Post by Admin on Oct 21, 2024 2:56:13 GMT -8
www.inchem.org/documents/pims/pharm/iodine.htm
"Presentation, Formulation
Iodine is available in solid form, in solution, and in
tinctures, e.g.
Povidone iodine antiseptic solution, surgical scrub 7.5%,
povidone iodine 200 mg pessaries, povidone antiseptic
ointment 100 mg/g.
Tincture of iodine, USP, contains 2% cent iodine and 2.4%
sodium iodide diluted in 50% ethanol.
Aqueous solutions of iodine are Strong Iodine Solution USP
(compound iodine solution, Lugol's solution) containing 5%
iodine and 10% potassium iodide, and Iodine Topical Solution
(USP) containing 2% iodine and 2.4% potassium iodide. Aqueous
Iodine Solution BP contains the same amount of free and
combined iodine per ml (130 mg/mL) as does the USP Strong
Iodine Solution. (Reynolds, 1993)
Potassium iodide aqueous cough expectorant.
Povidone-iodide (Betadine) is an organically bound iodide
compound containing 1% iodine in a water soluble base. Other
organically bound iodide compounds are undecoylium chloride,
diiodo hydroxyquin, tetraglycine hydroperiodide (60% iodine).
These organic iodide compounds release iodine slowly and have
a toxicity of one fifth of their iodine content (Haddad &
Winchester, 1983).
Povidone iodine antiseptic solution and surgical scrub are in
5 litre containers, pessaries, ointment (see 1.7).
2. SUMMARY
2.1 Main risks and target organs
Concentrated iodine is corrosive. Main risks in acute
exposure to high iodine concentrations are largely due to the
highly corrosive effect of iodine on the entire
gastrointestinal tract and resultant shock. If rupture occurs
mediastinitis or peritonitis develop.
Target organs are mucous membranes of pharynx, larynx and
oesophagus for the concentrated iodine, and thyroid for the
diluted form as a systemic effect. Iodine is not a frequent
cause of toxicity in the amounts available in the household.
2.2 Summary of clinical effects
Ingestion of iodine may cause corrosive effects such as
oedema of the glottis, with asphyxia, aspiration pneumonia,
pulmonary oedema and shock, as well as vomiting and bloody
diarrhoea. The CNS , cardiovascular and renal toxicity
following acute iodine ingestion appear to be due to the
corrosive gastroenteritis and resultant shock. Vomiting,
hypotension and circulatory collapse may be noted following
severe intoxication.
Eye
Eye exposure may result in severe ocular burns.
Cardiovascular
Tachycardia, hypotension and circulatory collapse may be due
to the ingestion of concentrated corrosive iodine solutions.
Respiratory
Inhalation of iodine vapour may result in severe pulmonary
irritation leading to pulmonary oedema. Oedema of the
glottis and pulmonary oedema have also resulted from oral
ingestion.
Neurological
Headache, dizziness, delirium and stupor may be noted
following severe intoxication.
Gastrointestinal
A severe corrosive oesophagitis and gastroenteritis
characterised by vomiting, abdominal pain and diarrhoea may
be noted following ingestion. The vomitus is blue if starch
is present in the stomach. A metallic taste may be noted.
Dermatological
Dermal application of strong iodine solutions may result in
burns.
Chronic ingestion may result in iodism characterised from
acne form skin lesions and other skin eruptions.
Cutaneous absorption may be significant and result in
systemic symptoms and death.
Endocrine
Hypothyroidism, as well as hyperthyroidism, has been
reported.
Immunological
Hypersensitivity reactions including angioedema and/ or serum
sickness-like reactions may be noted."
"Contraindications
Iodine preparations should not be taken regularly during
pregnancy and lactation.
Because iodine may cause burns on occluded skin, an iodine-
treated wound should be covered with a light bandage. As
iodine and iodides can affect the thyroid gland, the
administration of such preparations may interfere with tests
of thyroid functions (Reynolds 1989; McEvoy, 1990).
Potassium iodide should not be used in adolescent patients
because of its potential to induce acne and its effects on
the thyroid gland (Bouillon ,1988).
Iodine or iodides should not be administered to patients with
a history of hypersensitivity to such compounds."
"Teratogenicity
Iodides diffuse across the placenta. Infant and neonatal
death from respiratory distress secondary to goitre has been
reported in mothers taking iodides(Parmalee et al., 1940;
Galima et al., 1962).
Chronic topical maternal use of povidone-iodine during
pregnancy has been associated with clinical and biochemical
hypothyroidism in the infant (Danziger et al., 1987).
Exposure to I 131 can damage or ablute the developing thyroid
of the human foetus. Hypothyroidism, either congenital or of
late onset, has been reported in at least 5 children whose
mothers were exposed to I 131 during pregnancy (Shepard,
1980)"
"Main adverse effects
Endocrine system effects
Iodine and iodides produce goitre, hypothyroidism as well as
hyperthyroidism. These effects have also been reported in
infants born to mothers who had taken iodides during
pregnancy (Reynolds, 1989).
Side effects of iodine given for radioprotection
In iodine-induced goitre and iodine-induced hypothyroidism,
special risk groups are foetus and neonates. Iodine-induced
hyperthyroidism special risk group are people living in
iodine deficient areas and people with a history of
hyperthyroidism, (Bouillon, 1988). Extrathyroidal side
effects are gastrointestinal complaints (nausea, pain), taste
abnormalities, cutaneous and mucous membrane such as
irritation, rash, oedema (including face and glottis),
allergic-like reactions such as fever, eosinophilia, serum-
sickness-like symptoms, vasculitis. Special risk groups are
patients with hypocomplementic vasculitis, (Bouillon, 1988).
Allergic effects
Whether iodine is administered topically or systematically,
iodine and iodides can give rise to allergic reactions:
urticaria, angioedema, cutaneous haemorrhage or purpuras,
fever, arthralgia, lymphadenopathy and eosinophile, acne-form
or severe eruptions.
Iodism effects
A mild toxic syndrome called iodism results from repeated
administration of small amount of iodine. Iodism is
characterised by hyper-salivation, coryza, sneezing,
conjunctivitis, headache, laryngitis, bronchitis, stomatitis,
parotitis, enlargement of the submaxillary glands, skin
rashes and gastric upsets, (Reynolds, 1989, Gosselin et al,
1984). In rare cases jaundice, bleeding from mucous membranes
and bronchospasm may occur. Inflammatory states may be
aggravated by these adverse reactions, (Bouillon, 1988).
Gastrointestinal effects
Acute effects due to ingestion of iodine are mainly due to
its corrosive effects or action which arises at least in part
from oxidizing potential of this element on the
gastrointestinal tract. Symptoms include a metallic taste,
vomiting, abdominal pain, and diarrhoea. Oesophageal
stricture may occur if the patient survives the acute stage,
(Reynolds, 1989; Gosselin et al., 1984).
Cardiovascular and respiratory effects
Death may occur due to circulatory failure, oedema of the
glottis resulting in asphyxia, aspiration pneumonia, or
pulmonary oedema, (Reynolds, 1989, Sittig 1981).
Kidney effect
Anuria may occur 1 to 3 days after exposure, (Reynolds,
1989)."
"Acute poisoning
9.1.1 Ingestion
Ingestion of iodine may cause corrosive effects such as
oedema of the glottis, with asphyxia, aspiration
pneumonia, pulmonary oedema and shock, vomiting and
bloody diarrhoea. The CNS, cardiovascular and renal
toxicity following acute iodine ingestion appear to be
due to the corrosive gastroenteritis and resultant
shock. Vomiting, hypotension and circulatory collapse
may be noted following severe intoxication.
9.1.2 Inhalation
Inhalation of iodine vapour is very irritating to
mucous membranes. Headache, dizziness, delirium,
collapse and stupor, death due to circulatory collapse,
asphyxia from oedema of glottis, aspiration pneumonia
or pulmonary oedema has been reported. Occasionally
haemorrhagic nephritis may occur within 1 to 3 days,
oesophageal and pyloric stenosis have been reported,
(Gosselin et al., 1984).
9.1.3 Skin exposure
Skin contact with iodine may give rise to
hypersensitivity reaction, fever and skin eruption.
Death following skin contact covering one third of body
surface is reported to have occurred, (Gosselin et al.,
1984).
9.1.4 Eye contact
Iodine vapour causes irritation and lachrymation in
human eyes, (Grant, 1974).
9.1.5 Parenteral exposure
Injection of iodine compounds may cause sudden fatal
collapse (anaphylaxis) as a result of hypersensitivity.
Symptoms are dyspnea, cyanosis, fall of blood pressure,
unconsciousness and convulsions, (Dreisbach &
Robertson, 1987).
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
Repeated administration of small amounts of iodine may
result in a mild toxic syndrome called "iodism". It is
characterised by hyper-salivation, coryza, sneezing,
conjunctivitis, stomatitis, parotitis, enlargement of
the submaxillary glands, and skin rashes (Barker &
Wood, 1940; Ehrich & Seifter, 1949).
Hypotension, tachycardia, cyanosis and signs of shock
are frequent symptoms of iodine ingestion. (Gosselin et
al., 1984).
Iodated glycerol used as a mucolytic expectorant in the
treatment of respiratory disorders inhibited the
biosynthesis of thyroid hormone and induced
hypothyroidism (Drinka & Nolten, 1988; Gommolin, 1987).
Amiodarone, an iodine rich drug widely used in the
treatment of tachyarrhythmias, represents one of the
most common sources of iodine-induced thyrotoxicosis
(Martino et al., 1987; Regouby et al., 1985).
Tablets of seaweed, sold over the counter, is one of
the less common sources of iodine-induced
hyperthyroidism (Shilo & Hirsch, 1990).
9.2.2 Inhalation
No data available.
9.2.3 Skin exposure
Intact skin
Irritant contact dermatitis caused by povidone-iodine
has been reported, (Okano, 1989). Liberal application
of the tincture or povidone-iodine to the skin resulted
in significant plasma and urine iodine levels and may
cause systemic iodine toxicity (Luckhardt et al., 1920;
Smerdely et al., 1989; Pyati et al., 1977; Chabrolle &
Rossier, 1978; Coakley et al., 1989; L'Allemand et al.,
1987; Dantzigen et al., 1987; Schoenberger & Grim,
1982).
Injured skin
Continuous postoperative wound irrigation with
povidone-iodine resulted in death of a patient. Toxic
manifestations of systemic iodine absorption appeared
to cause the death, (D'Auria et al., 1990; Glick et
al., 1985).
Application of povidone-iodine on skin burns may cause
systemic iodine toxicity (Lavelle et al., 1975; Peitsch
& Meakins, 1976).
9.2.4 Eye contact
Iodine-containing eye drops caused hyperthyroidism
(Geisthoevel, 1984).
9.2.5 Parenteral exposure
Iodine-containing contrast media may cause
hyperthyroidism; the most frequent thyroid disorders,
usually of a temporary nature, occur after choledochal
contrast media (Steidle, 1989). In premature infants
they cause hypothyroidism (L'Allemand et al., 1987).
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
If the patient survives 48 hours after the ingestion of
iodine, recovery is likely, although stricture of the
oesophagus or pyloric sphincter may be a complication,
(Dreisbach & Robertson 1987). It is probable that the
pathological changes recorded in fatal cases of iodine
poisoning and attributed to the systemic effects of iodine
are largely the result of shock due to massive loss of fluid
from the gastrointestinal tract and tissue hypoxia (Gilman et
al.,1990).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Cardiovascular effects are not due directly to iodine
or iodide. Hypotension, tachycardia circulatory
collapse may occur secondary to corrosive
gastroenteritis due to ingestion of highly concentrated
iodine solutions. In acute iodine inhalation,
hypotension and tachycardia have been reported,
(Gosselin et al., 1984).
9.4.2 Respiratory
Inhalation of fumes leads to irritation of mucous
membranes of the respiratory tract, which may result in
asphyxia. Oedema of the glottis from ingestion was
reported in early literature as a frequently mentioned
cause of death, (Finkelstein & Jacobi, 1937).
Pulmonary oedema and tachypnoea have been reported
following ingestion of an unspecified large quantity of
Lugol's solution, (Dyck et al., 1979).
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
Headache, dizziness and delirium have been
reported in severe intoxications. Altered
sensorium (agitation, confusion,
hallucinations) have occurred in association
with elevated serum iodine concentrations,
(Alvarez, 1979; Gosselin et al., 1984).
Continued administration of iodine may lead to
mental depression, nervousness and insomnia
(Reynolds, 1989).
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
Excessive ingestion of iodine solutions can lead to
gastrointestinal irritation, vomiting and ulceration at
various levels of the upper gastrointestinal tract.
Late oesophageal and pyloric stenosis have been
reported, (Gosselin et al., 1984).
If the stomach contains starch the emesis is coloured
blue.
9.4.5 Hepatic
Elevated serum transaminases and bilirubin
concentrations have been reported occasionally in
patients with elevated serum iodine concentrations,
(Lavelle et al., 1975; Peitsch & Meakins, 1976).
9.4.6 Urinary
9.4.6.1 Renal
Poisoning is manifested by serum creatine and
levels up to 3.5 mg/dL (309 mmol/L) has been
reported, (Dela Cruz et al., 1987). The renal
lesions, which sometimes resemble acute
tubularnecrosis, may be exacerbated by
haemolytic anaemia, (Gosselin et al., 1984).
Nephrotoxicity by iodine contrast media is
reported by Cacoub et al., (1987).
9.4.6.2 Others
No data available.
9.4.7 Endocrine and reproductive systems
Transient hypothyroidism characterised by elevated
urinary iodide concentrations, elevated serum iodine
concentrations, elevated TSH concentrations, and low T4
concentrations have been demonstrated in povidone-
iodine exposed mothers and their infants (L'Allemand et
al., 1987).
Iodine induced thyrotoxicosis is a condition that may
develop in older patients with long-standing iodine
deficiencies who receive high doses of iodine
(Kobberling et al., 1985; Fradkin, 1983; Klein & Levey,
1983).
Iodine containing drugs caused thyrotoxic crisis
(Mackenroth, 1990).
Excessive iodine intake can cause thyroid autoimmunity
in endemic goitre, (Boyages et al., 1989).
Organically bound iodine in the form of iodinated
glycerol used as a mucolytic expectorant can inhibit
the biosynthesis of thyroid hormone and induce
hypothyroidism, (Drinka & Nolten, 1988).
Hypothyroidism has also been described in neonates
treated with topical povidone-iodine (Cosman et al.,
1988). Topical iodine containing antiseptics may induce
hypothyroidism in very-low-birthweight infants,
(Smerdely et al., 1989). Multiple applications of
povidone iodine in pregnancy, and lactation caused
transient congenital hypothyroidism in a 6 week old
girl, (Danziger et al., 1987).
Iodine in contrast agents and skin disinfectants is the
major cause for hypothyroidism in premature infants
during intensive care, (L'Allemand et al., 1987).
Iodated glycerol, an organic form of iodine, prescribed
as a mucolytic-expectorant induced a mild
hypothyroidism in a patient with a previous history of
severe potassium iodide-induced hypothyroidism.
Amiodarone, an iodine-rich drug widely used in the
treatment of tachyarrhythmias, represents one of the
most common sources of iodine-induced thyrotoxicosis.
It developed not only in patients with underlying
thyroid disorders, but also in subjects with apparently
normal thyroid gland. Thyrotoxicosis occurred either
during treatment with or at various intervals after
withdrawal of amiodarone. Classical symptoms were often
lacking, the main clinical feature being a worsening of
cardiac disorders, (Martino et al., 1987).
Tablets of seaweed, sold over the counter, is a real
source of iodine. A 72-year-old female developed
hyperthyroidism while ingesting these tablets. After
stopping, the symptoms of hypothyroidism disappeared,
(Shilo & Hirsch, 1990).
Continuous povidone-iodine irrigation caused iodine
toxicity with symptoms of metabolic acidosis, changes
in mental status and the patient died (Glick et al.,
1985).
Administration of iodine containing eye-drops used as a
cataract treatment caused hyperthyroidism (Geisthoevel,
1984).
9.4.8 Dermatological
A case of fatal dermatitis following the use of a 2.5%
solution of resublimated iodine in pure industrial
alcohol before a surgical operation has been reported.
The reaction was thought to be due to idiosyncrasy to
iodine. Skin disinfection with iodine has caused goitre
and hypothyroidism in 5 of 30 newborns under intensive
care (Bouillon, 1988).
Prolonged exposure to tincture of iodine can induce
superficial necrosis. At least one death has been
reported consequent to extensive skin involvement.
Solutions of iodine applied to the skin should not be
covered with occlusive dressings.
Topical application of povidone-iodine on burn patients
may lead to increased iodine/iodide absorption (Lavelle
et al., 1975) and the development of a metabolic
acidosis, renal failure and an altered mental status
although a cause and effect relationship has not been
definitely established.
The older literature reports systemic symptoms which
occurred immediately to 24 hours later, rarely
following cutaneous application of one-half to one
normal strength iodine tincture. Symptoms included
fever, diarrhoea, pain, headache and delirium. Skin
eruptions included urticaria to erythema to exfoliative
dermatitis. Mortality was 47% in those 15 cases
reported (Seymour, 1937).
Repeated applications of iodophors may cause contact
dermatitis. Allergic reactions occur 12 to 20 hours
after application (Harvey, 1985; Kudo et al., 1988).
9.4.9 Eye, ear, nose, throat: local effects
Exposure to iodine vapour may cause burning in the
eyes, blepharitis, and severe ocular burns (Finkelstein
& Jacobi, 1937).
Iodine vapour may cause rhinitis.
Stomatitis and pharyngitis may result from exposure to
iodine vapour or solutions and mucous membranes are
coloured brown. (Finkelstein & Jacobi, 1937).
9.4.10 Haematological
Neutropenia has been reported in association with
elevated serum iodine concentrations, (Alvarez, 1979).
Thrombotic thrombocytopenic purpura has been observed
after repeated administration of small amounts of
iodine, (Ehrich & Seifter, 1949)
Haemolysis has also been reported (Dyck et al., 1979).
9.4.11 Immunological
Reactions to iodine may occur acutely or after chronic
use and may be characterised by coryza, headache,
salivary gland pain, conjunctivitis, fever or skin
reactions (urticaria, acneform, eruptions, erythema,
bullous, ioderma). Oral and intravenous iodine
containing radio-contrast media (e.g Telopaque ®;
I125, I131) may cause iodine hypersensitivity reaction
as well as anaphylactic type reactions, (Crocker &
Vadam, 1963).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Metabolic acidosis may be associated with
iodine toxicity. There is an increased anion
gap due to elevated serum lactate levels (47
micromol/L) (Dyck et al., 1979; Dela Cruz et
al., 1987)
9.4.12.2 Fluid and electrolyte disturbances
Elevated serum sodium (hypernatraemia) (156
mEq/L) has been reported (Dela Cruz et al.,
1987).
Hyperchloremia (127 mEq/L) has also been
reported but probably represents a spurious
elevation due to interference in the assay by
iodine (Dela Cruz et al., 1987).
Elevations in calculated osmolarity (340 in
Osm/L) have also been reported (Dela Cruz et
al., 1987).
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
Intolerance to iodised X-ray contrast media may cause
reactions consisting of fever, chills, malaise, nausea
and vomiting, skin rash, diarrhoea and even
hypotension. These may be classified as idiosyncratic.
In patients with a history of idiosyncratic reaction
premedication with corticoids and histamines is
indicated or non-ionic contrast reagents should be
used,(Soyer & Levesque, 1990). After interleukin-2
administration an increased incidence of
hypersensitivity to iodine was observed, (Zukiwski et
al., 1990).
Hypersensitivity reactions were reported in 14 cases,
secondary to the application of iodine-alcohol
solutions to the skin. Symptoms reported were fever
and generalised skin eruption of varying types.
Despite the wide use of tincture of iodine the
incidence of systemic reactions is low (Seymour,
1937).
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy
Maternal ingestion of iodine containing substances
during pregnancy can cause (transient) primary
hypothyroidism in the newborn, (Coakley et al., 1989).
Exposure to iodine and radioactive iodine in pregnancy
may lead to permanent hypothyroidism or goitre in the
newborn. Such goitres may become very large and even
create problems during delivery or mechanical
compression during early postnatal life (Bouillon,
1988).
Breast feeding
Similar warnings to those given for pregnancy against
the use of iodine or iodine-containing drugs applies
during lactation since iodine is actively secreted in
milk, (Bouillon, 1988)."
"ILLUSTRATIVE CASES
11.1 Case reports from literature
Case 1
Continuous irrigation with povidone-iodine in a 34-month-
old patient with mediastinitis was associated with iodine
toxicity, resulting in fatalities, (Glick et al., 1985). It
is suggested that povidone-iodine continuous irrigation of
the mediastinum be a contraindication.
Case 2
A 63-year-old woman with a suppurative mediastinitis,
treated with continuous Polyvinyl-pyrrolidone-iodine (PI)
irrigation developed an acute oliguric renal failure due to
systemic toxicity of PI. The withdrawal of PI was followed
by a complete improvement of renal function, (Campistol et
al., 1988).
Case 3
Two patients with leg ulcers got worse after the
application of a compound mixture of sugar and povidone
iodine (sugar/PI compound). Patch-tests showed positive
reactions to 10% povidone-iodine in water and 5% potassium
iodide in water with no response to sugar. They were also
tested with sugar/PI compound containing 3% povidone
iodine, resulting in another positive reaction. They
improved after the application of sugar/PI compound was
discontinued, (Kudo et al., 1988).
Case 4
A 34-year-old male with burns covering 80% BSA and a 22-
year-old female with a 45% BSA burn, showed hyperthyroidism
induced by topical treatment with 1% povidone-iodine. After
topical treatment with povidone-iodine was discontinued
circulating thyroid hormones returned to normal values
within weeks (Rath and Meissl,1988).
Case 5
Fifteen episodes of infection due to Pseudomonas
aeruginosa, including peritonitis and other site
infections, occurred in nine patients receiving continuous
ambulatory peritoneal dialysis over a 27 month period.
Occurrence of P. aeruginosa infection was significantly
associated with use of povidone-iodine solution to cleanse
the catheter site. Local irritation and alteration in skin
flora caused by antiseptic solution or low-level
contamination of povidone-iodine solution are potential
mechanisms of infection (Goetz and Muder, 1989)
Case 6
Vaginal douching with polyvinyl pyrrolidone iodine (PVP-I)
during pregnancy resulted in maternal iodine overload and
increased the iodine content of amniotic fluid. The
possible effect of this therapy was evaluated on the
thyroid of the fetus by investigating 62 women with a mean
duration of amenorrhoea of 20 weeks who solicited
controlled abortion. Nineteen of them douched daily with
PVP-I for 2 consecutive days before abortion (treated
group). The other 43 women were not treated (control
group). In both groups the iodine content was determined in
the foetal thyroid and in amniotic fluid and maternal urine
at the time of abortion. In addition, in the treated group
the concentrations of iodine were also determined in
amniotic fluid and urine before therapy and in urine after
4 days of therapy. There were no differences in the
concentrations of iodine in urine and amniotic fluid in the
control group and in the treated group before therapy.
Iodine content increased more rapidly in the treated group
(from 1 to 7.7 micrograms) than in the control group (from
1 to 2.5 micrograms) P less than 0.05 (Mahillon et al.,
1989).
Case 7
Approximately 570,000 newborns were tested for congenital
hypothyroidism between May 1977 and December 1986. One
hundred and sixty cases of primary hypothyroidism, were
later found to be transient. 14 out of the transient cases
were due to excessive intake of iodine. In two, this was
due to maternal ingestion of iodide during pregnancy and in
12 the babies received large amounts of topical iodine
antiseptic. Two cases were caused by maternal anti-thyroid
antibodies and in eight instances the cause was unknown.
The large number of cases due to topical application of
iodine antiseptic emphasizes the need for caution when
using this substance in neonates (Coakely et al., 1989)."
"Presentation, Formulation
Iodine is available in solid form, in solution, and in
tinctures, e.g.
Povidone iodine antiseptic solution, surgical scrub 7.5%,
povidone iodine 200 mg pessaries, povidone antiseptic
ointment 100 mg/g.
Tincture of iodine, USP, contains 2% cent iodine and 2.4%
sodium iodide diluted in 50% ethanol.
Aqueous solutions of iodine are Strong Iodine Solution USP
(compound iodine solution, Lugol's solution) containing 5%
iodine and 10% potassium iodide, and Iodine Topical Solution
(USP) containing 2% iodine and 2.4% potassium iodide. Aqueous
Iodine Solution BP contains the same amount of free and
combined iodine per ml (130 mg/mL) as does the USP Strong
Iodine Solution. (Reynolds, 1993)
Potassium iodide aqueous cough expectorant.
Povidone-iodide (Betadine) is an organically bound iodide
compound containing 1% iodine in a water soluble base. Other
organically bound iodide compounds are undecoylium chloride,
diiodo hydroxyquin, tetraglycine hydroperiodide (60% iodine).
These organic iodide compounds release iodine slowly and have
a toxicity of one fifth of their iodine content (Haddad &
Winchester, 1983).
Povidone iodine antiseptic solution and surgical scrub are in
5 litre containers, pessaries, ointment (see 1.7).
2. SUMMARY
2.1 Main risks and target organs
Concentrated iodine is corrosive. Main risks in acute
exposure to high iodine concentrations are largely due to the
highly corrosive effect of iodine on the entire
gastrointestinal tract and resultant shock. If rupture occurs
mediastinitis or peritonitis develop.
Target organs are mucous membranes of pharynx, larynx and
oesophagus for the concentrated iodine, and thyroid for the
diluted form as a systemic effect. Iodine is not a frequent
cause of toxicity in the amounts available in the household.
2.2 Summary of clinical effects
Ingestion of iodine may cause corrosive effects such as
oedema of the glottis, with asphyxia, aspiration pneumonia,
pulmonary oedema and shock, as well as vomiting and bloody
diarrhoea. The CNS , cardiovascular and renal toxicity
following acute iodine ingestion appear to be due to the
corrosive gastroenteritis and resultant shock. Vomiting,
hypotension and circulatory collapse may be noted following
severe intoxication.
Eye
Eye exposure may result in severe ocular burns.
Cardiovascular
Tachycardia, hypotension and circulatory collapse may be due
to the ingestion of concentrated corrosive iodine solutions.
Respiratory
Inhalation of iodine vapour may result in severe pulmonary
irritation leading to pulmonary oedema. Oedema of the
glottis and pulmonary oedema have also resulted from oral
ingestion.
Neurological
Headache, dizziness, delirium and stupor may be noted
following severe intoxication.
Gastrointestinal
A severe corrosive oesophagitis and gastroenteritis
characterised by vomiting, abdominal pain and diarrhoea may
be noted following ingestion. The vomitus is blue if starch
is present in the stomach. A metallic taste may be noted.
Dermatological
Dermal application of strong iodine solutions may result in
burns.
Chronic ingestion may result in iodism characterised from
acne form skin lesions and other skin eruptions.
Cutaneous absorption may be significant and result in
systemic symptoms and death.
Endocrine
Hypothyroidism, as well as hyperthyroidism, has been
reported.
Immunological
Hypersensitivity reactions including angioedema and/ or serum
sickness-like reactions may be noted."
"Contraindications
Iodine preparations should not be taken regularly during
pregnancy and lactation.
Because iodine may cause burns on occluded skin, an iodine-
treated wound should be covered with a light bandage. As
iodine and iodides can affect the thyroid gland, the
administration of such preparations may interfere with tests
of thyroid functions (Reynolds 1989; McEvoy, 1990).
Potassium iodide should not be used in adolescent patients
because of its potential to induce acne and its effects on
the thyroid gland (Bouillon ,1988).
Iodine or iodides should not be administered to patients with
a history of hypersensitivity to such compounds."
"Teratogenicity
Iodides diffuse across the placenta. Infant and neonatal
death from respiratory distress secondary to goitre has been
reported in mothers taking iodides(Parmalee et al., 1940;
Galima et al., 1962).
Chronic topical maternal use of povidone-iodine during
pregnancy has been associated with clinical and biochemical
hypothyroidism in the infant (Danziger et al., 1987).
Exposure to I 131 can damage or ablute the developing thyroid
of the human foetus. Hypothyroidism, either congenital or of
late onset, has been reported in at least 5 children whose
mothers were exposed to I 131 during pregnancy (Shepard,
1980)"
"Main adverse effects
Endocrine system effects
Iodine and iodides produce goitre, hypothyroidism as well as
hyperthyroidism. These effects have also been reported in
infants born to mothers who had taken iodides during
pregnancy (Reynolds, 1989).
Side effects of iodine given for radioprotection
In iodine-induced goitre and iodine-induced hypothyroidism,
special risk groups are foetus and neonates. Iodine-induced
hyperthyroidism special risk group are people living in
iodine deficient areas and people with a history of
hyperthyroidism, (Bouillon, 1988). Extrathyroidal side
effects are gastrointestinal complaints (nausea, pain), taste
abnormalities, cutaneous and mucous membrane such as
irritation, rash, oedema (including face and glottis),
allergic-like reactions such as fever, eosinophilia, serum-
sickness-like symptoms, vasculitis. Special risk groups are
patients with hypocomplementic vasculitis, (Bouillon, 1988).
Allergic effects
Whether iodine is administered topically or systematically,
iodine and iodides can give rise to allergic reactions:
urticaria, angioedema, cutaneous haemorrhage or purpuras,
fever, arthralgia, lymphadenopathy and eosinophile, acne-form
or severe eruptions.
Iodism effects
A mild toxic syndrome called iodism results from repeated
administration of small amount of iodine. Iodism is
characterised by hyper-salivation, coryza, sneezing,
conjunctivitis, headache, laryngitis, bronchitis, stomatitis,
parotitis, enlargement of the submaxillary glands, skin
rashes and gastric upsets, (Reynolds, 1989, Gosselin et al,
1984). In rare cases jaundice, bleeding from mucous membranes
and bronchospasm may occur. Inflammatory states may be
aggravated by these adverse reactions, (Bouillon, 1988).
Gastrointestinal effects
Acute effects due to ingestion of iodine are mainly due to
its corrosive effects or action which arises at least in part
from oxidizing potential of this element on the
gastrointestinal tract. Symptoms include a metallic taste,
vomiting, abdominal pain, and diarrhoea. Oesophageal
stricture may occur if the patient survives the acute stage,
(Reynolds, 1989; Gosselin et al., 1984).
Cardiovascular and respiratory effects
Death may occur due to circulatory failure, oedema of the
glottis resulting in asphyxia, aspiration pneumonia, or
pulmonary oedema, (Reynolds, 1989, Sittig 1981).
Kidney effect
Anuria may occur 1 to 3 days after exposure, (Reynolds,
1989)."
"Acute poisoning
9.1.1 Ingestion
Ingestion of iodine may cause corrosive effects such as
oedema of the glottis, with asphyxia, aspiration
pneumonia, pulmonary oedema and shock, vomiting and
bloody diarrhoea. The CNS, cardiovascular and renal
toxicity following acute iodine ingestion appear to be
due to the corrosive gastroenteritis and resultant
shock. Vomiting, hypotension and circulatory collapse
may be noted following severe intoxication.
9.1.2 Inhalation
Inhalation of iodine vapour is very irritating to
mucous membranes. Headache, dizziness, delirium,
collapse and stupor, death due to circulatory collapse,
asphyxia from oedema of glottis, aspiration pneumonia
or pulmonary oedema has been reported. Occasionally
haemorrhagic nephritis may occur within 1 to 3 days,
oesophageal and pyloric stenosis have been reported,
(Gosselin et al., 1984).
9.1.3 Skin exposure
Skin contact with iodine may give rise to
hypersensitivity reaction, fever and skin eruption.
Death following skin contact covering one third of body
surface is reported to have occurred, (Gosselin et al.,
1984).
9.1.4 Eye contact
Iodine vapour causes irritation and lachrymation in
human eyes, (Grant, 1974).
9.1.5 Parenteral exposure
Injection of iodine compounds may cause sudden fatal
collapse (anaphylaxis) as a result of hypersensitivity.
Symptoms are dyspnea, cyanosis, fall of blood pressure,
unconsciousness and convulsions, (Dreisbach &
Robertson, 1987).
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
Repeated administration of small amounts of iodine may
result in a mild toxic syndrome called "iodism". It is
characterised by hyper-salivation, coryza, sneezing,
conjunctivitis, stomatitis, parotitis, enlargement of
the submaxillary glands, and skin rashes (Barker &
Wood, 1940; Ehrich & Seifter, 1949).
Hypotension, tachycardia, cyanosis and signs of shock
are frequent symptoms of iodine ingestion. (Gosselin et
al., 1984).
Iodated glycerol used as a mucolytic expectorant in the
treatment of respiratory disorders inhibited the
biosynthesis of thyroid hormone and induced
hypothyroidism (Drinka & Nolten, 1988; Gommolin, 1987).
Amiodarone, an iodine rich drug widely used in the
treatment of tachyarrhythmias, represents one of the
most common sources of iodine-induced thyrotoxicosis
(Martino et al., 1987; Regouby et al., 1985).
Tablets of seaweed, sold over the counter, is one of
the less common sources of iodine-induced
hyperthyroidism (Shilo & Hirsch, 1990).
9.2.2 Inhalation
No data available.
9.2.3 Skin exposure
Intact skin
Irritant contact dermatitis caused by povidone-iodine
has been reported, (Okano, 1989). Liberal application
of the tincture or povidone-iodine to the skin resulted
in significant plasma and urine iodine levels and may
cause systemic iodine toxicity (Luckhardt et al., 1920;
Smerdely et al., 1989; Pyati et al., 1977; Chabrolle &
Rossier, 1978; Coakley et al., 1989; L'Allemand et al.,
1987; Dantzigen et al., 1987; Schoenberger & Grim,
1982).
Injured skin
Continuous postoperative wound irrigation with
povidone-iodine resulted in death of a patient. Toxic
manifestations of systemic iodine absorption appeared
to cause the death, (D'Auria et al., 1990; Glick et
al., 1985).
Application of povidone-iodine on skin burns may cause
systemic iodine toxicity (Lavelle et al., 1975; Peitsch
& Meakins, 1976).
9.2.4 Eye contact
Iodine-containing eye drops caused hyperthyroidism
(Geisthoevel, 1984).
9.2.5 Parenteral exposure
Iodine-containing contrast media may cause
hyperthyroidism; the most frequent thyroid disorders,
usually of a temporary nature, occur after choledochal
contrast media (Steidle, 1989). In premature infants
they cause hypothyroidism (L'Allemand et al., 1987).
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
If the patient survives 48 hours after the ingestion of
iodine, recovery is likely, although stricture of the
oesophagus or pyloric sphincter may be a complication,
(Dreisbach & Robertson 1987). It is probable that the
pathological changes recorded in fatal cases of iodine
poisoning and attributed to the systemic effects of iodine
are largely the result of shock due to massive loss of fluid
from the gastrointestinal tract and tissue hypoxia (Gilman et
al.,1990).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Cardiovascular effects are not due directly to iodine
or iodide. Hypotension, tachycardia circulatory
collapse may occur secondary to corrosive
gastroenteritis due to ingestion of highly concentrated
iodine solutions. In acute iodine inhalation,
hypotension and tachycardia have been reported,
(Gosselin et al., 1984).
9.4.2 Respiratory
Inhalation of fumes leads to irritation of mucous
membranes of the respiratory tract, which may result in
asphyxia. Oedema of the glottis from ingestion was
reported in early literature as a frequently mentioned
cause of death, (Finkelstein & Jacobi, 1937).
Pulmonary oedema and tachypnoea have been reported
following ingestion of an unspecified large quantity of
Lugol's solution, (Dyck et al., 1979).
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
Headache, dizziness and delirium have been
reported in severe intoxications. Altered
sensorium (agitation, confusion,
hallucinations) have occurred in association
with elevated serum iodine concentrations,
(Alvarez, 1979; Gosselin et al., 1984).
Continued administration of iodine may lead to
mental depression, nervousness and insomnia
(Reynolds, 1989).
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
Excessive ingestion of iodine solutions can lead to
gastrointestinal irritation, vomiting and ulceration at
various levels of the upper gastrointestinal tract.
Late oesophageal and pyloric stenosis have been
reported, (Gosselin et al., 1984).
If the stomach contains starch the emesis is coloured
blue.
9.4.5 Hepatic
Elevated serum transaminases and bilirubin
concentrations have been reported occasionally in
patients with elevated serum iodine concentrations,
(Lavelle et al., 1975; Peitsch & Meakins, 1976).
9.4.6 Urinary
9.4.6.1 Renal
Poisoning is manifested by serum creatine and
levels up to 3.5 mg/dL (309 mmol/L) has been
reported, (Dela Cruz et al., 1987). The renal
lesions, which sometimes resemble acute
tubularnecrosis, may be exacerbated by
haemolytic anaemia, (Gosselin et al., 1984).
Nephrotoxicity by iodine contrast media is
reported by Cacoub et al., (1987).
9.4.6.2 Others
No data available.
9.4.7 Endocrine and reproductive systems
Transient hypothyroidism characterised by elevated
urinary iodide concentrations, elevated serum iodine
concentrations, elevated TSH concentrations, and low T4
concentrations have been demonstrated in povidone-
iodine exposed mothers and their infants (L'Allemand et
al., 1987).
Iodine induced thyrotoxicosis is a condition that may
develop in older patients with long-standing iodine
deficiencies who receive high doses of iodine
(Kobberling et al., 1985; Fradkin, 1983; Klein & Levey,
1983).
Iodine containing drugs caused thyrotoxic crisis
(Mackenroth, 1990).
Excessive iodine intake can cause thyroid autoimmunity
in endemic goitre, (Boyages et al., 1989).
Organically bound iodine in the form of iodinated
glycerol used as a mucolytic expectorant can inhibit
the biosynthesis of thyroid hormone and induce
hypothyroidism, (Drinka & Nolten, 1988).
Hypothyroidism has also been described in neonates
treated with topical povidone-iodine (Cosman et al.,
1988). Topical iodine containing antiseptics may induce
hypothyroidism in very-low-birthweight infants,
(Smerdely et al., 1989). Multiple applications of
povidone iodine in pregnancy, and lactation caused
transient congenital hypothyroidism in a 6 week old
girl, (Danziger et al., 1987).
Iodine in contrast agents and skin disinfectants is the
major cause for hypothyroidism in premature infants
during intensive care, (L'Allemand et al., 1987).
Iodated glycerol, an organic form of iodine, prescribed
as a mucolytic-expectorant induced a mild
hypothyroidism in a patient with a previous history of
severe potassium iodide-induced hypothyroidism.
Amiodarone, an iodine-rich drug widely used in the
treatment of tachyarrhythmias, represents one of the
most common sources of iodine-induced thyrotoxicosis.
It developed not only in patients with underlying
thyroid disorders, but also in subjects with apparently
normal thyroid gland. Thyrotoxicosis occurred either
during treatment with or at various intervals after
withdrawal of amiodarone. Classical symptoms were often
lacking, the main clinical feature being a worsening of
cardiac disorders, (Martino et al., 1987).
Tablets of seaweed, sold over the counter, is a real
source of iodine. A 72-year-old female developed
hyperthyroidism while ingesting these tablets. After
stopping, the symptoms of hypothyroidism disappeared,
(Shilo & Hirsch, 1990).
Continuous povidone-iodine irrigation caused iodine
toxicity with symptoms of metabolic acidosis, changes
in mental status and the patient died (Glick et al.,
1985).
Administration of iodine containing eye-drops used as a
cataract treatment caused hyperthyroidism (Geisthoevel,
1984).
9.4.8 Dermatological
A case of fatal dermatitis following the use of a 2.5%
solution of resublimated iodine in pure industrial
alcohol before a surgical operation has been reported.
The reaction was thought to be due to idiosyncrasy to
iodine. Skin disinfection with iodine has caused goitre
and hypothyroidism in 5 of 30 newborns under intensive
care (Bouillon, 1988).
Prolonged exposure to tincture of iodine can induce
superficial necrosis. At least one death has been
reported consequent to extensive skin involvement.
Solutions of iodine applied to the skin should not be
covered with occlusive dressings.
Topical application of povidone-iodine on burn patients
may lead to increased iodine/iodide absorption (Lavelle
et al., 1975) and the development of a metabolic
acidosis, renal failure and an altered mental status
although a cause and effect relationship has not been
definitely established.
The older literature reports systemic symptoms which
occurred immediately to 24 hours later, rarely
following cutaneous application of one-half to one
normal strength iodine tincture. Symptoms included
fever, diarrhoea, pain, headache and delirium. Skin
eruptions included urticaria to erythema to exfoliative
dermatitis. Mortality was 47% in those 15 cases
reported (Seymour, 1937).
Repeated applications of iodophors may cause contact
dermatitis. Allergic reactions occur 12 to 20 hours
after application (Harvey, 1985; Kudo et al., 1988).
9.4.9 Eye, ear, nose, throat: local effects
Exposure to iodine vapour may cause burning in the
eyes, blepharitis, and severe ocular burns (Finkelstein
& Jacobi, 1937).
Iodine vapour may cause rhinitis.
Stomatitis and pharyngitis may result from exposure to
iodine vapour or solutions and mucous membranes are
coloured brown. (Finkelstein & Jacobi, 1937).
9.4.10 Haematological
Neutropenia has been reported in association with
elevated serum iodine concentrations, (Alvarez, 1979).
Thrombotic thrombocytopenic purpura has been observed
after repeated administration of small amounts of
iodine, (Ehrich & Seifter, 1949)
Haemolysis has also been reported (Dyck et al., 1979).
9.4.11 Immunological
Reactions to iodine may occur acutely or after chronic
use and may be characterised by coryza, headache,
salivary gland pain, conjunctivitis, fever or skin
reactions (urticaria, acneform, eruptions, erythema,
bullous, ioderma). Oral and intravenous iodine
containing radio-contrast media (e.g Telopaque ®;
I125, I131) may cause iodine hypersensitivity reaction
as well as anaphylactic type reactions, (Crocker &
Vadam, 1963).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Metabolic acidosis may be associated with
iodine toxicity. There is an increased anion
gap due to elevated serum lactate levels (47
micromol/L) (Dyck et al., 1979; Dela Cruz et
al., 1987)
9.4.12.2 Fluid and electrolyte disturbances
Elevated serum sodium (hypernatraemia) (156
mEq/L) has been reported (Dela Cruz et al.,
1987).
Hyperchloremia (127 mEq/L) has also been
reported but probably represents a spurious
elevation due to interference in the assay by
iodine (Dela Cruz et al., 1987).
Elevations in calculated osmolarity (340 in
Osm/L) have also been reported (Dela Cruz et
al., 1987).
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
Intolerance to iodised X-ray contrast media may cause
reactions consisting of fever, chills, malaise, nausea
and vomiting, skin rash, diarrhoea and even
hypotension. These may be classified as idiosyncratic.
In patients with a history of idiosyncratic reaction
premedication with corticoids and histamines is
indicated or non-ionic contrast reagents should be
used,(Soyer & Levesque, 1990). After interleukin-2
administration an increased incidence of
hypersensitivity to iodine was observed, (Zukiwski et
al., 1990).
Hypersensitivity reactions were reported in 14 cases,
secondary to the application of iodine-alcohol
solutions to the skin. Symptoms reported were fever
and generalised skin eruption of varying types.
Despite the wide use of tincture of iodine the
incidence of systemic reactions is low (Seymour,
1937).
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy
Maternal ingestion of iodine containing substances
during pregnancy can cause (transient) primary
hypothyroidism in the newborn, (Coakley et al., 1989).
Exposure to iodine and radioactive iodine in pregnancy
may lead to permanent hypothyroidism or goitre in the
newborn. Such goitres may become very large and even
create problems during delivery or mechanical
compression during early postnatal life (Bouillon,
1988).
Breast feeding
Similar warnings to those given for pregnancy against
the use of iodine or iodine-containing drugs applies
during lactation since iodine is actively secreted in
milk, (Bouillon, 1988)."
"ILLUSTRATIVE CASES
11.1 Case reports from literature
Case 1
Continuous irrigation with povidone-iodine in a 34-month-
old patient with mediastinitis was associated with iodine
toxicity, resulting in fatalities, (Glick et al., 1985). It
is suggested that povidone-iodine continuous irrigation of
the mediastinum be a contraindication.
Case 2
A 63-year-old woman with a suppurative mediastinitis,
treated with continuous Polyvinyl-pyrrolidone-iodine (PI)
irrigation developed an acute oliguric renal failure due to
systemic toxicity of PI. The withdrawal of PI was followed
by a complete improvement of renal function, (Campistol et
al., 1988).
Case 3
Two patients with leg ulcers got worse after the
application of a compound mixture of sugar and povidone
iodine (sugar/PI compound). Patch-tests showed positive
reactions to 10% povidone-iodine in water and 5% potassium
iodide in water with no response to sugar. They were also
tested with sugar/PI compound containing 3% povidone
iodine, resulting in another positive reaction. They
improved after the application of sugar/PI compound was
discontinued, (Kudo et al., 1988).
Case 4
A 34-year-old male with burns covering 80% BSA and a 22-
year-old female with a 45% BSA burn, showed hyperthyroidism
induced by topical treatment with 1% povidone-iodine. After
topical treatment with povidone-iodine was discontinued
circulating thyroid hormones returned to normal values
within weeks (Rath and Meissl,1988).
Case 5
Fifteen episodes of infection due to Pseudomonas
aeruginosa, including peritonitis and other site
infections, occurred in nine patients receiving continuous
ambulatory peritoneal dialysis over a 27 month period.
Occurrence of P. aeruginosa infection was significantly
associated with use of povidone-iodine solution to cleanse
the catheter site. Local irritation and alteration in skin
flora caused by antiseptic solution or low-level
contamination of povidone-iodine solution are potential
mechanisms of infection (Goetz and Muder, 1989)
Case 6
Vaginal douching with polyvinyl pyrrolidone iodine (PVP-I)
during pregnancy resulted in maternal iodine overload and
increased the iodine content of amniotic fluid. The
possible effect of this therapy was evaluated on the
thyroid of the fetus by investigating 62 women with a mean
duration of amenorrhoea of 20 weeks who solicited
controlled abortion. Nineteen of them douched daily with
PVP-I for 2 consecutive days before abortion (treated
group). The other 43 women were not treated (control
group). In both groups the iodine content was determined in
the foetal thyroid and in amniotic fluid and maternal urine
at the time of abortion. In addition, in the treated group
the concentrations of iodine were also determined in
amniotic fluid and urine before therapy and in urine after
4 days of therapy. There were no differences in the
concentrations of iodine in urine and amniotic fluid in the
control group and in the treated group before therapy.
Iodine content increased more rapidly in the treated group
(from 1 to 7.7 micrograms) than in the control group (from
1 to 2.5 micrograms) P less than 0.05 (Mahillon et al.,
1989).
Case 7
Approximately 570,000 newborns were tested for congenital
hypothyroidism between May 1977 and December 1986. One
hundred and sixty cases of primary hypothyroidism, were
later found to be transient. 14 out of the transient cases
were due to excessive intake of iodine. In two, this was
due to maternal ingestion of iodide during pregnancy and in
12 the babies received large amounts of topical iodine
antiseptic. Two cases were caused by maternal anti-thyroid
antibodies and in eight instances the cause was unknown.
The large number of cases due to topical application of
iodine antiseptic emphasizes the need for caution when
using this substance in neonates (Coakely et al., 1989)."