The prevalence of peripheral arterial disease (PAD) involving the lower extremities is increasing worldwide as a result of ageing populations, continued cigarette smoking, the diabetes epidemic and increasing obesity rates.1 Critical limb ischaemia (CLI) is the most advanced form of PAD, and is defined as the presence of chronic ischaemic pain at rest, ulceration or gangrene attributable to objectively proven arterial occlusive disease.2 CLI is associated with a high risk of cardiovascular events, including major limb loss, stroke and death.3 There are a number of treatments available for CLI, including pharmacologic therapy, interventional procedures and surgery, as well as other additional treatments, such as hyperbaric oxygen therapy, spinal cord stimulation4 and intermittent pneumatic compression.5
Maggot debridement therapy (MDT) plays an important role in the management of hard-to-heal infected wounds and is used worldwide. MDT has a long history in the clinical setting and its effectiveness has been recognised since ancient times. In more modern times, Baron Dominique Jean Larrey, Surgeon-General in Napoleon's army, was the first to describe the benefits of MDT in writing. In 1931, William Baer, an orthopaedic surgeon at Johns Hopkins Hospital in Baltimore, reported the usefulness of MDT in patients with chronic osteomyelitis.6 Although the mechanisms underlying MDT are still not completely understood, laboratory studies have identified various effects of larval secretions/excretions.7 MDT is now a widely accepted medical practice that has three main actions: debridement, disinfection and stimulation of tissue growth.8 Moreover, clinical and cellular evidence for the effect of MDT on wound healing has recently been discussed in detail.9
Ischaemia has been considered a relative contraindication to larval therapy because a non-perfused wound is unlikely to heal.10 However, with advances in the treatment of PAD, the indications for MDT have been extended to include ischaemic ulcers, including CLI. Our group has reported the effectiveness of MDT for CLI based on an increase in skin perfusion pressure (SPP) after treatment.11 A few reports also have documented its effectiveness in patients with ischaemic ulcers.12,13
This extension of the applications of MDT is supported by laboratory studies suggesting that amino acid derivatives in larval secretions had pro-angiogenic effects in a human endothelial cell line and accelerated the growth of blood cells.14 There are also other experimental data showing that larval secretions enhance the production of vascular endothelial growth factor.15,16
In this article, we describe five patients with CLI in the lower extremities who were treated by MDT and discuss the possibility of using MDT to treat ischaemic ulcers.
Methods
Four male patients and one female patient with CLI were treated with MDT between January 2013 and December 2017. All five patients had ulcers in the lower extremities that had not responded to revascularisation therapy. Therefore, MDT was used as an adjunctive therapy.
One or two cycles of MDT were performed between the patients (eight cycles in total). The maggots were applied to each necrotic ulcer at a density of 5–10 larvae/cm2 (Japan Maggot Company, Okayama City, Japan) and were removed 48 hours later, by which time they had grown to about 10mm. This was counted as one treatment cycle. MDT cycles could be consecutive or at intervals of 2–3 weeks. We measured SPP around the ulcer on the dorsal and plantar aspects of the foot in the 24 hours before and after MDT. We also evaluated the extent of ulceration in each case on the basis of the proportion of necrotic tissue in the total ulcerated area and the presence of exposed necrotic bone. Maggots favour necrotic tissue, so the proportion of necrotic tissue in patients with CLI is important. The proportion of necrotic tissue classified as NT 1+ (<25%), NT 2+ (25–50%), NT 3+ (50–75%), and NT 4+ (>75%) in each case is shown in Fig 1. Each wound was coded into regions using the Procreate digital illustration App (Savage Interactive Pty Ltd., North Hobart, Tasmania) as follows: good granulation as red and necrotic tissue as blue. The ratio of each region was then calculated using Image J free software (National Institutes of Health, Bethesda, MD, US).
The study was approved by the institutional ethics committee of participating hospitals and was conducted in accordance with the ethical principles of the Declaration of Helsinki. All patients provided written informed consent.
Results
Patient characteristics and results are summarised in Table 1. In total, eight cycles of MDT were performed in five patients of mean age 66.2 (range: 61–71) years (two cycles of MDT for Cases 1–3, and one cycle each for Cases 4 and 5). An increase in SPP was confirmed on both the dorsal and plantar aspects of the foot after five cycles of MDT (two patients with two cycles each and one with a single cycle), as measured by a skin perfusion pressure system (Sensilate PAD 4000, Kaneka Medix Corp., Osaka, Japan); in all cases, ulceration status was graded as NT 3+ or NT 4+ and no exposed necrotic bone was present. Wound healing was accelerated under these conditions. However, a decrease in SPP was confirmed on the dorsal and/or plantar surface of the foot after three cycles of MDT (one patient with two cycles and one with a single cycle); in these cases, the ulceration status was NT 2+ with or without exposure of necrotic bone. Clinically, maggots were observed to aggregate around necrotic bone when present on the surface of the ulcer; but since they cannot feed on bone tissue they could not increase in size. In two Cases (1 and 3), complete wound healing was achieved within three months and no ulcer was found at follow-up. As a result of other diseases, two patients died.
Table 1. Summary of changes in skin perfusion pressure after maggot debridement therapy
| Case | Age, gender | Ulcerated lesion | Complication | First MDT | Second MDT | Outcome | Prognosis |
|---|---|---|---|---|---|---|---|
| Ulceration status | |||||||
| SPP change (mmHg) dorsal/plantar | |||||||
| 1 | 71, male | Medial aspect of the left foot | Chronic renal failure→haemodialysis | NT 4+, bone exposure (-)20⇒ +42/18⇒ +34 | NT 2+ bone exposure (-) 62⇒ +7/52⇒ -17 | Healed with ointment in 2.5 months | No ulcer in 52 months |
| 2 | 63, male | Lateral aspect of the sole of the right foot | Chronic renal failure→haemodialysis | NT 4+, bone exposure (-)15⇒ +40/15⇒ +0 | NT 3+, bone exposure (-)55⇒ +11/15⇒ +12 | Died of other disease in 3 months | |
| 3 | 61, male | Lateral aspect of the right foot | Diabetes mellitus | NT 2+, bone exposure (+)57⇒ -12/9⇒ +14 | NT 1+, bone exposure (+)45⇒ -12/23⇒ -6 | Healed with ointment in 3 months | No ulcer in 29 months |
| 4 | 71, male | Lateral aspect of the left foot | Chronic renal failure→haemodialysis | NT 3+, bone exposure (-)34⇒ +16/32⇒ +3 | Died of other disease in 3 months | ||
| 5 | 65, female | Medial aspect of the left lower leg | Chronic renal failure→haemodialysis | NT 4+, bone exposure (-)36⇒ +8/41⇒ +10 | Continuing treatment 4 months later | Ulcer persists after 4 months | |
MDT—maggot debridement therapy; NT—necritic tissue
Case reports
Case 1
A 71-year-old man presented with severe ulceration on the medial aspect of the left foot. He had a history of hypertension, kidney failure and atrial fibrillation, but no diabetes mellitus. He had already undergone several catheter interventions for CLI. The wound was non-responsive to our initial conservative therapy, including administration of hyperbaric oxygen, vasodilator and basic fibroblast growth factor. The ulcerated area was covered with a sufficient amount of necrotic tissue (Fig 2a) to be conducive to maggots, and therefore we applied two cycles of MDT. After the first cycle, the SPP on the dorsal aspect of the foot increased from 20mmHg to 62mmHg and that on the plantar aspect increased from 18mmHg to 52mmHg. Most of the necrotic tissue was removed (Fig 2b). After the second cycle of MDT, SPP was 69mmHg on the dorsal aspect and 35mmHg on the plantar aspect. Even though there was an insufficient amount of necrotic tissue in the wound before the second round of MDT (Fig 2c), most of the residual necrotic tissue was removed (Fig 2d). Wound healing seemed to have been successfully achieved by MDT. The wound was completely healed three months after MDT (Fig 2e).
Case 3
A 61-year-old man presented with dry gangrene of the fifth toe of the right foot. He was also found to have a swollen and reddish area under the right ankle, indicating severe infection. SPP in the right foot was 23mmHg dorsally and 11mmHg on the plantar aspect. Untreated diabetes mellitus was diagnosed. Catheter intervention was planned as first-line treatment, to be followed by surgical debridement with broad spectrum antibiotics and antidiabetic drugs. Anticipating progression of infection after reperfusion as a result of catheter intervention, debridement was scheduled to be performed on the next day of the intervention. After the intervention, SPP in the right foot increased to 51mmHg dorsally and 36mmHg on the plantar aspect. After surgical debridement and amputation of the fifth toe, we implemented conservative therapy comprising application of antibiotic ointment and administration of basic fibroblast growth factor. Still, the tissue around the surgical site became necrotic, and the wound did not respond to conservative treatment (Fig 3a). We thus performed two cycles of MDT, applied to the necrotic ulcers at a density of 5–10 larvae/cm2 for two days. Approximately 200 larvae were used in total. After the first cycle, the SPP decreased from 57mmHg to 44mmHg on the dorsal aspect of the foot and increased from 9mmHg to 23mmHg on the plantar aspect. There was exposed necrotic bone on the surface of the ulcer, and the maggots aggregated at this site (Fig 3b). After the second cycle of MDT, SPP decreased from 45mmHg to 33mmHg on the dorsal aspect of the foot and from 23mmHg to 17mmHg on the plantar aspect. Although the necrotic soft tissue had been removed, the necrotic bone remained (Fig 3c). The ulcer healed gradually after surgical removal of the necrotic bone. Complete epithelialisation was achieved after three months of treatment with antibiotic ointment (Fig 3d).
Discussion
This study presents two important clinical issues. First, an increase in SPP was observed after MDT in patients with CLI providing that there was sufficient necrotic soft tissue on the surface of the wound. Second, if exposed necrotic bone is present in the wound, maggots will selectively aggregate at this site causing a decrease in SPP, and thus impeding wound healing.
Regarding the first issue, SPP reflects the perfusion pressure at the level of skin, so is an index of the microcirculation in the skin and subcutaneous tissue. In laser Doppler therapy for foot ulceration, for example, the target is the blood at the capillary level.17 Therefore, an increase in SPP indicates increased blood supply at the skin level and improved peripheral circulation. Moreover, measuring SPP is a noninvasive procedure. In our cases, it is likely that the microcirculation in the superficial layer of the skin was improved by the increase in SPP observed in the tissue around the ischaemic area. Taken together, the above-mentioned laboratory findings and the clinically observed increased SPP suggest that MDT could improve local perfusion in patients with CLI.
Clinically, recalcitrant ulcers have been considered as being responsive to conservative therapy after MDT, ultimately resulting in complete healing. The efficacy of MDT has been proven in randomised clinical studies,18,19 and other beneficial effects of larvae on wounds, including antimicrobial activity, immunomodulation, angiogenesis, and tissue remodelling and regeneration, have been widely reported clinically and supported by experimental studies.14,20,21 In the cases presented here, recalcitrant ischaemic ulcers healed within 2–3 months after MDT. Recently, Pritchard et al. reported the concept of TIME management using medicinal larvae (Tissue, Infection and inflammation, Moisture imbalance and a non-migrating Edge).22 The healing process in our patients is consistent with this concept. In our experience, MDT provides conditions conducive to healing for ischaemic ulcers previously nonresponsive to conservative therapy.
The second clinical issue highlighted by this case report is the decrease in SPP observed after three of the rounds of MDT. The success of MDT is usually confirmed by the finding of grown maggots consuming necrotic tissue and by signs of wound healing, such as a decreased amount of necrotic tissue. However, in some cases, SPP decreased after MDT cycles and no grown maggots or signs of wound healing were observed. One reason for failed MDT is an insufficient amount of necrotic tissue in the ulcer for the larvae to feed on, meaning they cannot grow to their maximum size. Maggots favour macerated tissue, and so MDT is not usually indicated for dry gangrene.23 Our findings suggest that ulcers containing predominantly macerated necrotic tissue are good candidates for MDT, regardless of the degree of ischaemia. It is noteworthy that in our study, the maggots tended to selectively aggregate at the site of exposed necrotic bone on the surface of the ulcer. It is thought that the maggots could not grow because they cannot feed on hard necrotic bone. This is supported by the result that deeper wounds including infected bone and tendon negatively influenced the outcome of MDT.24
Study limitations
Our study has some limitations in that it had a retrospective design and the number of cases (five) was too small for statistical analysis or for any clear conclusions to be drawn. However, given the limited number of reports specifically addressing the use of MDT in CLI,25 our findings could help to pave the way for use of MDT in patients with CLI.
Conclusion
Our findings indicate that ischaemic ulcers are good candidates for MDT used as an adjunct to standard conservative treatment. Our observations also support the concept that MDT accelerates healing with the concept of TIME management of ulcers. However, more clinical data are needed and the efficacy and safety of MDT in CLI needs to be assessed in appropriately designed trials in the future.
Reflective questions
- Is maggot debridement therapy (MDT) considered to be contraindicated in ischaemic ulcers?
- What is the rationale supporting the possibility that MDT might be effective in critical limb ischaemia (CLI)?
- What are the necessary ulcer conditions in CLI for MDT to have the maximum effect?