REPLACEMENT
TRANSFUSION
AS
A TREATMENT
FOR
ERYTHROBLASTOSIS
FETALIS
By LouIs K. DIAMOND, M.D. Boston, Mass.
T
HE treatment of hemolytic anemia of the newborn often requires support by com-patible blood transfusions. In the years before the discovery of the Rh factor, such blood was usually compatible only according to the A-B-O group, and for convenience the patient’s father was often used as a donor. This meant the use of Rh-positive blood.It: was found frequently at this time that the infants’ blood levels tended to fall rapidly even with repeated transfusions. In many such cases the infused Rh-positive cells are
de-stroyed much more rapidly than are Rh-negative cells as shown by Mollison in England and confirmed by us. It seemed best, therefore, as a first step in improving treatment, to use only Rh-negative blood as a means of achieving the highest blood levels for
pro-tection of the patient, and this step was logically inaugurated after 1941.
In the more acute and severe cases of erythroblastosis the infant’s anemia often
pro-gressed so rapidly in the first 48 hours that several small transfusions proved inadequate. In such patients, by recently developed technics, it has been possible to demonstrate
that the serum of the baby still contains free maternal anti-Rh agglutinins and that all of the infant’s own red blood cells are often completely coated with this antibody leading probably to a more rapid destruction of the infant’s cells. The removal of as much as
possible of the baby’s own blood should theoretically help diminish the damage resulting from the presence of this free and bound antibody in the circulation and in the tissues.
Such reasoning led to the trial of replacement transfusion for the treatment of erythro-blastosis. Replacement transfusion is not a new procedure in pediatric practice as many
of you know, but to perform it in a newborn infant has added difficulty to an inherently difficult technic.
The earlier method consisted of entering the longitudinal sinus and a peripheral vein,
or two peripheral veins, or a vein and an artery. These usually required more or
less body exposure for a newborn infant on an operating table, often requiring an hour or more for the procedure and this sometimes caused shock-like symptoms from cold and trauma. In addition, the fragile small vessels and a tendency for the blood to clot
as it was being removed further complicated the procedure. The intravascular injection of heparin to keep the blood flowing can be dangerous because of existing hypopro-thrombinemia, possible platelet deficiency or capillary fragility-all contributing to the bleeding tendency which is so common in the neonatal period. In fact, massive
hemor-rhage has been found in a few cases of heparinization of a newborn infant.
The pediatrician faced with the prospect of finding vascular channels for transfusion
of a recently delivered infant with erythroblastosis cannot help but be attracted to the large and readily accessible vein which presents itself in the umbilical cord. Earlier
at-tempts were made to use this channel as a site for exsanguination, but these were not uniformly successful. The development by Dr. Ingraham of our Neurosurgical
Depart-Mead Johnson Award address recorded at the Annual Meeting of the American Academy of
ment and his associates of a bland polyethylene plastic catheter, which could be left in
contact with human tissue for long periods of time without harm, overcame some of the major difficulties of exsanguination transfusion technic. The use of this catheter in
the umbilical vein has permitted the performance of prolonged replacement transfusion
with relative ease and safety. Much of the technic must be acquired through personal
experience and handling of the material. These polyethylene catheters are made by a plastic manufacturer and then tested by Dr. Ingraham’s surgical laboratory for several weeks to make sure that no irritation results from the intravascular use of this
cathe-ter. As originally used the apparatus consisted of the polyethylene catheter which could
be easily threaded through the umbilical vein, through either the ductus venosus into the vena cava or occasionally by passing the ductus venosus and lying in the portal
vein. The catheter was then attached by means of a needle to a glass tube, a rubber
connecting tube and finally to two three-way valves and a 20 cc. Luer-lock syringe. The blood could be exhausted through the first valve as it was withdrawn from the child,
the syringe then refilled through the second valve with blood from the donor’s bottle and this blood reinjected into the child in alternating maneuvers.
More recently, because of some difficulty with clotting of the blood in the valve and
the glass tubing, the apparatus has been slightly modified by omiting the glass tube and the rubber connecting tube, using a longer length plastic catheter and needle and then
connecting the two three-way valves directly to the needle. This has helped materially in diminishing the difficulty of clotting and the need for frequent irrigation of the valve
and the syringe. These catheters are prepared by immersing them for 18 hours or longer in zephrin alba-1 :1000 aqueous solution. In fact, the catheters are allowed to remain in
the solution indefinitely until ready for use, at which time irrigation with warm sterile saline is carried out. The catheter is threaded through the umbilical vein and is attached to
the needle, then attached to the two tubes, and glass and rubber tubes are attached to the valve and the syringe; the two metal basins are used for purposes of irrigation of the
syringe when the blood begins to be a bit thick and the procedure tends to slow down. One of the advantages of being able to use the umbilical vein is that the patient does not need to be exposed on the operating table and hence can be kept warm in a Hess
bed or some similar warming bed for a newborn or premature infant. The baby is placed
in the Hess bed which has previously been warmed, the extremities somewhat restrained
by towels, and a nurse constantly watches over the infant to make sure that the naso-pharynx is kept clear of secretions by suction. Oxygen is administered if necessary. The
procedure is carried out through the lower window of the Hess bed when the top has
been placed in position. The umbilicus is washed as clean as possible and then cut short so that only about a half inch of cord remains above the skin margin. The catheter is
then usually tied relatively easily and, with a syringe attached to the needle at first merely to localize the position of the vessel-either the vena cava or portal vein-where blood
will flow easily, some blood is withdrawn. Then the syringe is replaced by the three-way valve-the first valve is connected by tubing to a pail in which the exhaust blood can be placed, and the syringe placed again in connection with the second valve to the bottle of blood. By alternate maneuvers of first removing and next putting in blood 20 cc. at
a time, the infant can gradually be exsanguinated and most of its blood volume replaced
with relatively little trauma.
is replaced almost immediately and the 20 cc. exchanges do not upset the infant’s
circulation to any extent that we have noticed. Usually we use about a pint of group 0 blood or group specific blood of the Rh-negative type in replacing the infant’s own
blood volume. In the course of about an hour to an hour and a half this 500 cc. of blood replaces by actual measurement between 90 and 95% of the infant’s own circulating
erythrocytes. In this way, one is able to remove the large part of the infant’s red cells, cells coated with maternal antibody which are quite likely to be destroyed later and whatever free antibody exists in the infant’s circulation. Occasionally we have used more
than 500 cc. in a more desperately ill infant but have seen very little benefit from using
as much as 1000 cc. The whole procedure takes between one and two hours and the infant at the end of that time usually is in much better condition than at the start of the
procedure.
One or two additional points that are worthy of mention are that the infant is generally given calcium at the end of the procedure, having washed out the tube, in an effort to
overcome the possible alkalotic tetany that might result from the use of so much sodium that is in the sodium citrate in the bottle of blood. In addition, too, it may be wise to use
prophylactically penicillin and sulfadiazine for 48 hours. and we have done so because of the danger of infection working through this relatively unsterile field-the
cord-which cannot be adequately washed at first. The operators are draped sterilely and the patient also protected so that a minimum of possible infection may occur.
Occasionally it is necessary to transfuse such an infant again in the second, third or fourth week because the blood levels have not been maintained adequately throughout this time but we have rarely had to offer more than a single small transfusion in the second or third week to infants that have had a complete replacement transfusion and
even this single transfusion has had to be given in less than a quarter of the cases. One immediate advantage we noted is that these infants can be discharged usually with the mother; that is, sometime before the eighth day has passed, whereas previously the
average period of hospitalization for infants with severe erythroblastosis requiring mul-tiple transfusions was three weeks or more which meant a danger period, a real danger
when secondary infections could complicate the course of the child’s hospitalization.
It is important here to emphasize that not every infant with possible erythroblastosis requires replacement transfusion. In fact, even though many of the patients sent to us are
referred only because of the possible need for such drastic treatment, in the past year we have so treated only about one out of every eight babies with erythroblastosis which have been sent to us. There should be clear indications for such treatment. Otherwise,
serious harm may result needlessly. We insist on having available a specimen of the mother’s blood, if we have not followed the mother before delivery, by asking every
doctor who refers a patient with symptoms or signs of erythroblastosis to be sure to
send the mother’s blood along before admission of the child. We can thereby prove to our own satisfaction whether or not the mother has anti-Rh agglutinins which can act
on the infant’s Rh-positive red cells. Having demonstrated the presence of antibodies in the mother’s circulation, further evaluation of the case is based on the following points:
the clinical signs of erythroblastosis; that is, anemia, jaundice, edema, splenomegaly and hepatomegaly and other signs that you know so well. We assume that the presence of these clinical signs with antibodies in the mother’s circulation implies the need for
But even in the absence of these clinical signs certain laboratory evidence may suggest the need for immediate treatment and these evidences are based on our previous experience
with such tests. First, one must prove that the baby is definitely Rh-positive and occasionally this is difficult if the baby’s cells are completely coated with the mother’s antibody. Then, if the baby’s cells are coated and the baby has free antibody in its circulation we
know from our selected data over several years that such infants quite regularly develop
severe symptoms within the second, third or fourth days of life and, therefore, those laboratory signs alone, even in the presence of a relatively normal appearing infant, are sufficient indications, we believe, for replacement transfusion.
The absence of clinical evidences, however, and the absence of these clear cut laboratory
findings of free and bound antibody, suggest that the infant will do well enough without
such drastic treatment. This has been the basis of our withholding such treatment.
Before analyzing our results, two further points must be made. First, in a disease which
has so variable a course as erythroblastosis it may be dangerous to draw conclusions as to the value of any mode of therapy unless one has an adequate controlled basis in past
experience to make a comparison and also a sufficient number of cases treated by a
single method so that valid statistical information may be obtained. Too often it has been forgotten that some infants with erythroblastosis recover easily with no spectacular treatment even though the mother has had a high titer of anti-Rh agglutinin ; others die despite heroic therapeutic measures and that again has no direct relationship to the level
of antibody in the mother’s circulation. A second consideration is that we have recently received more and more cases diagnosed very early, in fact often anticipated, and an
increasing number of the patients have had severe erythroblastosis. Ten years ago we
rarely saw an infant with erythroblastosis before the age of 36 hours and the average age
of entry was three days. This meant that the sickest infants had already died and the remaining patients were more likely to recover under any form of supportive therapy. At present some of our patients have been practically moribund with severe anemia,
jaundice, edema and the other complications all within the first 24 hours of delivery.
A few have had erythrocyte levels of a million or less at birth. It is obvious that such patients are in a precarious state no matter how good the supportive treatments.
As a background for an evaluation of our present mode of therapy we have statistics collected over the past 15 years or more. All cases have been observed personally.
Prior to 1941, taking all the infants sent to us whether or not we could institute therapy promptly and the therapy was successful, there was a 35 to 40% mortality rate. Between
1941 and 1945 our work became known and, therefore, we possibly had a larger number of children with this disease sent to us. We treated such children with Rh-negative blood, and whether because of earlier diagnosis or more successful treatment, our mortality rate
dropped to 30% or slightly less. Between 1943 and 1946 again possibly because of better
diagnostic procedure, but also possibly because during this time the obstetricians became accustomed to looking for the disease, for antibodies in the mother and also delivering the baby two to three weeks before term, thereby saving infants that might otherwise
have been stillborn in the last few weeks, our mortality rate dropped. With Rh-negative transfusion, our data at this time showed about a 20% mortality rate.
We are still somewhat hesitant about drawing conclusions from our present data which now covers about 15 months of experience and 95 infants treated personally by
only through the umbilical vein using this plastic catheter. One other point is very important and has convinced us of the value of this treatment in many instances. Of the
95 cases, 20 occurred in families where a previous child had died with erythroblastosis. In such families, the chance of a subsequent infant’s survival is less than 10% in our statistical analysis. Yet, in these 20, 14 infants survived, completely well without any residual damage. Two died and four lived but showed evidence of kernicterus later. In other words, 70% recovered completely, rather than the previous recovery rate of about
10%. Of the 85 infants treated by umbilical vein replacement transfusion, 65 are now
living and well and show no evidence of residual damage even after repeated, careful
examination-some of them right up to 1 5 months ; all of them over three months. Seven patients died, but not of erythroblastosis. The causes of death in these children, were prematurity or immaturity, congenital atelectasis tI the lungs, massive cerebral
hem-orrhage due to tentorial tears and other factors, which cannot be directly related to
erythroblastosis. Seven patients died of the disease despite early or immediate
transfu-sion. Six patients showed kernicterus. We feel at present that kernicterus is not avoided by this mode of therapy since our statistical data is just as poor by this mode of therapy as it formerly was; that is, so far as we know the incidence of kernicterus has not been materially affected since it is not apparently dependent upon anemia and therefore one
could hardly expect successful transfusion treatment alone to prevent this disturbing
complication. Our statistics, therefore, show close to a 90% recovery rate in comparison to a previous 80% recovery rate at its best and this despite the fact that we are being
presented with poorer and poorer specimens considering the severity of the disease and
other facts for operation.
I wish to point out that this mode of therapy first has the advantage of ease and
greater safety in performance. Many physicians who have previously been unable to
transfuse one of these babies by scalp vein or peripheral vein use have carried out this procedure relatively easily. Secondly, and an added advantage, is the earlier discharge of the patient from the hospital at seven or eight days, rather than at two to three weeks. We feel we have saved a certain number of the babies that appeared gravely ill at or shortly after birth, particularly in families that have formerly lost such
infants; and, finally, it seems obvious that although this is not a panacea for
erythroblas-tosis it does offer a definite advance in the mode of handling these cases. As an indication of possibly future beneficial therapy, we all agree that the most successful treatment would consist of prevention rather than merely the repair of hemolytic anemia of the
newborn. This would require the prevention of antibody formation in the mother or the neutralization in the mother and in the infant of the anti-Rh agglutinins already present.
But, until such specific cures can be developed, replacement transfusion seems to be a
better method of treatment for many cases of erythroblastosis.
SPANISH ABSTRACT
Not available for publication.
