ArticlePDF AvailableLiterature Review

Benefit and harm of iodine in wound care: A systematic review

Authors:
  • Amsterdam University Medical Centers - location Academic Medical Center - University of Amsterdam

Abstract and Figures

Nowadays many products are available to combat infections and thus to promote wound healing. Iodine is one of these products, but reports are conflicting as to the effectiveness and adverse effects of iodine in the treatment of wounds. A systematic review was performed of 27 randomised clinical trials, reporting on chronic, acute, burn wounds, pressure sores, and skin grafts. Main outcome parameters were wound healing, bacterial count, and adverse effects. Iodine did not lead to a reduction or prolongation of wound-healing time compared with other (antiseptic) wound dressings or agents. In individual trials, iodine was significantly superior to other antiseptic agents (such as silver sulfadiazine cream) and non-antiseptic dressings, but seemed inferior to a local antibiotic (Rifamycin SV MMX(®)) and, when combined with alcohol, to crude honey in reducing bacterial count and/or wound size. Adverse effects, including thyroid function derailment, did not occur more frequently with iodine. Based on the available evidence from clinical trials, iodine is an effective antiseptic agent that shows neither the purported harmful effects nor a delay of the wound-healing process, particularly in chronic and burn wounds. The antiseptic effect of iodine is not inferior to that of other (antiseptic) agents and does not impair wound healing. Hence, iodine deserves to retain its place among the modern antiseptic agents.
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Review
Benet and harm of iodine in wound care: a systematic review
H. Vermeulen
a
, S.J. Westerbos
b
, D.T. Ubbink
a
,
b
,
*
a
Quality Assurance & Process Innovation Department, Academic Medical Center at the University of Amsterdam, The Netherlands
b
Surgery Department, Academic Medical Center at the University of Amsterdam, The Netherlands
article info
Article history:
Received 19 October 2009
Accepted 23 April 2010
Available online 12 August 2010
Keywords:
Adverse effects
Antiseptics
Bacterial count
Iodine
Wound infection
summary
Nowadays many products are available to combat infections and thus to promote wound
healing. Iodine is one of these products, but reports are conicting as to the effectiveness and
adverse effects of iodine in the treatment of wounds. A systematic review was performed of 27
randomised clinical trials, reporting on chronic, acute, burn wounds, pressure sores, and skin
grafts. Main outcome parameters were wound healing, bacterial count, and adverse effects.
Iodine did not lead to a reduction or prolongation of wound-healing time compared with other
(antiseptic) wound dressings or agents. In individual trials, iodine was signicantly superior to
other antiseptic agents (such as silver sulfadiazine cream) and non-antiseptic dressings, but
seemed inferior to a local antibiotic (Rifamycin SV MMX
Ò
) and, when combined with alcohol,
to crude honey in reducing bacterial count and/or wound size. Adverse effects, including
thyroid function derailment, did not occur more frequently with iodine. Based on the available
evidence from clinical trials, iodine is an effective antiseptic agent that shows neither the
purported harmful effects nor a delay of the wound-healing process, particularly in chronic
and burn wounds. The antiseptic effect of iodine is not inferior to that of other (antiseptic)
agents and does not impair wound healing. Hence, iodine deserves to retain its place among
the modern antiseptic agents.
Ó2010 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction
Wound healing can be negatively inuenced by many factors.
One major contributor of impaired healing is wound infection, due
to a plethora of pathogens. It is therefore not surprising, consid-
ering the increasing prevalence of multi-resistant micro-organisms
in hospitals, that many (modern) antiseptic products such as silver,
honey and (local) antibiotics are available to prevent and combat
wound infection.
Iodine is probably the best known antiseptic and has been used
for more than a century.
1
However, the use of iodine to treat or
prevent wound infection is under discussion. Iodine (as well as
antiseptics in general) in wound treatment is believed to cause
allergic reactions, to be less effective due to poor penetration, or to
negatively inuence tissue regeneration due to a toxic effect on the
host cells.
2e4
These reports, however, were published more than
25 years ago.
On the other hand, other reports suggest that these fears may be
unjustied as they arebased on sometimes inappropriatelyperformed
studieswithanimals,orinalaboratorysettingwithstandardised
wound conditions, and are therefore not applicable to humans.
5,6
In this systematic review of randomised clinical trials (RCTs) we
investigated the possible benecial and harmful clinical effects of
iodine in the treatment of all kinds of (contaminated) wounds.
Methods
Literature search
The search for potentially relevant RCTs was performed in
Cinahl, Embase, and Medline, from inception of the databases to
August 2008, and the Cochrane Controlled Trials Register up to
Issue 3, 2008. The searches were performed without restrictions on
language, publication date, or publication status. In addition,
references in relevant articles were searched for other potentially
relevant publications.
*Corresponding author. Address: Academic Medical Center at the University of
Amsterdam, Meibergdreef 9, Room A3-503, 1105 AZ Amsterdam, The Netherlands.
Tel.: þ31 20 5666892; fax: þ31 20 5669432.
E-mail address: d.ubbink@amc.nl (D.T. Ubbink).
Available online at www.sciencedirect.com
Journal of Hospital Infection
journal homepage: www.elsevierhealth.com/journals/jhin
0195-6701/$ esee front matter Ó2010 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.jhin.2010.04.026
Journal of Hospital Infection 76 (2010) 191e199
Inclusion criteria
Eligible RCTs needed to report on a local wound care product
containing iodine in patients with any kind of (more or less
contaminated) wound. Any concentration or manufacturer of
iodine as well as any type of control treatment was allowed.
Primary endpoints were bacterial load or wound infection and
wound healing (expressed as time to complete healing, change in
wound surface, survival rate of split-thickness skin grafts, and
wound ready for surgical closure).
Secondary endpoints were adverse events (such as pain and
erythema), costs, and length of hospital stay.
Study selection
Titles and abstracts of studies identied by the search strategy
were assessed by two reviewers (H.V. and D.U.) independently in
terms of relevance and design. Any disagreement was solved by
discussion. The full versions of the articles were obtained if they
fullled the selection criteria.
Study quality
Methodological quality of each trial was assessed systematically
and independently (S.W., H.V. and D.U.) with the aid of the Dutch
Cochrane Collaboration checklist (online), extended with some
other relevant criteria. Again, any disagreement was solved by
discussion.
Data extraction
Trial data were extracted and summarised by one investigator
(S.W.) and checked bya second reviewer independently (D.U.). Data
included trial and patient characteristics, and details on interven-
tions and outcomes. Attempts were made to contact trial authors in
order to settle any uncertainties.
Data analysis
Quantitative data were entered and analysed in RevMan 4.2.8
(Cochrane Collaboration). For each outcome, summary estimates of
treatment effect [with 95% condence interval (CI)] were calculated
for every comparison. For continuous outcomes, mean difference
(MD) was presented. For dichotomous outcomes, the absolute risk
reduction, i.e. risk difference (RD), was presented, which is an
absolute effect measure that expresses the difference between the
experimental and the control event rates and allows calculation of
the number needed to treat (NNT).
Meta-analysis was planned only in case of clinical homogeneity
and statistical heterogeneity, as expressed by means of the I
2
statistic, of <60%, using a random effects model. If meta-analyses
were impossible, individual study data were presented, which were
also summarised in vote-counting tables. Such tables show the
number of studies in favour or against the index intervention
(iodine), irrespective of the size of the treatment effect found, in
order to estimate a general tendency as to the effectiveness of the
index intervention. Statistical analysis of the differences in vote
count totals in favour or against iodine was performed with the
McNemar sign test.
Results
The search yielded 266 potentially relevant studies. Of these, 29
publications met our inclusion criteria. Trial ow and reasons for
exclusion are shown in Figure 1.
Of the 29 studies included, Reimer et al. and Vogt et al. used the
same patient set as did Hauser et al. and Vogt et al.
7e10
Thus, this
review comprised 29 publications on 27 RCTs. Relevant data were
extracted from all publications. Trial sizes ranged from 27 to 1089
patients, totalling 4495. More than half (52%) of the trials were
published more than 10 years ago. For a detailed description of the
studies included see Table I.
Table S1 supplies a complete listing of the methodological
characteristics. Overall trial quality was limited. The most common
aws are mentioned below. Four out of the 27 trials (15%) used
a form of quasi-randomisation, if described at all. Allocation
concealment was applied and described in 11 trials (41%). The
intention-to-treat principle was mentioned in 10 trials (37%). The
nature of the treatment made blinding of patients and healthcare
professionals impossible. Only ve trials (19%) declared the use of
an independent outcome assessor. Nine trials (33%) declared
sponsorship by a manufacturer of medical devices.
In the 29 publications on RCTs found, a large variety of wound
care products, wound types, and outcome parameters were
investigated (Table I). Because of this clinical heterogeneity no
meta-analyses could be performed. The results are categorised by
the various wound types studied.
Chronic wounds
In 12 trials the effectiveness and possible harm of iodine was
studied in patients with chronic ulcers.
11e22
Many different
Cochrane
210
publications
Medline
221
publications
Embase
214
publications
Cinahl
198
publications
843 publications
577 duplicates
266
titles and abstracts
screened for
relevance
77 full-text papers
189 excluded:
No RCT
No iodine
No treatment
48 excluded:
No RCT
No treatment
No primary
endpoints
Asian language
No full text 29 publications
on RCTs
Figure 1. Flow chart of trial inclusion. RCT, randomised controlled trial.
H. Vermeulen et al. / Journal of Hospital Infection 76 (2010) 191e199192
Table I
Characteristics of the 29 included publications on 27 studies
Publication Trial characteristics
a
Patients
b
Intervention
c
Outcomes Remarks
Al-Waili and
Saloom
26
1. Unknown
2. Up to 1 month
3. 24/26
4. Hospital
5. 1
6. United Arab Emirates
7. None reported
1. 25 years
2. Postoperative wound
infections following
caesarean sections and
hysterectomies
1. 70% ethanol and povidone
iodine
2. Honey
Culture, healing, hospital
stay, antibiotics use, scar
size
Altman et al.
11
1. Every alternating case
2. Up to 14 months
3. 72/88
4. Outpatient
5. 1
6. USA
7. None reported
1. Mean not reported age
range 32e87 years
2. Patients with chronic
leg ulcers and gangrenous
lesions in the vascular
clinic
1. Tri-iodine solution
(0.5 g potassium iodide
in 100 mL of water with
0.5e1.0 g iodine crystals)
2. Best treatment in
physicians opinion
Healing time Preliminary report,
subgroup study
Apelqvist et al.
14
1. Computer-generated list
2. 12 weeks
3. 22/19
4. Outpatient
5. 1
6. Sweden
7. Perstorp Pharma
(Iodosorb
Ò
),
Swedish Diabetic Association
1. Not reported
2. Diabetic patients with
exudative foot ulcers
below the ankle
1. Cadexomer iodine
(Iodosorb
Ò
)
2. Gentamicin solution;
Garamycin
Ò
,
streptodornase; Varidase
Ò
,
dry saline gauze; Mesalt
Ò
Complete healing or
>50% ulcer area
reduction, costs
Daróczy
15
1. Unknown
2. 12 weeks up to 5 months
3. 21/21/21
4. Outpatient
5. 1
6. Hungary
7. None reported
1. 58 years
2. Patients with ulcerated
stasis dermatitis due to
deep venous reuxes
1. Povidone iodine
(Povidone) with
compression
2. Betadine
Ò
without
compression, and amoxicillin
Healing rate, elapse
of supercial
bacterial infection
Three treatment
groups
Denning
31
1. Day of surgery
2. Till wound closure
3. 36/58
4. Outpatient
5. 1
6. England
7. None reported
1. 38 years for the iodine
group/32 years for the
control group
2. Patients requiring
nail surgery
1. Povidone iodine
(Inadine
Ò
)
2. Release
Ò
Healing time,
infection rate
Dovison and
Keenan
30
1. Not reported
2. Until wound healing; up
to 2 months
3. 13/13/16
4. Outpatient
5. 2
6. Australia
7. Patim Pty Ltd
(research grant),
Briggate Medical Supplies
1. Not reported
2. phenolised partial nail
avulsion wounds of hallux
1. Betadine
Ò
(10% povidone iodine)
2. Parafn gauze, and
intrasite gel and parafn
Healing time,
clinical infection
rate
Three treatment
groups
Groenewald
12
1. Not reported
2. 21 days
3. 50/50
4. Outpatient
5. 1
6. South Africa
7. None reported
1. Not reported
2. Patients with chronic
venous leg ulcers
1. Povidone iodine and zinc
oxide-impregnated gauze
2. Debrisan
Ò
Healing time,
wound cleansing,
wound size reduction,
graft take, oedema,
pain, bacterial
contamination
Han and Maitra
33
1. Random permuted
block allocation
2. Till complete healing,
max. 53 days
3. 111/102
4. Hospital/outpatient
5. 1
6. England
7. None reported
1. Not reported, range
0e75 years
2. Patients with <10%
TBS partial thickness burns
1. Inadine
Ò
2. Bactigras
Ò
Bleeding, pain, visits,
treatment time,
off work,
contamination
Hansson
16
1. Not reported
2. 12 weeks
3. 56/48/49
4. Outpatient
5. 4
6. Sweden, Denmark,
Netherlands, and UK
7. Perstorp Pharma
1. 74 years in the iodine
group, 74 and 72 years
in the two others
2. Patients with exudating
or sloughy venous leg ulcers
1. Cadexomer iodine
(Iodosorb
Ò
/Iodoex
Ò
)
2. Hydrocolloid dressing
(Duoderm E
Ò
,
Granuex
Ò
), and gauze
dressing (Jelonet
Ò
)
Ulcer size, stop
exudation, costs
Three treatment
groups
Hauser et al.
9
See Vogt et al. (2006)
10
See Vogt et al. (2006)
10
See Vogt et al. (2006)
10
See Vogt et al. (2006)
10
Same dataset as
Vogt et al. (2006)
10
(continued on next page)
H. Vermeulen et al. / Journal of Hospital Infection 76 (2010) 191e199 193
Table I (continued )
Publication Trial characteristics
a
Patients
b
Intervention
c
Outcomes Remarks
Holloway et al.
20
1. Not reported
2. 24 weeks; cross-over
at 12 weeks
3. 38/37
4. Outpatient
5. 4
6. USA
7. TIL Medical Ltd
1. 63 in the iodine group/61
in the control
2. Patients with a venous
stasis ulcer present
for >3 months
1. Cadexomer dressing
2. Saline wet-to-dry
dressing
Wound healing,
pain, wound
condition
Homann et al.
34
1. Programme
Rancode 3.6
2. 21 days
3. 43/43
4. In- and outpatient
5. 5
6. Germany
7. Mundipharma GmbH
1. 37.2
2. Patient with two partial
thickness burn wounds
1. PVP-I hydrogel Repithel
Ò
2. Flammazine
Ò
Wound healing,
safety
Two wounds in
each patient
randomised to
receive either
treatment
Iselin et al.
27
1. Chronological order
2. Up to 4 weeks
3. 134/134
4. Hospital?
5. 1
6. France
7. None reported
1. 33 in the iodine group/30
in the control
2. Patients presenting in the
emergency hand surgery
1. Povidone iodine
2. Rifamycin SV MMX
Ò
Healing rate, infection,
adverse effects
Jurczak et al.
28
1. Sealed envelopes
2. 2 weeks
3. 32/35
4. Hospital
5. 7
6. Germany, France,
Great Britain
7. ConvaTec
1. 43 in the iodine group/34
in the control
2. Patients with an open
surgical or traumatic wound
1. Povidone-iodine
2. Hydrobre Ag dressing
Pain, change in wound
size, comfort, bleeding,
dressing removal
Kaya et al.
23
1. Not reported
2. Till complete healing
3. 15/12
4. Hospital
5. 1
6. Turkey
7. None reported
1. 30 in the iodine group/35
in the control
2. Patients with spinal cord
injury having pressure ulcers
1. Povidone-iodine gauze
2. Hydrogel-type dressing
(Elasto-gel
Ò
)
Healing rate
Kucan et al.
25
1. Computer-generated
table
2. 21 days
3. 11/14/15
4. Hospital
5. 1
6. USA
7. None reported
1. Not reported, range 16e102
2. Patients with chronic
pressure ulcers
1. Povidone iodine
2. 0.9% NaCl solution, and
silver sulfadiazine
Bacterial count,
clinical response
Three treatment
groups
Laudanska and
Gustavson
13
1. Not reported
2. 6 weeks
3. 30/30
4. Hospital
5. 1
6. Sweden
7. None reported
1. 64.8 in the iodine group/63.5
in the control
2. Patients with chronic
venous ulcers
1. Cadexomer iodine
(Iodosorb
Ò
)
2. Zinc paste dressing,
saline dressing, and
Gentian Violet
Reduction in ulcer
size and healing
within 6 weeks
McCreal et al.
29
1. Sealed envelope
2. 4 weeks
3. 86/88
4. First hospital, later
outpatient
5. 1
6. Ireland
7. Not reported
1. 20.5 in the iodine group/23
in the control
2. Patients who underwent
appendicectomy
1. Wound wick soaked in
1% povidone iodine
2. Subcuticular suture
Infection rate and
time to wound
healing, patient
discomfort and
cosmetic result
Michiels et al.
32
1. Randomisation list
2. 12 days
3. 20/20
4. Hospital
5. 2
6. Belgium
7. None reported
1. 45.2 in the iodine group/45.5
in the control
2. Patients with infected
postoperative wounds
1. Polyvinylpyrrolidone
2. Dextranomer paste
(Debrisan
Ò
)
Cleansing, inammation
reduction, wound healing
Children in study
Moberg et al.
24
1. Unknown
2. 8 weeks
3. 19/19
4. Hospital
5. 2
6. Sweden
7. None reported
1. 72.6 in the iodine group/80.1
in the control
2. Patients with pressure ulcers
1. Cadexomer iodine
2. Saline dressings,
debriding agents,
non-adhesive dressings
Wound area reduction,
pain, and pus and debris
Partial cross-over
at 3 weeks
H. Vermeulen et al. / Journal of Hospital Infection 76 (2010) 191e199194
treatments were used as comparator. Individual trial results for this
type of wound are presented in Table S2. Vote counting of the
overall trial results is presented in Tables S2 and II.
Primary outcomes
Bacterial load and wound infections. Groenewald et al. reported on
bacterial cultures only in a qualitativeway.
12
Moss et al. reported on
bacterial load, graded semiquantitatively (0, þ,þþ,þþþ).
21
This
was reported at the beginning and after six weeks of treatment for
b
-haemolytic Streptococcus,Staphylococcus aureus,Pseudomonas,
and Proteus. No changes in bacterial load could be found in either
treatment group.
Skog et al. reported on bacteriology but the proportion of
patients per treatment group with an initial infection was unclear,
so we could not estimate any treatment effect on bacteriology.
22
Wound healing. In nine trials comparing 11 wound care products
this outcome was reported (Table S2). Two trials found a signicant
Table I (continued )
Publication Trial characteristics
a
Patients
b
Intervention
c
Outcomes Remarks
Moss et al.
21
1. Unknown
2. 26 weeks
3. 21/21
4. Outpatient
5. 1
6. UK
7. TIL Medical Ltd
1. 70 in the iodine group/68
in the control
2. Patients with chronic resistant
varicose ulcers
1. Cadexomer iodine
2. Dextranomer
Ulcer reduction,
bacterial load
Partial cross-over
at 6 weeks
Ormiston et al.
17
1. Sealed envelope
2. 24 weeks
3. 30/30
4. Outpatient
5. 1
6. UK
7. TIL Medical Ltd and
Perstorp
1. 67.3 in the iodine group/70.3
in the control
2. Patients with chronic resistant
varicose ulcers present for >3 months
1. Cadexomer iodine
2. Gentian Violet and
Polyfax
Ò
ointment
Healing rate
cm
2
/week, granulation,
oedema, pain, exudates,
pus and debris,
and erythema
Partial cross-over
at 12 weeks
Reimer et al.
7
See Vogt et al.
8
See Vogt et al.
8
See Vogt et al.
8
See Vogt et al.
8
Same data set as
Vogt et al.
8
Sinha et al.
35
1. Alternatively
2. 46 days
3. 1053/1089
4. Hospital
5. 1
6. India
7. None reported
1. Not reported
2. Patients with supercial burns
1. Povidone iodine þ
neosporin
2. Silver sulfadiazine
Bacterial counts,
rate of epithelialisation
and mortality
Skog et al.
22
1. Not reported
2. 6 weeks
3. 38/36
4. Outpatient
5. Multicentre
6. Sweden, and Norway
7. TIL Medical Ltd
1. 68.1 in the iodine group/72.1
in the control
2. Patients with chronic
venous ulcers
1. Cadexomer iodine
powder
2. Mostly
parafn-impregnated
gauze and saline
Change in ulcer size,
pain, pus and debris
exudates, granulation,
erythema, and oedema
Smith et al.
18
1. Block randomisation
2. 4 months
3. 101/99
4. Outpatient
5. 1
6. UK
7. Clinimed Ltd
1. 73 in the iodine group/75
in the control
2. Patients with a venous
leg ulcer >2cm
1. Betadine
Ò
and Jelonet
Ò
2. Hydrocolloid dressing
(biolm)
Time to complete
healing, pain and cost
Patients divided in
two ulcer groups:
2e4 cm and >4cm
Tarvainen
19
1. Sealed envelope
2. 8 weeks
3. 14/13
4. Outpatient
5. 1
6. Finland
7. None reported
1. 67.7 in the iodine group/68.8
in the control
2. Patients with chronic leg ulcers
1. Cadexomer iodine
2. Dextranomer
Clinical response,
adverse events and
healing
Vogt et al.
8
1. Block randomisation
2. 13 days
3. 21/14
4. Hospital
5. 1
6. Germany
7. None reported
1. Not reported
2. Patients with wounds receiving
meshed transplants
1. PVP-I hydrogel
2. Bactigras
Ò
Epithelialisation,
impedance, clinical
evaluations of graft
sites
Vogt et al.
10
1. Block randomisation
2. 20 days
3. 83/84
4. Hospital
5. 1
6. Germany
7. None reported
1. Not reported
2. Patients with wounds receiving
meshed transplants
1. PVP-I hydrogel
complex (Repithel
Ò
)
2. Jelonet
Ò
Wound healing,
graft take, bacterial
load, and impedance
a
1. Randomisation method. 2. Duration of follow-up. 3. No. of patients included per group (I
2
/controls). 4. Setting. 5. No. of participating centres. 6. Country. 7. Source of
funding.
b
1. Age (I
2
/controls). 2. Type of wound.
c
1. Type of iodine dressing. 2. Type of control dressing.
H. Vermeulen et al. / Journal of Hospital Infection 76 (2010) 191e199 195
difference in favour of (cadexomer) iodine over local best practice,
zinc paste, saline gauzes, and Gentian Violet.
11,13
The results of one
trial favoured Debrisan
Ò
over iodine.
11
Six trials found no signi-
cant differences.
Six studies comparing seven wound care products used reduc-
tion in wound surface as surrogate endpoint for wound
healing.
13,16e18,20,21
Cadexomer iodine resulted in a quicker wound
size reduction than parafn gauze or dextranomer.
16,17
However, no
signicant differences in reduction speed were observed between
iodine and hydrocolloids or zinc paste.
13,16
Three studies did not
give standard deviations in their results.
18,20,21
Secondary endpoints
Adverse events. Seven trials reported on adverse effects: erosions or
ulcerations, pain, dermatitis and allergic reactions, effect on serum
iodine levels, and patientwithdrawalsbecause of increased ulcersize.
Hanson et al. reported on serum iodine levels.
16
However, we
could not compare these serum levels to known reference
values in the literature to assess their (ab)normality. The total
number of patients and time of measurement was not stated, so
we could not calculate any P-values. Holloway et al. reported no
signicant changes in thyroid functions in either treatment
group.
20
Two studies reported on the number of patients experiencing
pain on application of cadexomer iodine.
13,22
Although the indi-
vidual study results showed an insignicant trend, the pooled data
showed an RD of 0.10 (95% CI: 0.01e0.19), to the detriment of
iodine. Smith et al. found signicantly more pain during the rst
month of treatment with iodine in ulcers smaller than 4 cm, but not
in larger ulcers.
18
Ormiston et al. found signicantly more eczema, stinging, itch-
ing or rashes in patients treated with iodine, whereas Tarvainen
et al. found no difference in erythema, oedema, stinging, or pain.
17,19
Overall, out of the 20 outcome comparisons in these seven trials
addressing adverse effects of iodine versus another wound dressing
or topical agent, ve showed a signicant difference in favour of
iodine and four against iodine (Table S2). These adverse events
were all reversible, without serious sequels. Nine comparisons
showed no signicant difference, and two could not be assessed
due to missing data.
Costs. Two trials reported on costs. Apelqvist et al. calculated the
costs on a weekly basis and allocated these to staff, transportation,
material, drugs, and total weekly costs.
14
The mean total weekly
costs were: (US)$111 (65e210) for iodine vs 175 (53e331) for the
control group. No standard deviations were given for any of the cost
calculations. The authors also calculated weekly costs per patient
healed: $379 for iodine vs $1579 for the control group, receiving
gentamicin solution, streptodornase, or saline gauzes.
23
Hanson et al. reported on material costs and the mean number
of dressing changes per week, so we could recalculate the material
costs per day.
16
These were $3.00 for cadexomer iodine paste, $0.65
for hydrocolloid gauze dressings, and $0.09 for parafn gauze
dressings.
Pressure ulcers
Three trials reported on patients with pressure ulcers.
23e25
Individual trial results for this type of wound are presented in
Table S3. Vote counting of the overall trial results is presented in
Tables S3 and II.
Primary endpoints
Bacterial load and wound infections. Kucan et al. reported the
number of patients who reached a bacterial count <10
5
per gram
of tissue during the three-week treatment period. Seven patients
(N¼11) in the iodine group compared with 11 (N¼14)inthe
saline group and 15 (N¼15) in the silver group reached this
endpoint.
25
Wound healing. All three studies reported on wound healing, but by
means of different outcome parameters, e.g. time to complete
wound healing, wound size reduction or readiness for surgical
closure.
23e25
In these studies, three wound healing outcomes were
signicantly in favour of povidone or cadexomer iodine; while two
were it was in favour of other debriding or antiseptic agents or
dressings.
Secondary endpoints
Adverse events. Only one trial has reported on pain and other
adverse effects.
24
No signicant differences were found in pain
Table II
Vote-counting table summarising the effects of iodine on different outcome
parameters according to wound types
Outcome In favour
of iodine
Indifferent In favour
of control
Total
Chronic ulcers (12 trials)
Bacterial load 1 1
Complete wound healing 7 1 3 11
Reduction in wound surface 6 2 8
Pain 2 6 8
Increased ulcer size 2 2
Erosions/ulcerations/irritation/
erythema/(allergic) dermatitis
347
Thyroid hormone levels 1 1
Serum iodine levels 2 2
Costs 1 2 3
Total 21 3 19 43
Pressure ulcers (3 trials)
Infection 2 2
Complete wound healing 1 1
Reduction in wound surface 3 3
Wound ready for surgical closure 2 2
Pain 1 1
Erosions/ulcerations/irritation/
erythema/(allergic) dermatitis
11
Total 4 1 5 10
Acute wounds (7 trials)
Infections occurring 1 3 4
Infections cured 1 1 2
Complete wound healing 3 1 1 5
Wound granulation 1 1
Pain 1 1 2
Hypergranulation 1 1
Erosions/ulcerations/irritation/
erythema/(allergic) dermatitis
123
Hospital stay 1 1
Total 7 2 10 19
Burn wounds (3 trials)
Complete wound healing 3 3
Pain 1 1
Erosions/ulcerations/irritation/
erythema/(allergic) dermatitis
11
Total 4 0 1 5
Skin grafts (4 publications on 2 trials)
Infection 1 1
Complete wound healing 1 1
Reduction in wound surface 1 1
Graft loss 2 2
Thyroid hormone levels 2 2
Total 5 2 0 7
Overall totals 41
a
83584
Numbers represent the numbers of studies that give results on the respective
outcome.
a
P¼0.031 (McNemar test).
H. Vermeulen et al. / Journal of Hospital Infection 76 (2010) 191e199196
scores, but signicantly more mild adverse effects were found in
the cadexomer iodine group than in those treated with debriding
agents, saline or non-adhesive dressings.
Acute wounds
Seven studies reported on patients with acute wounds.
26e32
Individual trial results for this type of wound are presented in
Table S4. Vote counting of the overall trial results is presented in
Tables S4 and II.
Primary endpoints
Bacterial load and infection. Five studies reported on bacterial load
and infection rates.
26e30
Al-Waili et al. found a nine-day longer time
to reach a negative culture with iodine plus ethanol than with
honey in gynaecological surgery wounds. In one study involving
emergency hand surgery, Rifamycin SV MMX
Ò
prevented post-
operative infection better than povidone iodine.
26,27
Another study
found no signicant differences as to infection prevention by iodine
after appendicectomy, and the study by Dovison in nail surgery
showed no differential protective effect of iodine, parafn gauze or
Intrasite
Ò
gel.
29,30
No differences were found between povidone
iodine and a silver-containing hydrobre to cure open wound
infections.
28
Wound healing. Five trials reported some measurement of wound
healing. Four trials reported on the number of days until complete
wound healing. With povidone iodine, nail wounds healed 7 days
quicker than with Release
Ò
, but no signicant difference was found
as compared with parafn gauze or Intrasite gel.
31
In wounds after
gynaecological surgery, iodine plus alcohol resulted in an 11 day
slower healing than honey.
28
In open surgical wounds no signi-
cant differences were observed.
28
In another study no differences
were seen in wound granulation improvement.
32
Secondary endpoints
Adverse events. Iodine was found to cause signicantly less hyper-
granulation than Intrasite gel, but more trauma to the wound than
a silver-containing hydrobre.
28,30
Hospital stay was found to be
signicantly longer when iodine plus alcohol was used than with
honey.
26
No signicant differences in skin reactions were found.
28
Pain scores could not be analysed due to missing standard
deviations.
28,29
Burn wounds
Three studies reported on patients with burn wounds.
33e35
Individual trial results for this type of wound are presented in
Table S5. Vote counting of the overall trial results is presented in
Tables S5 and II.
Primary endpoints
Bacterial load and infection. One trial reported a similar number of
patients with a positive wound culture between InadineÔand
Bactigras
Ò
, but it was unclear when the wound swabs were
obtained.
33
Wound healing. One trial showed a signicantly (two days) quicker
wound healing with povidone iodine-impregnated gauze than with
a chlorhexidine-impregnated gauze.
33
Such a difference was also
found in another trial comparing povidone iodine with silver
sulfadiazine.
34
Another (large) trial reported that signicantly more
patients were healed within six weeks with iodine plus neosporin
than with silver sulfadiazine.
35
It is unclear whether healing was
due to iodine; neosporin, or both.
Secondary endpoints
Adverse events. Pain during dressing removal did not differ signif-
icantly between povidone iodine-impregnated gauzes and chlor-
hexidine-impregnated gauzes.
33
Nor did adverse event rates differ
between povidone iodine and silver sulfadiazine.
34
Skin grafts
Four studies reported on patients withskin grafts
7e10
: Hauser et al.
and Vogt et al.
8
used thesame patient sets,as did Reimer et al.and Vogt
et al.
10
We therefore only report the data of Vogt et al.
8,10
Individual
trial results for this type of wound are presented in Table S6.Vote
counting of the overall trial results is presented in Tabl es S6 and II.
Primary endpoints
Bacterial load and infection. One trial showed no signicant differ-
ence in infection rates between povidone iodine and parafngauze.
10
Wound healing. Three trials reported wound healing. In one trial
povidone iodine resulted in a (three days) quicker wound healing
than parafn gauze,
10
whereas two trials showed signicantly less
graft loss when using povidone iodine than with parafn gauze
with or without chlorhexidine.
8,9
Secondary endpoints
Adverse events. One trial reported no adverse events and T
3
and T
4
levels remained within the normal range.
8
Vogt et al. also reported
normal T
3
and T
4
levels.
10
Discussion
Iodine has been used as an antiseptic for more than a century.
Despite its reputation, this systematic review yielded only 27
randomised trials conducted since 1976 on the effectiveness of
various iodine-containing products to treat or prevent infection in
wound care. To date, however, iodine is one of the best-documented
antiseptic agents. The majority of trials showed no substantial
differences in benecial or adverse reactions between iodine and
other methods of local care for various chronic and acute wound
types. Most of these studies used povidone or cadexomer iodine and
the results did not differ among the various wound types.
A few trials did show a difference. In these studies, iodine was
found superior to non-antiseptic dressings (parafn dressings,
dextranomer, zinc paste), and other antiseptic agents (such as
silver sulfadiazine cream or chlorhexidine dressings), but inferior
to a local antibiotic (Rifamycin
Ò
) or, when combined with
alcohol, to crude honey, in reducing bacterial count and/or
wound size. This seeming inferiority to honey may well be due to
the addition of 70% alcohol, which can be cytotoxic.
26
Another
trial comparing povidone iodine with honey did not show this
effect.
36
Recently introduced antiseptic agents, such as poly-
hexamethylene biguanide, are now being evaluated against
iodine products.
37e39
In three trials, no harmful effect of iodine on thyroid function
was observed, as opposed to initial alarming reports about this risk,
particularly in premature neonates.
40
Also, no major adverse effects
were seen with iodine regarding allergic responses or cytotoxicity,
inasmuch as it did not reduce wound healing speed, which has
been a longstanding opinion.
4
As it seems that iodine has no (dis)
advantages compared with other products, the overall cost could
eventually be the deciding factor for rejecting or accepting the use
of iodine in the treatment of wounds.
One of the limitations of this review is the fact that many RCTs
were more than 10 years old. Several of the trials predate the
publication of the CONSORT statement. Hence, they were not
H. Vermeulen et al. / Journal of Hospital Infection 76 (2010) 191e199 197
performed or described according to present-day standards. This
makes the interpretation of the methodology of the trials difcult
and may have caused bias, one being the nding that the results of
most trials were in favour of the experimental rather than the
control treatment used (Table S7).
41
Also, relatively few direct
comparisons between iodine and another antiseptic agent were
available.
Second, this review does not offer evidence for other clinically
relevant questionsabout the effectiveness of iodine to prevent wound
infection, the optimum method of administration (forexample in the
form of povidone, cadexomer or liposome),or the antiseptic of choice
for particular (e.g. pseudomonas) infections or wound types. These
questions deserve further and proper investigation.
Third, interpretation of trial results by means of vote counting
when meta-analyses are not possible is under debate as it does not
take into account study size or effect size. On the other hand,
appreciating only the statistically signicant results may also be
biased by the usually underpowered study sizes, the high number
of outcomes analysed, and by publication of the signicant results
only. Hence, we have presented both in an attempt to summarise
the available data as objectively as possible.
Fourth, the evaluation of severe adverse effects, if any, may not
have become clear from RCTs, as they are not the appropriate study
design for this purpose. Cohort or caseecontrol studies, if available,
might shed more light on this, but were excluded here to present
evidence with the least risk of bias.
Despite its long history, the use of iodine in wound treatment is
still defendable because the best available evidence supports
neither the purported harmful effects nor a delay of the wound-
healing process, particularly in chronic and burn wounds. In addi-
tion, the effects of iodine are the best documented among the
presently available antiseptic agents. Given the increasing micro-
bial resistance against antibiotics, clinicians should rely more
heavily on the use of local antiseptic therapies instead of (local)
antibiotics if an indication for the use of antimicrobials is present.
There is a need for high quality RCTs addressing the effective-
ness of iodine to treat or prevent wound infection, in order to
clearly determine the place of iodine in present-day wound care.
With the increasing cost of healthcare, future studies should also
incorporate the cost-effectiveness of antiseptics.
Acknowledgements
We thank Prof. Dr A. Voss, clinical microbiologist, Dr K. Munte,
dermatologist, Dr A.F.P. Vloemans, surgeon and M.J. Lubbers,
surgeon-intensivist, for reviewing the manuscript. Furthermore we
are grateful to Mrs H. Vriends, one of our university clinical
librarians, for assistance with the development of the search
strategy.
Conict of interest statement
None declared.
Funding sources
An unrestricted nancial grant from Meda Pharma BV, The
Netherlands, made the production of this review possible. They
did not inuence the analysis and interpretation of the data in
this review. The authorsconclusions may not necessarily
coincide with those of Meda Pharma BV.
Appendix. Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.jhin.2010.04.026.
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Objectives In this review and meta-analysis, we analyse the evidence to compare the efficacy of honey and povidone iodine-based dressings on the outcome of wound healing. Method A systematic literature search was performed using PRISMA guidelines in academic databases including MEDLINE, Scopus, Embase and CENTRAL. A meta-analysis was carried out to assess the effect of honey and povidone iodine-based dressings on mean healing duration, mean hospital stay duration and visual analogue scale (VAS) score of pain. Results From the search, 12 manuscripts with a total of 1236 participants (mean age: 40.7±11.7 years) were included. The honey-based dressings demonstrated a medium-to-large effect in reduction of mean healing duration (Hedge's g: –0.81), length of hospital stay (–3.1) and VAS score (–1.2) as compared with the povidone iodine-based dressings. We present evidence (level 1b) in favour of using honey for improvement of wound recovery as compared with povidone iodine. Conclusion This review and meta-analysis demonstrate beneficial effects of honey-based dressings over povidone iodine-based dressings for wound recovery.
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This article aims to provide an overview of the studies focused on using coordination compounds as antiviral agents against different types of viruses. We present various strategies so far used to this end. This article is divided into two sections. The first collects the series of designed antiviral drugs based on coordination compounds. This approach has been developed for many years, starting from the 70s with the discovery of cis-platin (cis-DDP). It has been mainly focused on studying the synergistic effect of a wide variety of new compounds obtained by combining metal ions with organic antiviral ligands. Then, we collect various strategies analyzing the coordination compounds interacting with viruses using different processes such as wrapping viruses, rapid detection of RNA or DNA virus, or nanocarriers. These recent and novel insights help to study viruses from other points of view, allowing to measure their physical and chemical properties. We also highlight a section in which it is addressed the issue of viruses from a disinfection viewpoint, using coordination compounds as a tool able to control the release of antiviral and biocide agents. This is an emerging and promising field but this approach is actually little developed. We finally provide a section with a general conclusion and perspectives.
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The review summarizes the data on the main chemical and physiological properties of iodine and its capability of complexation with natural and synthetic polymers. Iodine is the best known antiseptic used to prevent and treat microbial infections. Its unique capability of complexation with certain polymers opens wide opportunities for targeted and prolonged delivery to target organs. Polymeric complexes with iodine have another color, other morphology, a higher electrical conductivity, and higher biological activity as compared with initial polymers. The formation of and ions is associated with iodine-polymer complexation. Iodine-containing biocompatible adhesive controlled-release formulations are designed as part of research into iodine-polymer complexes. The field is promising in terms of treating certain diseases because tolerance to iodine compounds does not usually develop in microbial cells.
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• Three topical antibiotics and four antiseptics (1% povidone-iodine, 0.25% acetic acid, 3% hydrogen peroxide, and 0.5% sodium hypochlorite) were directly applied to cultured human fibroblasts to quantitatively assess their cytotoxicity. The four antiseptics were found to be cytotoxic; all of the cytotoxic agents except hydrogen peroxide were subsequently found to adversely affect wound healing in an animal model. Comparison of bactericidal and cytotoxic effects of serial dilutions of these four topical agents indicated the cellular toxicity of hydrogen peroxide and acetic acid exceeded their bactericidal potency. Bactericidal noncytotoxic dilutions of povidone-iodine and sodium hypochlorite were identified. These experiments provide evidence that 1% povidone-iodine, 3% hydrogen peroxide, 0.5% sodium hypochlorite, and 0.25% acetic acid are unsuitable for use in wound care. This sequence of experiments could be used to identify bactericidal, noncytotoxic agents prior to their clinical use.(Arch Surg 1985;120:267-270)
Article
• Complexing iodine with povidone (polyvinylpyrrolidone) or surfactants significantly limits the quantity of free iodine. Reduction of the free iodine level eliminates the adverse properties of staining, instability, and irritation and also alters bactericidal activity. Addition of detergents to create surgical scrub solutions further reduces the activity of iodine. In vitro testing indicated that the bactericidal activity of iodophors was inferior to that of uncomplexed aqueous iodine. In vivo tests proved that aqueous iodine significantly potentiated the development of infection. Although the povidone iodophor did not enhance the rate of wound infection, it offered no therapeutic benefit when compared with control wounds treated with saline solution. Addition of detergents to the povidone iodophor was deleterious, with the wounds exposed to this combination displaying significantly higher infection rates than untreated control wounds. Based on these results, aqueous iodine solutions and iodophor surgical scrub solutions should not be used on broken skin. Aqueous iodophors can be used in wounds, but no therapeutic benefit from such use was found in this study. (Arch Surg 1982;117:181-186)
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After nail matrix ablation using phenolization, a medicated wound dressing (10% povidone iodine), an amorphous hydrogel dressing (Intrasite Gel), and a control dressing (paraffin gauze) were evaluated. Forty-two participants, randomly divided into three dressing groups, were evaluated. Healing time did not differ between the 10% povidone iodine (33 days), amorphous hydrogel (33 days), and the control dressing (34 days). For all groups, the clinical infection rate was lower than in previous studies, and there was no clinical difference between groups (one infection in the povidone iodine and control groups; none in the amorphous hydrogel group). However, in the amorphous hydrogel group, other complications, such as hypergranulation, were more likely. This investigation indicated that medicated or hydrogel dressings did not enhance the rate of healing or decrease infection rates. (J Am Podiatr Med Assoc 91(5): 230-233, 2001)
Article
Objective Comparison of Biofilm dressing with Jelonet and Betadine in the treatment of venous leg ulcers. Design Randomized parallel-group controlled trial, stratified by initial maximum ulcer diameter of 2–4 cm or >4 cm. Setting Community. Patients Five hundred and twenty-nine patients were assessed and 200 patients with clinical evidence of venous leg ulceration and initial ulcer diameter >2 cm were recruited to the trial. Patients with appreciable arterial disease (ratio of ankle to brachial systolic pressure <0.75) were excluded. Interventions Ulcers were treated with either Biofilm (a hydrocolloid dressing) or Betadine and Jelonet in the community for 4 months or until the ulcer healed, if sooner. All patients wore standardized graduated compression. Main outcome measures Time to complete healing of the ulcer, subjective assessment of pain and total cost of treatment. Results Healing was more rapid in patients using Biofilm dressing (relative risk 1.16, 95% confidence interval 0.8–1.8), but not significantly so p = 0.48. Patients' subjective pain scores after 1 month of treatment indicated there was significantly less pain experienced by patients treated with Biofilm ( p = 0.02). The total cost of treatment (including dressings and nursing time) was similar for Biofilm and Betadine for small ulcers (<6 cm) but Biofilm cost three times as much for larger ulcers. Conclusion Provided that standardized graduated compression was used, the primary dressing did not significantly affect the time to complete healing of the ulcer.
Article
Hintergrund Da PVP-Iod bei Schilddrüsenerkrankungen und vorliegender Iodallergie nicht zur prophylaktischen Antiseptik in der Augenheilkunde angewendet werden kann, wurde als Alternative das polyhexanidhaltige Präparat Lavasept® untersucht. Patienten und Methoden Im Rahmen einer prospektiven, randomisierten, kontrollierten Doppelblindstudie untersuchten wir 67 Patienten mit mindestens 5 koloniebildenden Einheiten (KbE) im Bindehautsack, die neben einem standardisierten Kataraktoperationsverfahren mit intraoperativer Iodantiseptik präoperativ zusätzlich je 3 Tropfen eines Studienpräparats(I=Lavasept® 0,2%, II=PVP-Iod 1,25% oder III=Ringerlösung) erhielten. Die Wirksamkeit und Verträglichkeit wurde beurteilt. Ergebnisse Nach Gabe von Lavasept® oder PVP-Iod sank die Zahl der KbE bei diesen beiden Patientengruppen. Lavasept® reduzierte die Erregerzahl signifikant stärker als PVP-Iod (p=0,05). Beim Vergleich der Verträglichkeit unterschieden sich die Studienpräparate nicht voneinander. Schlussfolgerung Lavasept® reduziert die mikrobielle Besiedlung im Bindehautsack bei präoperativer Anwendung signifikant effektiver und tendenziell dauerhafter als PVP-Iod. Damit stellt Lavasept® eine gleichwertige Alternative zur präoperativen Antiseptik mit PVP-Iod dar.
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Une étude comparative randomisée ouverte a été réalisée chez des blessés présentant une plaie de la main nécessitant une intervention chirurgicale, dans le but de comparer l'efficacité de la rifamycine SV en application locale à celle de la polyvidone iodée en solution dermique, sur la qualité et la vitesse de cicatrisation évaluée par le clinicien. 268 patients ont été inclus dans l'essai et 223 d'entre eux ont participé à l'analyse des résultats. L'analyse met en évidence les résultats suivants : des signes d'infection sont apparus chez huit patients du groupe rifamycine SV (7 %) et chez 20 patients du groupe polyvidone iodée (18,5 %). Cette différence est significative (p = 0,011) en faveur de la rifamycine SV. La vitesse de cicatrisation est estimée accélérée chez 10 % des patients du groupe rifamycine SV et chez 4 % de ceux du groupe polyvidone iodée. Elle est estimée ralentie chez 14 % des sujets du groupe rifamycine SV et 21 % de ceux du groupe polyvidone iodée. Cette différence est également significative en faveur du groupe rifamycine SV (p = 0,038). Sur le plan de la tolérance locale, 32 patients également répartis dans les deux groupes de traitement ont présenté des signes d'intolérance cutanée.
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This prospective, randomised clinical trial compared pain, comfort, exudate management, wound healing and safety with Hydrofiber dressing with ionic silver (Hydrofiber Ag dressing) and with povidone-iodine gauze for the treatment of open surgical and traumatic wounds. Patients were treated with Hydrofiber Ag dressing or povidone-iodine gauze for up to 2 weeks. Pain severity was measured with a 10-cm visual analogue scale (VAS). Other parameters were assessed clinically with various scales. Pain VAS scores decreased during dressing removal in both groups, and decreased while the dressing was in place in the Hydrofiber Ag dressing group (n = 35) but not in the povidone-iodine gauze group (n = 32). Pain VAS scores were similar between treatment groups. At final evaluation, Hydrofiber Ag dressing was significantly better than povidone-iodine gauze for overall ability to manage pain (P < 0.001), overall comfort (P < or = 0.001), wound trauma on dressing removal (P = 0.001), exudate handling (P < 0.001) and ease of use (P < or = 0.001). Rates of complete healing at study completion were 23% for Hydrofiber Ag dressing and 9% for povidone-iodine gauze (P = ns). No adverse events were reported with Hydrofiber Ag dressing; one subject discontinued povidone-iodine gauze due to adverse skin reaction. Hydrofiber Ag dressing supported wound healing and reduced overall pain compared with povidone-iodine gauze in the treatment of open surgical wounds requiring an antimicrobial dressing.
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The vast majority of chronic leg ulcers and gangrenous lesions are associated with local infection. Attempts to control this infection with antibiotics alone have been disappointing. The use of an aqueous triple iodine solution topically, alone or sometimes together with antibiotics systemically, produces control of the infection with a consequent favorable response in the healing process. This solution was found to be an effective antimicrobial agent, non toxic to the host, non irritating to skin or ulcerated areas, an aid in producing demarcation and mummification of gangrenous tissue and having a beneficial effect upon the healing of chronic leg ulcers. This solution is considered a valuable adjunct in the local treatment of such lesions.