Unexplained death from exchange transfusion

UNEXP LA I N E D DEATH FROM EXCHANGE TRANSFUSION WILLIAM C. TAYLOR, M.B., CH.B., LLOYD C. GRISDALE, M.D., AND ALLAN G. STEWART, P h . D . EDMONTON, ALBERTA CASE REPORTS URING the 11 years that have elapsed since the introduction of CASE 1.--Cardiac Arrest During Exexchange transfusion for the treatchange Transfusion.ment of hemolytic disease of the newThis female infant was delivered by born, attention has been periodically cesarean section on the tenth of Sepfocused on the fact that this pro- tember, 1957. Cesarean section was cedure is not without its dangers and performed at 35 weeks' gestation because of a rise in maternal D antibody may occasionally be associated with titer to ~2, and because of the death unexpected fatality. Allen and Dia- of the 3 preceding siblings from hemond 1 have recently pointed out that, molytic disease. The infant weighed with few exceptions, it has been im- 2,220 Gin. She cried spontaneously and on examination appeared normal possible to explain the deaths that except for yellow staining of the verarise during or shortly after exchange nix and the umbilical cord. The spleen transfusion. Walker and Mollison2 was not palpable. The cord blood have listed the causes of death occur- serum bilirubin was 6.4 mg. per cent, ring in association with hemolytic dis- hemoglobin 9.5 Gm. per cent, hematoease of the newborn in England and crit 26 per cent, and reticulocyte count 14.4 per cent. The direct Coombs' test Wales during the years 1953 and was positive. 1955. In 88 (16 per cent) of 550 The first exchange transfusion was deaths, the fatality arose during or carried out within one hour of delivery. Using a 10 c.c. syringe, 415 c.c. within 4 hours of exchange transof blood were withdrawn and 384 c.c. fusion. The immediate cause of death of packed cells injected. Throughout was not apparent in these cases but, the 1-hour procedure the infant's confrom the clinical information avail- dition remained satisfactory. Followable, it seemed that death should not ing the exchange, the serum bilirubin otherwise have taken place at that was 2.5 mg. per cent, the hemoglobin 13.4 Gm. per cent, and the hematocrit time. 35 per cent. The following case reports are preAt the age of 7 hours, the serum sented in the belief that they repre- bilirubin had risen to 9.0 mg. per cent and a second exchange transfusion sent a sequence of events which must was given. Using the same technique occur in a certain but at present un- as before, 310 c.c. of blood were withknown proportion of sudden deaths drawn and 290 c.c. injected in less arising during exchange transfusion. than 1 hour. The infant's condition remained satisfactory throughout and From the Department of Paediatrics, Uniperiodic electrocardiographic (ECG) versity of Alberta and University of Alberta Hospital, Edmonton, Alberta. tracings taken with a direct writing

D

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Sanborn electrocardiograph revealed no abnormalities in the standard leads. A few minutes after the exchange had been completed the infant developed

Fig.

1.--Case

1. L e a d

Fig.

2.--Case

1. L e a d

Fig. 3.--Case

L Time from start of exchange--28 c.o. ; s l o w n o d a l r h y t h m , r a t e - - 5 3

I. T i m e

.........

from

~ i

start

1. L e a d

rain.; volume per minute.

rain. ; volume per minute.

to exehange--30~

rain.

of blood

of blood

Ventricular

injected--

injected--70

fibrillation.

:~~T+~!~ii:'~!Ji~"~!~ ~!

N;

Fig. 4.--Case

At the age of 22 hours, the serum bilirubin was 13.6 rag. per cent, the hemoglobin 8.3 Gin. per cent, and the hematocrit 21 per cent. A third ex-

I. T i m e f r o m s t a r t o f e x c h a n g e - - 1 7 30 e.o. ; n o r m a l n o d a l r h y t h m , r a t e - - 1 3 5

1. L e a d

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L Time from start

a generalized convulsion which responded to intramuscular injection of 2 c.c. calcium glucoheptonate. During the next few hours, a few petechial hemorrhages developed on the skin of the face and trunk.

of exchange--32

rain.

Cardiac

arrest.

change was attempted using 7-day-old blood which had been packed by removal of supernatant p]asma a few hours before the exchange. After 80 c.c. of blood had been withdrawn and 70 c.c. injected, an ECG tracing taken

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28 minutes a f t e r the commencement of the e x c h a n g e showed evidence of slow n o d a l r h y t h m . (Fig's. 1, 2, 3, and 4,) D u r i n g the n e x t 4 minutes, the cardiac slowing p r o g r e s s e d to ventricular fibrillation and complete cardiac arrest. A t the time of detection

of the cardiac slowing the infant's condition appeared satisfactory. There were no signs of respiratory distress, cyanosis, or pulmonary adventitious sounds. Clinical signs of collapse were only a p p a r e n t w h e n the ECG t r a c i n g showed evidence of ventricnlar fibrillation. The cardiac a r r h y t h mia was uninfluenced b y discontinuing the exchange and immediate injection of 2 c.c. calcimn glucoheptonate into the umbilical vein. The h e a r t r e m a i n e d in asystole for a period of 5 minutes, b u t responded to intracardiac injection of Adrenalin, and artificial respiration with tracheal intubation and intermittent positive pressnre oxygen.

Fig.

5,---Case

2. ] , e n d I. T i m e f r o m s t a r t 80 c.e. ; n o r m a l n o d a l

OF P E D I A T R I C S

sis which showed no response to intravenous injection of ~ M lactate solution or sodium b i c a r b o n a t e solution. D e a t h occurred at the age of 38 hours.

Biochemical estimations on donor b~ood for the third exchange P l a s m a potassium ~ > 2 0 m E q . / L . (Colorimeter standardized to 20 mEq./L.) CO~ combining power = 7.7 m E q . / L . p H ~ 6.1 Biochemical estimations on infant's blood Before third exchange transfusion Potassium ~ 4.3 m E q . / L . A t time of cardiac arrest Potassium ~ 12.0 m E q . / L . At time of cardiac arrest Ca]cimn ~ 3.5 m E q . / L . At time of cardiac arrest CO2 combining power ~ 12.2 m E q . / L .

of e x c h a m g e - - 2 7 rain. ; v o l u m e rhythm, rate--156 per minute.

of blood

i n j e c t e d ....

itii i~ .i:;

Fig.

6.--Case

2. L e a d

I. T i m e f r o m s t a r t o f e x c h a n g e - - 2 7 185 c.e. ; s l o w n o d a l r h y t h m , r a t e - - 8 0

F o r the remaining 14 hours of her life the infant remained in a precarious condition. She was nursed in a high concentration of oxygen, but her r e s p i r a t o r y rate became irregular with i n t e r m i t t e n t periods of apnea and eyanosis. H e r serum biochemistry showed evidence of a persistent acido-

min, ~ volume Per minute.

of

blood

injected--

Autopsy.--This was p e r f o r m e d 12 hours a f t e r death. There was a slight icteric tinge to the skin as well as subeonjunctival hemorrhages and petechiae over the trunk. Petechial hemorrhages were also seen subpleural]y in the region of the trachea and lungs, in the heart, kidneys, and liver. The

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lungs were hemorrhagic in appearance in the lower portion and fleshy in consistenee. Microscopic examination revealed areas of extramedullary hematopoiesis, which were marked in the liver but also present in the kidney. Hemorrhages were present within the lung', kidney, thymus, and adrenal. The lungs showed moderate atelectasis. Sections of the heart showed no remarkable histopathological change. The causes of death were finally designated, according to their presumed degree of importance, as follows: (1) post-transfusion electrolyte imbalance; (2) hemolytic disease of the newborn; (3) prematurity; (4) hypoxia; and (5) pulmonary atelectasis. CASE 2.--Cardiac Arrhythmia During Exchange Transfusion.Experience with electrocardiography in 50 exchange transfusions performed on 36 infants has revealed one other example of gross cardiac arrhythmia. This infant weighed 2,160 Gin. and was of 35 weeks' gestation. The cord blood hemoglobil-~ was 7.0 Gin. per cent and the bilirubin 6.82 rag. per cent. He received an exchange transfusion at the age of 1 hour, using 5-day-old partially packed blood. After injection of 185 c.c. of blood in 15 c.e. aliqnots, the heart rate was suddenly slowed although the infant's general condition remained satisfactory. The ECG showed marked sinus bradyeardia and occasional ectopie beats (Figs. 5 and 6). The arrhythmia was uninfluenced by injection of 1.5 e.c. calcium glueonate (10 per cent solution) and persisted until the end of a cautiously executed exchange of 450 c.c. of blood. The bradycardia alternated with periods of normal ECG configuration. ECG tracings taken on the first, second, third, and seventh days after the exchange transfusion were not remarkable and the infant's subsequent progress was uneventful. Biochemical estimations on donor b~ood Potassium = 9.7 mEq./L. Calcium = 5.2 mEq./L.

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Biochemical estimations on infant's blood Before exchange transfusion Potassium ~ 6.9 mEq./L. Calcium ~ 5.0 mEq./L. ~r Potassium = 5.1 mEq./L. Calcium = 6.6 mEq./L. Post-transfusion Potassium = 7.6 mEq./L. Calcium = 8.6 mEq./L. The high figures for calcium in the mid- and post-transfusion samples could be due to contamination from immediately preceding injections of cMMum glueonate solution. DISCUSSION

Two examples of 2:1 aurieuloventricular heart block detected by electrocardiographic examination during exchange transfusion have been reported by Joos, Yu, and Miller 3 (Table I). One infant, transfused with donor blood containing a plasma potassimn of 8.0 mEq./L., developed parasystoles and 2:1 block intermittenly during the fourth and fifth 100 c.c. of the exchange. The arrhythmia was uninfluenced by calcium administration and the infant's serum potassium did not rise above 5.40 mEq./L. The second infant, a premature weighing 1,190 Gin., was transfused with donor blood containing a plasma potassium of 18.6 mEq./L. Arrhythmia consisting of 2:1 heart block developed during administration of the second 50 c.e. of exchange, persisted for 4 minutes, and then reverted to normal rhythm following the intravenous injection of 0.1 Gin. of calcium glueonate. The serum potassium just before the onset of the 2:1 b l o c k was 9.12 mEq./E. This baby died within 24 hours of the exchange transfusion. Autopsy revealed the findings of prematurity, severe hemolytic disease of

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the newborn, and kernicterus. Tile heart was not abnormal. Examples of cardiac arrest during exchange transfusion have been reported by Walker and Neligan (1 ease). ~ Pew (1 case), 5 and Bolande, Traisman, and Philipsborn (4 cases).* These cases are summarized in Table I. CampbelF in a study of potassium levels in exchange transfusion has referred to 7 deaths in association with the transfusion. In 4 of these cases the infant's maximmn potassium ]eve] ranged between 6.13 and 10.23 m E q . / L . TABLE I .

COMPARISON OF BIRTH WEIGtIT, VOLU]~IE OF BLOOD TRANSFUSED, AND BLOOD C~EMISTI~Y IN I~EPOKTED CASES SHOWING CARDIAC ARlCHYTtIMIA OI~ ARREST DURING EXCI~ANGE TRANSFUSION

TVT.

OF

BABY AUTHOR Case Case Joos, goes,

manifested itself with clinical signs of p u l m o n a r y or cardiac distress, which have included r a p i d respiratory rate, cyanosis, pulmonary crepitations, gagging, and production of :frothy mucus. I n contrast to this, the clinical state of the infants, r e f e r r e d to in Table I, was such that no anxiety was felt regarding their condition until the sudden onset of the cardiac manifestations. I t is most likely t h a t these infants suffered from a complication of exchange transfusion other than that of congestive heart failure.

(G~.)

] 2 Yu, and Millers Yu, and Millers

2,220 2,]60 -1,190

Walker and Neligan4 Pews B o l a n d e et al.s BolandeS Bolandes Do]andeS

2,400 -----

VOL. OF BLOOD INJECTED BEFORE CARDIAC ARREST O~ ONSET OF ARRHYTHMIA

(o.c.)

DONOR BLOOD POTASSIU~ (MEQ./L.)

W~th E~ectrocardiography 60 ~20.0 185 9.7 400 -75 18.6 W~thout Electrocardiography 230 ]6.52 350 --9.55 -22.70 -21.10 -20.50

Table I shows an analysis of 10 infants who shared in common the electrocardiographic features of sudden onset of arrhythmia, 2:1 heart block, or the clinical features of sudden cardiac arrest. In so far as it can be ascertained from reading tile reports of these cases, it seenled unlikely that any of them suffered from the type of congestive heart failure described by Walker and Neligan, 4 and Allen and Diamond. 1 Congestive heart failure in hemolytic disease of the newborn can be an insidious process but has usually

INFANT BLOOD AT TXI~E CALCIUIV[ OF CARDIAC ARREST OR] GIVEN _ END OF EXCI=IANGE I DUP~ING POTASSIU]~[ CALCIUM ] EX( M E Q . / L . ) ( ] ~ E Q . / L . ) CHANGE 12.0 7.6 4.63 9.12 14.58 4.5 5.16 5.30 6.55 7.75

3.5 8.6 --3.2 --

2.85 --- - -

Yes Yes Yes Yes ~o

Yes Yes Yes

Yes Yes

There was no definite evidence other than the clinical features and the electrocardiographic findings t h a t the mechanism of the cardiac arrhythmia was the same in all 10 cases. Case 1 which showed a sudden progression from a state of slow nodal rhythm, without associated clinical features, to complete cardiac arrest in a period of 4 minutes suggested that there was a possible interrelationship in this group of cases. It seemed likely that in this case there was some biochemical derangement or other factor which,

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acting over a short period of time, severely embarrassed the heart action. I I y p e r p o t a s s e m i a was not considered to be a likely cause. S e r u m potassium levels up to 7.8 m E q . / L , have not been considered unusual (lVicCance and Young s) during the normal newborn period. Sudden cardiac arrest occurred with a potassium level as low as 4.5 InEq./L. in the i n f a n t reported by Pew2 I n addition, Bolande ~ has reported 1 infant with a serum potassium of 17 m E q . / L , who did not develop cardiac arrest d u r i n g exchange and who survived the exchange transfusion for a period of 17 hours. A comparison of the potassium in the donor blood and the potassium in the infant's circulation in Table I suggested t h a t m o s t i n f a n t s could handle c o m p a r a t i v e l y large loads of infused potassium. This confirmed the observations of C a m p b e W a n d of Bolande. 6 The possibiIity of cardiac a r r e s t f r o m h y p e r p o t a s s e m i a also a p p e a r e d unlikely f r o m the e x p e r i m e n t a l w o r k of B a k e r and his co-workers. 9 T h e y have r e p o r t e d the use of potassium citrate in the a r r e s t of the p e r f u s e d isolated h e a r t s obtained f r o m 4 stillborn fetuses of 16 to 20 weeks' gestation. A concentration of potassium citrate equivalent to 14.8 m E q . / L . (calculated as t r i p o t a s s i u m citrate) had to be directed as a continuous infusion into the c o r o n a r y circulation to produce cardiac arrest. The volume of the p o t a s s i u m citrate solution required to produce this effect was not specified. Effler and his co-workers 1~ have r e p o r t e d the use of potassium citrate solutions equivalent in s t r e n g t h to 230.0 m E q . / L . (calculated as t r i p o t a s s i u m citrate) and 6-20 c.c. volume to produce cardiac arrest in children u n d e r g o i n g cardiac surgery.

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I n both r e p o r t s the potassium solutions were directed into the c o r o n a r y arteries and there was no o p p o r t u n i t y for dilution to occur f r o m m i x t u r e with venous biood. They h a v e not, however, r e p o r t e d on the efflcaey of w e a k e r solutions of potassium. In exchange transfusion, the donor blood has ample o p p o r t u n i t y to become diluted with the i n f a n t ' s venous blood before being directed to the c o r o n a r y circulation. I I y p o e a l c e m i a was also considered as a cause of cardiac arrest. I n 9 out of the 10 eases, calcium was given as a p r o p h y l a c t i c m e a s u r e d u r i n g the exchange transfusion. I n 2 eases of h e a r t block and one of cardiac arrest, there was no response to i m m e d i a t e administration of calcium. I t app e a r e d unlikely, therefore, t h a t calcium deficiency p e r se was the cause of the cardiac phenomena. Pew ~ drew attention to tile fact that his ease of cardiac arrest followed shortly a f t e r the i n t r o d u c t i o n of a bottle of cool blood into the exchange t r a n s f u s i o n and t h a t the h e a r t felt cold when it was massaged. I n Case 1 no a t t e m p t was m a d e to w a r m the blood other t h a n allowing it to stand at room t e m p e r a t u r e for a b o u t 10 to 15 minutes. I n f o r m a t i o n with r e g a r d to w a r m i n g of the blood is not available on the other eases. Hoff and Stansfield 11 and D e t e r l i n g and his cow o r k e r s 12 have p r o v i d e d e x p e r i m e n t a l evidence in the dog t h a t v e n t r i e u l a r fibrillation could develop w h e n the b o d y t e m p e r a t u r e was reduced below 73 ~ P. or the local v e n t r i e u l a r temp e r a t u r e below 50 ~ F. One f a c t o r which has not been given m u c h consideration in previous reports is the effect t h a t the acid-cit r a t e dextrose anticoagulant m i x t u r e

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has on reducing the ptI and C02 combining power of donor blood. On samples of donor blood tested at this hospital, the average p i t was 6.2 and this level varied little with the duration of storage. In Case 1, severe and irreversible acidosis was an outstanding feature following the third replacement transfusion. Deterling ~ demonstrated that the ventrieular fibrillation induced in dogs by hypothermia did not develop when the blood was maintained in a state of alkalosis by hyperventilation. At the present thne it is not possible to state that any one specific factor or combinations of factors is responsible for the occurrence 02 cardiac arrest in infants undergoing exchange transfusion. According to circumstances several or all of the following factors raay be present: hyperpotassemia, hypoealcemia, cooling of the heart, acidosis, prematurity, and the disease process of hemolytic disease. There may be other factors at present unsuspected. The combined use of electrocardiography and adequate biochemical study is one way of further elucidating the problems involved and, at the same time, ensuring maximum safety for the infant. SUMMARY

Attention is drawn to the fact that sudden and unexpected death may occur during or shortly after exchange

transfusion for hemolytic disease of the newborn. One case is reported of bradycardia, ventricular fibrillation, and cardiac arrest after 70 c.e. of blood had been exchanged. A second case is reported of bradycardia and arrhythmia developing after an exchange of 185 c.e. of blood.

These cases are compared with 8 other case reports in which there is a similarity of clinical or electrocardiographic findings. It is not possible from the data available to determine a common etiological factor for tile sudden alteration in cardiac function. It is suggested that possible factors which might be operating singly, or in combination, are hyperpotassemia, hypoealcemia, hypothermia, acidosis, prematurity, and the disease processes of hemolytic disease. REFERENCES

1. Allen, F. tI., and Diamond, L. K.: Erythroblastosis Foetalis, New England J. Med. 257: 761, 1957. 2. Walker, W., and 3r P. L.: Haemolytic Disease of the Newborn, Lancet 272: 1309, 1957. 3. Joos, H. A., Yu, P. N., and Miller, G.: Electrocardiographic Changes During Replacement Transfusion, A. M. A. Am. J. Dis, Child. 88: 471, 1954. 4. Walker, W., and Neligan, G. A.: Exchange Transfusion in Haemo]ytic Disease of the Newborn, Brit. i~I. J. 332: 681, 1955. 5. Pew, W. L.: Cardiac Arrest During Exchange Transfusion, J. PEDIA~. 47: 645~ 1955. 6. Bolande, R. P., Traisman, H. S., and Philipsborn, H. F., Jr.: Electrolyte Considerations in Exchange Transfusions for Erythroblastosis Feta]is, J. PE])IAT. 49: 401, 1956. 7. Campbell, W. A . B . : Potassium Levels in Exchange Transfusion, Arch. Dis. Child. 30: 513, 1955. 8. McCance, R. A., and Young, W. F.: Secretion of Urine by Newborn Infants, J. Physiol. 99: 265, 1941. 9. Baker, J. B. E., Bentall, ~I. It., Dreyer, B., and Melrose, D. G.: Arrest of Isolated Heart With Potassium Citrate, Lancet 273: 555, 1957. I0. Effier, D. B., Groves, L. ]{., Sones, •. ~r Knight, ~t. F., and Kolff, W. J: Elective Cardiac Arrest, J. Thoracic Surg. 3~: 500, 1957. 11. IEIoff, H. E., and Stansfield, H.: Veto trleu!ar Fibrillation Induced by Cold, Am. t{eart J. 38: 193, 1949. 12. Deterllng, 1~. A., Nelson, E., Bhonslay, S., and Howland, W.: Study of Basic Physiologic Changes Associated With tIypothermia, A. IV[. A. Arch. Surg. 70: 87, 1955.