G.
Reybrouck
25 Antiseptic drugs and
disinfectants
ACIDS
Boric acid (SED-IO, 424; SEDA-8, 243;
SEDA-9, 227)
From 1974 to March, 1984, 134 cases of
intoxication by boric acid or borates were
recorded by the Poisons Center in Paris (ICe),
88 of which were accidental and only 31 due to
therapeutic measures. Among the notable cases
were a 13-year-old girl, treated by bathing with
3% boric acid for burns, who developed delir-
ium; a case of dermatitis due to an excessively
concentrated (14%) borate solution; and a 53-
year-old woman treated for an infected hip
prosthesis by irrigation with a boric acid solu-
tion (24g in 7 days) who on the third day
developed vomiting, mental confusion, meta-
bolic acidosis and hyponatremia.
ALCOHOLS
Ethanol (SED-IO, 420)
Ethanol-containing mouthwashes Despite their
significant ethanol content (up to 26.9%),
mouthwashes are rarely regarded as potentially
harmful and they are often easily accessible for
children. Their use is encouraged in advertise-
ments, and they are attractive and good-tasting
products. It is not surprising that cases of
accidental ingestion continue to occur.
Selbst et al (2c) described alcoholic intoxica-
tion in a 4-year-old boy who ingested approxi-
mately 24 ounces of Topco brand mouthwash
containing 10% ethanol. Although the lethal
dose (3.8 ml/kg absolute ethanol for a toddler)
was not reached, the patient died, probably
from the induced hypoglycemia (10 mg/100
ml). This is believed to be the first reported
Side Effects of Drugs Annual 10
M.N.G. Dukes, editor
9 Elsevier Science Publishers B.V., 1986
death from the accidental ingestion of an
alcohol-containing mouthwash.
Use of ethanol in local treatment of omphalo-
celes When it is not possible to perform surgi-
cal treatment for omphalocele, alcohol applica-
tion is probably the safest method. Dosage and
frequency of application, however, should bc
as limited as possible since absorption with
clinical intoxication may be observed (3c).
Alcohol abuse Alcohol abuse is another
unexpected - side effect of disinfectants (4c):
A patient with alcoholic cirrhosis and hepatic
decompensation denied ingestion of alcoholic bever-
ages over the previous 3-year period, but admitted
that he had ingested weekly the contents (540 ml
each) of 3 cans of a household spray disinfectant
containing 79% ethanol (Lysol spray disinfectant).
This resulted in a daily alcohol consumption of
approximately 170 g, which is equivalent to 1 pint of
whiskey. The disinfectant also contained 0.1% o-
phenyl-phenol, but this compound is of low toxicity.
Benzyl alcohol (SED-IO, 421; SEDA-8, 243;
SEDA-9, 225)
Shmunes (5 cr) observed a case of an allergic
contact dermatitis traceable to benzyl alcohol;
it was characterized by erythema, palpable
edema, and raised borders. In this case, the
benzyl alcohol was present as a preservative in
an injectable solution of sodium tetradecyl
sulfate, a sclerosing agent used for the treat-
ment of varicose veins. The F D A provided the
author with a listing of 151 injectable prepa-
rations, 48 of which were for subcutaneous
administration, that contained benzyl alcohol
as a preservative in the range 0.5 2%. The list
included hormones and steroids, antihyperten-
sives (reserpine), vitamin preparations (vita-
mins B12 and B6), acid-base chemicals (am-
monium sulfate), antihistamines, antibiotics,
heparin 0 7 brands), tranquilizers and sclero-
sing agents (sodium morrhuate and sodium
tetradecyt sulfate).
230
ALDEHYDES
Formaldehyde (SED-IO, 422; SEDA-8, 244;
SEDA-9, 225)
A 2% formaldehyde solution was used as a
scolecidal agent for injection in hydatid cysts of
the liver in 3 patients, but the cysts had rup-
tured into the bile ducts. One to 5 months later,
sclerosing cholangitis developed, leading to the
death of I patient, while the remaining 2 had to
undergo liver transplantation (6cr). These ob-
servations should be sufficient to discourage
the use of formaldehyde to sterilize hydatid
cysts of the liver.
C H L O R H E X I D I N E (SED-IO, 426; SEDA-8,
244)
Some patients have been reported to suffer
temporarily from hyposmia after Hardy's
operation for pituitary adenoma. Since this
olfactory disturbance improved after 3-7
weeks, it was assumed that it was caused by the
preoperative disinfection of the nasal cavity
with chlorhexidine (7c). Degeneration of the
olfactory epithelium was also seen in guinea
pigs whose nasal cavities were irrigated with 3
times 5 ml of a 0.5% chlorhexidine solution;
regeneration of the epithelium started after 14
days and the surfaces appeared normal after 1
month; these results suggest that chlorhexidine
may indeed be responsible for the temporary
hyposmia after surgical intervention.
IODOPHORS
Povidone-lndine (PVP-I) (SED-IO, 435;
SEDA-8, 245; SEDA-9, 226)
Iodine absorption Gl6bel et al (8 c) studied
iodine absorption from a PVP-I-containing
mouthwash, vaginal gel and liquid soap in
volunteers with normal thyroid function and
also its influence on thyroid function. The
increase in the iodine supply was up to 2 mg
daily, of which more than 75% was organi-
cally-bound iodine. In none of the test subjects
was there evidence of their developing hyper-
or hypothyroidism and the triiodothyronine
(T3), thyroxine (T~) and thyrotrophin (TSH)
values remained in the normal range.
Iodine absorption occurred also in patients
in whom burns (average area 50%) were
treated with PVP-I ointment (9c) or in patients
with osteomyelitis treated by irrigation-
suction drainage with a 0.2% PVP-I solution
(10c). Increased iodine serum and urine levels
Chapter 25 G. Reybrouck
returned to normal soon after termination of
treatment. No clinical signs of iodine intoxica-
tion were observed. These forms of treatment
are contraindicated in pregnant women and in
patients with adenomas of the thyroid gland.
In a patient with a multinodular goiter receiv-
ing suppressive therapy with levothyroxine
sodium, thyrotoxicosis developed after PVP-I
had been applied to the surface of a granulat-
ing hip wound (1 lC).
Statement On behalf of the scientific board of
the German Bundesfirztekammer a working
group has studied the benefits and the risks of
the use of PVP-I complexes. The following
recommendations were approved and pub-
lished (12):
a. The application of PVP-I formulations
cannot be recommended for surgical hand dis-
infection since active iodine-free preparations
are available.
b. The activity of PVP-I in case of the preop-
erative skin disinfection in adults is well proven.
c. PVP-I is appropriate for skin disinfection
before an incision, a puncture, with use of
intravenous or arterial catheters, and for the
prophylaxis of iatrogenic clostridial infections.
d. In the case of superficial wounds, PVP-I can
be applied occasionally or also repeatedly in
spite of increased iodine absorption through
the broken skin surfaces.
e. Lavage of wound and body cavities with
PVP-I or its instillation is not indicated due to
increased iodine absorption.
f. Routine body washing of patients in inten-
sive care units should be avoided for cost-
benefit considerations.
g. PVP-I for vaginal application in infection
or on hygienic grounds is not recommended.
h. Due to the special risks for premature and
newborn infants and babies the application of
PVP-I is contraindicated in this age group.
This also applies to prophylactic disinfection of
the umbilical stump.
i. The clinical usefulness of PVP-I in the
treatment of burns is well proven.
j. Local mouth antiseptics serve no thera-
peutic purpose. This is also true for PVP-I
preparations.
MERCURY COMPOUNDS
Merbromin (SED-IO, 429; SEDA-8, 246)
Immediate hypersensitivity to mercurials
with anaphylactic shock is a rare, but life-
threatening complication of local antisepsis
(13cr):
Antiseptic drugs and disinfectants Chapter 25
A 25-year-old man suffered widespread abrasions
on the medial surface of his thighs after running in a
14-kilometer marathon. Three minutes after topical
application of a merbromin solution, he experienced
intense dyspnea, an acute sensation of giddiness, and
fleeting episodes of heat and exanthema of the face
and thorax. There was intense smarting and erythema
on the thighs, but no urticaria or eczema. After
treatment with methylprednisolone and dopamine the
hypotension and dyspnea improved. A prick test,
intradermal test and a modified passive transfer test
(P.K.) were positive (immediate reactions) with mer-
bromin, thiomersal, mercuric chloride and mercuric
nitrate. The histamine-release test gave a positive
result of 13% (normally < 10%) for merbromin.
Mercuric chloride ( S ED A-8, 246)
Despite accumulated warnings over many
years, the use of mercuric chloride solutions
during operations in an attempt to kill cancer
cells implanted on healthy tissue persists in
some countries. Especially intraperitoneal
application, where seeding of a visceral cancer
is feared, carries the risk of mercury absorption
and nephrotoxicity. Laundy et al (14 cR)
described the 10th reported case (and the 5th
known death) of intoxication after peritoneal
lavage with a mercuric chloride solution. The
characteristic clinical picture of acute mercury
poisoning includes sudden, profound circula-
tory collapse with tachycardia, hypotension and
peripheral vasoconstriction, vomiting, and
bloody diarrhea (due to hemorrhagic colitis).
Renal failure usually develops within 24 hours
and is associated with albuminuria, epithelial
cell casts and red cells in the urine, glycosuria,
and aminoaciduria. Oliguria may proceed to
complete anuric failure. There is further a
neutrophil leukocytosis due to tissue necrosis.
Thiomersal (SED-IO, 430; SEDA-9, 227)
Many vaccines contain thiomersal (Merthi-
olate) as a preservative. O f 30 patients with
adverse reactions to tetanus or tick-borne-
encephalitis vaccination, 8 patients showed
positive epicutaneous and/or intracutaneous
tests with thiomersal (15cr). The problem is
that in some countries (e.g. Austria) thiomer-
sal-free tick-borne-encephalitis vaccines are not
available.
P H E N O L A N D ITS D E R I V A T I V E S
Hexachlorophene (SED-IO, 432; SED-9, 227)
N a g y and Orosz (16 c) described a case of
occupational asthma in a children's nurse who
231
had been working in contact with hexachloro-
phene (HCP) for 15 years. Initially her symp-
toms were of rhinitis, but for the last 2 years
there were frequent and sometimes very severe
attacks of asthma with symptoms of chest
tightness and breathlessness some minutes
after starting work with HCP. Skin testing with
1% H C P was negative. Inhalation challenge
tests showed an immediate airway reaction and
an increase in neutrophil chemotactic activity
after inhalation of H C P powder, which were
blocked by pretreatment with cromoglicate
disodium, suggesting that the mechanism was
mast-cell-dependent.
QUATERNARY AMMONIUM
COMPOUNDS
Benzalkonium chloride (SED- IO, 436)
Like other quaternary a m m o n i u m com-
pounds, benzalkonium chloride shows very low
local and systemic toxicity. In a study on a
contraceptive vaginal tampon impregnated
with benzalkonium chloride cream, Serfaty and
Cohen (17 c) found that of the 219 women
involved, only 7 patients complained of irrita-
tion, pruritus or a burning sensation, and 1
patient of vulval edema.
Cetrimonium bromide (cetrimide) (SED-IO,
437)
In general the irrigation of hydatid cysts with
cetrimide solution causes no side effects; the
occurrence of methemoglobinemia is quite rare
(SED-10, 437). M o m b l a n o et al (18 c) described
a case of severe metabolic acidosis without signs
of peritonitis.
A 44-year-old man was operated on for multiple
disseminated intra-abdominal hydatid cysts; more
than 1 liter of 1% cetrimide was instilled into the
cysts. After the 1st postoperative hour, blood gas
measurements revealed metabolic acidosis, which
remained unchanged for 5 hours despite alkali load-
ing. During the 8th hour, the patient experienced
vasoplegic collapse with low central venous pressure,
oligoanuria, abdominal tension, persistent hypochlor-
emic acidosis, hyperkalemia, and increased anion
gap. Sustained alkalinization and fluid loading led to
rapid recovery 3 hours later. This postoperative
complication was probably caused by resorption of
cetrimide instilled; bromide anion reabsorption may
directly lower plasma bicarbonate levels and increase
the anion gap, since the cetrimonium cation may
enter the red blood cells, leading to transfer hyperka-
lemia, worsened by metabolic acidosis itself. The late
cardiovascular collapse was probably due to the pro-
232
longed duration of the acidosis and to the peritoneal
exudation. The authors recommend monitoring
blood pH after operations on hydatid cysts when
large quantities of cetrimide have been used.
SULFITES (SEDA-8, 246)
Sulfites are effective antioxidants, widely
used as additives in processed beverages and
foods, including restaurant salads and fresh
fruits, fruit juices, soft drinks, wines, beers,
vinegar, potato chips, dried fruits, and vege-
tables, but also as preservatives in drugs
(19R-21R). Six sulfites have been listed as gener-
ally recognized and safe by the F D A for use in
foods. They are (with the European code in
parenthesis): sulfur dioxide (E 220), sodium
sulfite (E 221), sodium bisulfite (E 222), potas-
sium bisulfite, sodium metabisulfite (E 223),
and potassium metabisulfite (E 224). Neverthe-
less, side effects to sulfite additives do occur,
and the F D A has received reports of over 90
cases of adverse reactions to sulfite-containing
drugs. The major symptoms are flushing, acute
bronchospasm and hypotension. Most of the
patients reported in the medical literature had
a prior history of asthma. All had a positive
oral challenge to bisulfite; all had reactions
within 15 minutes from challenge. The
frequency of sulfite sensitivity in an asthmatic
population is estimated to be about 10%.
Many bronchodilator inhalant solutions con-
tain sulfites as antioxidants. Those listed in the
United States (sometimes there are national
variations) are: Alupent (orciprenaline; meta-
proterenol sulfate), Bronkephrine (ethylnorepi-
nephrine HCI), Bronkosol (isoetarine HCI),
Isuprel hydrochloride solution (isoprenaline;
isoproterenol HCI), Metaprel (orciprenaline;
REFERENCES
1. Elmalem J, Efthymiou M-L, Fournier E (1984)
R66valuation de la toxicit6 des borates: fi propos de
134 intoxications au centre anti-poisons de Paris. J.
Toxicol. Mbd., 4, 317.
2. Selbst SM, DeMaio JG, Boenning D (1985)
Mouthwash poisoning: report of a fatal case. Clin.
Pediatr., 24, 162.
3. Schr6der CH, Severijnen RSVM, Monnens
LAH (1985) Vergiftiging door desinfectans bij con-
servatieve behandeling van twee pati~nten met om-
falok61e. Tijdsehr. Kindergeneesk., 53, 76.
4. Morse JMD, Thomas E (1984) Hepatic toxicity
from disinfectant abuse. J. Am. Med. Assoc., 252,
1904.
Chapter 25 G. Reybrouck
metaproterenol sulfate), Vaponefrin and
Micronefrin (racemic epinephrine). These prep-
arations can liberate sulfur dioxide when
nebulized. Since the asthmatic airway has a
heightened reactivity to sulfur dioxide, such
exposure could place the asthmatic patient at
risk. Instead of bronchodilatation a paradoxi-
cal decrease in expiratory flow rates can be
observed (22 c, 23c).
G E N E R A L TOPICS
Adverse effects in hand antiseptics and other
disinfectants
Health-care personnel have more frequent
and more intensive contact with antiseptics and
disinfectants than the general population and
the prevalence of allergic and toxic skin re-
actions is therefore higher. In a German hospi-
tal 9.1% of the 2282 hospital employees
(14.6% of the cleaning-staff, 8.6% of the
nurses) complained of contact dermatitis (24c).
The allergens of the proven cases of allergic
contact dermatitis were mainly aldehydes, am-
photeric detergents and alcoholic disinfectants.
In a Scottish survey (25cr), the prevalence of
skin reactions associated with the surgical
scrub-up was 37.2% of the theatre personnel,
but only 5% consulted a dermatologist. The
most likely explanation for the majority of the
skin reactions is reported to be a drying effect
of the scrub solution on the subject's skin
rather than a true hypersensitivity to the anti-
septic used. Moisturizing hand creams are
effective in controlling symptoms in 25% of
those developing~ reactions. Apart from skin
care, the avoidance of primary irritative dam-
age is essential (26R).
5. Shmunes E (1984) Allergic dermatitis to benzyl
alcohol in an injectable solution. Arch. Dermatol.,
120, 1200.
6. Bories P, Mirouze D, Aubin J-P et al (1985)
Cholangite scl~rosante apr~s traitement chirurgical
de kystes hydatiques du foie: r61e probable de la
formolisation des voies biliaires. Gastroentbrol.
Clin. Biol., 9, 113.
7. Yamagishi M, Kawana M, Hasegawa S e t al
(1985) Impairment of olfactory epithelium treated
with chlorhexidine digluconate (Hibitane): postop-
erative olfactory disturbances after Hardy's opera-
tion and results of experimental study. Pract. Otol.,
78, 399.
Antiseptic drugs and disinfectants Chapter 25
8. G16bel B, Gl6bel H, Andres C (1984) Resorption
von Jod aus PVP-Jod-Prfiparaten nach Anwen-
dung am Menschen. Dtsch. Med. Wochenschr., 109,
1401.
9. Balogh D, Bauer M, Riccabona G (1985) The
influence of povidone-iodine treatment on thyroid
hormones in severe burns. J. Hosp. Infect., 6,
Suppl. A, 147.
10. Matzen KA, Briickl R, Knolle P (1984)
Behandlung der Osteomyelitis mit PVP-Jod-
L6sung in Spfil-Saug-Drainagen. Z. Orthop. Ihre
Grenzgeb., 122, 320.
11. Reith PE, Granner DK (1985) Iodine-induced
thyrotoxicosis in a woman with a multinodular
goiter taking levothyroxine. Arch. Intern. Med.,
145, 355.
12. Wissenschaftlicher Beirat der Bundes~irztekam-
mer (1985) Zur Anwendung yon Polyvinylpyrroli-
don-Jod-Komplexen (Polyvidonjod: PVP-Jod).
Dtsch. Arzteblatt, 82, 1434.
13. Corrales Torres JL, De Corres F (1985)
Anaphylactic hypersensitivity to Mercurochrome
(merbromin). Ann. Allergy, 54, 230.
14. Laundy T, Adam AE, Kershaw JB et al (1984)
Deaths after peritoneal lavage with mercuric chlor-
ide solutions: case report and review of the
literature. Br. Med. J., 289, 96.
15. Lindemayr H, Drobil M, Ebner H (1984)
Impfreaktionen nach Tetanus- und Friihsommer-
meningoenzephalitis-Schutzimpfungendurch Mer-
thiolate (Thiomersal). Hautarzt, 35, 192.
233
16. Nagy L, Orosz M (1984) Occupational asthma
due to hexachlorophene. Thorax, 39, 630.
17. Serfaty D, Cohen J (1904) Le tampon contra-
ceptif au chlorure de benzalkonium. Contracept.
Fertil. Sex., 12, 569.
18. Momblano P, Pradere B, Jarrige N el al (1984)
Metabolic acidosis induced by cetrimonium bro-
mide. Lancet, 2, 1045.
19. Sogn D (1984) The ubiquitous sulfites. J. Am.
Med. Assoc., 251, 2986.
20. Settipane GA (1984) Adverse reactions to
sulfites in drugs and foods. J. Am. Acad. Dermatol.,
10, 1077.
21. Simon RA (1984) Adverse reactions to drug
additives. J. Allergy Clin. Irnmunol., 74, 623.
22. Koepke JW, Christopher KL, Chai H et al
(1984) Dose-dependent bronchospasm from sulfites
in isoetharine. J. Am. Med. Assoc., 251, 2982.
23. Sher TH, Schwartz HJ (1985) Bisulfite sensi-
tivity manifesting as an allergic reaction to aerosol
therapy. Ann. Allergy. 54, 224.
24. Just I, Ringelmann R, Gloor M (1984)
Toxische und allergische Hautreaktionen durch
Desinfektionsmittel im Krankenhaus. Hyg. Med.,
9, 136.
25. Mitchell KG, Rawluk DJR (1984) Skin
reactions related to surgical scrub-up: results of a
Scottish survey. Br. J. Surg., 71, 223.
26. Tronnier H (1984) Primfire Hautirritation
durch H~indedesinfektionsmittel. ,4"rztl. Kosmetol.,
14, 455.