572
PEDIATRICS
Vol. 86
No. 4 October 1990Vancomycin-Induced
Red Man Syndrome
Maurice
Levy,
MD; Gideon
Koren,
MD; Lee Dupuis,
MSc
Pharm;
and
Stanley
E. Read,
MD
From the Divisions of Clinical Pharmacology and Toxicology and Infectious Diseases and
the Drug Information Service, the Departments of Pediatrics and Pharmacy, the Research
Institute, Hospital For Sick Children, and the Departments of Pediatrics and
Pharmacology, University of Toronto, Toronto, Ontario, Canada
ABSTRACT. A total of 11 cases of red man syndrome
collected among 650 children who had received
vanco-mycin in our hospital between 1986 and 1988 (estimated
prevalence 1.6%) were retrospectively analyzed. These 11
children were compared with 11 age-matched children
who received vancomycin in whom red man syndrome
did not develop. Of the patients with red man syndrome,
73%, and ofthe patients with no reaction, 45.4% received
vancomycin for penicillin-resistant Staphylococcus
epi-dermidis-positive cultures, or because of history of peni-cillin allergy. No difference was observed in the dose per kilogram given to both groups (12.9 ± 3.5 mg/kg per dose
in those with red man syndrome vs 12.3 ± 6.9 mg/kg per
dose in control childrens. The duration (mean ± standard
deviation) of vancomycin infusion was 45.9 ± 16.7
mm-utes (range 10 to 90 minutes) in patients with red man
syndrome and 54.5 ± 7.6 minutes (range 45 to 65 minutes)
in the control group (P = .07). In the 5 children with red
man syndrome rechallenged with vancomycin, slower
infusion rates prevented or reduced the syndrome, which
emphasized the fact that the rate of administration is the
important determinant of red man syndrome in
suscep-tible cases. Clinically, the syndrome developed at the end
of the infusion in most patients, but appeared as early as
15 minutes after initiation of the infusion. It was mostly
manifested as a flushed, erythematous rash on the face,
neck, and around the ears. Less frequently, the rash was
distributed all over the body. Pruritus was usually
local-ized to the upper trunk but was also generalized (2 of 11
children). Associated signs and symptoms were
hypoten-sion, watery puffy eyes, tachycardia, respiratory distress, dizziness, agitation, and mild temperature increase. A
premature infant with the red man syndrome had skin
rash associated with poor perfusion, cold extremities,
increased need for oxygen, and severe hypotension. The
rash disappeared within 20 minutes (range 5 minutes to 7 hours) after vancomycin infusion was stopped. There
was no association between serum vancomycin
concen-trations and red man syndrome; in both groups of
pa-Received for publication Jun 26, 1989; accepted Sep 25, 1989. Reprint requests to (G.K.) Division of Clinical Pharmacology, Hospital for Sick Children, 555 University Aye, Toronto, On-tario, Canada M5G 1X8.
PEDIATRICS (ISSN 0031 4005). Copyright © 1990 by the
American Academy of Pediatrics.
tients therapeutic as well as subtherapeutic concentra-tions were observed, suggesting that this is an
idiosyn-cratic and not a concentration-dependent phenomenon.
Pediatrics 1990;86:572-580; vancomycin, red man syn-drome.
Vancomycin was introduced clinically in the late
1950s for serious infections caused by
Staphylococ-cl’s for which penicillin and other antimicrobial
agents were often ineffective. Because of
unaccept-able incidence of adverse reactions, especially
thrombophlebitis, ototoxicity, and
nephrotoxic-ity,2 the drug was judged inferior to semisynthetic
penicillins. Since the late seventies, vancomycin is
increasingly used because of the appearance of
methicillin-resistant Staphylococcus aureus and
multiple-resistant Staphylococcus epidermidis.36
Although the incidence of adverse reactions from
vancomycin is reported to be small,37 red man
syndrome, also called red neck syndrome or red
person syndrome, appears to be the most common.
The incidence of such untoward effect in children
is unknown and most of the clinical data describing
the syndrome is derived from cases reported in
adults. The syndrome is generally characterized by
localized skin rash and/or hypotension. Although
usually it is a self-limiting reaction that subsides
when administration of the drug is stopped, it may
be life threatening.
Using our pharmacy-based adverse drug-reaction
network, we retrospectively calculated the
preva-lence of red man syndrome in a large tertiary care
pediatric hospital and evaluated possible
determi-nants predisposing for this serious adverse effect.
PATIENTS AND METHODS
Between January 1986 and December 1988, 650
infants and children received vancomycin therapy
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at the Hospital For Sick Children, Toronto. This
number was calculated from the pharmacy list of
inpatients for whom vancomycin was prescribed
and from the list of patients who had vancomycin
serum concentration determined at the therapeutic
drug monitoring laboratory. Among those, 11
pa-tients who experienced red man syndrome following
vancomycin therapy had been reported to the
hos-pita! pharmacy. Reports were either spontaneously
generated by nurses, pharmacists, or physicians
caring for these patients or were prepared by the
hospital quality assurance staff during their routine
chart reviews. Those patients were compared with
11 age-matched hospitalized children who also
re-ceived vancomycin but in whom the syndrome did
not develop.
Through a retrospective chart review, the
follow-ing data were retrieved: age, sex, body weight,
un-derlying disease(s), concomitant drug therapy, site
of infection, cultured bacterial pathogen, and
rea-son for selection of the drug. The vancomycin
ad-ministration regimen was recorded and included
dose rate and route of administration. Other clinical
data associated with the reaction were collected,
including the time of appearance and description,
in relation to vancomycin infusion, of skin rash,
associated hypotension, tachycardia, itching or
pyr-exia, and any other accompanying symptoms or
signs. Laboratory tests included serum creatinine,
urea, and electrolytes. Vancomycin serum
concen-trations during therapy (including peak and trough)
were recorded. Peak vancomycin concentrations
were obtained 60 minutes after completion of
in-fusion; the aimed steady state therapeutic range is
between 25 and 40 1g/mL, whereas the trough level,
obtained prior to the next dose, is targeted at 5 to
10 g/mL. Vancomycin serum concentrations were
determined by Enzyme-Multiplied Immunoassay
Technique (Abbot Laboratories, North Chicago,
IL). The coefficient of variation for this test in our
laboratory is less than 5%.
Differences in means between the red man
syn-drome and control groups were compared using
Student’s t test for paired data. Data are expressed
throughout the text as means ± standard
devia-tions.
RESULTS
Patients’ Characteristics
The mean age of the 11 children in whom the
syndrome had developed (8 boys; 3 girls) was 4.3
years (range, premature infant to 8 years of age)
(Table 1). Their mean weight was 14.4 ± 8.7 kg
(range 1230 g to 32.3 kg). Vancomycin was
admin-istered in 8 out of 1 1 patients whose cultures were
positive for S epidermidis or cerebrospinal fluid, or
whose blood cultures were sensitive to vancomycin.
Two children were treated with vancomycin for
cellulitis. Three patients with red man syndrome
and one control child had a history of penicillin or
cephalosporin allergy.
The mean age of the 8 boys in the matched
control group (Table 2) was 3 years (range, newborn
to 7 years of age). Their mean weight was 12.6 ±
4.5 kg (range 3.9 to 19 kg). They received
vanco-mycin because of positive cultures of cerebrospinal
fluid or synovial fluid, blood cultures for S
epider-midis that were sensitive to vancomycin, or past
history of penicillin allergy.
Vancomycin Administration Regimen
Vancomycin was administered through an
intra-venous central line in three patients with red man
syndrome and five control subjects. In the
remain-der ofboth groups, vancomycin was infused through
a peripheral line. None of the patients received
vancomycin intraperitoneally. The mean duration
time of vancomycin infusion was 47.5 ± 14.7
mm-utes (range 10 to 60 minutes) in the group of
patients with red man syndrome, and 55.2 ± 6.9
minutes (range 45 to 60 minutes) in the control
group (P = .07).
The administered dose of vancomycin was 12.9
± 3.5 mg/kg (range 9.9 to 21.1 mg/kg) in the red
man syndrome group and 12.3 ± 6.9 mg/kg (range
8 to 31.7 mg/kg) in the control group. The
differ-ence between the two groups was not significant.
Patient 8 with red man syndrome had three
infu-sions of vancomycin. He received a dose of 11 mg/
kg. At an infusion rate of 50 mL/h, the reaction
developed during the 10-minute administration and
again when the drug was administered during a
45-minute period, but not when the dose was
admin-istered throughout 1 hour at an infusion rate of 100
mL/h. Similarly, in patient 9 the syndrome
devel-oped while vancomycin was administered during a
30-minute period, but not when it was administered
during 75 minutes. In the newborn (patient 1),
prolonging the duration of vancomycin infusion
from 60 to 90 minutes prevented the reaction. In
patient 5, red man syndrome developed while he
received vancomycin during a 30-minute period; the
boy’s reaction was milder when the same dose was
infused during a 2-hour period.
Clinical
Aspects
of the Red Man Syndrome
The red man syndrome was generally manifested
as an erythematous, flushed rash of the face and
around the ears (Table 3). Less frequently, the rash
Patient Age Sex Body Serum Plasma Primary Diagnosis Vancomycin Duration Post! Concomitant
No. (y) Wt
(kg) Urea (mmol/L)
Creatinine (tmol/L)
and Reason of Vancomycin Administration
Dosage (mg/kg! dose)
21.1
of Vanco-mycin infusion
(mm)
60
Pre-Vanco-mycin Concentration
(g/mL)
33.3/14.7
Therapy! Comments
Aminoglycoside (?)
11.2 45-60 ND Cloxacillin
16.1 45 ND Tobramycin,
pi-peracillin
10 60 ND Cloxacillin
9.9 30 13.9/’z25 Cloxacillin
Gentamycin
14 60 ND Oxybutinin
10 45 12.6/<5 Gentamycin
10/4 10 34.4/11.5 Gentamycin
13.9 TABLE 1. Patients with Red Man Syndrome-General Data*
574 VANCOMYCIN AND RED MAN SYNDROME
1 0.04 M 1.23 4.9 109 Respiratory distress
syn-drome, Staphylococcus
epidermidis sepsis with necrotizing enterocoli-tis
2 0.66 M 7.1 7.5 20 Cystic fibrosis,
hydro-cephalus, VP shunt, nutritional problems; S epidermidis sepsis from CVL
3 3 M 15.5 2.3 71 Undifferentiated occipital
sarcoma; fever, celluli-tis of back, hand
4 3.5 F 13.5 2.6 23 Cellulitis of third toe &
leg swelling
5 4.5 F 12.6 2.0 40 Acute lymphocytic
leuke-mia; fever, S
epidermi-dis sepsis from CVL
6 4.5 M 15 6 15 Myelodysplasia,
hydro-cephalus; S epidermidis
VP-shunt infection; history of amoxil, ceph-alexin allergy
7 5 M 15.9 2.2 15 B-cell lymphoma, fever;
positive S epidermidis;
culture; history of peni-cillin allergy
8 5 M 16.7 2.8 46 Neuroblastoma, stage IV,
fever; S epidermidis
sepsis, from CVL; his-tory of Amoxicillin al-lergy
9 5.5 M 22.7 2.9 35 Convulsive disorder,
fe-ver; S epidermidis,
sep-sis
10 7.33 F 32.3 7.5 30 Hydrocephalus, VP shunt;
S epidermidis, shunt, infection
11 8 M 30.5 2.1 21 Hydrocephalus, VP shunt;
suspect arachnoiditis
1 1 30 ND Carbamazepine
Phenytoin
60 ND Phenobarbital,
phenytoin, clox-acillin
15 60 ND Rifampin
*Abbreviations: CVL, central venous line; VP, ventriculoperitoneal; ND, not done.
over the body. In two patients, it was associated
with watery, puffy eyes. The rash developed at the
end of vancomycin infusion in most patients but
appeared as early as 15 minutes after initiation of
the infusion. In the newborn, the rash was
associ-ated with poor perfusion, cold extremities,
in-creased oxygen requirement, and lethargy. When
the newborn had received vancomycin infusion
dur-ing a longer time (90 minutes) he had no reaction.
Associated pruritus was localized to the head and
sometimes all over the body in 8 patients (73%).
Although it was mostly mild, in a few patients it
was described as severe. The rash started
disap-pearing when the infusion was stopped or soon after
(5 to 15 minute) but could persist for as many as 7
hours with or without antihistamine medications.
Other associated signs and symptoms such as
tachycardia, hypotension, respiratory distress,
diz-ziness, agitation, and mild increase in temperature
were noted, but stable vital signs were more
fre-quent.
Laboratory
Data
In all patients in whom the syndrome developed
except the newborn (patient 1), results of
labora-tory tests, including sodium, potassium, chloride,
urea, creatinine, and electrolyte tests, were normal
(Table 4). The newborn had an increase in
creati-nine but with a normal urine output. Vancomycin
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Patient Age Sex Body Serum Plasma Primary Diagnosis Vancomycin Duration Post/Pre- Concomitant
No. (y) Wt
(kg) Urea
(mmol/L)
Creatinine (Mmol/L)
and Reason of
Vancomycin Administration
Dosage (mg/kg! dose)
of Vanco-mycin Infusion
(mm)
Vancomycin Concentration
(zg/mL)
Therapy! Comments
Cefazolin,
hydrocorti-8.9 60 14.4/<5 Gentamicin
8.4 60 9.2/<5 Gentamycin;
metroni-dazole, acyclovir, cy-closporine, ticarcil-lin
Allergy to metoclo-pramide Asparaginase
TABLE 2. Age-Matched Control Subjects with no Adverse Reaction to Vancomycin-General Data*
1 0.12 F 3.98 2.3 49 Cardiomyopathy, prolonged QT syndrome; fe-ver,
pneumo-coccal sepsis
2 0.9 M 8 3.6 20 Gastroenteritis
3 2 M 10.2 1.9 23 Cerebral palsy;
pneumonia
4 2 M 11 1.8 21 Neuroblastoma;
fever
5 2.75 M 14 1.4 14 Bone marrow
transplant
6 3 M 15 1.8 21 ALL; fever;
his-tory of peni-cillin allergy
7 3 M 11.8 4.7 29 Down syndrome;
Staphylococcus epidermidis
sepsis
8 3.5 F 14.6 2.1 26 Ventricular
sep-tal defect, fe-ver, pneu-monia; S
epi-dermidis sepsis
9 3.5 F 12.6 1.0 12 ALL; fever,
sep-tic hip; S epi-dermidis re-sistant to pen-icillin
10 5 M 19 62 28 Hydrocephalus,
ventriculoperi-toneal shunt; fever, vomit-ing; S
epider-midis shunt infection
11 7 M 18.2 2 16 ALL; fever
9 60 2&3/20.7 Isoproterenol
17.5 45 22.9/6.7
9.8 45 10/5
9 45 ND
sone
Gentamicin, ticarcillin, furosemide, only 3 doses of vancomycin received
10.7 60 19.4/7.4 Spironolactone hydro-chlorothiazide, cef-tazidime immuno-globulin
12 60 ND Gentamicin,
nifedi-pine, allopurinol
8 60 18.2/6.7 Gentamicin,
allopuri-nol
31.7 60 10.8/<5 Cefuroxime
10.5 45-60 24.8/7 Cloxacillin
Allergic to amoxycillin, peanut butter
SAbbreviation: ND, not done; ALL, acute lymphoblastic leukemia.
serum concentrations were not determined in seven
patients because they had the adverse reaction to
vancomycin during their first dose, and the drug
was discontinued. Of the remaining four patients,
two had concentrations less than the therapeutic
range and two had levels within the therapeutic
range. In the control group, therapeutic drug
mon-itoring was not performed in three patients; one of
them had only three doses of vancomycin. Three
patients had drug concentrations less than the
ther-apeutic range. Except for the newborn (patient 1),
the remaining patients had levels within the
ther-apeutic range. The newborn, who had
cardiomyop-athy, had a 9 mg/kg dose of vancomycin infused
during a 60-minute period and also received
isopro-terenol and cefotaxime. Before vancomycin
infu-sion, the baby’s serum concentration was 20.7 sg/
1
TABLE 3. Clinical Aspects of Red Man Syndrome*
Patient
No.
Clinical Appearance Treatment Comments
.
Hypotension Pruritus Others Rash
+++ ?
Rash started 15-30 mm Poor perfusion, cold Increase fluids Associated
in-after beginning vanco- extremities & to Albumin creased 02
re-mycin infusion; baby touch quirements;
re-flushed, red, mottled peat infusion
throughout 90 mm, no com-plications; urine output 4.3 mL/h
2 Red face, with hives on + Tachycardia-mild AH(IV) Redness, pruritus,
arms, adbomen, legs; increase r#{176} & hives
de-rash appeared 10-15 creased rapidly
mm postinfusion (15 mm) after
diphenhydra-mine adminis-tration
lotion
AH
AH(IV)
AH
Hydrocorti-sone cream
AH
- +++ Patient agitated,
rolling in his bed
* Symbols: -, none; +, mild; +++, severe hypotension (mild is decrease in blood pressure of <15%); r#{176},temperature; G, generalized. Abbreviation: AH(IV), antihistamines (mostly diphenhydramine) (intravenous).
3 Red, erythematous rash all over the body
4 Sudden flushing of the
face & head & puffy wa-tery eyes when infusion was terminated
5 Red flushed rash in the face, neck, over the trunk, scalp. Neck, chest, back warm to touch, with papules
6 Red and blotchy face; ap-peared 15 mm after completion of infusion
7 Erythematous rash: face, neck around ears; ap-peared at end of first dose
8 Facial flushing, behind ears, increase heat.
Faded after 40 mm
9 Quite red rash on face, neck, axilla. Appeared at the end of infusion
10 Red, flushed face with puffy eyes. Rash ex-tended over the trunk, arms, buttocks, and ex-tremities
11 Patient burned, flushed, warm; erythema all over the body; rash appeared with completion of infu-sion
- +(G)
+ +++ Tachycardia,
tach-ypnea mild in-crease
- Tachycardia; stable
respiratory rate
+ + Tachycardia,
respi-ratory distress,
no fever
+ No chills or rigor
+ ++ Dizziness, mild
in-crease in r’
+ Stable vital signs
G
Symptoms im-proved imme-diately with discontinuation of infusion Rash appeared
with finishing first dose, lasted few mm-utes, then faded. Repeat infusion for 2 h, patients cheeks flushed slightly
AH; calamine After 40 mm,
heart rate and blood pressure normal Rash
disappear-ance after a few hours
Repeat infusion at 45 mm Infusion to same
reaction Repeat infusion
during 60 mm and at in-creased dilu-tion (50-100 mL) No complications Rash disappeared
after several
mm of AH Same dose for 75
mm, no com-plications Repeat
vancomy-cm but IV Diphenhydramine
prior to infu-sion, no com-plications
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8 3
8 3
TABLE 4. Children with Red Man Syndrome and Age-Matched Control Subjects
Characteristic Red Man No Reaction P Value,
Syndrome tTest
Sex M F
Age (y)
Mean ± SD
Range
Wt (kg)
Mean ± SD
Range
Dose (mg/kg body wt)
Mean ± SD
Range
Duration of infusion (mm)
Mean ± SD
Range
Concomitant drug therapy
(No. of drugs)
Mean ± SD
Range Urea (mmol/L)
Mean ± SD
Range
Creatinine (zmol/L)
Mean ± SD
Range
Peak concentration (tg/mL)
Mean ± SD
Range
Trough concentration (tg/mL)
Mean ± SD
Range
4.3 ± 2.4 0.04-8
3.0 ± 1.8
0.12-7
.17
14.4 ± 8.7
1.23-32.3
12.6 ± 4.5
3.9-19
.63
12.9 ± 3.5 9.9-21.1
12.3.± 6.9 8-31.7
.78
47.5 ± 14.7 10-60
55.2 ± 6.9 45-60
.07
1±1 0-3
2±1.41 0-5
.06
3.89 ± 2.18 2.0-7.5
2.61 ± 1.57 1.0-6.2
.13
38.6 ± 28.5 15-109
23.5 ± 10.0 12-49
.11
23.5 ± 11.9 12.6-34.4
18.4 ± 5.9 10.8-25.3
.47
9.05 ± 4.8 5-14.7
5.2 ± 2.4 5-20.7
.21
DISCUSSION
Most of the reported cases of
vancomycin-in-duced red man syndrome are occurred in adults; in
only one article8 was the syndrome described in two
neonates, and few studies included children. The
syndrome is most commonly manifested as flushing
and a macular or maculopapular rash of the neck,
face, upper part of the chest, and upper
extremi-ties.926 It occurs during or shortly after intravenous
administration of vancomycin (within 10 to 60
mm-utes). The syndrome may also involve large areas
of the body surface, including the abdomen, back,
and lower extremities; there may be tachycardia or
bradycardia; and occasionally shock or cardiac
ar-rest may accompany the rash. Associated signs and
symptoms include pruritus, rigor, mild pyrexia,
chest pain, dizziness, and swelling of the face, lips,
and eyelids. Hypotension and/or rash appear
rap-idly and resolve within minutes to hours (1 to 3
hours). Usually reaction is self-limiting and
sub-sides when administration of the drug is stopped;
however, in severe cases, the use of corticosteroids,
antihistamines, fluid resuscitation, or (in
new-borns) albumin infusion was necessary.
Although there were eight males in our series, a
review of the literature suggests that at least in the
adults red man syndrome appears with equal
fre-quency in both sexes. Rolston and Hoy’7 suggested
calling the red man syndrome “red person
syn-drome,” because, according to their experience, it
appears with approximately equal frequency in both
men and women.
The incidence of red man syndrome is unknown.
Odio et al,18 in their study of the prophylactic
administration of 15 mg/kg of vancomycin during
a 6-minute period in 20 children, found a 35%
incidence (7/20) of rash or hypotension or both. In
one infant the rash was associated with significant
hypotension and hypothermia. The syndrome was
described by Schaad et al27 in 4 of55 (7.3%) patients
who received vancomycin but only when the
van-comycin infusion rate was briefer than 30 minutes.
This figure is similar to that reported by Geraci28
and Woodley and Hall29 who noted rash in 5% and
12%, respectively, of vancomycin-treated adults. In
a prospective study,22 skin rashes were found in 3
of 50 (6%) patients treated with vancomycin
infu-sion during a 30-minute period. More recently,
Far-ber and Moellering#{176} analyzed retrospective
data
from 98 adult patients treated with vancomycin
alone or in combination with other drugs; in 14%,
drug therapy was ceased because of adverse
578
VANCOMYCIN
AND
RED
MAN
SYNDROME
3% of their patients. Our series is larger by an order
of magnitude than that of Farber and Moellering
(650 patients). Although it is possible that some of
the cases of red man syndrome in our hospital were
not recorded, our reporting system is unlikely to
miss many because it is focused on identification
and reporting of such events. In our experience, the
incidence among the total number of children who
received vancomycin throughout a 3-year period is
1.5%.
In only three of the patients with red man
syn-drome, hypotension was documented as associated
with vancomycin administration. The other
chil-dren could have experienced mild hypotension that
was not noticed. Except for the newborn who had
a substantial decrease in his blood pressure, none
of the other patients had severe hypotension or
shock such as those described by Newfield and
Roizen,’#{176}Mayhew and Deutsch’9 and Lacouture et
al.8 In the 76 patients undergoing intracranial
sur-gery they studied, Newfield and Roizen identified
marked vancomycin-induced hypotension in 11
pa-tients. Vancomycin was diluted in 10 mL of
intra-venous fluid and administered during a 10-minute
period. The decrease in blood pressure was between
25% and 50% and lasted 2 to 5 minutes. These
hypotensive reactions were prevented by
prolonga-tion of vancomycin infusion from 10 to 30 minutes.
The two newborns described by Lacouture et al8
received vancomycin as 15 mg/kg for 20 minutes
and had hypotension, flushing, generalized rash,
agitation, and tachycardia. One was noted initially
to be pale and lethargic with rash on the head and
thighs. These two latter patients and our newborn
patient with the syndrome point out that when
vancomycin is administered to newborn infants it
should be infused during a prolonged time (eg, 60
to 90 minutes) to prevent potentially fatal adverse
effects.
The hypotensive reaction to vancomycin has
been shown to be related to the rate of
administra-tion.28 Wold and Stanley31 showed that rapid
intra-venous administration of vancomycin to dogs
pro-duced a significant decrease in blood pressure that
could be prevented by pretreatment with
antihis-tamines. The duration of vancomycin infusion is
an important factor but not the only factor
respon-sible for the development of the syndrome.
Al-though red man syndrome developed in most of our
pediatric patients who were receiving a vancomycin
infusion at a rate of less than 60 minutes, red man
syndrome can develop despite slow infusion9’12’24 In
other children the syndrome did not develop at an
infusion rate of 45 minutes (Table 2). Our data with
children support the idiosyncratic nature of red
man syndrome and the dependence, in sensitive
subjects, on infusion of the drug rate. Which
chil-then will have vancomycin-induced red man
syn-drome compared with age- and disease-matched
controls cannot be predicted because of the wide
overlap in vancomycin infusion rate between the
two groups. Yet, there was a trend in children with
red man syndrome toward shorter infusion times
(P = .07). It is worth noting that whenever
vanco-mycin was repeated at a slower infusion rate, the
red man syndrome was abolished or became milder.
In their study of 10 male volunteers comparing
1-and 2-hour infusion, Healy et al32 concluded that a
2-hour infusion of vancomycin (1 g) results in a
significant decrease in the incidence and severity
of red man syndrome as well as the amount of
histamine release compared with 1-hour infusion.
In our pediatric patients, the dose of vancomycin
administered per kilogram of weight was not shown
to be a contributing factor because the patients in
whom red man syndrome developed and the control
subjects received the same dose range.
Although a possible synergistic nephrotoxic
in-teraction between aminoglycosides and vancomycin
has been recently reported in children,33 both
groups of patients in our studies were receiving
aminoglycosides, suggesting that such a
combina-tion does not predispose to red man syndrome.
Vancomycin and other aminoglycosides have been
shown to exert a negative inotropic effect on
myo-cardial tissue.34 This dose-dependent effect occurs
at clinically relevant concentrations and persists
for more than 1 hour after intramuscular injection
ofvancomycin. Cardiac arrest caused by myocardial
depression following administration of vancomycin
was considered the cause of death in a 2-year-old
child.19
One of our patients with red man syndrome had
been also receiving rifampicin (rifampin) and a
diffused rash developed following vancomycin
in-fusion. Rifampicin and its metabolites are highly
colored and in therapeutic doses may cause
tran-sient orange discoloration of skin and mucous
mem-branes. In a few reported cases, red man syndrome
has been associated with rifampicin ingestion alone
or accompanied by other drugs (isoniazid,
etham-butol). However, this association pertains only to
rifampicin overdosage.35
The mechanism underlying the red man
syn-drome is unclear. It has been suggested that
van-comycin-related hypotension can occur as a result
of peripheral vasodilation following histamine
re-lease,’#{176}myocardial dysfunction secondary to
endog-enous myocardial histamine release,35 or direct
in-otropic myocardial depression.34 A direct peripheral
vasodilating effect of vancomycin was also
pro-posed.34’36
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Vancomycin causes histamine release directly
from the mast cell, without antibody or complement
involvement.31’3739 In a recent study by Polk et al,4#{176}
plasma histamine concentrations were measured
every 10 minutes after 1000-mg and 500-mg doses
of vancomycin infused during 1 hour. Red man
syndrome developed in 9 of the 11 subjects after
they received 1 g of vancomycin, although none of
them had any reaction after a 500-mg infusion.
Histamine concentration increased in most
pa-tients given a 1-g dose, although only slight changes
were observed after a 500-mg dose. The authors
concluded that vancomycin causes an infusion
rate-dependent increase in plasma histamine
concentra-tion that also correlates with the severity of the
reaction. Intersubject differences in histamine
re-lease to the same concentration of vancomycin
remain an important source of unexplained
varia-tion. Recently, Comstock et a14’ studied the
re-sponse in 10 male patients with end stage renal
disease to 1 g of vancomycin infused during 1 hour
and histamine plasma concentrations. The authors
concluded that end stage renal disease may be
as-sociated with diminished histamine stores on
abil-ity to release histamine, or to altered end organ
sensitivity to histamine.
Physicians and nurses caring for children
receiv-ing vancomycin must be aware of signs and
symp-toms of this reaction and carefully monitor the
patient because the syndrome may occur even at a
slow infusion rate. Because of the
multicompart-ment pharmacokinetic behavior of this drug,
pro-longed infusion rates may produce different peak
concentrations; these have to be considered when
comparing peak concentrations at different
sched-ules. Because vancomycin is a preferred drug in
different clinical situations, labeling a patient as
allergic to vancomycin may have important
conse-quences for future treatment. Great care is needed
in the future administration of vancomycin after a
presumptive red man syndrome, and a decrease in
the infusion rate as well as premedication with
antihistamines with or without a corticosteroid
should be considered.
ACKNOWLEDGMENT
This work was supported, in part, by grant MA8544 of
the Medical Research Council of Canada.
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REVIEWS OF LAY LITERATURE ON CHILD CARE: WHAT PARENTS
ARE READING
Gardner RA. The Boys and Girls Book About Divorce. Toronto, Canada:
Bantam Books; 1988. List price $4.95 (No. 13 on the 1989 bestseller list of
books on child care from Ingram Book Co., distributors of trade books).
In this book, the author, a practicing psychiatrist, speaks directly and
real-istically to adolescents and late elementary-age children about their emotional
reactions to divorce: wishing parents would reunite, blaming themselves,
dis-comfort with parental dating and step-parents, fear of abandonment, anger,
love, and mixed feelings toward parents. The book also helps children
under-stand why divorce may be better than continuing a bad marriage. More
contro-versial is the suggestion that a noncustodial parent who fails to visit may not
have genuine love for his or her child. While this may be the case, such
statements might inflame already intense feelings rather than help children
gain perspective on their parents’ personal problems. Given the emotionally
volatile information presented in the book, parental supervision should be
required. The language and illustrations are often sexist and there is insufficient
emphasis on maintaining positive self-concept and dealing with step-siblings
and step-parents. However, a much needed revision should ensure that the
messages of this potentially valuable book are clearly sent and appropriately
received.
FRANCES P. GLASCOE, PHD
WILLIAM R. MOORE, MD
ELAINE D. MARTIN, MD
Child Development Center
Vanderbilt University
Nashville, Tennessee
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1990;86;572
Pediatrics
Maurice Levy, Gideon Koren, Lee Dupuis and Stanley E. Read
Vancomycin-Induced Red Man Syndrome
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