Anemia of Prematurity

Haresh Kirpalani

Anemia of Prematurity 1. ANEMIA

- Definitions- Clinical burden- Postulated effects

2. STRATEGIES TO REDUCE POST-NATAL TRANSFUSION- Placental Transfusion- Minimizing iatrogenic anemia- Objective guides to transfusion- Erythropoietin- Iron

3. TRIAL DATA ON WHICH LEVELS TO TRANSFUSE AT?- Possible Risks- Minimizing Risks- Randomized Trial Data

Hemoglobin and reticulocytes postnatal year one

Lundstrom1977

Saarnen and Siimes 1978

Cited by:Dallman PR 1981

Fetus and Newborn Committee CPS. Can Med Assoc J 1992;147:1781

Guidelines for transfusion to neonates

Shock or Loss of >10% blood volume within 72 hours

Hgb < 130 g/L (HCT 39%) with cardiorespiratory disease

Hgb < 80 to 100 g/L (HCT 24% - 30%)in neonates with tachypnea, tachycardia, apnea, failure to gain weight

FREQUENCY OF TRANSFUSIONS IN PRETERMS

NO RESPIRATORY SUPPORT

Mean 10 SD 1.6

Mean 8.0 SD 1.3

Mean 12.4 SD 1.4

Mean 10.5 SD 1.5

Fourth Week of life

First Week of Life

Fourth Week of life

First Week of Life

MECHANICAL VENTILATION

X-axis Hemoglobin Trigger

‘y’axis

RESPONSES

Total N= 1017

RBC transfusion critically ill children independently associated with increased mortality. Kneyber MC. Inten Care Med. 2007; 33 :1414

N = 278 PICU childrenSMR based on “Probability of Death” risk adjusted by PIM and TISS scores: From Dutch PICU net

Fetal Hb

OXYGEN CARRYING CAPACITY

Adult Hb O2 Content

66 ml

Fetal Hemoglobin

118 ml

Adult Hemoglobin

Arterial Partial Pressure of Oxygen

Oxygen

Content (ml)

Oxygen

Content (ml)

“2/3 of babies with symptomatic anemiadid NOT have high oxygen extraction by NIROSCOPY”

Wardle SP et al: Pediatr Res. 1998; 44:125-31

Pre Tx Hgb<97 Pre Tx 113-129 g/l Pre Tx Hgb<97

Pre Tx 113-129 g/l

Pre Tx 97-113 g/l Pre Tx 97-113 g/l

CARDIAC FUNCTION AND OUTPUT : “Are we allowing hematocrits to fall too low?” Alkaly A.L. Pediatrics: 2003: 112: 838

<21% >27%22-26%

Left V End Diastolic Diameter

Left V Output Stroke Volume

Left V End Sys Diameter

>100 ml Blood <100 ml BloodGA 28.7 (24.2-31.1) 25.4 (22.9-26.8)Total volume of blood transfused (ml)

201 (173-453) 35 (18-61)

serum iron (micromol/L)

23.0 (17.5-25.8) 13.0 (10.5-14.5)

serum ferritin(picomol/L)

7073 (2866-18524) 488 (299-1259)

and liver iron concentration (mg/g) 3.00 (1.15-5.18) 0.90 (0.50-1.10)

Ng PC, Arch Dis Child Fetal Neonatal Ed. 2001;84:F101-5

BODY IRON LOAD WITH TRANSFUSIONS

BLOOD TRANSFUSIONS may improve oxygen transport cardiac output weight gain apnea BUT may increase Infections - donor related iron stores

Anemia of Prematurity 1. ANEMIA:

- Definitions- Postulated effects

2. STRATEGIES TO REDUCE TRANSFUSIONS:- Placental Transfusion- Minimizing iatrogenic anemia- Objective guides to transfusion- Erythropoietin- Iron

3. THERAPEUTIC BENEFITS OF HIGHER HEMOGLOBINS

- Possible Risks- Minimizing Risks- Randomized Trial Data

“Frequently the child appears to be born dead, when it is feeble and when, before the tying of the cord, a flux of blood occurs into the cord and adjacent parts.

Some nurses who have already acquired skill squeeze (the blood) back out of the cord (into the child’s body) and at once the baby, who had previously been as if drained of blood, comes to life again.”

ARISTOTLE

History of animals (translated by R Cresswell, London.1878)

‘Resuscitate with the placental circulation intact’

David JR Hutchon, Indira Thakur (4 February 2008) Arch Dis Child (F)

Effect of timing of umbilical cord clamping on iron status in Mexican infants: an RCT. Chaparro CM, Lancet. 2006; 367(9527):1997

Infants' blood volume in a controlled trial of placental transfusion at preterm delivery. Aladangady N, Pediatrics. 2006 Jan;117(1):93-8

Infants' blood volume in a controlled trial of placental transfusion at preterm delivery. Aladangady N, Pediatrics. 2006 Jan;117(1):93-8

Blood Volume:

DCC ECC

Mean 74.4 62.7 ml/kg

Range 45-103 47-77

p<0.001

Vaginal delivery:

80.5 61.3

p<0.001

TRANSFUSIONS ANEMIA

RDS

RR 0.87 (0.77,0.99)

WMD 2.01 (1.24, 3.27)

Favors Delayed ClampFavors Early Clamp

Delayed Cord Clamping vs Early Cord Clamping: Rabe H Cochrane 2004

Umbilical cord milking reduces the need for red cell transfusions and improves neonatal adaptation in infants born at less than 29 weeks' gestation: a randomised

controlled trial. Hosono S, Arch Dis Child Fetal-Neonatal Ed. 2008;93:F14-9

Phlebotomy overdraw in the neonatal intensive care nursery.Lin JC, et al: Pediatrics. 2000;106(2) .

Ohlsson A, Aher SM. Early erythropoietin Cochrane 2006, CD004863.

Trials of early erythropoietin to avoid red cell transfusions

RR 0.8 (1.75, 0.86)N 944 881

Favors Epo Favors Control

Total 930 Infants

OUTCOME: RETINOPATHY > STAGE 3

Early Erythropoietin. Ohlsson A, Aher SM. Cochrane 2006

RR 1.71 (1.15, 2.54)

FAVORS EPO FAVORS CONTROL

BENEFITS:Reduced number of donors and transfusions BUT.. small reductions limited clinical importance.

RISKS: increase in ROP (stage >3).

Early EPO not recommended

Ohlsson A, Aher SM. Early Erythropoietin. Cochrane 2006 CONCLUSIONS

Anemia of Prematurity 1. ANEMIA:

DefinitionsPostulated effects

2. PREVENTIVE STRATEGIES:Placental TransfusionMinimizing iatrogenic anemiaObjective guides to transfusionErythropoeitinIron

3. TRIAL DATA OF LEVELS AT WHICH TO TRANSFUSEPossible RisksMinimizing RisksRandomized Trial Data

BLOOD TRANSFUSIONS may improve oxygen transport cardiac output weight gain apnea BUT may increase Infections - donor related iron stores

Transfusion safety: Where are we today?Luban NL. Ann N Y Acad Sci. 2005

Transfusion safety: Where are we today?Luban NL. Ann N Y Acad Sci. 2005

Two RCTs in Modern Era NICU

Primary Outcomes:Iowa : Number of transfusionsPINT: Composite death or Impaired Survival

(Severe ROP; BPD; PVL or Grade 4 or Ventriculomegaly) at 36 weeks;

PINT-Outcome Study Composite NDI at 18-24 m

Secondary Post-Hoc Analyses:Suggest improved outcomes in high hemoglobin Iowa: reduced PVL & Intracranial HemorrhagePINT-OS: improved MDI Bayley II < I SD

Comparison of Trial DesignIowa Trial PINT Trial

Restrictive Liberal Restrictive Liberal

Participating centers 1 10

No. of subjects 100 451

Treatment allocation Randomized Randomized

Stratification Birth weight Birth weight, center

Mean BW (g) 954 958 771 769

Mean GA (wk) 28 28 26 26

Liberal Restrictive

Tracheal IPPV <46% (152 g/L) <34% (112)CPAP or O2 >38% (125) >28% (92)No Support >30% (99) >22% (73)

IOWA ALGORITHM

Separation achieved in IOWA study

PRIMARY OUTCOME IOWA Number Transfusions

5.2 + 4.5

High HbLow Hb

p = 0.025

3.3 + 2.9

TRANSFUSION THRESHOLDS

Yes NoHigh Low High Low

Respiratory support

135 115

120 100

100 85

120 100

100 85

85 75

AgeWeek one

Week two

≥ Week three

PRIMARY OUTCOME PINTDeath, BPD, severe ROP, Brain Injury

165/223 (74%)

159/228 (70%)

High HbLow Hb

OR = 1.3 95% CI 0.8-2.0 p = 0.26

Percent Receiving Transfusion

-20

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40 45 50Days Post-randomization

% Transfused

High Threshold

Low ThresholdP<0.01

Transfused Low High 87% 94%

Donor Exposure

HighLow

3.7 (5.1) 4.2 (7.2) 0.21

p

All Blood Products

Red Cells 2.1 (2.0) 2.6 (2.7) 0.013

Donors n

PINTPINT--Outcome Study (PINTOutcome Study (PINT--OS)OS)PrimaryPrimary Outcome & aOutcome & a--priori componentspriori components

Favors Low Favors High

Composite

0.1 1 10 100

Death

Cerebral Palsy

Cognitive Delay <70

Blindness

Deafness

1.45 (0.94, 2.21)

1.18 (0.72,1.93)

1.32 (0.53, 3.27)

1.74 (0.98, 3.11)

2.16 (0.19, 24.1)

1.45 (0.32, 6.58)

OR

p=0.06

p=0.09

PINTPINT--Outcome Study (PINTOutcome Study (PINT--OS) OS) PostPost--Hoc Secondary Analysis Hoc Secondary Analysis

Favors Low Favors High

Composite

0.1 1 10 100

Death

Cerebral Palsy

Cognitive Delay <85

Blindness

Deafness

OR

1.71 1.12, 2.61

1.18 0.72 , 1.93

1.32 0.53 , 3.27

1.81 1.12,2.93

2.16 0.19 , 24.1

1.45 0.32 , 6.58

p=0.013

p=0.016

Iowa and PINT: Hemoglobin SeparationIowa Trial PINT Trial

Restrictive or Low

Liberal or High

Restrictive or Low

Liberal or High

Transfusion thresholds (hemoglobin, g/dl)

Highest 11.3 15.3 11.5 13.5Lowest 7.3 10.0 7.5 8.5Mean Hgb 8.3 11.0 10.1 11.2

Mean Hgbdifference

2.7 1.1

16th Century dissection

1. Low thresholds of PINT and Iowa studies were comparable

2. It is reasonable to maintain infants above these lower thresholds

3. The high threshold was much higher in Iowa than in PINT

4. The benefit of higher thresholds remains uncertain