Stefano Ricci
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Abstract To assess the occurrence of pulmonary embolism and long-term inflammatory activation after polidocanol foam injection, domestic rabbits, of both sexes, weighing around 2 kg were used: a control group (injection of saline solution, n = 4) and an experimental group (injection of polidocanol foam 1 and 3 mg/kg, n = 4 each dose), administered in the lateral superficial auricular vein as a slow bolus over 1 min. Foam (1 mL polidocanol 3%+ 4 mL air) 0.3 mL and 1.0 mL was injected respectively for the 1 mg/kg and the 3 mg/kg group. Technetium (Tc99m) lung scintigraphy was realized 15 min after injection, then the rabbits were killed and the lungs were removed for histopathological evaluation. A separated group of animals was reserved for histopathological evaluation 30 days after injection. The pulmonary perfusion showed an important reduction of pulmonary perfusion in all injected cases; while in the control group no alterations were found. The pathological exam at earlier times shows the presence of platelet-fibrin clots mainly in the small pulmonary veins, independent of the dose administered and occasional presence of droplets corresponding to fat embolism, and an acute inflammatory response. In later times it was observed chronic thrombus in small veins with mixed chronic inflammatory response, sparse or more limited. This work shows that the injection of polidocanol foam in experimental animals leads to acute and chronic alterations in pulmonary perfusion and lung inflammation. If few amounts of polidocanol foam can be deposited into the lung (in low quantity, not causing significant pulmonary embolism) it can induce inflammation in the pulmonary parenchyma. The use of rabbits does not allow using maneuvers that can reduce the incidence of embolism (leg elevation, immobility). In addition, the veins used to in the rabbits cannot reflect the veins used in humans, with a shorter time than the time needed to inactivate polidocanol. |
Comment by Stefano Ricci
Opposed opinions are always welcome, when useful to understand open problems. However, in this case study limitations are very important.
So evident lung lesions after foam injection, extremely rare in humans, may indicate that the right experiment animal has not been employed yet. It would have been interesting also to test if liquid polidocanol injection would cause some lung lesions due to this particular reaction in rabbits. Furthermore, 1 mL of foam in a 2 kg (=0.5 mL × kg) animal is a very high dosage if compared to the human suggested use (6 mL = 0.1 mL × kg). Same even for the lower dosage (0.15 mL × kg).
Comment by Lorenzo Tessari
The paper deals with a top priority matter in foam sclerotherapy: the safety profile. For this reason its conclusions are to be considered extremely important and to be taken into account with caution because potentially influencing a really delicate topic.
With these premises, some major bias must be pointed out.
1. It is obvious and already demonstrated that the bubbles reaches the lungs, but this doesn’t mean they are going to create harm in there. This was already demonstrated (Morrison, Parsi, Tessari) in papers and worldwide meeting lectures.
2. Scintigraphy only demonstrated the bubble hemodynamics pathway, not the possible induced damage.
3. Conversely, the histological report of sclerotherapy-induced thrombosis/embolism is strongly biased by the excessive dosage used in the animal model described in the Grandi paper. In everyday clinical practice POL maximum dosage is 0.4 mg/kg. The paper deals with dosages even 6-7 times higher!
4. Materials and methods strongly influence the foam sclerotherapy performance: a more detailed description of the used methods would have been necessary in the Authors’ description.
5. Moreover, the rabbit ear vein is more assimilable to a reticular vein: consequently an excessive sclerosing agent dosage together with the different hemodynamics when compared with the human lower limbs one, could explain the histological findings of the authors.
6. In the results the authors claim a reduction in the pulmonary perfusion after the foam injection. As demonstrated by Watkins the drug is fastly and easily inactivated by the plasma protein. The vasospasm is more probably due to an endothelial release of cathabolytes (endothelin like).
7. In the discussion the Authors use a totally personal opinion when claiming that the acute alterations observed in theses animals can only be the normal dynamic of polidocanol foam bubbles… as the bubble emboli entered the heart early after foam injections. Before such statement, the author should demonstrate the biocompatible gasses bubbles could, independently from the drug, cause lung damage (the same thing could happen when linked to the albumin if not). As already demonstrated by Grigolato and Tessari works, no pulmonary damage follow after foam sclerotherapy in humans.
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