REVIEW

Chemical and Microbiologic Characteristics and Toxicity of

Povidone-Iodine Solutions

Jose L. Zamora, MD, Syracuse, New York

Polyvinylpyrrolidone-iodine is a widely used anti- up to 70,000 daltons is excreted by the kidneys. If

septic introduced by Shelanski and Shelanski [I] in the molecular weight is higher than 70,000 daltons,
1956. It is a water-soluble compound that results the polymer is phagocytized by the reticuloendothe-
from the combination of molecular iodine and poly- lial system. No cutaneous or mucosal absorption of
vinylpyrrolidone [2-4]. polyvinylpyrrolidone under healthy conditions has
The preparations of polyvinylpyrrolidone-iodine been demonstrated in laboratory animals, but stud-
commercially available are povidone-iodine solu- ies in inflamed membranes are lacking. Low molec-
tion, scrub, ointment, and foam; of these, the solu- ular weight polyvinylpyrrolidone is regarded as a
tion is the most commonly used. The 10 percent safe agent for intravenous use. High molecular
polyvinylpyrrolidone-iodine solution generally con- weight polyvinylpyrrolidone, when used as a plasma
tains 90 percent water, 8.5 percent polyvinylpyrroli- expander, was accompanied by a high incidence of
done, 1 percent available iodine, and iodide [5]. The complications related to storage in solid organs 171.
free iodine concentration in such a product is typi- Iodine is complexed by polyvinylpyrrolidone and
cally 1 part per million (ppm) or 0.0001 percent [6]. iodide through a hydrogen bond between two pyr-
This product is highly soluble in water, has a red- roles [8] (Figure 1). Although most of the elemental
dish-brown color, and has a pH of approximately 4.5 iodine is complexed in association with polyvinyl-
[1,3]. Povidone-iodine scrub contains 7.5 percent pyrrolidone and iodide, a small amount of free io-
polyvinylpyrrolidone-iodine, 0.75 percent available dine is constantly released, remains in dynamic
iodine, and an anionic detergent added for scrub- equilibrium with the complex, and undergoes the
bing and lather-forming purposes [5]. Unless other- chemical reactions characteristic of iodine until the
wise indicated, the information contained herein available iodine is exhausted. The free iodine level is
refers to polyvinylpyrrolidone-iodine solution. dependent on the concentration of the solution and
Polyvinylpyrrolidone is a polymer similar to dex- follows a bell-shaped curve, with levels of 1 ppm in 1
tran. The molecular weight of the polyvinylpyrroli- percent and 10 percent polyvinylpyrrolidone-iodine
done utilized in polyvinylpyrrolidone-iodine solu- solutions, and a maximum level of 24 ppm in a 0.7
tions ranges from 10 to 40,000 daltons [7]. Data on percent solution [S] (Figure 2). Dilutions of less than
the pharmacodynamic nature of polyvinylpyrroli- 0.05 percent lose the polymer complex characteris-
done derives from clinical studies in which the com- tics of polyvinylpyrrolidone-iodine and behave like
pound was used intravenously as a plasma expan- aqueous iodine solutions [9]. Solutions of iodine
der. Polyvinylpyrrolidone is a flexible molecule that solubilized by iodide, such as Lugol’s iodine, contain
may be adequately excreted by the kidney even in much higher free iodine concentrations than poly-
high molecular weights, unlike proteins of similar vinylpyrrolidone-iodine solution (300 ppm) [6,
weight. Polyvinylpyrrolidone of a molecular weight 10-121. It has been suggested that free iodine is
of 30,000 daltons has a half-life of 11 to 15 hours, responsible for the irritating properties of Lugol’s
whereas polyvinylpyrrolidone of molecular weights solution. Polyvinylpyrrolidone-iodine has been re-
From the Department of Surgery, State University of New York, Upstate ferred to as “tamed iodine” because it is less caustic
Medical Center, Syracuse, New York. than aqueous iodine solutions. This effect provided
Requests for reprints should be addressed to Jose L. Zamora. MD,
Department of Surgery, State University of New York, Upstate Medical by polyvinylpyrrolidone is probably the introduc-
Center, 750 East Adams Street, Syracuse, New York 13210. tion of a “ceiling” for free iodine (12) levels.

TheAmerican Journal of Surgery

 Povidone-iodine Solutions

FREE
IODINE
PPM

m - 18n
Figure 1. Proposed structure of povidone-iodine. A hydrogen
triiodide is ionicaliy bound between two pyrroiidone rings.
(Reprinted with permission from The American Pharmaceutical
Association.)

Figure 2. Free iodine levels in povidone-iodine aqueous solutions

measured in parts per million.

Polyvinylpyrrolidone-iodine’s bactericidal activ-

ity is decreased by exposure to organic substances,
most likely due to iodine complexing and chemical of polyvinylpyrrolidone-iodine retain their bacteri-
reactions, such as the reduction to iodide. This ef- cidal power [18,21,2%32]. In low concentrations of 1
fect has been documented with polyvinylpyrroli- and 5 percent, relatively faster killing rates of 10 to
done-iodine when in contact with necrotic tissue, 30 seconds are noted. Their iodine content is lower,
whole blood, pus, fat, cornstarch, hemoglobin, bo- however, and once a balance is reached, the total
vine albumin, and nonionic and ampholytic surfac- number of bacteria killed may be smaller [6,33,34]
tant agents [6,13-161. It is likely that other organic (Figure 3). At concentrations of 2.5 percent, bacteri-
substances have the same effect. Whole blood has a al solutions, including Pseudomonas, Klebsiella,
profound inhibiting effect on polyvinylpyrrolidone- Proteus, Staphylococcus, and E. coli, were killed
iodine’s microbicidal activity [14,15], whereas he- after 15 seconds of exposure to the antiseptic [30]. In
moglobin binds approximately 46 to 59 mg of iodine vitro studies with bacteria commonly found in clini-
per gram of hemoglobin. cal settings have shown no bacterial resistance to
polyvinylpyrrolidone-iodine [35-371.
Antimicrobial Activity There have been reports of polyvinylpyrrolidone-
Polyvinylpyrrolidone-iodine is a microbicidal iodine intrinsically contaminated with Pseudomo-
agent and acts on a wide variety of bacteria, includ- nas cepacea [38-421. The cause of the contamina-
ing anaerobic and sporulated organisms, fungi, pro- tion in unopened bottles of polyvinylpyrroli-
tozoa, and viruses [1,20,15,17-251 (Table I). Poly- done-iodine solution was found to be a contaminat-
vinylpyrrolidone, the hydrophilic polymer that acts ed water source in the manufacturer’s plants. Inves-
as a carrier in povidone-iodine, does not have any tigations by the Food and Drug Administration, the
intrinsic antibacterial activity [26], but by virtue of Centers for Disease Control, and some independent
its affinity to cell membranes, it delivers diatomic investigators demonstrated that there was no inher-
free iodine (12) directly to the bacterial cell surface, ent resistance by the bacteria and its progeny, but
as shown by studies with radiolabeled polyvinylpyr- “acquired resistance” [38,40]. A slimy, sticky mate-
rolidone-iodine [4,11]. Delivery of complexed iodine rial was found coating the bacterial cells, and their
to the sensitive elements of the cell membrane acquired iodine resistance was attributed to this
seems to be the crucial event of antibacterial action protective coat and the formation of bacterial mi-
[4]. Iodine’s targets are located in the bacterial cyto- croaggregates [43]. This episode disproved the con-
plasm and cytoplasmic membrane [27], and its kill- cept that polyvinylpyrrolidone-iodine solutions are
ing action takes place in a matter of seconds [IO]. In self-sterilizing and prompted the use of sterile tech-
contact with polyvinylpyrrolidone-iodine, sulfhy- niques in the manufacturing and bottling process.
dry1 compounds, peptides, proteins, enzymes, vita-
Pharmacodynamics and Toxicity
min C, lipids, and cytosine are iodinated and oxidat-
ed by free iodine, resulting in inactivation of Ekperimental studies: Intraperitoneal adminis-
molecules that are essential for biologic viability tration of 10 percent polyvinylpyrrolidone-iodine
[28]. Lugol’s solution has a higher free iodine con- solution in healthy dogs and rats showed that all
tent but a lower bactericidal activity than polyvinyl- titratable iodine was absorbed from the peritoneal
pyrrolidone-iodine because it lacks the membrane cavity within 60 seconds. By this route, the lethal
affinity afforded by polyvinylpyrrolidone; thus, the dose was 8 ml/kg and the highest dose with no
amount of iodine seen by bacteria is less. What resultant deaths was 2 ml/kg [44]. However, if 2
matters is the concentration of free iodine at the cell ml/kg was administered 24 hours after the induce-
wall of the target bacterium [12]. Diluted solutions ment of peritonitis, the mortality was 100 percent

Volume 151. March 1996 401

 Zamora

TABLE I Slmpllfled Summary of Organisms Susceptible to Povldone-lodlne Solutlons

Gram-Negative Bacteria Fungi

Enterobacter aerogenes Aspergillus flavus

Escherichia coli Candida albicans
Haemophilus vaginalis Cryptococcus neoformans
Klebsiella pneumoniae Epidermophyton floccosum
Proteus mirabilis (all strains) Nocardia asteroides
Pseudomonas aeruginosa
Pseudomonaspyocyanea Viruses
Salmonella typhi
Serratia marcescens Cytomegalovirus
Shigella dysenteriae Influenza type A
Vibrio comma Polio type I, Mahoney & CHAT strains
Herpes genitalis
Gram-Positive Bacteria Herpes simplex type 1
Rabies
Bacillus subtilis Rubella
Clostridium perfringens Vaccinia
Clostridium tetani
Corynebacterium diphtheriae Protozoa and Other Organisms
Diphtheroids
Diplococcus pneumoniae Entamoeba histolytica
Staphylococcus albus Trichomonas vaginalis
Staphylococcus aureus (hemolytic) Treponema pallidum
Streptococcus (P-hemolytic) Chlamydia trachomatis
Streptococcus fecalis Mycoplasma hominis
Streptococcus pyogenes
Acid-Fast Bacteria

Mycobacterium tuberculosis

[35,44,49,50]. Th e methodology of these experi-

- PHARMADINF
- - BETADINP
ments is so varied that it is impossible to compare
----- POVIDINE” results among them or to extrapolate their findings
to clinical situations. There are several factors that
make these experiments liable to criticism: lack of a
standard animal model, high variability in the
amounts of solution and concentrations utilized,
and lack of adequate control groups [51]. Recent
discoveries of the chemical properties of polyvinyl-
pyrrolidone-iodine and the effects of dilution and
organic substances on free iodine render most of
these experimental studies obsolete [6,11,12,14].
Clinical studies: Local toxicity. It has been dem-
1:o 2:O 2:3 3b 314 3.7 4’0+
11.10.0001 (1.10001 ~1lOOi ,l 501 ,110, II 41 il i! lF”ll-StrenQlhl onstrated that blastogenesis of human lymphocyte
Avollable Iodme Concenlrotlon (Log10 PPM) cultures [52,53] and the viability of granulocytes
Figure 3. The effect of dilution on bacterial killing In commercial and monocytes is inhibited by the addition of poly-
preparations of povtdone-iodine. Note the paradoxically higher vinylpyrrolidone-iodine solution.
bactericidal power In tower concentrations.
The chemotaxis of human polymorphonuclear
leukocytes was studied in vitro by adding various
concentrations of polyvinylpyrrolidone-iodine to a
[32]. Other investigators have documented in- microscopic chamber containing polymorphonucle-
creased mortality rates and metabolic acidosis in ar leukocytes. There was inhibition of chemotaxis
experimental peritonitis using polyvinylpyrroli- first noted at a concentration of 10 pg/ml which
done-iodine solution in concentrations of 2 to 10 progressed to total arrest of chemotaxis at 75 pg/ml
percent [45,46]. Administration of polyvinylpyrroli- [52-541.
done alone did not have these adverse effects [46]. The cells of a fresh surgical wound are susceptible
Of the many studies that have addressed the thera- to damage by antiseptic agents [55]. An in vivo study
peutic use of polyvinylpyrrolidone-iodine in experi- that evaluated the effect of polyvinylpyrrolidone-
mental peritonitis, some have documented adverse iodine on human polymorphonuclear leukocytes
effects [32,45--4&J] and some beneficial effects and fibroblasts demonstrated significant inhibition

402 The American Journal of Surgery

 Povidone-iodine Solutions

TABLE II Correlailon of Topical Adminlsfratlon of Povldone-Iodine (PVP-I) Solution With Proteln-Bound lodlne (PI)
Levels and Renal Function

PBI Level
Mode of Administration Renal Function (Normal 4-8 ualdl)

Single administration of 1% PVP-I Normal Increased to 40 pg/dl, back

solution intraperitoneally [ 59,741 to normal in 72 hr
Single administration of 10% solution Normal Increased to 10 pglkg, back
as preoperative vaginal prep [SO,791 to normal in 48 hr
Multiple applications of 10% solution Normal Increased to 595 pg/dl, back
on 20% TBSA burn [85] to normal 7 d after
ceasing therapy
Multiple applications of 10% PVP-I Abnormal Increased to 4,900 pg/dl
solution on 85% TBSA burn [85]
Multiple applications of 10% Acute Increased to 48,000 pgldl,
PVP-I solution on 75 % TBSA burn [ 581 oliguria accompanied by severe
metabolic acidosis & death

TBSA = total body surface area.

of migration, fibroblastic activity, and wound cellu- [81]. There have been reports of erythema indura-
larity in situ at a 5 percent concentration of polyvin- tion and vesicular eruption secondary to polyvinyl-
ylpyrrolidone-iodine. A 1 percent solution showed pyrrolidone-iodine skin applications in patients
no significant difference when compared with the with altered immunity and underlying malignancy
control solution of normal saline solution, with good [82,83].
migration and wound cellularity. The investigator Iodine from polyvinylpyrrolidone-iodine is ab-
[56,57] concluded that the toxicity of polyvinylpyr- sorbed through the burn wound [52,58,84,85]. The
rolidone-iodine at the cellular level is directly pro- systemically absorbed iodine is carried in the blood-
portional to the concentration of the solution uti- stream bound to serum albumin and is excreted by
lized, and recommended a 1 percent solution as the the kidneys [52]. The level of protein-bound iodine
most appropriate dilution for wound irrigation increases to various degrees according to the con-
[56,57]. centration utilized, the frequency of polyvinylpyr-
Systemic toxicity. Polyvinylpyrrolidone-iodine rolidone-iodine administration, the depth and total
administered clinically through any route can result body surface area of burn, and renal function [85].
in systemic absorption of iodine. The amount of Various adverse effects may arise from this phe-
iodine absorbed will vary according to the concen- nomenon.
tration of the solution utilized, the number of appli- The classic report on iodism secondary to the use
cations, and the route of administration [58-61]. of topical polyvinylpyrrolidone-iodine on burn
When applied cutaneously there is some absorp- wounds is that of Lavelle et al [58] in 1975. They
tion, especially in infants and newborns [62-691. described systemic toxicity in a group of patients
When polyvinylpyrrolidone-iodine is administered with second and third degree burns with more than
in the subcutaneous tissue, mouth, gut, bladder, 25 percent of the total body surface area burned.
vagina, peritoneal cavity, and mediastinum, there is These patients received a topical application of 10
absorption of iodine with elevation of serum pro- percent polyvinylpyrrolidone-iodine three to four
tein-bound iodine [59-61,70-781. Serum levels re- times per day. Refractory metabolic acidosis and
turn to normal in 3 to 7 days if the renal function is acute renal failure developed 4 to 10 days after the
normal [79]. therapy was initiated, and three of the five patients
When polyvinylpyrrolidone-iodine solution is ap- reported died. This report alerted clinicians about
plied locally on intact skin or mucosa, the incidence iodine absorption and the potential problem of io-
of allergy and contact dermatitis in normal subjects dine administration in large doses to patients with
is extremely low, with 2 allergic reactions in 5,000 abnormal renal function, although further experi-
applications recorded [2]. A 0.5 percent solution of ence has failed to prove conclusively that high io-
polyvinylpyrrolidone-iodine was employed as a pre- dine levels cause renal failure.
operative preparation for intraocular lens surgery; In five burned patients treated aggressively with
of 929 eyes treated, only 4 demonstrated minor con- topical polyvinylpyrrolidone-iodine, protein-bound
junctival irritation attributable to the preparation iodine levels varied from 71 to 649 pg/lOO ml (nor-
[80]. In patients with known allergies to various mal levels 4 to 8 mg/lOO ml) [52]. Topical polyvinyl-
substances, including fish and iodine-containing pyrrolidone-iodine treatment of burn patients has
compounds, the incidence of allergic reactions was 2, revealed that serum protein-bound iodine levels
in 500 applications, with 16 cases of minor irritation and urinary iodine concentrations correlate directly

Volume 151, March 1986 403

 Zamora

with renal function. Levels ranged from 595 to 4,900 Sustained exposure, however, leads to a decrease in
pgldl, and the investigators detected hypernatre- iodine binding and synthesis of free triiodothyrox-
mia and hyperosmolarity that they attributed to the ine and free thyroxin. This is called the Wolff-Chai-
high protein-bound iodine levels [85]. No specific koff block [86]. Normally, this effect is transitory
toxic symptoms were reported in these patients and and a normal rate of hormone synthesis resumes by
all protein-bound iodine levels decreased to within the “escape” or “adaptation” phenomenon. Rarely,
normal limits 1 week after discontinuation of treat- the normal sequence of events is altered and leads to
ment. It is evident that excess iodine can be effec- iodine-induced hyperthyroidism, which is more
tively removed by hemodialysis [58,84]. The rela- likely to occur in subjects with underlying hyper-
tionship between polyvinylpyrrolidone-iodine functioning thyroid nodules or nodular goiter [87].
administration, renal function, and protein-bound The opposite reaction leads to hypothyroidism from
iodine levels is illustrated in Table II. It seems pru- failure to escape the Wolff-Chaikoff block. This
dent to avoid prolonged use of polyvinylpyrroli- phenomenon has been observed with relative fre-
done-iodine solution other than for skin cleansing in quency among newborns exposed repeatedly to po-
patients with abnormal renal function, or to use it in vidone-iodine for skin and umbilical cord cleansing.
the same manner recommended for iodinated radio- Cutaneous absorption in this population is greater
graphic dyes. than in the adult, and due to the immaturity of their
A clinical study on the absorption and excretion physiologic mechanisms, newborns are prone to hy-
of iodine after the use of polyvinylpyrrolidone-io- pothyroidism, potentiated by the fact that the early
dine surgical scrub, oral antiseptic, and vaginal gel postnatal period is one of critical brain development
showed absorption of excess iodide and other iodine dependent on thyroid hormones [57]. Some investi-
species from the polyvinylpyrrolidone-iodine prep- gators believe that the use of polyvinylpyrrolidone-
arations utilized [61]. Blood levels correlated well iodine is contraindicated in infants [BB],some have
with urine levels of iodine, resulting in prompt ex- suggested that sporadic use is not significantly
cretion of the excess iodine. Knolle et al [61] demon- harmful, and others have suggested that its use be
strated that there is absorption through adult intact monitored by thyroid function tests [BB-901. From
skin after five periods of 5 minutes of scrubbing with the endocrinologic point of view, it seems logical to
a polyvinylpyrrolidone-iodine scrub preparation. avoid prolonged or excessive use of polyvinylpyrro-
The amount of excess iodine absorbed was calculat- lidone-iodine compounds in patients with underly-
ed to be less than 200 pg, four times the normal daily ing thyroid disorders. Patients who deserve special
intake. Mucosal absorption resulted in serum and caution are pregnant women, since iodides cross the
urine levels at least 5 to 10 times greater than the placental barrier, and newborns, in whom the risk of
cutaneous applications. Their study contained an neonatal hypothyroidism should be taken into con-
extensive amount of original data on applications of sideration. In those persons, polyvinylpyrrolidone-
polyvinylpyrrolidone-iodine through various iodine should be used only under compelling cir-
routes, serum and urine iodine levels, and a review cumstances and with proper monitoring [87].
of the world literature.
Excess iodine absorption and an increase of pro-
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406 The American Journal of Surgery