3. E XCHANGE TRANSFUSION (ECT) was introduced in the
late 1940s to decrease the mortality of hemolytic
disease of the newborn (HDN) and to prevent ker-
therapy and intravenous immunoglobulin (IVIg), and
ECT-related complications.
Patients were divided into 2 groups, 1986 –1995 and
nicterus in surviving patients.1 ECT was subsequently 1996 –2006, based on the AAP guidelines for the man-
applied to neonatal hyperbilirubinemia from a variety of agement of hyperbilirubinemia published in October
causes and quickly became one of the most commonly 1994 and implemented in the NBSCU at Yale in late
performed neonatal procedures. 1995. Before this time, the threshold for ECT at YNHH,
In 1968 and 1971, Lucey2,3 accurately predicted that with or without evidence of hemolysis, was a total se-
prenatal interventions, particularly the development of rum bilirubin of 20 mg/dL for term infants, with thresh-
Rh-immunoglobulin, coupled with advances in postna- old levels decreasing based on birth weight.17 Beginning
tal care such as phototherapy, would lead to a dramatic in late 1995 and continuing to the present time, the
decline in the number of ECTs performed. Maisels4, in a threshold for ECT at YNHH was raised to 25 mg/dL for
review that combined data from 3 centers over 40 years, term infants 48 hours old without evidence of hemo-
observed a decline in the frequency of ECT and predicted lysis, but remained at 20 mg/dL for those with hemoly-
that it would lead to increased complications because of sis. Asymptomatic term infants were also provided the
inexperience with the procedure. More recent advances, opportunity to respond to intensive phototherapy before
such as use of intrauterine transfusions and improve- an ECT was initiated, and all infants were strictly mon-
ments in diagnostic ultrasound,5–8 have likely accelerated itored for hyperbilirubinemia as per the AAP guide-
this decline in the frequency of ECT.9,10 lines.15
Since the introduction of ECT, the level of bilirubin at A detailed, step-by-step protocol, provided in the
which to initiate this procedure has been a controversial YNHH NBSCU procedure manual, was used for ECT.
issue. Based on experience with HDN,11 a bilirubin level This technique, as described by Edwards and Fletcher,18
of 20 mg/dL was used by many centers, including Yale, did not change over the 21-year study period.
but some questioned whether it was appropriate to ap-
ply this cutoff to patients with nonhemolytic hyperbil- Indications and Comorbidities
irubinemia.12 This debate intensified in the late 1980s The indications for ECT were hyperbilirubinemia or
and early 1990s, when several reports demonstrated that anemia. Hyperbilirubinemia was further classified by eti-
term infants with nonhemolytic jaundice were not as ology (Rh disease, ABO incompatibility, idiopathic hy-
susceptible to kernicterus as infants with HDN.13,14 perbilirubinemia, and other hematologic diagnoses). Pa-
In 1994, the American Academy of Pediatrics (AAP) tients were considered to have a significant preexisting
published its first guidelines on the treatment of hyper- comorbidity if they were treated with blood pressure
bilirubinemia.15 These guidelines increased the bilirubin support and/or mechanical ventilation, if they had a
threshold for initiating ECT in term infants without he- major congenital anomaly, or if they had any of the
molysis and allowed for a trial of intensive phototherapy following diagnoses: respiratory distress syndrome, in-
before an ECT was initiated. In addition, these guidelines traventricular hemorrhage (all grades as defined by Pa-
encouraged prenatal testing of maternal ABO and Rh pile et al19), necrotizing enterocolitis (NEC; modified
types and recommended increased monitoring for hy- Bell’s criteria at least stage 2a20), or sepsis (defined as a
perbilirubinemia in all infants.15 These interventions had positive blood culture and/or signs and symptoms con-
the potential to cause a further decline in the number of sistent with sepsis treated with antibiotics for 7 days).
patients requiring ECT.16
We hypothesized that changes in prenatal and post- ECT-Related Complications
natal care have altered the patient population undergo- ECT-related complications were defined as any compli-
ing ECT, the indication for exchange, and the incidence cation, not present before the ECT, which occurred
of ECT-related morbidity and mortality. To examine this, within 7 days after the exchange. They were defined
we performed a longitudinal, 21-year review of ECT at a as follows: severe thrombocytopenia, platelet count
single center. 50 000/mm3; hypocalcemia, serum calcium 8.0
mg/dL or plasma ionized calcium 3.5 mg/dL; seizures,
PATIENTS AND METHODS clinical evidence of seizure-like activity treated with an-
Infants who required single- or double-volume ECT and tiseizure medication; bradycardia, heart rate 100 beats
had long-term admissions ( 24 hours) in the newborn per minute; apnea, cessation of respirations for 20
special care unit (NBSCU) at Yale New Haven Hospital seconds; catheter malfunction, central venous or arterial
(YNHH) from January 1, 1986, through December 31, catheter thrombosis or rupture; hyperkalemia, serum
2006, were included. Neonates who received partial ECT potassium 6.5 meq/dL associated with electrocardio-
for polycythemia or anemia were excluded. Data collec- gram changes; NEC, modified Bell’s criteria at least stage
tion included patient demographics, comorbidities, indi- 2a20 diagnosed after the ECT; and ECT-related mortality,
cation for exchange transfusion, treatment with photo- ECT-related mortality was defined as any death that was
28 STEINER et al
Downloaded from www.pediatrics.org by on July 9, 2009
4. directly related to the ECT and occurred within 7 days
after the exchange.
Statistical Analysis
SPSS 13.0 (SPSS Inc, Chicago, IL) and GraphPad Prism
3.0 (GraphPad Software, Inc, San Diego, CA) were used
for data analyses. Continuous data were compared by
using the Student’s t comparison of means. Dichoto-
mous data were compared by using a Pearson’s 2 anal-
ysis or Fisher’s exact test when at least 1 cell contained
a value 5. Trends were analyzed by using linear regres-
sion analysis. To incorporate both inborn and outborn
neonates into this analysis of trends, the number of ECTs
was evaluated per 1000 NBSCU admissions. In evaluat-
ing inborn neonates separately, the number of ECTs was
evaluated per 1000 live births. A P value of .05 was
considered statistically significant.
This study was approved by the institutional review
board of the Yale University School of Medicine.
RESULTS
From January 1, 1986, to December 31, 2006, there
were 98 901 live births at YNHH and 16 389 long-term
admissions, inborn and outborn, to the NBSCU. One
hundred seven infants underwent 141 ECTs from 1986 –
2006. Two patients in each time period received a single-
volume ECT, with the remaining patients receiving a
double-volume or near– double-volume exchange. Over
FIGURE 1
the entire study period, there was a statistically signifi-
Exchange transfusions at YNHH. A, Exchange transfusions in inborn neonates per 1000
cant decline in the number of ECTs performed per 1000 live births at YNHH: 1986 –2006 (r2 0.30; P .010). B, Exchange transfusions in inborn
live births in inborn neonates (r2 0.30; P .010; Fig and outborn neonates per 1000 NBSCU admissions at YNHH: 1986 –2006 (r2 0.49; P
.001).
1A) and per 1000 NBSCU admission in those both in-
born and outborn (r2 0.49; P .001; Fig 1B).
Demographic data were similar between the 2 groups, with Rh disease in the first group and in 64% of patients
with no statistically significant differences in gestational with Rh disease in the second group.
age, birth weight, race, gender, or age at ECT (Table 1). A smaller proportion of patients in the 1996 –2006
The rate of phototherapy before exchange did not differ group experienced an ECT-related complication (Table
significantly between groups. Neonates in the 1996 – 3). This result was not statistically significant, possibly
2006 group were significantly more likely to receive IVIg because of the small sample size. We observed a high
before ECT (P .016; Table 1). rate of thrombocytopenia and hypocalcemia after ECT in
There were no statistically significant differences in both the 1986 –1995 and the 1996 –2006 groups, com-
the indications for ECT when comparing the 1986 –1995 parable to previous studies.21,22 Despite similar rates of
and 1996 –2006 groups (Table 2). The most common thrombocytopenia and hypocalcemia, patients treated
indication for ECT was hyperbilirubinemia, which was from 1996 –2006 were significantly more likely to be
further subdivided into ABO incompatibility, Rh disease, transfused platelets or to be given intravenous calcium
idiopathic hyperbilirubinemia, and other hematologic (Table 4). The retrospective nature of this study and the
diagnoses. Other diagnoses included glucose-6-phos- small sample size make it difficult to determine the cau-
phate dehydrogenase deficiency, pyruvate kinase defi- sality of these observations. The higher proportion of
ciency, fibrosarcoma with large vascular compartment, preexisting comorbidities in the neonates undergoing
hemolytic anemia because of Gram-negative sepsis, con- ECT from 1996 to 2006 may have resulted in more
genital acute myelogenous leukemia, -thalassemia, he- aggressive management or, alternatively, the difference
reditary pyropoikilocytosis, and hereditary spherocyto- might stem from unidentified changes in our clinical
sis. The most common cause of hyperbilirubinemia practice over the last 2 decades.
requiring ECT was Rh disease. Antibodies to non–D Rh A total of 5 deaths occurred within 7 days of the ECT,
antigens were common, occurring in 40% of patients none of which were related to the ECT.
PEDIATRICS Volume 120, Number 1, July 2007 29
Downloaded from www.pediatrics.org by on July 9, 2009
5. TABLE 1 Demographic Data and Age at Exchange Transfusion
Total 1986–1995 1996–2006 Pa
(N 107) (N 71) (N 36)
Gestational age, mean SD, wk 35.3 4.7 35.7 4.8 34.6 4.5 .257
Birth weight, mean SD, g 2511.1 983.8 2469.4 956.4 2593.1 1044.7 .541
Birth weight 1000 g, n (%) 12 (11) 7 (10) 5 (14) .747
Birth weigh 1500 g, n (%) 19 (18) 12 (17) 7 (19) .740
Male gender, n (%) 61 (57) 43 (61) 18 (50) .296
Race, n (%)
Caucasian 63 (59) 43 (61) 20 (56) .617
Black 31 (29) 20 (28) 11 (31) .791
Hispanic 9 (8) 5 (7) 4 (11) .715
Asian 4 (4) 3 (4) 1 (3) .999
Transport, n (%) 34 (32) 23 (32) 11 (31) .841
Age at exchange, mean SD, d 3.6 3.1 3.4 2.9 4.0 3.6 .347
Phototherapy before ECT, n (%) 91 (85) 60 (85) 31 (89) .823
IVIg administration, n (%) 6 (17) 1 (1) 5 (14) .016
Intrauterine transfusions, n (%) 20 (19) 14 (20) 6 (17) .699
Comorbidities, n (%) 41 (38) 24 (34) 17 (47) .177
Mechanical ventilation 37 (35) 23 (32) 14 (39) .502
Blood pressure support 17 (16) 11 (15) 6 (17) .888
NEC 4 (4) 1 (1) 3 (8) .110
Hydrops fetalis 6 (6) 3 (4) 3 (8) .661
IVH 10 (9) 8 (11) 2 (6) .490
RDS 23 (21) 14 (20) 9 (25) .532
Sepsis 13 (12) 7 (10) 6 (17) .354
a Comparison of the 2 time periods.
TABLE 2 Indication for ECT TABLE 4 Hypocalcemia and Thrombocytopenia in Patients
Total 1986–1995 1996–2006 Pa Undergoing Exchange Transfusion
(N 141), (N 96), (N 45), Total 1986–1995 1996–2006 Pa
n (%) n (%) n (%) (N 141), (N 96), (N 45),
Hyperbilirubinemia 120 (85) 79 (82) 41 (91) .211 n (%) n (%) n (%)
Rh disease 58 (41) 41 (43) 17 (39) .578 Hypocalcemia 53 (38) 32 (33) 21 (47) .128
ABO incompatibility 39 (28) 28 (29) 11 (24) .560 Calcium replacement 24 (45)b 9 (28) 15 (71) .002
Idiopathic 28 (20) 17 (18) 11 (24) .351 Thrombocytopenia 53 (38) 36 (38) 17 (38) .999
Other 14 (10) 10 (10) 4 (9) .999 Platelet transfusion 26 (49)c 11 (31) 15 (88) .0001
Anemia 3 (2) 1 (1) 2 (4) .239 a Comparison of the 2 time periods.
a Comparison of the 2 time periods. b Percentage with hypocalcemia who received calcium replacement.
c Percentage with thrombocytopenia who received platelet transfusion.
TABLE 3 Exchange Transfusion-Related Complications Excluding
Thrombocytopenia and Hypocalcemia weight compared with those 1500 g. Infants 1500 g
Total 1986–1995 1996–2006 Pa did not experience increased rates of thrombocytopenia,
(N 141), (N 96), (N 45), hypocalcemia, calcium replacement, or platelet transfu-
n (%) n (%) n (%) sion (data not shown). The small sample size of this
Catheter malfunction 4 (3) 2 (2) 2 (4) .592 premature cohort (n 19) made it difficult to draw any
Seizures 3 (2) 3 (3) 0 (0) .551
valid conclusions from the analyses.
NEC 2 (1) 2 (2) 0 (0) .562
Apnea 1 (1) 1 (1) 0 (0) .999
Bradycardia 5 (4) 4 (4) 1 (2) .673 DISCUSSION
Hyperkalemia 1 (1) 1 (1) 0 (0) .999 These data demonstrate a dramatic decline in the fre-
Any complication 16 (11) 13 (14) 3 (7) .270 quency of ECT at YNHH over 2 decades, representing the
a Comparison of the 2 time periods. longest single-center, longitudinal documentation of
trends in ECT. This decline is likely multifactorial with
contributions from advances in both prenatal and post-
Authors of previous reports have hypothesized that natal care, such as middle cerebral artery Doppler studies
premature infants are more susceptible to complications to noninvasively follow fetal anemia,7,8 and IVIg treat-
from ECT.21,22 We observed no significant differences in ment for patients with hemolysis.23 In addition, adoption
either time period in the frequency of ECT-related com- of the 1994 AAP guidelines may have contributed to this
plications or their treatment in neonates 1500 g birth decline.15
30 STEINER et al
Downloaded from www.pediatrics.org by on July 9, 2009
6. The 1994 AAP guidelines recommend that all infants quency ventilation, dialysis, and extracorporeal mem-
jaundiced in the first 24 hours of life receive a total brane oxygenation than with ECT, a standardized pro-
serum bilirubin and all infants be assessed for jaundice tocol for performing ECT may be an important tool for
by a health care provider at 2 to 3 days of life. These decreasing the number of adverse, procedure-related
guidelines also recommend prenatal testing of maternal events. Inclusion of ECT in neonatal education will also
ABO and Rh types, prenatal screening for unusual ma- help minimize ECT-related morbidity and mortality,
ternal antibodies, and screening of the cord blood if the even as the frequency of ECT continues to decline.
mother was Rh negative or if the mother’s ABO type was
unknown. The heightened monitoring of all infants for
ACKNOWLEDGMENT
hyperbilirubinemia may have contributed to early de-
This work was supported, in part, by National Institute of
tection and treatment of infants with significant jaundice
Child Health and Human Development grant T32
(hemolytic and nonhemolytic) and, therefore, caused a
HD07094 (to Dr Steiner).
decline in the number of ECT necessary.
The declining rate of ECT has led to speculation that
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READ THIS AND WEEP: CRYING AT WORK GAINS ACCEPTANCE
“Crying at work has long been seen as verboten. But there’s evidence that a
growing number of workers, especially those in their 20s and 30s, see it
differently. Some think it’s old-fashioned to hide our emotions. Others are
quick to cry over negative feedback. And many find themselves at odds with
managers who grew up with a more repressive definition of professional
conduct. . . . Savvy bosses also avoid jumping to the conclusion that tears
signal weakness. In a survey of 182 medical students several years ago, Nancy
Angoff, an associate dean at the Yale School of Medicine, found 133 had cried
at least once during clinical training, for reasons ranging from stress or
mistreatment to compassion and empathy for patients. Instructors ‘need to
acknowledge that it is not only OK to cry,’ she wrote, ‘but it is understand-
able, appropriate and sometimes desirable.’”
Shellenbarger S. Wall Street Journal. April 26, 2007
Noted by JFL, MD
32 STEINER et al
Downloaded from www.pediatrics.org by on July 9, 2009
8. A Decline in the Frequency of Neonatal Exchange Transfusions and Its Effect on
Exchange-Related Morbidity and Mortality
Laurie A. Steiner, Matthew J. Bizzarro, Richard A. Ehrenkranz and Patrick G.
Gallagher
Pediatrics 2007;120;27-32
DOI: 10.1542/peds.2006-2910
Updated Information including high-resolution figures, can be found at:
& Services http://www.pediatrics.org/cgi/content/full/120/1/27
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