Efficacy and safety of neutral pH superoxidised solution in severe diabetic foot infections - Biofact
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CLINICAL TRIAL
Efficacy and safety of neutral
pH superoxidised solution
in severe diabetic foot
infections
Fermı́n R Martı́nez-De Jesús, Antonio Ramos-De la Medina, José Marı́a
Remes-Troche, David G Armstrong, Stephanie C Wu, Jose Luis Lázaro
Martı́nez, Juan V Beneit-Montesinos
Martı́nez-De Jesús FR, Ramos-De la Medina A, Remes-Troche JM, Armstrong DG, Wu SC, Lázaro Martı́nez JL,
Beneit-Montesinos JV. Efficacy and safety of neutral pH superoxidised solution in severe diabetic foot infections.
Int Wound J 2007;doi:10.1111/j.1742-481X.2007.00363.x.
ABSTRACT
The use of antiseptics in wound care is often controversial and there is definitely a need for a non toxic, highly
disinfective agent. This study assessed the efficacy of a neutral pH superoxidised aqueous solution (NpHSS) for
infection control, odour reduction and surrounding skin and tissue damage on infected diabetic foot ulcerations.
From November 2003 to March 2004, 45 patients with type 2 diabetes were randomised into a single-blind
clinical trial comparing NpHSS (intervention group; n ¼ 21) versus conventional disinfectant (control group;
n ¼ 16). All patients received comprehensive care including surgical debridement as appropriate, moist wound
care, intensive glucose control and broad spectrum antibiotics. Treatment groups were matched in terms of sex,
age (619 119 versus 678 116), years of diabetes duration (164 81 versus 17 102), obesity,
HgAlc (71 2 versus 67 18), initial fasting glycaemia (163 59 versus 152 658 mg/dl), ulcer
duration/week (137 24 versus 151 163), B/A Index (09 05 versus 114 07), depth and extent of
infection/periwound cellulitis (groups B and C of the Tampico Hospital Classification) as well as aetiology
(P ¼ 0647). Odour reduction was achieved in all NpHSS patients (100% versus 25%; P , 001) and
surrounding cellulitis diminished (P , 0001) in 17 patients (809% versus 437%). Nineteen patients in the
NpHSS group showed advancement to granulating tissue stage (904% versus 625%; P ¼ 005) with
significantly less tissue toxicity (94% versus 312%; P , 001). A non toxic, NpHSS, as part of a comprehensive
care regimen, may be more efficacious in infection control, odour and erythema reduction than conventional
disinfectants in treatment of diabetic foot infections.
Key words: Antiseptics • Cellulitis • Diabetic foot • Infections • Wound healing
Authors: FR Martı́nez De Jesús, MD, Diabetic Foot Salvage and Prevention Center San Elian, Veracruz, Ver, Academia Mexicana de
Cirugı́a, International Working Group on the Diabetic Foot, México; A Ramos-De la Medina, MD, Department of Education and
Research, Veracruz Regional Hospital, Veracruz, México; JM Remes-Troche, MD, San Elian Diabetic Foot Center, Ver, Mexico; DG
Armstrong, DPM, MSc, PhD, Department of Surgery, Dr William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of
Medicine and Science and Center for Lower Extremity Ambulatory Research (CLEAR), Dr William M. Scholl College of Podiatric Medicine
at Rosalind Franklin University of Medicine and Science; SC Wu, DPM, MS, Department of Surgery, Dr William M. Scholl College of
Podiatric Medicine at Rosalind Franklin University of Medicine and Science and Center for Lower Extremity Ambulatory Research
(CLEAR), William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine and Science; JLL Martı́nez DPM,
Diabetic Foot Unit, Universidad Complutense de Madrid, Madrid, Spain; JV Beneit, Diabetic Foot Unit, Universidad Complutense de
Madrid, Madrid, Spain
Address for correspondence: FR Martı́nez-De Jesús, San Elian Diabetic Foot Center, Orizaba 198, Col. Zaragoza, Ver, Ver, Mexico
91910.
E-mail: ferminmdj@yahoo.com
ª 2007 Blackwell Publishing Ltd and Medicalhelplines.com Inc 1
• International Wound Journal • doi:10.1111/j.1742-481X.2007.00363.x
Superoxidised solution in diabetic foot infections
INTRODUCTION properties. Some products as the wound
Key Points cleansers help to break the bond between
Infected foot ulcerations are a frequent cause
• most of the chemicals disinfec- of morbidity, hospitalisation and amputations contaminates, necrotic tissue and the surface
tants currently used in wound among persons with diabetes (1). The attribut- of the wound (15,16).
care can cause damage to the able cost of caring for a primary healing foot An effective non toxic antiseptic agent that
skin or granulating tissue
ulcer for 3 years after the initial diagnosis can cleanses the wound and removes bacterial
• an effective non toxic antiseptic
agent that cleanses the wound amount to over $26 000 (2). The survival rate contaminants without damaging healthy tissue
and removes bacterial contami- of patients who develop diabetic foot ulcers is is therefore needed to help diminish the bacterial
nants without damaging healthy reduced by about 15%, and at 5 years, these burden and prevent the substantial long-term
tissue is therefore needed to patients have approximately a 50% survival morbidity associated with amputations.
help diminish the bacterial bur-
rate usually after arterial interventions and Superoxidized aqueous solution is non toxic,
den and prevent the substantial
long-term morbidity associated amputations (3,4). neutral pH water that contains reactive oxygen
with amputations Diabetic patients are prone to develop foot species (ROS) generated by the electrolysis of
• in this randomised, controlled, ulcerations because of the lack of neurological sodium chloride and water. Components of
single-blind study, our aim was sensation and cycles of repetitive stress from this solution includes superoxide – neutral pH
to assess the efficacy of a non-
ambulation. Rates of ulceration, infection and water, chlorine ,85 parts per million (ppm),
toxic, neutral pH superoxidised
aqueous solution (NpHSS) in amputation have declined dramatically in ROS/free radicals, oxidised water H2O;
terms of infection control, some centres that have developed programmes 9999%, sodium hypochlorite (NaOCl) ,50
odour reduction and periwound and teams for foot care. Infection still remains ppm, hypochlorous acid (HOCl) ,60 ppm,
skin affection in infected dia- a common problem in diabetic patients (5–8). hydrogen peroxide (H2O2) ,4 ppm, ozone
betic foot ulcerations
Ulcerations are pivotal events leading to (O3) ,02 ppm, chlorine dioxide (ClO2) ,15
• between November 2003 to
March 2004, 45 consecutive diabetic foot infection, which has been shown ppm, sodium hydroxide (NaOH) ,8 ppm,
patients with type 2 diabetes to be the immediate cause of amputations in sodium carbonate (Na2CO3) ,21 ppm, sodium
and infected, deep diabetic 25–50% of the cases (2). This is especially true chloride (NaCl) ,110 ppm. The bactericidal
foot ulcers who presented for of deep space infection, which is associated advantages and wound healing properties of
care at the San Elian Diabetic
with an amputation rate of 52% (2). The ROS has been documented (13). Superoxidised
Foot Salvage and Prevention
Center (SEDFSPC) in Veracruz, resultant amputations are minor in 24–60% of water has been shown to be a powerful non
Mexico; they were initially the cases and major in 10–40% (2). toxic bactericidal against a variety of aerobics
selected for the study by use The spectrum of foot infections in diabetic Gram-negative and Gram-positive rods (17)
of a randomly alternate assign- patients ranges from simple superficial celluli- and is highly effective in treating infectious
ment to either NpHSS or
tis to chronic osteomyelitis. Infections in skin conditions and refractory ulcers associ-
standard management (control
group) patients with diabetes are often difficult to ated with diabetes mellitus or peripheral
treat because of impaired microvascular circu- circulatory insufficiency (18,19).
lation, which limits the access of phagocytic In this randomised, controlled, single-blind
cells to the infected area and results in a poor study, our aim was to assess the efficacy of
concentration of antibiotics in the infected a non-toxic, neutral pH superoxidised aqueous
tissues (9). Wound healing is delayed when solution (NpHSS) in terms of infection control,
acute infection persists (10–12). Infection con- odour reduction and periwound skin affection
trol along with appropriate debridement and in infected diabetic foot ulcerations.
good wound care are all essential factors in the
treatment of diabetic foot ulcerations. Most of
MATERIALS AND METHODS
the chemicals disinfectants currently used in
wound care can cause damage to the skin or Patients and baseline evaluations
granulating tissue. Topical antiseptics such as Between November 2003 to March 2004, 45
hypochlorite (Dakin’s solution), povidone consecutive patients with type 2 diabetes and
iodine (betadine) and others can cause signif- infected, deep diabetic foot ulcers who pre-
icant cell damage. This may not only interfere sented for care at the San Elian Diabetic Foot
wound healing process (13), but also could be Salvage and Prevention Center (SEDFSPC) in
cytotoxic or deleterious for the underlying Veracruz, México were initially selected for
tissues or proximal skin (14). Furthermore, the study by use of a randomly alternate as-
normal sterile saline or water, although non signment to either NpHSS or standard man-
cytotoxic, do not adequately remove surface agement (control group). All patients gave
contaminates and does not have antiseptic a written informed consent, and the study was
2 ª 2007 Blackwell Publishing Ltd and Medicalhelplines.com Inc
Superoxidised solution in diabetic foot infections
reviewed and approved by the human subjects Standard of care treatment and
Key Points
SEDFSPC Ethics Committee. therapeutic intervention
The inclusion criteria involved patients with Patients were randomised using randomly • patients were randomised using
type 2 diabetes older than 18 years of age with alternate assignment to either NpHSS or randomly alternate assignment
infected, deep wounds at or distal to the standard management (control group). Both to either NpHSS or standard
management (control group)
malleoli, presence of mal odour, active peri- groups received comprehensive care and the
• both groups received compre-
wound cellulites, loss of protective sensation control group included the use of chemical hensive care and the control
and at least one dopplerable pedal pulse. antiseptics such as soap or povidone iodine. group included the use of
Wound size was evaluated by measuring the Patients were blinded about the differences in chemical antiseptics such as
maximum length by the maximum width. soap or povidone iodine
treatment.
Exclusion criteria included severe arterial • all patients were treated using
All patients were treated using an outpa- an oupatient ambulatory model
disease (diagnosed by the criteria listed above tient ambulatory model, which included ap-
based on the absence of both foot pulses on propriate surgical debridement, aggressive
the affected extremity), brachial/ankle index parenteral/intramuscular broad spectrum anti-
below 05, the diagnosis of osteomyelitis total microbial administration, appropriate off load-
gangrene of the study foot or forefoot, severe ing and strict glycaemic control.
cardiovascular and renal failure and severe Broad spectrum antimicrobial use was
neurological problems that would make the started empirically and immediately at the
patient a poor candidate for the study (e.g. first visit to cover polymicrobial infection.
confined to the bed). Patients with no family Appropriate changes or adjustments were
assistance were also excluded from the study.
made after microbiological assessments of
Baseline demographic measurements were
deep wound cultures were determined
performed at the first visit. The diagnosis of
(2,22,23) Antibiotics were used for a minimum
diabetes was made prior to enrolment and
of 10 days in all patients in both groups.
confirmed by either communication with
Antibiotics were used for more that 10 days
primary care providers or review of medical
if clinical signs of infection continued to be
records. Doppler studies were performed and
present. All patients received pentoxyphylline
branch/ankle index calculated. Neuropathy
at a dose of 1200 mg/day as a haemorheologic
was evaluated by the Michigan (20), and the
as part of the San Elian’s outpatient ambula-
Rydel-Seiffer scores. The Michigan test in-
tory model irrespective of their degree of
cluded vibratory and 10 g Semmes-Weinstein
sensitivity protective response (21). Neuropathic, vascular compromise.
vascular assessments and wound characteristics Patients in both treatment groups were
initially followed on a daily basis and depend-
were included in the Tampico Hospital Dia-
betic Foot Classification system, which grades ing on the condition of the wound, were seen
wounds according to depth, the extent of every third day or once a week.
periwound cellulitis and the aetiology of injury. Patients randomised to the intervention
Stage A ulcer corresponds to skin surface group received an initial 15 to 20-minute
disruption, without cellulitis or bone affection, immersion of the affected foot in NpHSS.
stage B is a deep wound with probable bone Following appropriate debridement, the affected
involvement and 2 cm of periwound cellulitis foot soak was repeated either weekly or bi-
extension and a stage C ulcer encompasses weekly depending on the severity of the
all foot depths with abscess, necrosis, bone periwound cellulites followed by subsequent
infection and cellulitis greater than 2 cm in wound cleansings with NpHSS spray between
width. This is in correlation to the Definitions immersions. NpHSS was also used instead of
and Criteria of the International Working saline solution to remove gauzes. Foot immer-
Group on the Diabetic Foot International sions were discontinued on clinical improve-
Consensus (2). All patients in the study had ment of wound and surrounding skin or when
either a stage B or stage C ulcers. The second the first sign of maceration was observed.
part of the grading system defines the aetiol- NpHSS spray applications were continued
ogy, be it vascular, neuropathic or both. X-ray until either complete resolution of wound
radiography of the affected foot was also infection or the end of the 20-week study.
performed in order to help with the assessment The control group received the same treat-
of osteomyelitis. ment with the exception that saline was used
ª 2007 Blackwell Publishing Ltd and Medicalhelplines.com Inc 3Superoxidised solution in diabetic foot infections
in place of NpHSS. Povidone iodine was rash, epidermolysis or blister formation may
Key Points initially used after debridement to cleanse the be caused by the use of chemical disinfectants.
• forty-five patients were evalu- wound. When the infection resolved and The absence of this damage along with the
ated at baseline formation of granulation tissue was observed, presence of healthy tissue surrounding the
• eight patients had severe arte- the patient was switched to a surgical soap ulcers was considered as clinical signs of no
rial disease and did not meet
(Dermo Clean) with saline rinse to minimise or minimal tissue toxicity.
the inclusion criteria
• from the remaining 37 patients, the cytotoxic effects of povidone iodine. If Daily pictures and weekly measurements
21 received the NpHSS and 16 clinical signs of infection returned, the use of of the wound, periwound cellulitis, local skin
received control treatment povidone iodine was resumed. affection and granulation tissue were recorded
Both groups received conventional standard in a database as part of systematic data col-
method of wound care consisting of gauze lection previously designed independently of
saturated with Triticum vulgare (Italdermol, this study.
Italmex, S.A., Mexico) to moisten the wound For statistical analysis, significance was
followed by adhesive covering. Heavily exudat- considered at P , 005. Values of chi-squared
ing wounds were dressed with a calcium alginate with Yate’s correction or Fisher exact for 2 2
(e.g. Kaltostat, Bristol-Mayer Squib, Mexico). tables and of variance ratios for natural and
All patients in both groups were instructed treatment analysis of variance were calculated.
to reduce weight bearing on the affected foot
by using a wheelchair or crutches and by RESULTS
resting as much as possible. We are aware that Forty-five patients were evaluated at baseline.
most patients have difficulty complying with Eight patients had severe arterial disease and
these modalities. Compliance was assessed by did not meet the inclusion criteria. They were
directly questioning the patient and his/her sent to a vascular surgeon for either vascular
caretaker and by inspection of the dressings by intervention or amputation, and their data were
the health care team. not included in the report. From the remaining
37 patients, 21 received the NpHSS and 16
Primary objective and measurements received control treatment. All subjects com-
The primary outcomes were odour reduction, pleted the full length of the 20-week study.
infection control as indicators of antiseptic Subjects in both treatment groups were
efficacy and wound safety in the treatment of matched in terms of age, sex, years of diabetes
diabetic foot infections. Infection control was duration, obesity, mean HbA1c, ulcer duration/
assessed in terms of periwound cellulitis reduc- week and Yao B/A index (Table 1). No differ-
tion and the percentage of patients advancing ences were noted in the staging of ulcers
from infected, necrotic tissue to wound granu- (Table 2) of the Diabetic Foot Tampico Hospital
lation. Cellulitis reduction was considered Classification and the wounds were similar in
effective when the affected area of erythema aetiology (P ¼ 0873). Mean average of oral
decreased by more than 50% during the antibiotics treatment was of 26 31 days
infection phase. Two members of the staff for intervention versus 30 52 for control
assessed odour reduction independently at group (NS).
wound level. Kappa agreement index was All patients (100%) in the NpHSS group
performed via 2 2 tables to detect differences versus only 25% (n ¼ 4) of the control group
between the two observers for odour percep- showed odour reduction (Table 3). The NpHSS
tion. A kappa value (K ¼ PoPe/1Pe; Po ¼ group also showed statistically significant
observed agreement, Pe ¼ expected agreement reduction in cellulites, 81% compared with
by random) between 061 and 10 was repre- 44% for the control group. The periwound
sentative of substantial to excellent agreement. cellulitis remained unchanged or worsened for
Granulating tissue is the pink/red, moist four patients in the NpHSS group and for nine
tissue comprised of new blood vessels, connec- patients in the control group. Nineteen of the
tive tissue, fibroblast and inflammatory cells, 21 patients (904%) in the NpHSS group
which fills an open wound when it starts to heal. showed good outcomes advancing from in-
Erythema of surrounding skin and granu- fected, necrotic tissue to granulating tissue; this
lating tissue was assessed by direct clinical was seen in only 625% of the control group.
observation. Abnormal periulcer skin condi- Tissue damage was observed to be less
tions such as dryness, erythema, induration, severe in the intervention versus control group.
4 ª 2007 Blackwell Publishing Ltd and Medicalhelplines.com IncSuperoxidised solution in diabetic foot infections
Table 1 Baseline demographic and clinical characteristics of NIDDM patients with severe infected foot ulcers
Key Points
Characteristic NpHSS (n ¼ 21) Control (n ¼ 16) P value
• patients with diabetes have
Age (years)* 619 119 678 116 NS a higher risk of developing
Sex† deleterious infections
Male 9 (45) 8 (50) NS • defects in host immune re-
sponses are at least partially re-
Female 12 (55) 8(50)
sponsible for their susceptibility
Years of diabetes duration* 164 81 17 102 NS
and may include diminished
Mean of HbA1c* 71 2 67 18 NS polymorphonuclear leucocyte
Mean of fasting glycaemia* (mg/dl) 163 59 152 658 NS functions
Obesity† 6 (30) 4 (25) NS
Ulcer duration/week* 137 24 151 163 NS
B/A index (Yao)* 09 05 114 07 NS
Obesity is defined as body mass index .27 kg/m2.
HbA1c, haemoglobin A1c; NS, non significant; NIDDM, non insulin-dependent diabetes mellitus; NpHSS, neutral pH superoxide
solution.
*Values are given as mean SD or actual (per cent).
†Chi-squared and Yates’ correction.
Ninety per cent (n ¼ 19) of patients in the meaning that one in every three patients with
NpHSS group showed improvements in peri- periwound cellulitis will benefit from this
wound conditions compared with 31% (n ¼ 5) treatment. Thirty-seven per cent of control
of controls (Table 3). The majority of the subjects showed either no improvement of
patients in the control group showed granula- infected tissue to granulating tissue or pre-
tion as well as skin damage. Two and six sented worsening of the wound (Table 3),
patients in the intervention and control group, while only 95% of the NpHSS group had
respectively, showed no change in the percent- similar results. The ARR was 279% with a 95%
age of granulation tissue at the start and at end CI for this difference ranges from 114% to
of the 20-week study. Seventy-five per cent of 5482% and the NNT of 4. Sixty-nine per cent of
control subjects had a malodorous wound at control subjects had tissue toxicity, while only
the end of the study compared with zero 95% of NpHSS subjects had skin and tissue
patients in the NpHSS group. The absolute risk damage around the ulcer. The difference or the
reduction (ARR) is 75% [95% confidence ARR was 592 (95% CI: 3328–8518) with
interval (95% CI): 5378–9622] with a number a NNT of 2.
needed to treat (NNT) of 2. In 56% of the
control subjects, periwound cellulitis either DISCUSSION
worsened or remained unchanged; this was The use of antiseptics in wound care is often
seen in only 19% of NpHSS subjects. The ARR controversial and there is definitely a need for
is 37% (95% CI: 766–6675). The NNT was 3, a non toxic, highly disinfective agent. In this
randomised, controlled, single-blind study, we
found that the use of a non toxic, NpHSS, is
Table 2 Stage severity of diabetic foot tampico hospital more effective in infection control, odour
grading reduction and cause less skin affection than
conventional disinfectants in treatment of
NpHSS Control
diabetic foot infections.
Stage (n ¼ 21) (n ¼ 16) P value
Patients with diabetes have a higher risk of
B 12 9 0873 developing deleterious infections (24,25). De-
Vascular 4 1 NS fects in host immune responses are at least
Neuropathic 7 3 partially responsible for their susceptibility
Both 1 5 and may include diminished polymorphonu-
C 9 7
clear leucocyte functions such as abnormalities
Vascular 2 1
of migration, phagocytosis (26), intracellular
Neuropathic 2 2
killing and chemotaxis (27). Some evidence
Both 5 4
suggests that cellular immune responses may
ª 2007 Blackwell Publishing Ltd and Medicalhelplines.com Inc 5Superoxidised solution in diabetic foot infections
Table 3 Total of patients with good outcomes with NpHSS versus control group and clinical efficacy assessment by NNT
Key Points
NpHSS Control 95% CI
• poor granulation tissue forma- Outcome (n ¼ 21) (n ¼ 16) P value* NNT (min–max)
tion, prolonged persistence of
abscesses and impaired wound Fetid odour reduction 21 (100) 4 (25) 0001 2 1–19
healing may also help predis- Infection control
pose diabetic persons to infec-
Cellulitis reduction 17 (809) 7 (437) 001 3 15–131
tious complications
Advances from 19 (904) 10 (625) 005 4 18–879
• many of these immunodeficien-
cies are related to the meta- infection to granulating tissue
bolic perturbations caused by Improvement of skin 19 (904) 5 (312) 0001 2 12–3
poorly controlled diabetes around the ulcer
• one must determine whether
the failure to heal is secondary Percentage values are given in parentheses.
to persistent infection, antisep- NNT, number needed to treat. NNT significant clinical efficacy range ¼ 2–4.
tic chemical damage or because *Yates correction for chi-squared; significant results for P , 005.
of the persistence of abnormal
inflammatory response
be reduced as well (28). Poor granulation tissue with the primary focus on infection treatment,
• prompt empirical treatment
with antibiotics can prevent formation, prolonged persistence of abscesses while the possible associated cytotoxicity and
the infection from spreading and impaired wound healing may also help tissue damage becomes a secondary issue until
rapidly and reaching the blood predispose diabetic persons to infectious com- this phase ends. This study showed that the use
and organs plications. Many of these immunodeficiencies of NpHSS as compared with conventional
• adequate debridement and the
are related to the metabolic perturbations chemical antiseptic agents provides higher
use of local antiseptics for
wound cleansing are mandatory caused by poorly controlled diabetes (28–30). infection control while minimising skin and
Deleterious wound healing complicated by tissue damage. Once the severity of the infection
infections are often a challenge to clinicians has been reduced, more patients advanced to
even with the use of antibiotics. One must the granulating tissue phase with NpHSS
determine whether the failure to heal is treatment as compared with those who received
secondary to persistent infection, antiseptic conventional chemical antiseptics.
chemical damage or because of the persistence The subjects in the two groups were
of abnormal inflammatory response. Antibiot- matched in terms of their metabolic status,
ics are usually continued for 10 days or longer severity of wound depth, cellulitis extension
even though clinical symptoms of infection and vascular/neuropathic aetiology. This pre-
may disappear earlier. Prompt empirical treat- vented bias and showed that NpHSS, com-
ment with antibiotics can prevent the infection pared with conventional disinfectants, was an
from spreading rapidly and reaching the blood effective antiseptic agent with greater odour
and organs (2,21,23,31). Symptoms of cellulitis reduction and less tissue toxicity. The absence
usually disappear after a few days of antibiotic of malodour following cellulitis reduction was
therapy in non diabetic patients, but in diabetic seen in 100% of the patients who were treated
foot infections, not only are broad spectrum with NpHSS. The reduction of odour can be
antimicrobials necessary, adequate debride- explained by the action of free radicals in the
ment and the use of local antiseptics for wound NpHSS that react highly with putrefaction
cleansing are mandatory. substances from necrotic tissues and anae-
Prior to the introduction of superoxidised robes. Hydrogen peroxide, chlorine, hypochlo-
solution to our facilities, the use of antiseptic rite and hypochlorous acid all have known
agents had been a topic of controversy and deodorant properties. NpHSS’ bactericidal
debate. There are pros and cons to the use of actions and minimal cytotoxicity over granu-
cytotoxic but potent antiseptic solutions like lating tissue increased the number of patients
povidone iodine or less cytotoxic but weak advancing to the next wound healing stage,
antiseptics like soap. The resultant dry, dark, while patients in the control group had
indurated skin from povidone iodine applica- clinical signs of wound infection for a longer
tions made it difficult to distinguish whether period of time. The transition stage between
the delayed wound healing was secondary to inflammatory and granulating phases where
infection or chemical damage. Consequently ulcers although apparently uninfected are not
povidone iodine is often employed at the initial granulating are often highly time and resource
surgical debridement for severe deep infections consuming. Unlike invasive infection, which
6 ª 2007 Blackwell Publishing Ltd and Medicalhelplines.com IncSuperoxidised solution in diabetic foot infections
produces the classic signs of erythema, oedema The properties of NO on wound healing and
and induration, indicators for surface level immune response become deleterious when it
Key Points
infections are much more subtle: persistent reacts with superoxide to produce peroxyni- • NpHSS contains ROS and free
high volume exudate, sudden deterioration in trite, a compound involved in DNA damage to radicals similar to those pro-
the quality or quantity of granulation tissue, cell and bacteria wall. Fortunately, NO must duced and released during
the respiratory burst inside
continual formation of a thin layer of avascular compete to react with superoxide molecules
the mitochondria to produce
tissue and increased pain (32). The reinforce- that are continuously producing reactive oxy- energy (ATP), CO2 and water
ment of patients care with NpHSS along this gen intermediates (ROI), thereby reducing the • further studies are needed to
transition stage showed better control of this production of peroxynitrite. Instead of reacting assess if NpHSS has additional
subtle infection, increasing the percentage of with NO to form peroxinitrate, superoxide properties on wound healing
plus its disinfectant action
patients that advanced to the granulating produces H2O2, other ROI, and ROS that are
phase. scavenged or reversed by primary and sec-
The preliminary NpHSS success in this trial ondary antioxidants defences. Catalysed by
could be explained by its ROS properties the granule enzyme myeloperoxidase (MPO),
that simultaneously act to kill bacteria, react H2O2 combines with chloride to form the
with odour putrefaction substances while highly microbicidal chemical, hypochlorous
causing less cytotoxicity and tissue damage acid. Organisms such as Staphylococcus aureus
to granulating tissue, and surrounding healthy and Candida albicans require NADPH oxi-
tissue. dase activity to be effectively killed and are
NpHSS contains ROS and free radicals particularly susceptible to the action of ROS
similar to those produced and released during and MPO in both in vitro and in vivo
the respiratory burst inside the mitochondria experiments (33). Both oxidase activity and
to produce energy (adenosine triphosphate, protease action are necessary to destroy these
ATP), CO2 and water. Microbial killing re- organisms.
quires the ability of leucocytes to generate The electrical energy of the superoxide
ROS, as well as the action of various micro- solutions destroys microorganisms including
bicidal enzymes and peptides contained in fungi, viruses, mycobacteria, spirochetes and
leucocyte secretory granules. Superoxide anion bacteria (32). Former acid solutions lose both
and granule microbicidal enzymes are the its electrical potential and its germicidal action
mechanisms phagocytic leucocytes use to kill when it comes into contact with multicellular
their targets. Superoxides act as degradative organic matter, and it reverts to ordinary
oxygen free radicals killing directly by their water. Conversely, NpHSS appears to be more
oxidising capacity, they are highly reactive effective in retaining its germicidal action in
with bacterial cell wall and membrane compo- this condition because of the trigger of ROS in
nents, and ‘signalling’ protease activation via a potassium- and pH-dependant mechanism.
the highly pH-dependent nicotinamide ade- Further studies are needed to assess if NpHSS
nine dinucleotide phosphate (NADPH) oxi- has additional properties on wound healing
dase electrogenic process (32). plus its disinfectant action. We hypothesised
Dismutation of the superoxide generates that the increased granulating tissue patients
OH, the accumulating negative charge must proportion on the intervention group may be
be compensated by an influx of Hþ and/or explained as an additional property of the ROS
Kþ. The hypertonicity resulting from Kþ that might trigger early wound healing
transport promotes the release of inactive through fibroblast migration and proliferation
cationic granule proteases bound to an anionic (34). One basic study shows that the H2O2
sulphated proteoglycan matrix. The highly Kþ neutrophil and macrophage production acts on
hypertonic environment solubilises bacterial human keratinocytes causing Rac1 gene over-
proteases and allows them to participate in the expression to improve histological architecture,
killing response. enhance deposition of connective tissue, higher
Superoxide anion dismutes to form H2O2 cell density and a hyperproliferative epithelial
and several other ROS and reactive intermedi- region (13).
ates (Figure 1). The reactive intermediates are The success of treatment modalities must be
products of nitrogen or oxygen reactions. The determined in order to choose a new proposal
reactive nitrogen intermediates derivate from of treatment, significant statistic results are not
endothelial cell nitric oxide (NO) metabolism. always enough to make clinical decisions. For
ª 2007 Blackwell Publishing Ltd and Medicalhelplines.com Inc 7Superoxidised solution in diabetic foot infections
Key Points
• much progress has been made
in the past two decades to
treat and prevent diabetic foot
infections
• the results of this study have
shown that patients with mild
to severe, non limb-threatening
infections can be treated as
outpatients with antibiotics
and NpHSS local antiseptic
therapy
• accumulating evidence sug-
gests that infection may be
controlled by proper wound
care; optimal metabolic con-
trol; and early, aggressive,
surgical and antibiotic therapy
• in this randomised, controlled, Figure 1. Oxidative stress and body primary and secondary defences. HOCl, hypochlorous acid; ILK-1, interleukin-1; MPO,
single-blind study, we found myeloperoxidase; NpHSS, neutral pH superoxidised aqueous solution; NTF, necrosis tumor factor; ROI, reactive oxygen
that the use of a non toxic, intermediates; ROS, reactive oxygen species; RNI, reactive nitrogen intermediates; VEGF, vascular endothelial growth factor.
NpHSS, is more effective in
infection control, odour reduction
and cause less skin affection this reason, we calculated the NNT to assess medical consequences. Fortunately, much
than conventional disinfectants the clinical impact of our statistical outcomes. progress has been made in the past two
in treatment of diabetic foot The relative benefit of an active treatment over decades to treat and prevent diabetic foot
infections
a control is usually expressed as the relative infections. The results of this study have
risk, the relative risk reduction or the odds shown that patients with mild to severe, non
ratio. For clinical decision making, however, it limb-threatening infections can be treated as
is more meaningful to use the NNT (35). Of outpatients with antibiotics and NpHSS local
clinical importance in decision making is the antiseptic therapy. Accumulating evidence
ability of NpHSS to reduce odour in one suggests that infection may be controlled by
patient of every three treated; its significant proper wound care; optimal metabolic control;
cellulitis reduction in one of every three and early, aggressive, surgical and antibiotic
patients, and advancement from infection to therapy (36,37).
granulating stage with less tissue toxicity in All these factors or components work
one of every two patients. synergistically to help with limb preservation
Diabetic foot infections are a common and in the large majority of patients (Figures 2, 3).
complex problem with serious economic and The continued development of new treatments
Figure 2. A 48-year-old woman with severe diabetic foot infection condemned previously to our assessment for below-knee
amputation. Left picture shows the patient foot at initial surgical debridement. Fetid odour, necrosis, cellulitis area of more than
10 cm deep abscess, necrotic injuries and ‘browned’ coloured purulent discharge were present. Right picture shows 2–3 weeks later
that granulating tissue increased and improving of skin condition around ulcer after neutral pH superoxidised aqueous solution
treatment.
8 ª 2007 Blackwell Publishing Ltd and Medicalhelplines.com IncSuperoxidised solution in diabetic foot infections
Figure 3. Nine weeks later, after use of neutral pH superoxidised aqueous solution. Granulating tissue, wound contraction and
healthy skin around the ulcer. Right picture shows total wound healing in a patient visit 4 months later.
like NpHSS may take us one step closer to 9 Raymakers JT, Houben AJ, Van Der Heyden JJ,
a more efficacious and cost-effective algorithm Tordoir JH, Kitslaar PJ, Schaper NC. The effect of
diabetes and severe ischaemia on the penetration
to treat diabetic foot ulcerations.
of ceftazidime into tissues of the limb. Diabet Med
2001;18:229–34.
10 Ovington L. Bacterial toxins and wound healing.
ACKNOWLEDGEMENT Ostomy Wound Manage 2003;49(7A Suppl):8–12.
The authors thank Nicolas Martı́nez Montañez 11 Edwards R, Harding KG. Bacteria and wound
for statistical support and assistance in data healing. Curr Opin Infect Dis 2004;17:91–6.
collection and analysis. 12 Robson MC. Wound infection. A failure of wound
healing caused by an imbalance of bacteria. Surg
Clin North Am 1997;77:637–50.
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