• 1

  Preparation should be conducted in a vertical laminar flow hood. The facility was not audited by the occupational health authorities.

• 2

  The hood must be cleaned with alcohol 96° and sterile gauze. A sterile surgical drape should be placed at the bottom of the hood.

• 3

  Insert the empty (previously sterilized) BD 10 mL oral opaque propylene syringes into the hood together with the white “tip caps”.

• 4

  Introduce 250 mL sevoflurane bottles, which should have been cleaned previously with alcohol 96% and sterile gauze, plus 1 glass of 500 mL precipitates and a glass stir rod. All the materials should have been previously sterilized.

• 5

  Pour the sevoflurane (Sevorane®) into the flask containing the 500 mL precipitates with the help of the stir rod, pressing the valve of the sevoflurane bottle. Flasks from different manufactures can be used on condition that they are provided with a safety cap.

• 6

  Load the 10 mL syringes with sevoflurane by drawing 10 mL from the precipitate flask. Once the syringe has been loaded, place the cap on the syringe.

• 7

  Place the syringes into sterilized plastic bags, entering the number of syringes in each bag on the labels provided and sticking each label on the outer surface of its corresponding bag.

• 8

  Keep in the refrigerator.

Previously, a study on the physicochemical stability of sevoflurane (preloaded into polypropylene syringes) was carried out to find out how long these preloaded syringes could be stored for34 as there were no studies on the subject and the idea was to provide patients with a enough number of syringes to tide them over for a month, which is when they would have their next visit to the Pain Unit. The physicochemical study was carried out using two analytical imaging techniques (magnetic resonance imaging and gas chromatography with flame ionization detection) recommended by the European and US Pharmacopoeias and by the International Conference for Harmonization Good Clinical Practice Guidelines to study the chemical stability of drugs35-37.

The study confirmed the structural integrity of the sevoflurane molecule as conserved in propylene syringes at a wide range of temperatures (-10 °C, 4 °C and 25 °C) for 45 days34. Subsequently, another study was conducted under the same conditions as the previous one but over a total of 365 days at temperatures ranging from 4 °C to 25 °C. Once again, this study found a lack of sevoflurane as packed in polypropylene syringes.

The protocol above has now been in operation for 7 years, which provides for an accumulated experience of over 70,000 applications of topical sevoflurane. The analgesic effect observed in our patients following application of a dose of approximately 1 mL/cm2 is characterized by a rapid onset of action (a few minutes), a highly intense analgesic effect [with reductions on the visual analog scale (VAS) of up to 7-8 points], and a long duration (it usually persists for several hours, up to 48 on some occasions)15. These characteristics have been described by all the authors who have applied topical sevoflurane to SUs4,11-33.

Sevoflurane's quick onset of action and short latency set it far apart from EMLA® cream, the only drug currently approved for debriding venous ulcers, which must be applied between 30 and 45 minutes before debridement of cleaning of the ulcer. Even in the absence of comparative studies, sevoflurane appears to be a more effective alternative for high-temperature working environments.

As regards the intensity and duration of the analgesic effect, the fact that the pain can often be controlled almost fully and for a period of 10-12 hours, is associated with the added advantage that patients will lower their consumption of other analgesics16-19,30, which is particularly useful in the case of opioids. Furthermore, none of the tolerance and/or dependence issues typically related to opioid consumption have so far been reported, which constitutes a significant advantage for topical sevoflurane.

Topical application of sevoflurane has shown itself to be effective not only with regard to somatic pain but also vis-à-vis neuropathic pain7,10,25,32. It has also demonstrated its effectiveness in extreme clinical situations where common analgesic procedures had failed, helping in some cases avoid amputations25 and notably improving the patients’ quality of life7,10,25,32.

Quality-of-life improvements were formally documented in a series of patients with painful venous ulcers18, especially in the setting of palliative care. These were frail patients where administration of systemic analgesics, especially opioids, would have probably resulted in adverse events and in an impairment of their quality of life. In our experience, topical sevoflurane can also be useful in cancer patients to relieve the refractory pain caused not only by vascular ulcers10,33, but also by neoplastic ones23. In these cases, sevoflurane made it possible to reduce the administration of opioids and, allowing a progressive disappearance of adverse clinical events and improving the patients’ quality of life until their death. These published experiences could serve as a proof of concept of the usefulness of sevoflurane in the setting of palliative care.

A negative aspect regarding the duration of the effect of sevoflurane that could be considered a limitation to its use is that on occasion the analgesic effect obtained is insufficient to cover the whole period between dressings, making it necessary to provide patients with additional systemic analgesia to relieve their pain.

It has been observed that ulcers tend to heal gradually but fully following application of sevoflurane. This unexpected finding should be considered within the context of our clinical protocol, which included patients with ulcers not amenable to revascularization who presented with associated comorbidities such as diabetes, which often compromised wound healing. Moreover, these patients usually have their ulcers treated at home, which means that they are treated in a much less controlled environment than the hospital setting14,30.

Other authors also reported on sevoflurane's highly favorable healing profile either with similar data to ours, or even higher healing rates4,9,16.

There are two aspects worth mentioning about our findings, based on a series of 67 patients with VUs treated with sevoflurane. Firstly, ulcers were often seen to recur in patients with poorly controlled underlying conditions. In these situations, sevoflurane's analgesic performance was similar to the performance exhibited at the first application. Secondly, when ulcers treated with sevoflurane did not decrease in size or even worsened, a biopsy was considered mandatory to rule out potentially infrequent conditions not related to vascular disease. Such biopsies led to identification of tuberculous ulcer and two Marjolin ulcers.

The antimicrobial effect of sevoflurane was observed in vitro vis-à-vis clinical and ATCC (American Type Culture Collection) strains of de Staphylococcus spp, Pseudomonas spp and Escherichia coli38. Imbernon et al. also described the drug's antimicrobial effect in vivo in a patient with a CU superinfected by a strain of multiresistant Pseudomonas aeruginosa11, with other authors subsequently reporting on its potential antimicrobial effect in vivo9,12,31,32. Although sevoflurane's bactericidal mode of action remains to be elucidated, some authors have suggested that both ether and its halogenated derivatives act as solvents at the level of the cell membrane11,12,39,40.

Our experience in the antimicrobial field does not indisputably demonstrate that infections caused by pathogens present in the ulcer site may be controlled only by sevoflurane instillations. For example, presence of a bacterial infection was a common complication in our series of critical patients with pressure ulcers (PUs). Specifically, 70% of patients treated with sevoflurane presented with an infection, caused mainly my organisms such as Staphylococcus, Enterobacter, Pseudomonas, and Enterococcus30. In the present study, debridement, cleaning, dressing change and intraoperative intravenous antibiotic administration may account for the significant bacterial load reduction observed in the two patient groups. Nonetheless, we did not find the decrease in bacterial load found in the ulcers of patients treated with topical sevoflurane to be significantly greater that the decrease observed in the group not treated with the drug.

Patients on ambulatory treatment with sevoflurane were followed up at the Pain Unit in the course of specific consultations which could last up to 5 hours. Considering that these patients were administered sevoflurane at the wound dressing room that same day, it was a foregone conclusion that the healthcare providers seeing to the patient were exposed to the drug. This exposure could, on some occasions, result in a mild headache.

For that reason, an environmental measurement study was undertaken to evaluate the safety of the room where sevoflurane is instilled41.

The US National Institute for Occupational Safety and Health (NIOSH) is working on a specific environmental exposure threshold for sevoflurane42, with most European countries, including Spain, still lacking a specific regulation on the subject43,44. It should also be mentioned that the few countries that do possess a regulation, among them the Nordic countries, have not so far established uniform threshold levels of sevoflurane43,45. Threshold levels for sevoflurane range between 5 parts per million (ppm) in Denmark46 and 20 ppm in Norway47. Finland and Sweden have established two threshold levels: one for long-term exposure (along an 8-hour working day), which is 10 ppm, and another for short-term exposure (up to 15 minutes), which is 20 ppm48,49. In Spain, the National Health and Safety Institute's Best Practice Guidelines mention that mild short-term sequelae have been reported (confusion, vertigo, nausea and drowsiness) associated with acute exposure to isoflurane, sevoflurane y desflurane at the concentrations required for anesthesia (1,000 to 10,000 ppm, depending on the gas used)44.

In our experience41, the conditions under which topical sevoflurane is applied seem to be environmentally safe for healthcare providers as exposure levels are within the ranges accepted in several European countries for anesthetic procedures47,48. As a result, we consider it important to recommend that sevoflurane be applied in well-ventilated spaces or ensuring that the air is exchanged at least three times an hour. These were the conditions under which our environmental study was conducted41.

The local adverse events most commonly associated with the treatment were heat, pruritus and erythema around the ulcer, which were often transient and did not result in discontinuation14,30. As regards sevoflurane's safety with respect to systemic absorption, none of our patients exhibited symptoms attributable to a systemic effect of sevoflurane.