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KEYWORDS Summary A multitude of household and occupational compounds have the potential to
Chemical burn; induce chemical burns to the eye and skin. Without prompt intervention, irreversible visual
Diphoterine; loss and disfigurement may prevail. Diphoterine and Hexafluorine are amphoteric and hyper-
Hexafluorine; tonic chelating solutions used in the management of general chemical and hydrofluoric acid
Review burns, respectively. They rapidly neutralise both acid and alkali agents without heat release
and limit diffusion, making them superior to water irrigation alone. However, although
Diphoterine and Hexafluorine uptake is slowly increasing in industrial workplaces, there is
a paucity of education and use in both emergency departments and plastic surgery units world-
wide. Herein, we present a case report of combined ocular and cutaneous acid burn treated
with Diphoterine, together with a review of the current supporting literature.
Crown Copyright ª 2017 Published by Elsevier Ltd on behalf of British Association of Plastic,
Reconstructive and Aesthetic Surgeons. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564
Case study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564
Pathophysiology of chemical burn injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564
Traditional management strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564
The evidence for Diphoterine and Hexafluorine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565
Recommendations for practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
* Corresponding author. Department of Plastic Surgery, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 3AB, UK.
E-mail address: christopher.lewis@nuth.nhs.uk (C.J. Lewis).
http://dx.doi.org/10.1016/j.bjps.2017.02.013
1748-6815/Crown Copyright ª 2017 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. All rights
reserved.
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564 C.J. Lewis et al.
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The role of Diphoterine 565
clothing) followed by copious flowing irrigation to dilute the compelling. Gérard et al.30 identified that early eye irri-
chemical.2,15,16 This strategy is taught worldwide and is pro- gation with Diphoterine following ammonia treatment
moted in a number of life support courses including the dramatically neutralized the base effect, with preservation
Advanced Trauma Life Support (ATLS) and Emergency of cytological architecture and reduced stromal oedema
Management of Severe Burns (EMSB) courses. Although compared to those in eyes treated with saline alone.
sound in its objectives, this management strategy is not Similarly, Langefeld24 identified that the buffering capacity
perfect17,18 as there is no measure for the adequacy of lavage of Diphoterine was greater for acids and bases than for
apart from pH monitoring of the burn site.17 Irrigation may be phosphate buffer or Hartmann’s solution. Schrage31 illus-
performed for up to 2 h2 to return the skin’s pH to between 5.5 trated further encouraging results, finding that
and 9 (safe limits). However, this puts the patient at risk of Diphoterine could reduce anterior chamber pH following
profound hypothermia, both from evaporative losses from the an alkali burn with as little as 5 min of irrigation compared
burn and the unwarmed lavage fluid.2 Furthermore, as water to that in saline-treated controls. Rihawi32 exposed ex vivo
is hypotonic, it has been suggested that it may propagate cornea to sodium hydroxide and once again found that
further penetration of chemicals into tissues.13,18,19 water and saline were less efficient than Diphoterine in
Changes to Management - What options are available returning pH to within an acceptable range. Fosse33 illus-
other than water lavage? trated that tetramethylammonium hydroxide, a quaternary
ammonium compound used in etching, required 17 times
1. If newer compounds are not available, irrigation with more water to normalise pH, after which only one-third of
isotonic or hypertonic crystalloid solutions and not hy- the cells remained viable compared to the two-thirds after
potonic water is recommended, the hypothesis being to being treated with Diphoterine.
draw out the damaging agent rather than causing ab- In addition to rapidly changing the tissue pH through
sorption of hypotonic water, increasing intracellular chelation, Diphoterine may also modulate inflammation
distance and perpetuating the environment for the and pain25 through effects on neurotransmitters.34 Circu-
injurious chemical.13,18,19 lating levels of substance P, which plays regulatory roles in
2. Diphoterine is a commercially available amphoteric and inflammation and pain modulation, were lower when skin
hypertonic chelating solution used to decontaminate and burns were treated with Diphoterine than with saline.
irrigate chemical splashes20,21 and is produced by Labo- Levels of beta-endorphin, which is an endogenous opioid
ratoire Prevor (Valmondois, France). It is available in neuropeptide, are increased following Diphoterine irriga-
several sizes depending on the volume of chemical splash: tion of cutaneous chemical burns.34 Taken together, this
50/500 mL eyewash, 100/200 mL spray canister and 5 L suggests that inflammation is abated and pain is improved
canister. Initially developed as a readily accessible following Diphoterine treatment,25 potentially because of
eyewash for those based in industrial environment, it has the limitation of tissue destruction.
been shown to be effective in vitro in neutralizing acid and Following successful ex vivo and murine in vivo studies,
base splashes to the eyes and skin and is water soluble.20,21 focus has now turned to the role of neutralizing agents in
It has low toxicity and does not irritate the skin or eyes.20e25 clinical practice, and a number of case studies have advo-
3. Hexafluorine (Laboratoire Prevor; Valmondois, France) cated its use. To confirm animal data, Langefeld24 and
is an amphoteric, hypertonic and polyvalent chelating Lynn25 assessed the efficacy of Diphoterine for eye and
solution designed specifically for the decontamination of skin irrigation, finding it to have safety comparable to that
HF cutaneous and ocular splashes.26 It is available as a of saline. Nehles35 reported the first clinical use of
portable and wall-mounted eyewash and 5 L canister. In Diphoterine in the management of cutaneous and ocular
addition to the irrigation effect, the hypertonic acid/alkali burns during the 1990s, with further studies
Hexafluorine limits tissue penetration27 and neutral- highlighting its potential role in both the management of
ises/chelates the free hydrogen and fluoride ions ocular and cutaneous burns. Merle36 reported their expe-
responsible for tissue damage. Because of the nature of rience of Diphoterine in the management of alkali ocular
HF, dilution with water is not sufficient to prevent burns burns, finding corneal re-epithelialisation time to be
and potentially life-threatening hypocalcaemia. Indeed, significantly shorter following amphoteric wash than with
in vivo research26 demonstrated that a single saline. Donoghue20 evaluated the role of Diphoterine in
Hexafluorine application significantly limited burn cutaneous alkali burns, finding significantly better out-
evolution when applied to a cutaneous HF injury comes in those treated with the solution than those treated
compared to both water and calcium gluconate appli- with water, with a significant reduction in the number of
cation. Serum calcium levels remain stable in vivo patients exhibiting blistering and other clinical stigmata of
following Hexafluorine wash and drop after water irri- a chemical burn. Zack-Williams37 reported that in a large
gation.26 Ex vivo data has histologically illustrated limi- cohort study, delayed application of Diphoterine signifi-
tation of HF ingress and tissue damage following cantly altered cutaneous wound pH compared to that with
Hexafluorine wash in both the skin28,29 and cornea.14 saline irrigation but did not alter the need for surgery or
time to healing. This study, however, lacked a time-
matched injury control group.
The evidence for Diphoterine and Research has also focussed on the role of chelating
Hexafluorine washes in the management of chemical warfare agents.
Nitrogen mustards are an abundant warfare agent, pri-
Ex vivo and in vivo murine data supporting the role of marily designed to affect the eyes.38,39 The use of this gas is
Diphoterine in the management of chemical injuries is not historic, and it has recently gained notoriety again for
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566 C.J. Lewis et al.
its use during the Syrian conflict.40 Goldich41 identified that Funding
immediate ocular irrigation with Diphoterine was more
effective than saline in reducing corneal, iris and anterior The authors received no funding from an external source.
chamber injury secondary to mustard gas, with corneal
opacity and corneal neovascularization attenuated and iris
atrophy delayed.38 Viala42 assessed the role of amphoteric Conflict of interest
wash in the treatment of ortho-chlorobenzylidene malo-
nonitrile (CS) ‘tear gas’, finding rapid relief or negation of
The authors declare no conflict of interest.
symptoms when applied prior to gas exposure in military
personnel, although this study was limited by the less
number of participants and an absent control group.43
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The role of Diphoterine 567
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