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Journal of Plastic, Reconstructive & Aesthetic Surgery (2017) 70, 563e567

Review

Is it time for a change in the approach to


chemical burns? The role of Diphoterine
in the management of cutaneous and ocular
chemical injuries
C.J. Lewis*, A. Al-Mousawi, A. Jha, K.P. Allison

Department of Plastic Surgery, James Cook University Hospital, Middlesbrough, UK

Received 22 December 2016; accepted 17 February 2017

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.

Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566


References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566

Introduction Corneal pH was 7, but fluorescein uptake was evident in the


central cornea. Further irrigation with 2 L of normal saline
Chemical agents include acids, alkalis, oxidising and maintained a pH of 7. Blistered areas were de-roofed, and
reducing agents, alkylating and chelating agents, and sol- liquid paraffin and Polyfax (Polymyxin B, Bacitracin, Teva,
vents. They cause injury by producing a chemical interaction UK) ointments were regularly applied to the face, ears and
that can lead to extensive tissue destruction and extreme forearm and Hypafix (BSN Medical, UK) dressing applied
pain. Injuries may not be immediately obvious, and there directly to the back and left shoulder burns. He was dis-
can be a delay in presentation.1 These injuries account for charged 5 days following admission with outpatient follow-
only 3% of all burns but lead to approximately 30% of burn up in the ophthalmology and plastic surgery dressing clinics
deaths,2 usually secondary to ingestion in children. and psychology referral for further support. Follow-up at 1
Chemical ocular burns account for between 7.7% and week showed the wounds to be healing well with no signs of
18% of all eye trauma3 Typically, young males working in infection, erythema or discharge. No further ocular
industrial environments such as factories, chemical plants sequalae were identified.
or laboratories are the most common patient group,4e7 with
more than 70% of eye burns occurring at work and sec- Pathophysiology of chemical burn injuries
ondary to an alkali.6 In addition to accidental and occupa-
tional exposure, increasing numbers of men and
A chemical splash to the skin or eye causes a sudden change
particularly women both in the UK and overseas are the
in tissue pH followed by pH-dependent tissue destruction
victims of violent assault when acid is thrown on their face,
and denaturation of proteins.4,9e11 However, pH alone is
resulting in life-changing cutaneous and ocular injuries.8
not the sole determinant of damage; a multitude of factors
The main determinants of the degree of injury are con-
are involved including chemical temperature, volume,
centration of the agent and site and duration of exposure.
impact force, concentration and osmolality.2,4,12
Without prompt intervention, irreversible visual loss and
Alkaline agents, such as sodium hydroxide found in drain
cutaneous disfigurement may prevail.4 Immediate contin-
cleaner, typically penetrate more deeply than acids, and
uous irrigation with water has been the usual first-line
through the processes of liquefactive necrosis, hydroxyl
treatment for chemical burns, regardless of the nature of
ions cause the saponification of fatty acids in cell mem-
the chemical involved, with the aim to mechanically rinse
branes and cell lysis.4,11 In the eye, once the corneal
and dilute the agent and limit the injury. Diphoterine is an
epithelium is breached, alkaline solutions can destroy the
amphoteric and hypertonic chelating solution used in the
trabecular network leading to secondary glaucoma4 and
management of chemical burns. It rapidly neutralises both
penetrate the anterior chamber causing inflammation of
acid and alkali agents without heat release and limits diffu-
the iris, lens and ciliary body.4 In contrast, acids cause a
sion, making it a superior agent than water for irrigation as an
coagulative necrosis, i.e. the free hydrogen ions denature
active treatment for chemical injuries. Although
and precipitate proteins, which results in a mechanical
Diphoterine uptake is slowly increasing in industrial work-
barrier to limit further damage.4
places,7 there remains a paucity of both education and use in
Hydrofluoric acid (HF) burns are rare but dangerous. HF
emergency departments and plastic surgery units world-
is a solution of inorganic anhydrous hydrogen fluoride in
wide. Herein, we present a case report of combined ocular
water. It is used extensively in a variety of industries, e.g.
and cutaneous acid burn treated with Diphoterine, together
glass etching, aerospace industry (where it is used to clean
with a review of the current supporting literature.
aluminium), for scouring metal and as a leather tanning
agent. It is also present in household rust removal and
cleaning products.13 HF is transported and stored under
Case study high pressure, with concentrations varying from approxi-
mately 100% for industrial use to 0.5% for domestic use.13
A 37-year old chemical engineer was sprayed with hot sul- Although a weak acid, HF does not readily dissociate,
phuric acid (35% concentration at 85  C) to the face, eyes allowing it to penetrate through the skin and corneal
and upper body whilst at work. First aid at scene comprised epithelium easily.13 Once in the deeper tissues, HF disso-
of decontamination with both a Diphoterine autonomous ciates and free fluoride ions cause liquefactive necrosis and
portable shower and Diphoterine eyewash within minutes chelation of intracellular calcium and magnesium,14
of the injury. resulting in rapid irreversible damage.
Burn size was evaluated as being 4.5% of the total body
surface area: mixed-depth dermal burns to the face, right
eye, back, left shoulder and posterior neck. There was mild Traditional management strategies
swelling and blistering of the lips but no evidence of airway
compromise or ingestion of the chemical. Ophthalmic First aid for chemical burns of the skin and eyes involves
evaluation demonstrated visual acuity to be 3/3.75. removing the compound from body contact (e.g. removing

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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
However, Diphoterine does have limitations and is not References
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