Transfusion Medicine - State of the Art
October 26, 2013 1-5 PM
When/how/why should we
transfuse newborn?
Benefits/hazards?
Robert D. Christensen, MD
Disclosure Statement
●Neither I nor any member of
my immediate family has a
financial relationship or interest
(currently or within the past 12
months) with any entity
producing, marketing, re-selling,
or distributing health care goods
or services that I will discuss in
this presentation.
● I do not intend to discuss an unapproved/investigative
use of a commercial product/device.
Bring me
the chart!
RISKS
BENEFITS
1. Managing NICU RBC
transfusions in a
multihospital system: how
are we doing?
Outline
2. What about the association
between early RBC
transfusion and severe IVH?
3. Serum bilirubin levels
before vs. after transfusion:
is hyperbilirubinemia a
transfusion risk for certain
neonates?
?
1. Managing NICU RBC
transfusions in a
multihospital system: how
are we doing?
Outline
2. What about the association
between early RBC
transfusion and severe IVH?
3. Serum bilirubin levels
before vs. after transfusion:
is hyperbilirubinemia a
transfusion risk for certain
neonates?
?
Intermountain Healthcare
Quality Improvement: Transfusions
● 2004 - Transfusion guidelines
● 2007 - Evaluated compliance, audited every NICU
transfusion given in 2006.
● 2008 - Devised methods to improve guidelinecompliance and set a system-wide goal to
increase from 60% to 90%.
● 2010 - Analyzed benefits/risks of the
new program to improve compliance.
● 2011 - Analyzed transfusion practice
one year after new program ceased.
Transfusion Guidelines
Calhoun DA, Christensen RD et al. Consistent Approaches to
Procedures and practices in neonatal hematology Clin Perinatol
2000;27: 733-53.
RBC
●Transfuse if Hct ≤35% if intubated and ≥40% O2
●Transfuse if Hct ≤28% if intubated on <40% O2 or unexplained
lethargy, poor wt gain, tachycardia, apnea.
●Transfuse if Hct ≤20% any neonate
PLATELETS
●Transfuse if PL ≤100,000 and bleeding, pre or post op, ECMO
●Transfuse if PL ≤50,000 if “unstable”
●Transfuse if PL ≤25,000 any neonate
Transfusion Guidelines
Calhoun DA, Christensen RD et al. Consistent Approaches to
Procedures and practices in neonatal hematology Clin Perinatol
2000;27: 733-53.
RBC
●Transfuse if Hct ≤35% if intubated and ≥40% O2
●Transfuse if Hct ≤28% if intubated on <40% O2 or unexplained
lethargy, poor wt gain, tachycardia, apnea.
●Transfuse if Hct ≤20% any neonate
Adopted as NICU Transfusion
Guidelines at Intermountain
PLATELETS
Healthcare
inpre2004
●Transfuse if PL
≤100,000 and bleeding,
or post op, ECMO
●Transfuse if PL ≤50,000 if “unstable”
●Transfuse if PL ≤25,000 any neonate
How well
are we
complying
with our
transfusion
guidelines?
How Well
Do We
Comply
with Our
In 2007, Reviewed every
NICU transfusions given
during 2006
July 2008
Adherence to NICU transfusion
guidelines: data from a
multihospital healthcare system.
Baer VL, Lambert DK, Schmutz N, Henry E, Stoddard RA,
Miner C, Wiedmeier SE, Burnett J, Eggert LD,
Christensen RD
RESULTS:
2008
● Overall 60% of RBC transfusion were
compliant with the guidelines.
● Most violations were RBC transfusions
given “late”.
“...the greatest
exposure to liability
in the practice of
medicine occurs
when physicians fail
to follow their own
rules (practice
guidelines).”
Perry Mason, 1959
2008 – A program
to make it easier
for busy
clinicians to
comply with
the transfusion
guidelines
2009 – Jan 1,
program
instituted in all
NICUs
Transfusion Compliance
Program
1.Electronic physician order entry
for transfusions.
2.Training in all hospitals with a NICU.
3.Guidelines displayed on the screen at the
time transfusion orders are entered.
4.Monthly report cards to each NICU director
and nurse manager of their previous month’s
compliance figures.
5. “Board Goal” to increase compliance to >90%
of all transfusions.
System 2009
Percent of transfusions given within
100%
80%
60%
40%
20%
0%
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Percent of transfusions given
within guidelines.
NICU A - 2009
100%
80%
60%
40%
20%
0%
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Percent of transfusions given
within guidelines.
NICU B- 2009
100%
80%
60%
40%
20%
0%
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Associated with the improved
compliance were the following…
•
•
•
•
Fewer transfusions administered
More neonates receiving no transfusions
Lower blood bank charges
No observed harm (no change in LOS or
mortality rate, and trends toward
improvements in IVH, NEC, ROP, BPD)
Percent of NICU patients
receiving one or more Tx
Percent of NICU admissions that
received one or more transfusions
20
18
16
14
12
10
8
6
4
2
0
2007
PRBC
2008
Platelets
2009
FP
A total of 3923 NICU transfusions
were administered in 2009. This was
down from an average of 4907 during
the two previous years.
 A decrease in RBC transfusions of
554/year.
 A decrease in platelet transfusions of
174/year.
 A decrease in frozen plasma transfusions
of 256/yr.
Effect on Blood Bank Charges
•
•
•
•
RBC: 554 @ $847/transfusion…………..$469,238/year
Platelets: 174 @ $1,398/transfusion…….$243,252/year
Frozen Plasma: 256 @ $264/transfusion…$67,584/year
Reduction in transfusion service charges…
……………...$780,074/year
No evidence that outcomes
were adversely affected.
Primary Children’s Hospital
• Mortality unchanged at 6%
• Length of stay consistent at a median of 8 days.
• Non-significant decrease in BPD, ROP, IVH,NEC.
Perinatal Centers
• Mortality unchanged at 1%
• Length of stay consistent at a median of 9 days.
• Non-significant decrease in BPD, ROP, IVH, NEC.
The system-wide
transfusion compliance
program finished
December 31, 2009.
No further report
cards, monthly
reminders, corporate
emphasis.
Computerized
transfusion order entry
remained.
In the two subsequent
years (2010 and 2011)
the rate of compliance
with guidelines
continued to improve
(99%) and the
transfusion rate
continued to decline,
for each NICU and for
the corporation.
2012
1. Managing NICU RBC
transfusions in a
multihospital system: how
are we doing?
2. What about the association
between early RBC
transfusion and severe IVH?
3. Serum bilirubin levels
before vs. after transfusion:
is hyperbilirubinemia a
transfusion risk for certain
neonates?
?
A robust statistical association between early
RBC transfusion of ELBW neonates and the
development of IVH.
Dos Santos et al. Transfusion 2010 (Brazil)
Baer et al. Transfusion 2011 (USA)
Baer et al. Transfusion 2011 (USA)
Clear:
A robust statistical
association
exists
in
ELBW
In ELBW neonates,
neonates between early RBC transfusion and
early
RBC transfusion
the subsequent
development ofisIVH.
associated with severe IVH
Unclear:
●Why?
Baer et al. Transfusion
2011
●Cause
and
effect?
Baer et al. Transfusion 2011
Dos Santos et al. Transfusion 2010
●Co-morbidities?
Two “new” ways to eliminate or
reduce early RBC transfusion:
1. Stripping (milking) umbilical cord blood
of small preterm infants before the cord is
clamped and cut.
2. Drawing baseline NICU blood tests from
fetal blood in the placenta, thus initially
drawing no blood from the neonate.
Why do we typically clamp/cut the
umbilical cord immediately after birth?
Why do we typically clamp/cut the
umbilical cord immediately after birth?
So where does this blood go?
DELAYED CLAMPING
Many obstetricians
& neonatologists
have been
uncomfortable
delaying cord
clamping, in VLBW
deliveries, because
of the desire to
quickly hand-off
the small neonate
to the NICU resuscitation team.
Dec 2012
A more rapid alternative to delayed
cord clamping was proposed in 2008 –
umbilical cord “milking”.
Placental End
CORD MILKING
Dr. Hosono,
Dept. Pediatrics,
Nihon University,
Tokyo, Japan
Baby End
Umbilical cord “milking”
reduces the need for red cell
transfusions in VLBW
neonates. Tokyo, 2008
Studies of Benefits of Cord Milking
@ VLBW Delivery
● More normal blood pressure
● Less vasopressor use
● Fewer early transfusions
● Lower incidence of IVH
Dec 2012
Blood tests upon NICU admission: Blood culture, CBC
with differential count and platelets, state metabolic screen,
other tests (blood type, Coombs, coagulation profile)
Blood tests that can be
drawn from a neonate on
NICU admission
Very low birth weight premature birth
Very low birth weight premature birth
Initial phlebotomy for laboratory tests
Very low birth weight premature birth
Initial phlebotomy for laboratory tests
Transfusion of donor blood
Another way to obtain fetal blood for all of
the NICU admission laboratory tests
Another way to obtain fetal blood for all of
the NICU admission laboratory tests
PROSPECTIVE STUDY: All baseline blood tests obtained
from the umbilical vein in 100 VLBW neonates, matched
with 100 drawn in the standard way (from the neonate).
● Feasible in actual practice (Ogden, Provo, St. George)
● 95% of attempts were successful
● Successfully drawn even at 23 weeks gestation
Higher hemoglobin 24 hrs after birth (2.5±0.4 g/dL, p=0.000)
Fewer RBC transfusions during the first three days (p=0.04).
Fewer RBC transfusion during the first five days (p=0.000).
Fewer RBC transfusions during the first week (p=0.000).
Less use of vasopressors for hypotension (p<0.001)
Lower prevalence of grade 3 and 4 IVH (p=0.05)
2013
After cord milking, an adequate volume of
fetal blood remains in the VLBW placenta
(97% of instances) for all needed blood tests.
COMMITTEE OPINION
The American College of
Obstetricians and Gynecologists
Committee on Obstetric Practice
Dec 2012
December 2012: Delayed Clamping (or
Cord milking)
…50% reduction in RBC transfusion
…50% reduction in IVH.
Unresolved issue: Effect of the placental
transfusion on whole blood viscosity in
VLBW neonates.
Blood Viscosity (THICKNESS)
can be measured in the
laboratory using an instrument
called a “CONE AND PLATE
VISCOMETER”
The fourEvidence:
with the highest viscosity
measurements
vs. the 16 others
Best
@ VLBW
delivery,
cord milking –
● Reduces early RBC transfusion
● Maintains more normal BP
● Reduces odds of IVH
● Does not cause hyperviscosity
Ranked in order
of highest to
lowest peak
viscosity
Patient 1
Peak
Visc
(cP)
Peak
Hct
(%)
Gest
age
(w)
Hypotonic
Plethora
Peak bili
(mg/dL)
Lowest
gluc
(mg/dL)
Lowest
pl count
(109/L)
9.5
55.5
31
No
No
9.8
39
322
Patient 2
7.7
59.7
31
No
No
10.2
45
153
Patient 3
6.9
61.2
30
No
Yes
8.2
51
207
Patient 4
6.5
59.4
31
No
No
6.1
43
212
Four highest
viscosity X±SD
(%)
7.7±1.3
59.0±2.4
31±1
0/4
(0%)
1/4
(25%)
8.6±1.8
44±5
224±71
Patients 5-20
X±SD (%)
5.1±0.7
46.6±5.7
28±3
1/16
(6%)
2/16
(13%)
9.0±2.0
54±19
181±71
P value, highest
three vs.
remaining
0.001
0.001
0.074
1.000
0.508
0.672
0.310
0.297
2013
If the rate of early
RBC transfusions of
VLBW neonates is
brought down, using a
transfusionmanagement program,
what will happen to the
incidence of IVH?
Hypothesis: If RBC transfusion is causally-linked
with IVH in some cases, successful efforts to
eliminate (or reduce) early RBC transfusions should
diminish the incidence of IVH.
Hypothesis: If RBC transfusion is causally-linked
with IVH in some cases, successful efforts to
eliminate (or reduce) early RBC transfusions should
diminish the incidence of IVH.
Hypothesis: If RBC transfusion is causally-linked
with IVH in some cases, successful efforts to
eliminate (or reduce) early RBC transfusions should
diminish the incidence of IVH.
Hypothesis: If RBC transfusion is causally-linked
with IVH in some cases, successful efforts to
eliminate (or reduce) early RBC transfusions
should
E=mc2
diminish the incidence of IVH.
Baby Einstein
NICU Transfusion Compliance/Management Program
Percent of VLBW
neonates with a
RBC transfusion
during their first
week (n=2761)
Percent of VLBW
neonates with a
RBC transfusion
during their first
week (n=2761)
As the early RBC transfusion
rate fell in half over this
period, what happened to the
severe IVH rate?
Percent of
VLBW neonates
with a GRADE 3
or 4 IVH
% with a grade
3 or 4 IVH -○-
Percent of
VLBW neonates
with a GRADE 3
or 4 IVH
% with a grade
3 or 4 IVH -○-
As the early RBC transfusion
rate fell in half, the severe IVH
rate, in parallel, fell in half.
Percent of
VLBW neonates
with a GRADE 3
or 4 IVH
% with a RBC
transfusion
in 1st week -●-
% with a grade
3 or 4 IVH -○-
As the early RBC transfusion
rate fell in half, the severe
IVH rate had a parallel fall.
2013
Do we want to
consider doing this
in our hospital?
VLBW Deliveries
● Cord milking
● Drawing no blood
initially from the neonate
What are the
proposed
mechanisms
explaining
transfusionassociated IVH?
Mechanism for TA-IVH?
1. Banked RBC lose elasticity as well as nitric oxide
synthase
2. Stiff transfused RBC get “stuck” temporarily in
capillary beds
3. Lack of pericytes in cerebral capillaries <28 weeks
render the capillaries more likely to rupture during
down-stream occlusion.
Capillaries in the germinal matrix of the VLBW
brain are particularly susceptible to rupture,
because they lack supporting cells (pericytes).
RBC traverse the
smallest capillary beds
one at a time, in line.
RBC traverse the
smallest capillary beds
one at a time, in line.
RBC pass through capillary spaces smaller
than themselves. This can only occur because;
1) RBC deform, 2) RBC release nitric oxide
thereby dilating the capillaries.
Banked RBC (even after a few days) develop
a “storage lesion” that involves; 1) less
deformability and 2) depletion of nitric oxide
synthase.
Transfused RBC (poor deformability and lacking
nitric oxide synthase) can clog capillaries.
Transfused RBC (poor deformability and lacking
nitric oxide synthase) can clog capillaries.
Transfused RBC with
poor deformability
Transfused RBC (poor deformability and lacking
nitric oxide synthase) can clog capillaries.
Transfused RBC with
poor deformability
If transfused RBC clog capillary flow, pressure
can increase upstream leading to capillary rupture.
1. Managing NICU RBC
transfusions in a
multihospital system: how
are we doing?
2. What about the association
between early RBC
transfusion and severe IVH?
3. Serum bilirubin levels
before vs. after transfusion:
is hyperbilirubinemia a
transfusion risk for certain
neonates?
?
Are RBC transfusions a risk factor
for hyperbilirubinemia?
● Bilirubin load from hemolysis of effete donor
RBC or cells lysed during the transfusion
process?
● Type specific vs. “universal donor” blood?
● What are the odds that a RBC transfusion
will result in a ≥10 mg/dL increase in TSB?
METHODS and RESULTS
454 RBC transfusions where a TSB was obtained in
the 8 hour period before and also in the 48 hour
period after transfusion.
● Phototherapy on before/during the transfusion – TBS
increased by 1 mg/dL
● No phototherapy on before/during the transfusion – TSB
increased by 3 mg/dL (p<0.0001)
●No phototherapy on before/during the transfusion – 80%
had phototherapy begun within 1 day after the transfusion.
(p<0.0001)
METHODS and RESULTS
● Type specific blood gave a smaller increase in TSB than
did “universal donor” blood (p<0.0001) but the clinical
significance was nil (0.3 mg/dL difference).
● 7% of transfusions were followed by a >5mg/dL rise in
TSB
● 1% of transfusions were followed by a >10 mg/dL rise in
TSB (with no other clear explanation, i.e. Coombs -).
Are RBC transfusions a risk factor
for hyperbilirubinemia?
● Not a major risk factor (3 mg/dL)
● Type specific and “universal donor” blood equivalent in
this regard.
● 7% of transfusions associated with a >5mg/dL rise in TSB,
1% with a >10 mg/dL rise.
● Worth considering this as a risk factor among selected
neonates already at risk for extreme hyperbilirubinemia.
1. Managing NICU RBC
transfusions in a
multihospital system: how
are we doing?
RECAP
2. What about the association
between early RBC
transfusion and severe IVH?
3. Serum bilirubin levels
before vs. after transfusion:
is hyperbilirubinemia a
transfusion risk for certain
neonates?
?
When/how/why should we transfuse newborn?
Benefits/hazards?
Thanks for your
kind attention !
Robert D. Christensen, MD