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Larval therapy for leg ulcers (VenUS II): randomised controlled trial

BMJ 2009; 338 doi: (Published 20 March 2009) Cite this as: BMJ 2009;338:b773

Wound Pain in Larval Therapy (Part 1)

Heike Elfriede Heuer, Lutz Heuer, AGILTERA GmbH & Co. KG,
Dormagen, Germany Christian Fleck, Institute of Pharmacology and
Toxicology, Friedrich Schiller University Jena, Germany Dormagen, 2011-02-

Dear Editor:

Published in 2009 and studied in the years before hydrogels and
larval therapy have been compared in a randomized controlled clinical
trial (VenUS II) [1]. The primary outcome of this study was time to heal
of the largest eligible ulcers. Not surprisingly the authors found that
healing was not significantly different between larvae and hydrogels, as
the cause for the ulcer cannot be removed by debridement only. The cost
occurred of both techniques were found to be equal, too [2]. One secondary
outcomes of VenUS II was the ulcer related pain during debridement. The
mean pain scores doubles for the larvae treated patients compared to the
hydrogel treated ones. This occurred without significant difference
between loose and contained larvae. It's known that pain is one possible
consequence of larval debridement [3,4]. Nevertheless its intensity
compared to hydrogels was surprisingly high.

We were interested in the reason for pain during larval treatment. As
larvae are believed to remove dead tissue only, pain is something which
should not occur. On the other hand previously published studies assume
the pain to arise from the damage of sensitive edges of wound. Hereby,
unprotected skin surrounding the wound is the main reason for pain
[4,5,6]. In case maggots would attack vital cells of living tissue, this
cannot be observed on patients, as it is always unclear, if the tissue
remove by larval debridement was dead or still alive. In a human cell
tissue experiment we checked for the possible toxicity of larval fluids.
As a cell tissue in a matrix would be destroyed by the movement of the
maggots within minutes, we used contained maggots only for this study. In
this 3D reconstructed model of human skin, which shows the natural layers
of stratum basale, stratum spinosum, stratum granulosum and stratum
corneum the interaction of larvae's juices on human fibroblasts were
studied [7]. After 72 h (37?C, 5% CO2, 95% humidity) of contact of human
skin to larvae, which are placed in a gauze bag to focus on chemical and
exclude mechanical interaction, the human skin model was analysed after
fixation in paraffin and dyeing the cells using haematoxylin-eosin (HE-
dying). Nearly all cells of stratum basale, stratum spinosum, stratum
granulosum and stratum corneum have been destroyed on contact with the
larvae's juices where the untreated samples show the usual texture of
living human skin. Only some single cells existed but are not in their
typical shape. Vital cells were removed in almost all parts of the human
skin matrix model and fibroblasts were destroyed. Only a few, ball-shape
fibroblasts were seen in the cell matrix. The observation that fibroblasts
were almost fully destroyed was most confusing as there are two literature
reports that the juices of Lucilia sericata maggots should have - doses
dependant - positive effects on fibroblasts [8,9].

Finally we checked the influence of larvae on a restricted area of
unhurt human skin in self treatment experiments. In case the larvae would
attack the viable skin, pain would be expected. In these experiments
Larvae therapy was investigated using five different materials / products
of the biggest known producers in Europe and USA. Suprasorb F (Lohmann
& Rauscher, Neuwied, Germany) was used to cover an unhurt skin area of
10 x 10 cm. Into the dressing a diagonal hole of 1 cm was cut allowing the
larvae free access to the unhurt skin. Onto this "wound edge" the
different dressings as directed by the producers' were placed and kept
moist by 0.9% of sodium chloride solution. The time to the first onset of
pain was measured and the experiment was followed until pain becomes
unbearable or after reaching the mean recommended time of using larvae
dressing (3 days). The analysis of skin treatment by larvae was done
optically and documented by photography. The results recorded in the
categories: no effect, clear effect, strong effect. The only correlation
observed was the amount of larvae used. More larvae meant more deletion of
skin and tissue and more pain.

In a second experiment larvae were again allowed to stay on unhurt
human skin and their interaction with the skin was now documented by video
of a microscope (dnt DigiMicro 2.0 Scale digital microscope camera) at a
magnification of about 30-35x. For easy observation the crystal clear
bottom of a Petri dish was used as a window for the video camera within
the dressing. Pictures were taken during the whole time of about 24 h and
the experiment was stopped, when pain becomes unbearable. In this study
design optical impressions and pain could be studied parallel. In a rather
short time (some hours to one day) the larvae attack the skin and etch a
wound on all contact to skin surface by their juices. Pain is very strong
when larvae have opened the epidermis. The intensity of pain depends on
the actual physical presence onto the new wound. Many larvae meant strong
pain, fewer larvae less pain, and no larvae itching only. All larvae were
bred from own sources or bought from BioMonde, Barsb?ttel, Germany (BioBag
50). The larvae used were all very agile medical grade maggots. Larval
therapy was undertaken according to producers' recommendations.
Surprisingly within hours the larvae fluids attacks both viable skin and
healthy tissue; this was followed by considerable pain. No major
difference was observed if larvae were loose or contained; in the case of
latter only the larvae fluids could interact with skin.

Discussion and references in Part 2

Competing interests: Correspondence author (E.H.) and Co-author (L.H.) declares that as producers of larval products for debridement in wound therapy we have an interest in progress of larval therapy. Co-author (C.F.) declares that there is no conflict of interest to the rules of the International Committee of Medical Journal Editors.

07 March 2011
Heike Elfriede Heuer
Lutz Heuer, Christian Fleck
Agiltera GmbH & Co.KG