Effect of polidocanol foam administration into rat peripheral veins on pulmonary parenchyma

Introduction

Sclerotherapy has gained increasing acceptance and popularity in recent years, being considered an effective therapy for the treatment of varicose veins. ¹ This attention has increased the interest in the safety and potential complications associated with sclerotherapy, particularly foam sclerotherapy. ²

Foam may potentially cause local damages, such as matting, skin staining and pigmentation, in an average rate of 17.8% (range: 0–66.7%), with different concentrations of polidocanol (0.25–3%) and in different types of veins. ³ Deep venous thrombosis (DVT) following foam sclerotherapy has a reported incidence between 0.3 and 1%. Pulmonary embolism is a rare event, occurring in approximately 0.1% of patients. ⁴ A systematic review of foam sclerotherapy noted an average rate of visual disturbances of 1.4% in 14 studies. ³ Brain damage was reported, particularly in patients with a patent foramen ovale or a right-to-left shunt. From 1994 to 2015, 16 cases of stroke were published.^2,5–7 Thoracic symptoms, such as oppression and cough, have also been reported after foam sclerotherapy. When air is used, the incidence of those symptoms varies from 16 to 18%, while with CO₂, from 1.6 to 3.1%. ⁸ These symptoms warrant caution because they lack a well-understood etiology. ²

Efforts have been made in order to create foams with ultra-low nitrogen content and well-defined physical–chemical properties (for example, Polidocanol Endovenous Microfoam), in order to reduce potential side-effects while preserving foam cohesiveness. ⁹

Foam sclerotherapy may be responsible for pulmonary capillary lesions. There is no evidence for this complication in humans, although animal studies have shown possible damage.^10–12 A recent paper reported acute morphological alterations in the pulmonary parenchyma of rabbits after the injection of 1% and 3% polidocanol foam into peripheral veins. ¹⁰

The objective of this study was to examine the histological findings associated with pulmonary parenchyma after injection with 1% polidocanol Tessari foam at a 4:1 proportion of air: 1% polidocanol, using a semi-quantitative analysis of inflammatory and fibrosis processes.

Methods

Results

During the removal of the lungs, no areas with abnormal external macroscopic alterations were identified, and the quantity of pleural fluid was considered normal. The values obtained after the semi-quantitative histological analysis are shown in Table 1.

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Table 1.

Distribution of semiquantitative variables in the 24 h, seven-day, and 28-day polidocanol groups and the control group.

	Control group		Polidocanol groups
			24 h		7 Day		28 Day
	N	%	N	%	N	%	N	%	P
Alveolar edema, %									0.005
Absent	6	100.0	2	33.3	6	100.0	6	100.0
<25	0	0.0	1	16.7	0	0.0	0	0.0
25–50	0	0.0	2	33.3	0	0.0	0	0.0
50–75	0	0.0	1	16.7	0	0.0	0	0.0
Vessel wall thickening									<0.001
Absent	6	100.0	5	83.3	0	0.0	0	0.0
Occasional	0	0.0	0	0.0	3	50.0	2	33.3
<25%	0	0.0	0	0.0	2	33.3	1	16.7
25–50%	0	0.0	1	16.7	1	16.7	3	50.0
Interstitial fibrosis									0.006
Absent	6	100.0	6	100.0	6	100.0	2	33.3
<25%	0	0.0	0	0.0	0	0.0	4	66.7
Venous thrombosis									–
Absent	6	100.0	6	100.0	6	100.0	6	100.0
Arterial thrombosis									–
Absent	6	100.0	6	100.0	6	100.0	6	100.0

There was an increased prevalence of alveolar edema in the 24 h polidocanol group (P = 0.005) (Figure 2(a) and (f)). The seven-day and 28-day polidocanol groups showed the greatest amount of vessel wall thickening (Figure 2(b) and (c)). The distribution of these changes was not homogeneous; only occasional findings were observed in the seven-day group, whereas 25 to 50% was observed in the 28-day group. However, a statistically significant difference was found, when those two groups were compared to the control group (P < 0.001). Only the 28-day group displayed interstitial fibrosis (P = 0.006) (Figure 2(d)). There was no predominance of neutrophilia in any of the group. None of the animals showed venous or arterial thrombosis. None of the variables were found in the control group (Figure 2(e)). OPEN IN VIEWER

Discussion

There is intense and progressive concern regarding the potential short- and long-term side effects and complications caused by foam sclerotherapy. This study shows the effects of physician-compounded polidocanol foam (Figure 3(a) and (b)) on pulmonary parenchyma following its injection into rat peripheral veins. OPEN IN VIEWER

A prospective study that analyzed 1025 patients found temporary chest pain in 1.1% of the cases (12 patients). The average injected volume in patients who presented chest oppression was 4.54 + 1.92 mL (median: 4 mL; range: 1–10 mL). After a detailed cardiac investigation, no signs of changes were detected in any of the affected subjects. Therefore, an explanation for the symptoms remained uncertain. ¹⁵

In a recent study, the respiratory function was analyzed after foam sclerotherapy in volunteer patients. There was no sign of impairment in gaseous exchanges detected by pulmonary function tests. Other mechanisms may be responsible for the respiratory symptoms that were previously reported and related to foam sclerotherapy. ¹⁶

In another study, the kinetics of foam distribution in the pulmonary circulation was demonstrated after its injection into human peripheral veins. Lung perfusion scintigraphy was performed, including the acquisition of 30 images (one every 15 s), after the injection of 5 mL of foam obtained by mixing 0.25 mL of 1% polidocanol and 0.2 mL of ^99mTc solution with 4 mL of filtered ambient air, according to the Tessari technique. ¹⁷ Radioactivity was detected in the lungs 30 s after the foam injection. The distribution was homogeneous in the pulmonary parenchyma, with increased captation after 75 s. The foam likely loses its sclerosing properties as it enters the pulmonary arterial bed due to its dilution in the large surface area of the gaseous exchange of this organ. ¹⁸

An experimental model using rabbits injected with 3% polidocanol foam revealed venous thromboembolisms and chronic lung inflammation. The pulmonary histopathological analysis of the animals euthanized immediately after the foam injection revealed the presence of fibrin-platelet thrombus and an inflammatory response suggestive of capillary inflammation. Thromboembolism of fibrinous aspect and a mixed chronic inflammatory response were observed in the animals euthanized 30 days after foam injection. ¹⁰

In contrast to the report by Grandi et al., no thromboembolic events were observed in the present study. This difference can be explained by the location where the foam was injected. These authors selected a puncture site in the ear of the experimentation animals, thereby decreasing the time of contact between the polidocanol foam and the blood, which was in contrast to injections that are performed more distally in the limbs. ¹⁰ The prolonged time of contact between the foam and the blood may inactivate the harmful properties of polidocanol due to its binding to albumin.

In the current study, the rats in the 24 h polidocanol group presented significant alveolar edema. This finding suggests that acute parenchymal injury is associated with foam injection. In general, the walls of the pulmonary capillaries are extremely thin so that gaseous exchange can be easily accomplished, even though it also predisposes the vessel wall to damage in severe stress situations. This damage may cause changes in vascular permeability with edema, and in some cases, bleeding. ¹⁹

A study on the impact of polidocanol foam on lungs was conducted on a group of 80 rats and examined the action of the foam at the following concentrations: (1) 0.5%, (2) 2% and (3) 3%. A 0.5 mL foam solution was injected into each animal. No thromboembolic events were observed, though microscopic evaluation of the parenchyma was not performed in this study regardless of the polidocanol concentration. ¹¹

The initial contact of the sclerosing agent with the vessel wall causes platelet aggregation and the initiation of the coagulation process. Adhesion between the vessel wall and the formed thrombus occurs 2 and 3 h after the initial contact, with subsequent fibrosis observed in the following days. Perivascular inflammatory reactions may occur after the agent reaches the vessel adventitia, ²⁰ which may explain the fibrosis found in the lungs of the 28-day polidocanol group.

We emphasize that 0.4 mL is a large volume for the experimentation animal chosen in this study (the equivalent proportion in humans would be around 120 mL). However, the handling of samples smaller than 0.4 mL has been difficult, carrying the risk of different infusion volumes among specimens. The aim of the study, though, is not to mimic a human model in animals, but to assess the effects that polidocanol foam generates in the circulation and lung parenchyma. Other limitations were the absence of a polidocanol-only control group and time-related control groups. Furthermore, larger animal studies need to be performed.

Other aspects should be emphasized when studying the effects of polidocanol in remote organs. For example, measuring pulmonary capillary pressure during and after treatment would provide more information on whether the foam actually generates acute stress that might lead to short- and long-term parenchymal endothelial responses. Larger animal models may also facilitate the acquisition of more accurate physiological data.

According to the recommendations of a recent consensus, reducing the amount of polidocanol foam is important to avoid possible negative effects in the pulmonary circulation, which may appear many years after treatment. With the aim of improving foam stability and production consistency, automated systems have been recently proposed as an alternative to manual techniques. ²¹ Additionally, more studies are needed to evaluate foam kinetics in the lungs, ¹² including more methods of foam production and formulations to be tested to draw a clearer conclusion on the effects of foam sclerotherapy.

Conclusion

Polidocanol physician-compounded foam injections into rat peripheral veins cause alveolar edema in the early stages, interstitial fibrosis, and vessel wall thickening in a later phase.