth range, and a different blood flow velocity within the lumen, they all affect the dispersion rate of medical glue in blood vessels. Hence, injecting the same volume of glue may lead to a different range of solidification. At present, the quantitative relationship between the amount of medical glue injected and the volume of the lesion has not been established. At the same time, considering the adverse reactions of medical glue, we recommend that re-injecting according to the scope of solidified vascular malformation and the lesion size is not an absolute indication. Our key finding and clinical recommendations were, first when applying medical glue to superficially located vascular malformations, attention should be paid to avoid leaving glue residues; all glue should be removed to minimize complications. Next, when applying medical glue into a deeply located orbital vascular malformation, be sure to protect the surrounding normal structure and to ensure “intratumoral injection.” Additionally, when applying medical glue to the vascular mass closely located near the optic nerve or eyeball wall, attention should be paid to the amount of glue used. It can be used for a small amount and multiple times, to avoid its impact on eye blood supply. Finally, lesions rich in blood flow and affecting a large area, it is recommended to first ligate the supplying blood vessels, manage the mass separately, and then inject glue for embolization.

Orbital and eyelid vascular malformation is a very complicated illness, which is difficult to manage, so an indication for surgical resection should be critically evaluated. The application of medical glue can reduce the risk of intra- and post-operative hemorrhage, as well as may provide a ‘bloodless’ surgical field for surgeons. After molding and solidification using medical glue, malformed blood vessels are easy to remove. Such application of glue facilitates the complete resection of ill-defined lesion and reduces post-surgical recurrence. Its application is not simply a local injection and thus requires extensive experience in orbital surgery and techniques, as well as adequate preparation for the timely management of sudden onset complications.