Current address for Dr Keenan is: Cardinal Glennon Memorial Hospital for Children, 1465 S Grand Blvd, St Louis, MO 63014.
PEDIATRICS (ISSN 0031 4005). Copyright © 1985 by the
American Academy of Pediatrics.
Morbidity
and Mortality
Associated
with
Exchange
Transfusion
William
J.
Keenan,
MD,
Kathy
Kazmaier
Novak,
PhD,
James
M.
Sutherland,
MD,
Dolores
A.
Bryla,
MPH,
and
Karen
L.
Fetterly,
BS
From the Department of Pediatrics, Newborn Division, University of Cincinnati, College of Medicine, Cincinnati, and Epidemiology and Biometry Research Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
The
frequency
and
effects
of exchange
transfu-sion
in
a large
number
of
prospectively
studied
neonates
in the
National
Institute
of Child
Health
and
Human
Development
(NICHD)
phototherapy
study of 1974 to 1976, who were randomly assigned
to receive
phototherapy
or not,
are
reported
here.’8
Previously
published
studies’4’52’78”#{176}2on the
morbid-ity and
mortality
rates
of exchange
transfusion
are
based
upon
experience
accumulated
prior
to 1970.
MATERIALS
AND
METHODS
A total
of
190
patients
received
331
exchange
transfusions. Data concerning each exchange
trans-fusion
were
collected
and
analyzed
by the
NICHD
Phototherapy
Study
Statistical
Center.
Statistical
comparisons
were
done
by
x2
and
Student’s
t testwhen
appropriate.
A narrative
description
of events
surrounding
an exchange
transfusion
was
obtained
if morbidity
requiring
clarification
was
reported,
such as a cyanotic episode associated with the
pro-cedure.
Additional
information
was
obtained
from
the
postmortem
report
on every
infant
who
received
an
exchange
transfusion
and
died,
and
for
whom
an autopsy
was
performed.
All centers
used
fresh
donor
blood
anticoagulated
with
a solution
of citrate,
phosphate,
and
dextrose.
Patients
in
two
centers
routinely
received
small
doses
of calcium
gluconate
periodically
during
the
procedure. Calcium gluconate was given to the
oth-ers only if tachycardia or unusual irritability
devel-oped.
All procedures
were
performed
using
modifi-cations
of
the
technique
described
by
Allen
and
Diamond.2
Aliquots
of blood
used
in the
exchange
ranged
from
5 to 20 mL;
the
smaller
aliquots
were
used in the low-birth-weight patients. Indications
for
exchange
transfusion
by
birth
weight,
serum
bilirubin
concentration,
and
other
clinical
indices
of risk
were
contained
in the
study
protocol.
The
presence
of one
or more
high-risk
criteria
dictated
the initiation of an exchange transfusion at a lower
serum
bilirubin
level
than
indicated
by birth
weight
alone
(Table
1). Control
patients
who
received
three
or more
exchange
transfusions
were
allowed
to
re-ceive
phototherapy
at the
discretion
of the
investi-)8
RESULTS
Frequency
A total
of
190
infants
(14%)
among
the
total
study population of 1,339 received 331 exchange
transfusions. Thirty-nine (6%) of the 672 infants
in the
phototherapy
group
as
compared
with
151
(23%) of the 667 infants in the control group
re-ceived
one
or more
exchange
transfusions
(x2
= 78,P
<.001).
The
difference
in frequency
of exchange
transfusions in the phototherapy and control
groups
was
significant
for
all
birth-weight
cate-gories
except
infants
with
a birth
weight
of 2,500
g
or more
(Table
2).
Including
all
weight
categories,
16 repeat
exchange
transfusions
were
done
in the
phototherapy
group
as
compared
with
125
in the
control
group
(x2
=95, P
< .001).<1.250 1,250-
1,500-1,499 1,999
TABLE 2. Exchange Transfusion Rate by Birth Weight
for Phototherapy (P) and Control (C) Groups
TABLE 4. Effects of Exchange Transfusion on Levels
of Serum Bilirubin and 2-(4-Hydroxyazobenzene)
Ben-zoic Acid (HBABA)
* Data from 190 first exchange procedures. (Differences
are also highly significant using only paired values.)
TABLE 1. Serum Bilirubin Level (Milligrams per
Deciliter) as Criterion for Exchange Transfusion* Birth Weight (g)
Standardrisk 13 15 17
High riskt 10 13 15
* Both treated and untreated infants received an
ex-change transfusion if bilirubin levels exceeded these
val-ues in each weight category.
1High risk criteria are met when one or more of the
following apply: birth wejght less than 1,000 g,
five-minute Apgar score less than 3, Pao, < 40 mm Hg for
more than two hours, pH < 7.15 for more than one hour,
rectal temperature <35’C for more than four hours,
se-rum total protein value less than 4 g/dL
x
2, serumalbumin level less than 2.5 g/dL x 2, hemolysis, or clinical
deterioration.
Birth Total No. of No. of
Weight Infants Patients Exchange
(g) Exchanged
Transfu-sions
P C P C P C
<1,250* 108 108 10 40 13 90
1,250_1,499* 88 107 7 37 10 71
1,500_1,999* 266 245 5 33 13 60
(<2,000) (462) (460) (22) (110) (36) (221)
2,000_2,499* 70 71 3 18 4 27
2,500t 140 136 14 23 15 28
Total 672 667 39 151 55 276
*x2>
12,P<.001.t,2= 2.84,P= .09.
entry
into
the
study
to
the
initiation
of the
first
exchange
transfusion
were
significantly
different
between
phototherapy
and
control
groups
except
for
those
infants
between
2,000
and
2,499
g birth
weight.
In this
weight
group,
the
mean
(±SD)
time
from
entry
to exchange
transfusion
in the
photo-therapy-treated
infants
was
1 1.3
±9 hours
as
corn-pared
with
41.4
±26 hours
in the
control
group
(t=
3.3,P<
.005).The
patients
who
received
exchange
transfusion
are
shown
by risk
and
treatment
groups
in Table
3.
In the
groups
with
less
than
2,000
g birth
weight,
15/22 (68%) phototherapy-treated infants were in
the high-risk category compared with 44/110 (40%)
control
infants.
The
proportion
of infants
who
met
one
or more
of the
high-risk
criteria
among
these
phototherapy-treated
infants
was
significantly
greater
than
among
the
control
infants
(x2
=5.89,
P
= .015).Effects
on Bilirubin,
Bilirubin
Binding,
and
Hematocrit
Levels
The
effects
of
exchange
transfusion
on
serum
2,000- 2,500
2,499
18
17 20 18
TABLE 3. Number of Patients Receiving Exchange
Transfusion by Risk Group, and
Birth
Weight,
in
Pho-totherapy (P) and Control (C) Groups
Birth Patients No. of Patients
Weight in Study Receiving Exchange
(g) Transfusion
P C Standard .
Risk High Risk
P C P C
<2,000* 462 460 7 66 15 44
2,000t 210 207 15 35 2 6
*x2=
5.89,P<.01.t x2
= 0.08,P
= NS.N* Mean ± SE P Value
Bilirubin (mg/dL)
Before
exchange
188 16.2 ± 0.2 <.001 transfusionAfter
exchange
188 8.1 ± 0.2transfusion
HBABA
(%)
Before
exchange
137 62.5 ± 1.4 <.001 transfusionAfter
exchange
126 75.3 ± 1.6transfusion
bilirubin
and
bilirubin
binding
as measured
by the
2-(4-hydroxyazobenzene)
benzoic
acid
(HBABA)
method are shown in Table 4. As expected, mean
serum
bilirubin
concentration
was
reduced
follow-ing
exchange
transfusion.
The
binding
capacity
as
measured
by HBABA
increased
from
a mean
value
of 62.5%
before
exchange
transfusion
to
a mean
value
of
75.3%
after
exchange
transfusion.
These
differences
are
highly
significant
(P
< .001).Mean
hematocrit
levels
before
and
after
exchange
trans-fusion
were
not
different.
Morbidity
and
Mortality
Clinical
status just prior to the initiation of eachtransfu-TABLE
5.
Clinical Condition at Initiation of ExchangeTransfusion by Birth Weight for Phototherapy (P) and
Control (C) Groups*
Birth Weight g Go No. od % Critical/ Stable No. % Critical! Unstable No. % Mori-bund No. % <2,000t
P 2 6 15 43 16 46 2 6
C 62 29 131 61 20 9 3 1
2,000
P
17 95 2 5 0 0 00C
46
84
815 1 1 00* Includes first and subsequent exchange transfusions,
data
missing
on three
exchange
transfusions.
t’ 38.6,P< .001.
:1:x2
= NS.sions, 51% were critical/unstable or moribund
corn-pared
with
10%
of the
control
group
who
received
exchange
transfusions.
All
but
one
of the
infants
with
birth
weight
of 2,000
g or more
were
in good
or stable
clinical
condition
at the
initiation
of the
exchange
transfusion.
Morbidity
of exchange
transfusion
was
evaluated
by recording any change in the clinical status either
just before, during, or after the procedure. As an
initial
index
of
possible
moribidity,
investigators
were
asked
to compare
the
infant’s
condition
im-mediate before
v after
transfusion,
defined
by
din-ical
stability
and
the
extent
of supportive
measures
required,
as
either
being
worse;
better,
or
un-changed.
The
status
following
315
procedures
was
unchanged.
Six
infants
were
thought
to be
worse
and
seven
were
thought
to be
improved
following
their
exchange
transfusion.
There
were
no
signifi-cant
differences
between
the
treatment
groups.
The
data
concerning
all adverse
clinical
changes
or events
that
occurred
during
or immediately
after
the
exchange
procedures
for
which
information
is
available
are
shown
in
Table
6.
One
infant
had
three
exchange
transfusions
for
which
morbidity
data
are
not
available,
but
these
were
thought
to
have
been
trouble-free.
Of
the
exchange
transfu-sions, 22 of 328 (6.7%) were associated with some
adverse
clinical
problem.
Of the
22 adverse
events,
six
were
mild
episodes
of
bradycardia
associated
with
calcium
infusion.
In
60
low-birth-weight
infants,
72
exchange
transfusions
were
done
via
the
umbilical
artery.
Four
of these
infants
had
color
changes
in the
legs
or
feet
associated
with
the
exchange
transfusion.
Subsequently,
two
of
these
infants
exhibited
no
sequelae,
but
the
other
two
infants
with
indwelling
arterial
catheters
had
evidence
of the
onset
of
pro-longed
vascular
insufficiency
of the
lower
limbs
at
the
time
of the
exchange
transfusion
and
had
large
TABLE 6. Morbidity of Exchange Trans
totherapy (P) and Control (C) Groups
fusio n for
Pho-Morbidity Event P C Total
Transient bradycardia with 1 5 6
calcium
Transient bradycardia without 0 2 2
calcium
Transient cyanosis 1 2 3
Transient vasospasm 0 2 2
Vasospasm with thrombosis 2 0 2
Apnea and/or bradycardia 3 4 7
requiring treatment
22
* Morbidity events -i-Noofexchange transfusions = 22/
328 = 6.7%. Data missing on three exchange transfusions.
occlusive thrombi in the abdominal aorta at
post-mortem
examination.
Elimination
of the
six
exchange
transfusions
in
which
transient
bradycardia
occurred
at
the
time
of calcium
infusion,
and
the
two
exchange
trans-fusions during which there was arterial spasm
with-out
apparent
sequelae,
leaves
14 exchange
transfu-sions (5.22%) in which serious morbidity was
as-sociated with the procedure itself. Of the seven
instances of apnea or bradycardia that required
therapeutic
intervention,
three
were
in
photother-apy-treated
infants
and
four
in the
control
group.
Of the
14 infants
with
serious
events
related
to the
exchange
transfusion,
all
but
two
were
in critical
clinical
condition
prior
to the
procedure;
these
two
patients
had
birth
weight
greater
than
2,000
g, and
each
had
an
episode
of bradycardia
minutes
after
the completion of the exchange transfusion.
In the
exchange
transfusion
group
31 (16.3%)
of
the infants died as compared with 103 (9.0%) of the
infants who did not receive an exchange transfusion
(x2
9.78,P
= .002). This difference appears toreflect
the
large
proportion
of sick
and
low-birth-weight
infants
who
received
exchange
transfusions.
Three
infants
died
within
24
hours
of
the
ex-change
procedure.
The
clinical
condition
of two
of
these
did
not
change
with
the
procedure,
and
their
deaths
were
thought
to be attributable
to unrelated
clinical
problems.
The
third
patient,
a white
male
infant
with
a birth
weight
of 850
g in the
photo-therapy
group,
had
severe
respiratory
distress
syn-drome,
hypocalcemia,
and
thrombocytopenia.
His
condition
was
critical
and
unstable
at the
initiation
of the
exchange
transfusion.
Toward
the
end
of the
two-volume
exchange
procedure,
he
was
noted
to
be cyanotic
and
hypotensive,
and
he died
3’/2 hourslater
in spite
of further
supportive
measures.
Au-topsy examination showed hyaline membrane
dis-ease
and
a large
intraventricular
hemorrhage.
He
was the only patient who died within six hours of
defini-tion of exchange transfusion-related mortality used
in four major studies on that subject.’452’78’#{176}2 Using
that definition, the mortality in this study was 0.53/
100 patients and 0.3/100 procedures. Of the 172
patients who were in good or critical-but-stable
clinical
condition
and
treated
with
exchange
trans-fusion, none died.
DISCUSSION
This study demonstrates that phototherapy
re-duces the requirement for exchange transfusion
among
low-birth-weight
infants
even
when
the
se-rum bilirubin criteria for exchange transfusion are
set at moderately low values in each weight group.
The rate of repeat exchange transfusion in the
phototherapy-treated
infants
was
also
substantially
lowered.
Five
times
as many
exchange
transfusions
were
done
in the
control
group
as in the
photother-apy group.
Phototherapy’s apparent lack of effect in
reduc-ing the number ofexchange transfusions among the
infants
with
birth
weight
greater
than
2,500 g isprobably
secondary
to the
large
number
of patients
with
ABO
isoimmune
hemolytic
disease
in
this
group6’
and
the
bilirubin
level
at
entry
into
this
phase of the study. Criteria for admission into the
study for patients with birth weight of 2,500 g or
more
included
a serum
bilirubin
level
of 13 mg/dL
within
96 hours
of birth.
Arkans
and
Cassady3
have
reported
decreases
in
the concentration of unbound bilirubin after
ex-change
transfusion
in
infants
with
hyperbilirubi-nemia. In the current study, values for the reserve
albumin
binding
of
bilirubin
as
measured
by
HBABA
were
significantly
improved
after
ex-change
transfusion,
an
expected
and
comforting
finding.87
The
severity
of initial
clinical
problems
appeared
to be equally
distributed
between
the
phototherapy
and
control
groups,
but the proportion of infantswith high-risk factors who received transfusions
was higher in the phototherapy compared with the
control group. A higher proportion of
phototherapy-treated infants were in unstable or moribund
con-dition prior to the initiation of the first exchange
transfusion, and a higher proportion of
photother-apy-treated infants required therapy for apnea and
for bradycardia during the exchange procedure. The
design of the study established a lower serum
bili-rubin concentration as an indication for exchange
transfusion in more seriously ill neonates. It is not
surprising, therefore, that the phototherapy group,
with fewer total infants requiring exchange
trans-fusion, had a greater proportion of high-risk
in-fants. These observations may also indicate that
phototherapy is more likely to control the serum
bilirubin concentration in patients without
severe-clinical complications than those with
complica-tions. This finding is in contrast to findings
re-ported by Tan97 in a group of 38 infants in whom
phototherapy was equally effective in reducing
Se-rum bilirubin in matched “healthy” and “ill”
pa-tients. The contrasting findings may be accounted
for by differences in the distribution of birth weight
and severity of illness between the two studies. A
higher proportion of infants in the present study
were less than 2,000 g birth weight and a higher
proportion had major clinical illness.
The incidence of serious clinical problems
asso-ciated with exchange transfusion was 4.2%. Five
problems occurred in the phototherapy group and
nine in the control group. Patients who were more
ill appeared more likely to have complications of
exchange transfusions.
In 60 infants 72 exchange transfusions were done
via the umbilical artery. Circulatory changes in the
lower extremities were recorded in four infants, and
two of these patients had sizable occlusive thrombi
in the abdominal aorta at autopsy. The arterial
catheters in both of these patients were used for
periodic blood sampling over several days, and,
therefore, may have been responsible for the
for-mation of thrombi rather than the procedure used
for exchange transfusion.
The deaths of three patients occurred within 24
hours of the exchange transfusions. Of these, only
the death of a very low-birth-weight
phototherapy-treated infant, who died 3’/2 hours following an
exchange transfusion, was felt to be related to the
exchange transfusion itself. Within six hours of the
procedure, which is the accepted definition of a
procedure-related death used in previous studies,
the mortality was one in 190 (0.53%) patients given
transfusions or one in 331 (0.3%) procedures
per-formed. The following per-patient mortalities have
been recorded: Boggs and Westphal, 3.2%; Weldon
and Odell,’#{176}20.86%’; Panagopoulos et al,78 0.79%;
and Kitchen,52 0.65%.
Boggs and Westphal’4 reported one death among
163 “vigorous” infants, and Kitchen52 reported no
procedure-related deaths among 184 infants
weigh-ing 2,000 g or more at birth. None of the 172 infants
in this study who were in good or critical-but-stable
clinical condition prior to the exchange transfusion
died. The declining procedure-related death rate
reported in studies completed from 1958 through
1976 suggests that much of the related mortality
was preventable through an increased
understand-ing of neonatal pathophysiology and improved
tech-niques in patient management.
The large proportion of low-birth-weight infants
which most of the procedures were done should in intensive care nurseries, and physicians
experi-influence the interpretation of these data. Of the enced in the care of sick neonates were present
exchange transfusions performed, 77% were admin- when an exchange transfusion was done.
istered to infants of less than 2000 g birth weight,
many of whom were quite ill at the time of the
used
in
the
clinical
trial
of phototherapy
demon-
considered
reliable.
Problems
such
as
these
must
strated
potential
for
efficiently
obtaining
light
ex-
be resolved
before
the
photodosimeter
system
could
posure
data
integrated
over
time
for a large
number
reach
widespread
clinical
usefulness.
of
infants.
However,
because
of variation
in
per-formance
of the
badge
and
probable
deterioration
in
some
badges
over
time,
the
system
cannot
yet
be
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