Abstract
Recently, it has been reported that topical irrigations of liquid sevoflurane on the bed of painful wounds produce a rapid, intense, and lasting analgesic effect. In this paper, A cohort of 112 patients with painful pressure ulcers who were refractory to opioids (or who exhibited undesirable adverse events to them) was treated with topical sevoflurane as per local institutional policy. These patients were recruited from an intensive care unit for a period of 3 years. The main aim was to determine the effectiveness of topical sevoflurane in reducing the pain of PUs and reducing the ulcer area. Study findings are reported and discussed herein and suggest that sevoflurane is a viable and promising treatment option for PUs.
Keywords: opioid, pain, pressure ulcer, sevoflurane, topical treatment
1. INTRODUCTION
Pressure ulcers (PUs) represent one of the most frequent health problems in hospitalised patients. PUs are localised injuries to the skin and/or underlying tissue, usually over a bony prominence, as a result of pressure, possibly in combination with shear.1 Critical patients admitted to intensive care units (ICUs) have a higher risk of developing PUs, which can worsen their clinical condition, and have also been associated with higher mortality and decreased quality of life on one hand and an increase in the length and cost of their hospital stay on the other.2, 3 Several risk factors contribute to skin damage in critically ill patients, including nutritional deficits, decreased tissue perfusion, long‐term use of a mechanical ventilator, the presence of moisture, and circulatory changes and vasopressor infusion. Separately, comorbid conditions such as hypertension, spinal cord injury, respiratory disease, vascular disease, and diabetes mellitus have also been found to increase the risk of PUs.4
The pharmacological management of PUs is complex and includes pain control and the prevention and treatment of infection. Non‐steroidal anti‐inflammatory drugs usually constitute the first choice for mild to moderate painful acute soft‐tissue lesions, whereas opioids like morphine sulphate and transdermal fentanyl are reserved for severe pain.5 Cleansing and debridement are also crucial in preventing over‐infection of wounds, but these can be extremely painful, even after administration of large doses of opioids. High morbidity and mortality associated with opiates prompted the Centre for Disease Control and Prevention and the Food and Drug Administration to provide new opioid‐prescribing guidelines for patients suffering from acute and chronic pain.6
Sevoflurane (C4H3F7O) is a highly fluorinated, ether‐derived molecule widely used as an inhaled anaesthetic in the induction and maintenance of general anaesthesia. In recent years, some evidence has emerged highlighting its central and peripheral analgesic effects, even after topical application, as well as its wound‐healing properties in skin ulcers.7 Furthermore, halogenated anaesthetics have shown potent bactericide activities in liquid state, seemingly via a direct toxic action over the cellular membranes.8, 9
The aim of this study was to determine the effectiveness of topical sevoflurane in reducing the pain of PUs, as well as in decreasing the ulcer area in a cohort of opioid‐refractory patients or those who presented unacceptable toxicities.
2. METHODS
A prospective observational study was conducted in a surgical ICU of a university‐affiliated hospital. All adult patients admitted between October 2013 and October 2016 who met the following criteria were included: age ≥18 years and ICU length of stay ≥96 hours. Exclusion criteria were known or suspected malignancy of the current ulcer and stages I and IV PUs.
Patients were followed up for 28 days post‐discharge from ICU and were divided into two groups based on the presence or absence of severe opioid toxicity (constipation, decreased bowel motility, ileus, postoperative nausea and vomiting, sedation, and delirium). All patients were provided standard‐of‐care treatment according to the treating clinician. Analgesia in patients who exhibited severe opioid toxicity consisted of topical sevoflurane in addition to the minimum required opioids as per off‐label protocol by the local ethical committee (local ref: CCF‐SEV‐2014‐01; approved date: 24 September 2013). The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in approval by the institution's human research review committee. Informed consent was obtained. Undiluted sevoflurane (Sevorane, AbbVie, Campoverde di Aprilia, Italy) in preloaded syringes was topically applied to the PUs at a dose of 1 mL per cm2 of ulcerated area, up to four times a day as required, to maintain a visual analogue score (VAS) of 20 to 30.
To reduce the selection bias, we performed a propensity score pairwise matching of patients maintained with opioids with patients maintained on topical sevoflurane. We stratified them by age, gender, comorbidity, basal comorbidity, APACHE II score, cancer, obesity, immunosuppression, diabetes, type of nutrition, type of emergency surgery, surgical re‐intervention, days with ventilation mechanical‐central venous catheter, urinary catheter, and mortality.
Wound severity at enrolment was established by the physician using the National Pressure Ulcer Advisory Panel (PUs were staged according to the classification system as follows: (a) stage I, (b) stage II, (c) stage III, (d) stage IV, (e) non‐stageable, and (f) suspected deep tissue injury) and the wound surface area (WSA) using a 100‐mm horizontal VAS.10 The WSA for all patients was measured using the same method (the contours of wounds were transferred onto transparent film. Ulcer measurement was performed with a graded ruler (length × width × depth) in all patients and was accompanied by digital photography. Wounds were considered completely healed or closed when their surface area decreased to 0. Partial healing was defined by a reduction of at least 50% of sore area. The percentage of change in WSA at weeks 1 and 3 was calculated as follows:
A scar assessment was performed using the modified Vancouver scar scale with the following categories: pigmentation, vascularity, pliability, and height.11
Any unusual signs and symptoms of clinical infection or allergic reactions, as well as any other laboratory abnormalities or undesired side effects, were recorded. PU prevention measures, wound care, and physical treatment were administered to all patients using the same protocol, which is defined as follows: (a) pressure‐redistribution surfaces, devices, and pillows were provided as needed; (b) patients who could change position were asked to do as often as possible to relieve pressure on the ulcer area; (c) the attending physician regularly examined patients to determine the need for care and treatment, which included tissue debridement, infection and inflammation control, maintenance of moisture balance, and monitoring the epithelisation process; and (d) wounds were cleaned with topical antiseptics and then covered with hydrogel or hydrocolloid dressing to trigger autolysis.
Patients from group 1 (no severe opioid toxicity) were given breakthrough opioids for 1 hour prior to debridement. The total amount of opioids was calculated as the morphine sulphate equivalent as follows: 1 μg of fentanyl equal to 1 μg of remifentanil and 100 μg of morphine sulphate.12 Patients from group 2 (those who presented pain refractory to opioids or exhibited previous severe opioid toxicity) were treated with topical sevoflurane as described above. PUs were covered with plastic cling film, forming an occlusive dressing. Immediately after debridement, the patient rated the pain from the procedure on a verbal scale and VAS. The patient was asked about the presence of post‐procedural pain in the wound area and the time of occurrence of first pain. The patient global impression of improvement (PGI‐I) and clinical global impression of improvement (CGI‐I) scales were used to assess patient and clinician perception of improvement, respectively.13When bacterial infection was suspected, patients were administered antibiotics as clinically indicated.
The primary outcome in both groups was reduction of pain in relation to the baseline and reduction of pain from sharp debridement. Secondary outcomes were as follows: (a) percentage of reduction in healing progress regardless of wound shape, (b) average percentage of change in wound area by weeks, and (c) percentage of patients who had bacterial infections.
Descriptive and bivariate analyses were conducted (t test or non‐parametric U Mann‐Whitney test to compare the quantity variables with respect the two groups—opioids vs sevoflurane). In addition, repeated‐measure analyses of variance or the non‐parametric Friedman test were used to compare the quantity variables over the time. Finally, the Chi‐squared or Fisher's exact test was used to test differences for categorical variables. All statistical testing was two‐sided, with a significance level of 5%. Continuous variables are presented as mean ± SD and categorical variables as percentages. Statistical analyses were performed using Stata, version 7 (StataCorp LP, College Station, TX).
This manuscript has a statement which confirms that all experimental protocols were approved by the Hospital Universitario Torrecárdenas ethical committee (local ref: CCF‐SEV‐2014‐01; approved date: 24 September 2013).
3. RESULTS
A total of 112 patients, 73 (65.18%) in the opioids group, met the inclusion criteria, of which 51 were stage II (45.5%) and 61 were stage III (54.5%). The top three locations were the sacrum (47.3%), heels (10.7%), and back (9.8%). Of the Pus, 19.6% were caused by moisture, and 13.3% were caused by friction, whilst the rest were categorised as multifactorial. Because of the propensity score, patients of the total sample were matched; 24 patients maintained with topical sevoflurane were matched with 24 patients maintained with opioids to allow for comparison.
Baseline demographic and epidemiologic characteristics before and after matching in both groups (opioids and sevoflurane) are summarised in Table 1 (mean age 64.4 years [54‐84], 51.7% females, American Society of Anaesthesiology (ASA) physical status of 3 or 4 (61.6%)).
Table 1.
Baseline demographic and epidemiologic characteristics
| Before matching | After matching | |||||
|---|---|---|---|---|---|---|
| IV opioids (n = 73) | Topical sevoflurane (n = 39) | P | IV opioids (n = 24) | Topical sevoflurane (n = 24) | P | |
| Age | 65.5 ± 12 | 63.8 ± 10.3 | 0.65 | 66.8 ± 11.8 | 67.8 ± 12 | 0.82 |
| Days since hospital admission | ||||||
| Pre‐ICU | 4.2 ± 3 | 3.2 ± 2.3 | 0.06 | 2.9 ± 3.1 | 3 ± 2 | 1.00 |
| Post‐ICU | 16.7 ± 20 | 13.7 ± 15.9 | 0.42 | 14.9 ± 16 | 13.1 ± 11.9 | 0.62 |
| Global | 26.3 ± 24 | 27.9 ± 22.7 | 0.67 | 21 ± 18.1 | 22.9 ± 16.1 | 0.68 |
| Days of mechanical ventilation | 12 ± 8.3 | 6.9 ± 5.1 | <0.01 | 9.2 ± 4.2 | 7.9 ± 5.3 | 0.44 |
| Days with CVC | 20.1 ± 16.1 | 17.3 ± 12.9 | 0.31 | 16.1 ± 13.1 | 15.5 ± 11.1 | 0.77 |
| Days with urinary catheter | 21.1 ± 16.1 | 16.4 ± 11.0 | 0.08 | 19.1 ± 15.8 | 18.1 ± 15.9 | 0.82 |
| Antibiotics per patient | 3.9 ± 2.9 | 3.6 ± 2.1 | 1.0 | 3.1 ± 2.6 | 3.3 ± 2.4 | 1.00 |
| Antifungal drugs per patient | 0.6 ± 0.8 | 0.5 ± 0.6 | 1.0 | 0.6 ± 0.2 | 0.5 ± 0.5 | 1.00 |
| APACHE II | 16.4 ± 6.8 | 13.4 ± 8.2 | 0.04 | 15.7 ± 7.8 | 14.8 ± 8.2 | 0.66 |
| Male | 34 (46.58) | 20 (51.28) | 0.69 | 13 (54.17) | 12 (50.00) | 1.00 |
| ASA (>2) | 47 (64.38) | 22 (56.41) | 0.42 | 15 (71) | 16 (78) | 1.00 |
| McCabe Score Forecast (fatal) | 35 (47.94) | 25 (64.10) | 0.11 | 13 (54.17) | 16 (66.67) | 0.55 |
| Basal comorbidity | ||||||
| Haemodynamics | 39 (53.42) | 28 (71.79) | 0.07 | 17 (70.83) | 20(83.33) | 0.49 |
| Respiratory | 29 (39.73) | 25 (64.10) | <0.01 | 15 (65.20) | 17 (70.33) | 0.76 |
| Renal | 22 (30.14) | 14 (35.90) | 0.53 | 5 (20.83) | 3 (12.50) | 0.70 |
| Hepatic | 14 (19.18) | 10 (25.64) | 0.47 | 1 (4.17) | 1 (4.17) | 1.00 |
| Obesity (BMI > 30 kg/m2) | 13 (17.81) | 8 (20.51) | 0.80 | 4 (16.67) | 2 (8.33) | 0.66 |
| Cancer | 51 (69.86) | 22 (56.41) | 0.21 | 16 (66.67) | 13 (54.17) | 0.55 |
| Comorbidities (>2) | 55 (75.34) | 29 (74.36) | 1.0 | 21(87.50) | 21 (87.50) | 1.00 |
| Stage (NPUAP) (Stage III) | 38 (52.05) | 23 (58.97) | 0.55 | 11 (45.83) | 12 (50.00) | 1.00 |
| Number PUs by duration | ||||||
| 0–3 mo | 58 (79.45) | 31 (79.49) | 1.0 | 21 (87.50) | 22 (92.67) | 1.00 |
| 3.1–6 mo | 13 (17.81) | 7 (17.95) | 3 (12.50) | 2 (8.33) | ||
| >6.1 mo | 2 (2.74) | 1(2.56) | 0 (0.00) | 0 (0.00) | ||
| Diabetes mellitus | 42 (57.53) | 21 (53.85) | 0.84 | 15 (62.50) | 13 (54.17) | 0.77 |
| Immunosuppression | 34 (46.58) | 14 (35.90) | 0.32 | 9 (37.50) | 6 (25.00) | 0.53 |
| WLS | 15 (20.55) | 8 (20.51) | 1.0 | 5 (20.83) | 2 (8.33) | 0.41 |
| Enteral nutrition | 16 (21.92) | 13 (33.33) | 0.25 | 7 (29.17) | 4 (17) | 0.49 |
| Tracheotomy | 15 (20.55) | 10 (25.64) | 0.63 | 5 (20.83) | 5 (20.83) | 1.00 |
| Mortality ICU | 16 (21.92) | 8 (20.51) | 1.0 | 6 (25.00) | 3 (12) | 0.46 |
| Mortality hospital | 22 (30.14) | 13 (33.33) | 0.83 | 8 (33.33) | 6 (25.00) | 0.75 |
| Type of emergency surgery | 34 (46.58) | 19 (48.72) | 0.84 | 10 (41.67) | 12 (50.00) | 0.77 |
| Surgical re‐intervention | 52 (71.23) | 26 (66.67) | 0.66 | 16 (55) | 17 (59) | 1.00 |
| Reintubation | 19 (26.03) | 14 (35.90) | 0.28 | 7 (29.17) | 7 (29.17) | 1.00 |
| Prior antibiotic use | 41 (56.16) | 18 (46.15) | 0.32 | 13 (54.17) | 10 (41.67) | 0.56 |
Note: Quantitative variables: mean ± SD, qualitative variables: n (%).
Abbreviations: ASA, American Society of Anaesthesiology; BMI, body mass index; CVC, central venous catheter; ICU, intensive care unit; NPUAP, National Pressure Ulcer Advisory Panel; PUs, pressure ulcers; WLS, withholding/withdrawal of life support.
The variation of pain and wound healing during 4 weeks are show in Table 2. The baseline stage of the surface areas of ulcers did not differ significantly between groups after matching by the propensity score. In this study, by weeks 1 and 4, WSA in the topical sevoflurane group decreased by 39.7% compared with 38.5% in the opioid group, without significant statistical differences. The mean (±SD) opioid requirement during the study period was 6.2 ± 2.4 mg/d in the sevoflurane group and 32.2 ± 18.5 mg/d in the opioid‐only group (P < 0.01). The mean (±SD) reduction in pain score after sevoflurane application was 59.9 ± 20.1 points (P < 0.01).
Table 2.
Patient's assessment of pain and wound healing
| IV opioids (n = 24) | Topical sevoflurane (n = 24) | P | |
|---|---|---|---|
| PUs stage III | 11(45.83) | 12(50.00) | 1.00 |
| High pain (50–100) | 17 (70.83) | 19 (79.17) | 0.74 |
| VAS | 0.24 | ||
| Baseline | 73.3 ± 17.1 | 79.1 ± 18.2 | |
| 1 wk | 51.2 ± 21.1 | 19.2 ± 5.2 | <0.01 |
| 2 wk | 48.1 ± 24.3 | 14.2 ± 7.3 | <0.01 |
| 3 wk | 52.3 ± 21.2 | 12.1 ± 5.9 | <0.01 |
| 4 wk | 51.4 ± 27.2 | 14.3 ± 6.1 | <0.01 |
| Total morphine equivalent (mg) | 32.2 ± 18.5 | 6.2 ± 2.4 | <0.01 |
| WSA (cm2) | |||
| Baseline | 10.68 ± 8.34 | 9.74 ± 4.56 | 0.60 |
| 1 wk | 9.79 ± 7.56 | 9.23 ± 6.32 | 0.76 |
| 2 wk | 9.18 ± 7.13 | 8.56 ± 6.11 | 0.75 |
| 3 wk | 8.11 ± 5.23 | 7.35 ± 5.78 | 0.61 |
| 4 wk | 6.56 ± 4.67 | 5.87 ± 4.78 | 0.60 |
| Complete healing | 6 (25.00) | 9 (37.50) | 0.53 |
| Partial healing | 12 (50.00) | 12 (50.00) | 1.00 |
| No response | 6 (25.00) | 3 (12.50) | 0.46 |
| Proportion of PUs that increase in size | 4 (16.67) | 3 (12.50) | 1.00 |
| Complete healing time (d) | 20.5 ± 10 | 16.7 ± 9 | 0.46 |
| Infection | 13 (54.17) | 7 (29.17) | 0.15 |
| MVSS | 5.22 ± 2.12 | 4.86 ± 2.67 | 0.57 |
Note: Quantitative variables: mean ± SD. Qualitative variables: n (%). Partial healing: means that ≤ 50% of sore area was healed. Complete healing (100% wound closure).
Abbreviations: MVSS, scar assessment by modified Vancouver scar scale; PUs, pressure ulcer; VAS, visual analogue scale; WSA, wound surface area.
The mean VAS score for debridement‐related pain declined from 16 ± 12. The anaesthetic effect commenced at 4.1 ± 2.8 minutes and subsided after 7.3 ± 2.3 hours. No variation in analgesia duration throughout all cleanings with sevoflurane was observed in any patient. The patient's median VAS pain rating of the procedure (topical sevoflurane) was 16/100 (Table 3). A variable latency time of 4.1 ± 2.8 minutes was observed. The time of occurrence of first pain was 7.3 ± 2.3 hours vs 1.6 ± 1.4 hours (P < 0.01).
Table 3.
Patient's assessment of pain debridement
| IV opioids (n = 18) | Topical sevoflurane (n = 21) | P | |
|---|---|---|---|
| Doses morphine or sevoflurane | 11 ± 8.7 | 16 ± 12 | — |
| Latency time (min) | 7.6 ± 6.8 | 4.1 ± 2.8 | 0.03 |
| Pain from debridement (VAS) | 21 ± 12 | 16 ± 12 | 0.20 |
| Pain from debridement (VRS) | |||
| None | 4 (22.22) | 8 (38.10) | 0.41 |
| Slight | 10 (55.55) | 10 (47.62) | |
| Moderate | 2 (11.11) | 2 (9.52) | |
| Severe | 2 (11.11) | 1 (4.76) | |
| Post‐procedural pain | 4 (22) | 1(5) | 0.12 |
| Time occurrence first pain (hours) | 1.6 ± 1.4 | 7.3 ± 2.3 | <0.01 |
| Adverse effects | |||
| No | 9 (50.00) | 19 (90.48) | <0.01 |
| Systemic | 9 (50.00) | 0 (0.00) | |
| Local | 0 (0.00) | 2 (9.52) | |
| Total adverse effects | 9 (37.00) | 2 (8.00) | <0.01 |
| Opinion surgeon (best sevoflurane) | 16 (88.89) | 20 (95.24) | <0.01 |
| PGI‐I | 5.56 ± 1.32 | 2.87 ± 1.12 | <0.01 |
| CGI‐I | 5.89 ± 1.54 | 2.23 ± 1.07 | <0.01 |
Note: Quantitative variables: mean ± SD. Qualitative variables: n (%).Doses of morphine or sevoflurane expressed in mg and mL. Opinion surgeon: Best analgesic regimen according to surgeon.
Abbreviations: CGI‐I, clinical global impression of improvement scale; VAS, visual analogue scale; VRS, verbal rating scale (none, slight, moderate or severe); PGI‐I, patient or family global impression of improvement scale.
In the sevoflurane group, three patients experienced a slight burning sensation during the application. Two patients reported erythema and pruritus. No systemic adverse effects were detected. In 36 cases (92%), the surgeon considered the analgesic effect to be better than the opioid regimen. Differences in PGI‐I and CGI‐I scores between both groups were statistically significant and favoured the sevoflurane group (P < 0.01).
Results of bacterial cultures of PUs were positive in 144 cases (75 cases in the opioid group and 69 cases in the sevoflurane group) (Table 4). The predominant organisms were Staphylococcus, Enterobacter, Pseudomonas, and Enterococcus.
Table 4.
Patient's microbiology
| IV Opioids (n = 24) | Topical Sevoflurane (n = 24) | P | |
|---|---|---|---|
| Bacterial burden | 0.75 | ||
| Contamination | 16 (66.67) | 17 (70.83) | 0.55 |
| Colonisation | 10 (41.67) | 8 (33.33) | 0.71 |
| Infection | 8 (33.33) | 6 (25) | 0.53 |
| Pre‐treatment microbiology | |||
| Gram negative | 12 (50.00) | 11 (45.83) | 0.77 |
| Gram positive | 12 (50.00) | 14 (58.33) | 0.56 |
| Fungal | 3 (12.50) | 2 (8.33) | 0.63 |
| Microbiology | |||
| Gram negative | 29 | 24 | 0.63 |
| Gram positive | 42 | 45 | 0.85 |
| Fungal | 4 | 0 | 0.04 |
| VAP | 4 (16.67) | 1 (4.17) | 0.16 |
| Bacteraemia | 5 (20.83) | 4 (16.67) | 0.71 |
| Urinary tract infection | 3 (12.50) | 4 (16.17) | 0.68 |
| MDROs | 22 (29.00) | 27 (39.00) | 0.11 |
Note: Quantitative variables: mean ± SD. Qualitative variables: n (%). Levels of bacterial burden: (a) Contamination (bacteria in a wound), (b) colonisation (bacteria are replicating. Host remains in control), (c) infection (invasion of the soft tissues).
Abbreviations: VAP, ventilator‐acquired pneumonia; MDROs, multiple drug‐resistant organisms.
Variation of hepatic and renal functions during treatment with instillation of topical sevoflurane are shown in the Figure 1.
Figure 1.
Variation during treatment with instillation of topical sevoflurane for the renal function (BUN, blood urea nitrogen and creatinine), liver damage by glutamic pyruvic transaminase (ALT, alanine amino transferase) and glutamic oxaloacetic transaminase (AST, aspartate amino transferase), gamma‐glutamyl‐transpeptidase (GGT), plasma cholinesterase as evaluation of the liver reserve, and alkaline phosphatase (FA) as evidence of cholestasis
4. DISCUSSION
When compared with opioids at standard doses, this study found that topical sevoflurane achieved a more intense pain relief, which was had earlier‐onset and long‐lasting characteristics and included the cleaning and debridement‐related pain.
Sevoflurane is an inhaled halogenated anaesthetic agent whose efficacy by topical use in the treatment of vascular ulcers has been reported in a number of studies; however, the mechanism of action has not been fully elucidated, and larger studies are necessary.14, 15, 16, 17Some evidence suggests this might be related to its relatively high partial pressure on peripheral nociceptors. Fassoulaki et al showed a blockade of mechanical stimulus when sevoflurane and halothane were topically applied to skin.14 In addition, the inhibition of sodium and activation of potassium channels, as well as the calcium channel‐mediated vasodilation and temperature increase, have all been postulated to play a part in its analgesic action.15 PUs constitute a significant cause of pain and distress, leading to impaired quality of life.
The lidocaine‐prilocaine cream, EMLA (Eutetic Mixture of Local Anaesthetics, Astra Zeneca), is the only topical cream for reducing the pain from sharp debridement of chronic leg ulcers and burns after application for 30 to 45 minutes and decreased the occurrence of post‐debridement pain during the first 4 hours, compared with control patients.16 Our results with topical sevoflurane show a fast onset of action, as well as a durable response.
In recent years, a number of studies on the successful use of topical sevoflurane on vascular ischaemic ulcers has been published.17, 18, 19 In the same line, but conducted in a somewhat different setting, other authors have reported an improvement in pain scores after topical sevoflurane administration in patients with oncological ulcers, which was also associated with a decrease of opioid requirements.20, 21 In all these studies, sevoflurane achieved rapid, intense, and durable pain relief.
In our experience, incorporation of the topical sevoflurane produced a very fast and durable symptomatic relief and helped reduce the opioid requirement in the first 7 hours. Most of the patients and surgeons showed high satisfaction with treatment of topical sevoflurane. Aggressive opioid‐based pain control has important associated morbidity. The opioids can stimulate tumour growth by acting directly on mu opioid receptors by increasing angiogenesis or by inducing immunosuppression and the recurrence‐free or overall survival of patients.10 Opioid‐free and multimodal analgesia target different pain receptors and pain transmission pathways, both peripherally and centrally. The use of non‐opioid analgesics can have synergistic effects that optimise analgesia while simultaneously preventing adverse effects of opioid medications. With a new philosophy, anaesthetists should consider where we can safely achieve pain control using a different variety of receptors by utilising highly specialised agents such as sevoflurane. Patients treated with topical sevoflurane experienced less pain and a reduction of pain associated with toileting and debridement of PUs.
Furthermore, tolerance or loss of efficacy over time was not observed with sevoflurane use, which seems to indicate the absence of deafferentation phenomena common with other topical therapies such as capsaicin.22 Topical sevoflurane decreases or avoids use of other conventional analgesic drugs, improving the experience of wound cleaning without adversely affecting wound healing. The mechanism of action is unknown, but vasodilator, anti‐inflammatory, and analgesic effects are suggested. The anti‐inflammatory potential of sevoflurane has been confirmed in several clinical studies.23 As such, it cannot be excluded that clinical benefits are observed at higher concentrations. Although systemic toxicity limits the dosing, high local concentrations can be established during local, direct administration to an organ at risk. Systemic absorption from a venous ulcer appears to be slow and incomplete.
Wound size decreased progressively in patients after 4 weeks of treatment. The sevoflurane promoted wound healing because the WSA decreased more than that of the opioids group. In terms of comparisons, it is emphasised that topical sevoflurane did not show healing potential higher than standard care for PUs.
Multiple factors predispose patients to PUs in the ICU. In our patients, mean ± SD APACHE II, basal comorbidity, McCabe score, ASA, hospital stay, mortality, and history of surgery were not significantly different between the sevoflurane and opioids groups. Several topical agents such as zinc sulphate, phenytoin, ethosuximide, misoprostol, lidocaine, nifedipine, gentamicin, vitamin A, insulin, atorvastatin, and metronidazole are examples of drugs being prescribed to treat wounds (accelerate epidermal resurfacing and the healing process) in cream formulations, macerated pills, gel, and spray in off‐label prescribing.24 The exact mechanism through which topical medications induce tissue healing is unclear. The spectrum effects include anti‐inflammatory, anti‐oxidative, immunomodulatory, and antibacterial activities; improvement in microvascular function and reperfusion has been shown to be important in the wound‐healing process. In the future, we could work on a mixture of halogenated anaesthetics because of their important analgesic effect with topical medications that induce tissue healing.
In terms of safety outcomes, sevoflurane was well tolerated. The main local adverse effects were mild and transient, including hot sensation, pruritus, and erythema. No systemic adverse effects were detected. In all cases (39 patients), complete blood counts and results of electrolytes analyses and renal and liver function test were unremarkable.
Presence of bacterial infection is a common complication in PUs. Despite the results of bacterial cultures suggesting a high positive infection rate of the PUs wounds (79/112, 70%), severe and long‐lasting wound infection may significantly delay the healing time or result in the occurrence of refractory/non‐healing wound.25 Meanwhile, radical debridement and washout reduced the bacterial load on the wound significantly. Topical sevoflurane with a fast and long‐lasting analgesic effect helps in debridement. In this study, we found that bacterial colonisation clearance was not statistically significant when the two groups were compared. Dressing change and administration of culture‐sensitive antibiotics intravenously in the perioperative period may also account for the absence of postoperative infection.
Our study has three major limitations. First, it was conducted in only one public centre and had a small sample size, and the duration of our patient's follow‐up (28 days) was shorter in comparison with a number of similar clinical studies, which compromises its external validity; however, the simplicity of the intervention allows for eventual generalisation, and the follow‐up time appears to be sufficient for wound epithelisation and detection of clinically significant wound healing. Second, there was a lack of scientific measurements for the cutaneous wound healing, such as skin biopsy and histopathologic evaluation of healing process. Finally, we cannot ignore the fact that awareness of good clinical practices by nurses could have contributed to better clinical outcomes as they knew they were being observed (Hawthorne effect), regardless of any intervention. However, this is a collateral benefit that has been frequently described in before‐after quality studies. The main strength of this study is the possibility of generalisation to any hospital setting, no matter the available resources. Further large, multicentre studies are warranted to elucidate the beneficial clinical role and mechanisms of topical sevoflurane alone or in combination with other protective agents for treatment of PUs in patients in different clinical settings.
5. CONCLUSION
Study findings suggest that sevoflurane is a viable and promising treatment option for PUs. Future studies are needed to confirm these results and to examine the efficacy and feasibility of this drug for PUs across care settings.
Fernández‐Ginés FD, Cortiñas‐Sáenz M, Agudo‐Ponce D, et al. Pain reduction of topical sevoflurane vs intravenous opioids in pressure ulcers. Int Wound J. 2020;17:83–90. 10.1111/iwj.13235
This study is to be included in the work submitted by the corresponding author, F. Dámaso Fernández‐Ginés, as part of the Doctorate Program in Pharmacy by the University of Granada, Spain.
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