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KEYWORDS
Hyperviscosity;
Organ blood flow;
Partial exchange
transfusion;
Polycythemia
Summary Neonatal polycythemia and hyperviscosity are defined as a hematocrit 65% and
a viscosity value >2 standard deviations greater than the norm. Although polycythemia can reflect normal fetal adaptation, it has been thought to be responsible for abnormalities in the
neonate. Polycythemia and hyperviscosity are associated with blood-flow changes in some organs, which alter their function. Partial exchange transfusion (PET) has been used to treat both
symptomatic and asymptomatic patients. At present, no data support the use of PET in asymptomatic infants; the potential benefit in symptomatic infants depends on the symptoms. Studies of long-term neurodevelopmental status do not show any clear long-term benefits for PET.
Crystalloids are as effective as colloids in PET and have the advantage of being cheaper and
more readily available; also, they do not confer any risk of infection or anaphylaxis.
2008 Elsevier Ltd. All rights reserved.
Introduction
Polycythemia of the neonate was first mentioned in the Bible
(Genesis 25:25). In the 1970s, there were a number of case
reports and small series of infants with symptoms that were
thought to be secondary to an elevated hematocrit and blood
viscosity.1e3 This was followed by clinical studies of larger
populations of infants, with the emphasis on polycythemia
and cerebral function. In the 1980s, several investigators examined the relationship between polycythemia, hyperviscosity, and organ system dysfunction, which helped delineate
the changes in organ function as a result of increases in hematocrit, viscosity, and arterial oxygen content.
Incidence
The incidence of polycythemia and hyperviscosity at sea
level is 1e2%, whereas at 1600 ft (430 m) it has been shown
to be 5%.4 Infants who experience chronic or acute fetal
hypoxia have a higher incidence. Premature infants less
than 34 weeks gestation rarely have polycythemia or
hyperviscosity.
The measured values for hematocrit and viscosity are
affected by a number of factors. Capillary and peripheral
vein sources with poor flow overestimate the hematocrit.
Samples of blood from a free-flowing or central source will
yield a true value. They are also affected by the timing at
which it is drawn after birth. Finally, the hematocrit is
1744-165X/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2008.02.003
249
Definitions
Polycythemia and hyperviscosity are not synonymous
terms. Both values vary depending on the source of blood
(umbilical vein, peripheral vein, or capillary sample), age
of the infant at the time of measurement and the
methodology of processing the blood.5
Most researchers define neonatal polycythemia as a hematocrit 65% when obtained from a large, freely flowing
peripheral vein. Gross et al. defined hyperviscosity as
a value that was 2 standard deviations greater than the
mean6; Ramamurthy and Brans defined hyperviscosity as 3
standard deviations from the mean for blood obtained
from three different sites (peripheral vein, capillary, and
umbilical vein).5 This coincided with an umbilical venous
hematocrit value of 63%. Ramamurthy and Brans found
that the capillary values were higher than the peripheral
vein values, which were higher than the umbilical vein
values.
Polycythemia occurs as a result of increased red cell
mass, with a decreased, normal, or increased plasma
volume.7 The hematocrit peaks at 4e6 h of life, then drops
slowly over the next 12e18 h and, by 24 h, it has become
similar to the value at birth; thereafter it stays relatively
stable.8 These changes are caused by transudation of fluid
out of the intravascular space.
It is important to understand the physics of the flow of
fluids to understand how blood viscosity affects blood flow
in the newborn infant.9 Viscosity, as defined by Poiseuille,
is the ratio of shear stress to shear rate:
0
p p r p shear stress
Z
hZ
8lQ
shear rate
where h Z is blood viscosity (dynes/s per square centimeter or poise), (p p0 ) Z pressure gradient across the blood
vessel, r Z radius, l Z length of the blood vessel, and
Q Z blood flow.
The shear stress represents the pressure gradient
along the blood vessel expressed in dynes.10 The shear
rate represents the velocity between the two fluid planes
divided by the distance between them, expressed as per
second (s1). In homogeneous, or Newtonian fluids viscosity remains constant even as shear stress and shear rate
change. Blood, being a suspension of particles, does not
behave as a Newtonian fluid. The viscosity of blood
does not remain constant with variations in the shear
stress and shear rate (Fig. 1). The shear rates in large
vessels, such as the aorta, are greater (100e300 s1)
than those observed in the arterioles (11e25 s1). Thus
the viscosity in the aorta would be lower than the
arterioles.
Hematocrit
The hematocrit has a logarithmic relationship with blood
viscosity at different shear rates. The most significant
changes take place at the lowest shear rates and at
hematocrits that exceed 65% (see Fig. 1).
Plasma proteins
Plasma viscosity (1.0e1.5 centipoise (cP)) is similar to that
of water and could be considered a Newtonian fluid under
normal conditions. It does not contribute significantly to
the blood viscosity of the newborn. It may be a problem
in adults with hyperproteinemic states such as Waldenstroms macroglobulinemia.
250
viscosity unless their number significantly exceeds the
normal count, such as in congenital leukemia.
Fibrinogen
Fibrinogen contributes little to blood viscosity as it is
normally low in the newborn.
Platelets
Although the platelets are inflexible, under normal conditions they do not contribute much to blood viscosity. They
can affect blood viscosity in adults with conditions such as
vaso-occlusive disease, as platelet aggregates will increase
blood viscosity in small or narrow vessels.
Blood pH
Blood viscosity increases with acidosis. At a blood pH < 7
fluid enters the RBCs and alters their shape. This phenomenon might play an important role in increasing the viscosity in neonates with birth asphyxia.
Altered hemodynamics
Polycythemia and hyperviscosity are associated with alterations in organ blood flow. In general, there is a decrease in
organ blood flow due to changes in red cell mass, CaO2,
and/or viscosity.
The brain
Polycythemia and blood hyperviscosity were presumed to
cause brain hypoxia and ischemia due to a reduction in the
brain blood flow resulting from sludging of RBC within small
blood vessels. A series of experiments performed between
1980 and 1995 has clarified the changes in brain blood flow,
oxygen delivery, and utilization of glucose. Rosenkrantz
and Oh used Doppler techniques to demonstrate a reduction
of brain blood flow in neonates with polycythemia that
returned to normal after partial exchange transfusion
(PET).18 To understand the factors responsible for the reduction in brain blood flow they performed further experiments using newborn lambs. Data from these studies
revealed that the changes in the brain blood flow resulted
from an increase in the CaO2, a normal physiologic response
that correlated with an increase in the hematocrit.19
Therefore the decrease in cerebral blood flow in the newborn with polycythemia is a physiologic response and does
not cause cerebral ischemia.
251
accompanied by expanded blood volume, as with delayed
clamping of the umbilical cord, then the glomerular filtration
rate and urine output are normal.22 In summary, the renal
function is dependent on both hematocrit and blood volume.
Gastrointestinal tract
Nowicki et al. have demonstrated decreased intestinal
blood flow, oxygen extraction, and uptake in both the
unfed and fed state.23 Human studies have shown an elevated bile concentration in serum and a low lipase and trypsin activity in the duodenum on the first day of life.24
Partial exchange transfusion did normalize the bile and lipase levels but increased the risk of necrotizing enterocolitis (NEC), especially if the fluid used for PET was fresh
frozen plasma (FFP).25
Metabolic
Neonates with polycythemia are at risk for hypoglycemia.
It is unclear if this is due to decreased gluconeogenesis or
increased utilization. Glucose is present in the plasma
fraction of the blood. As many infants with polycythemia
have a reduced plasma volume, the whole blood glucose
concentration might be significantly reduced even when
the plasma concentration is normal. Studies in polycythemic newborn lambs demonstrated that at low to
normal plasma glucose concentration values, cerebral
glucose delivery and uptake was less than normal.26
These experiments also proved that it is the cerebral glucose delivery, not the glucose concentration, that is the
limiting factor in cerebral glucose uptake. Black et al.
found that concurrent hypoglycemia placed polycythemic
infants at the highest risk of poor neurologic function.27
The finding of decreased cerebral glucose delivery and
uptake associated with normoglycemia in the lamb model
leads to the speculation that this might be one reason for
the neurologic sequelae observed in human polycythemic
neonates.
Clinical features
Polycythemia and hyperviscosity can affect multiple organ
systems and the affected neonate can present with a variety
of symptoms. The neonate appears ruddy or reddish
(rubeosis) with sluggish capillary refill and poor peripheral
perfusion. The most common clinical features associated
with polycythemia include lethargy, tachypnea, tremulousness, irritability, jaundice, poor feeding, and vomiting.
Some of these features can be attributed to the associated
metabolic problems such as hypoglycemia (Table 1).28,29
252
Table 1 Frequency of clinical symptoms observed in association with polycythemia and hyperviscosity (from Ref. 29, with
permission)
Clinical symptoms
Gross et al.6
(n Z 18) (%)
Black et al.27
(n Z 111) (%)
Goldberg et al.29
(n Z 20) (%)
Cyanosis
Plethora
Tremulousness/jitteriness
Abnormal EEG
Seizures
Respiratory distress
Cardiomegaly
Lethargy/poor feeding
Hyperbilirubinemia
Abnormal blood smear
Thrombocytopenia
Hypoglycemia
Hypocalcemia
89
83
67
33
28
44
17
Nr
50
50
39
33
6
17
63
13
Nr
0
4
Nr
50
6
Nr
Nr
Nr
Nr
7
Nr
Nr
Nr
0
10
Nr
Nr
Nr
Nr
27
Nr
Nr
Nr
Nr
Nr
Nr
15
85
55
5
Nr
25
40
0
, Greater incidence compared with the control group; EEG, electroencephalogram; Nr, not reported or examined.
Cardiopulmonary
There is no evidence of lasting cardiopulmonary complications from neonatal polycythemia. Cyanosis, tachypnea,
cardiomegaly, pulmonary vascular congestion, pleural effusions, and pulmonary hypertension are due to elevated
pulmonary vascular resistance and increased intrapulmonary shunting secondary to increased blood viscosity.32 Murphy et al. demonstrated elevated right ventricular preejection to right ventricular ejection time ratios in 19
asymptomatic polycythemic infants. They also showed that
the peak rate of left ventricular emptying was lower in
a group of polycythemic infants than in age-matched controls. These infants also had evidence of decreased stroke
volume and cardiac output leading to the clinical manifestations of cyanosis, tachycardia, murmurs, and signs of congestive heart failure.34 Most investigators have reported
complete resolution of respiratory symptoms with PET.
Gastrointestinal
Multiple studies have reported on infants with polycythemia and poor feeding and vomiting35; some suggest an association between neonatal polycythemia and NEC.36 Most of
these infants had other risk factors for NEC, such as intrauterine growth retardation, birth asphyxia, or both. In
a randomized study, Black et al. observed that 6% of the untreated polycythemic infants exhibited gastrointestinal
symptoms, whereas 51% of those who received PET exhibited serious gastrointestinal symptoms, including NEC.
This study suggested that the most important risk factor
for developing NEC is PET, not polycythemia itself. Those
receiving FFP during PET were at highest risk.25 MartinezTallo et al. studied a group of polycythemic term infants
and showed little or no association between polycythemia
and NEC.37 Boehm et al. showed evidence of delayed postnatal development of lipase and trypsin activity and also altered enterohepatic circulation, which might explain the
feeding intolerance observed in these infants.24
Renal
Neonates present with a decreased urine output and reduced
excretion of sodium and potassium.21 In polycythemic infants
with normal blood volume, these renal changes are thought
to be due to decreased plasma volume, renal plasma flow,
and the glomerular filtration rate.22 PET will improve renal
function in these infants. Urine analysis sometimes shows
proteinuria and elevated levels of urinary N-acetyl-b-Dglucosaminidase, which signify renal tubular damage.38
Treatment
Therapy for polycythemia and hyperviscosity is fraught with
controversy. The recommended therapy for symptomatic
infants is hemodilution by PET. Before considering PET the
infant should be evaluated for other causes of the observed
problems. PET has been shown to decrease pulmonary
vascular resistance, increase cerebral blood flow,18 correct
hypoglycemia, and improve renal function. It does not correct neurologic abnormalities in the newborn period or prevent long-term neurologic dysfunction. Complications of
PET are thought to be similar to a single or double volume
exchange transfusion.
The goal of PET is to reduce the infants hematocrit and
viscosity while maintaining circulatory volume. The following formula is used to calculate the volume of blood that
requires to be exchanged:
253
regarding the treatment of neonatal polycythemia with
PET, especially in those without symptoms. The statement reflects the uncertainty regarding this modality of treatment42:
The accepted treatment of polycythemia is PET. However, there is no evidence that exchange transfusion
affects long-term outcome. Universal screening for polycythemia fails to meet the methodology and treatment
criteria and also, possibly the natural criterion.
Despite this ambivalent statement, the standard of care in
many neonatal intensive care units continues to be PET for
symptomatic infants with hematocrits >65% and asymptomatic infants with hematocrits >70%.43
Dempsey and Barrington performed a systematic review
evaluating short- and long-term outcomes following PET in
polycythemic infants.44 Their objective was to determine
whether PET is associated with improved short- and longterm outcomes. The outcome measures included the
following:
The proportion of infants with neurological diagnosis,
developmental delay, and or motor delay at 18 months
or older.
Short-term neurological and behavioral assessment scores.
Short-term resolution of clinical symptoms attributed
to polycythemia.
Adverse effects.
The five randomized, controlled trials that the authors included in their meta-analysis were: Van der Elst et al.,10
Goldberg et al.,30 Ratrisawadi et al.,31 Bada et al.,32 and
Black et al.33 The main results from the meta-analysis suggested that there is no evidence for an improvement in
long-term neurological outcome (mental developmental index, incidence of mental delay, and incidence of neurological diagnoses) after PET in symptomatic or asymptomatic
infants. Also, there was no evidence of improvement in early
neurobehavioral assessment (BNBAS). Partial exchange
transfusion might be associated with an early improvement
in some of the clinical symptoms associated with polycythemia and hyperviscosity but the data were insufficient to derive any conclusions. The incidence of NEC was increased,
but this was more often associated with the use of FFP as
the exchange fluid. The long-term outcome is most likely to
be related to the underlying cause of polycythemia.
Schimmel et al. made the following recommendations
based on the above studies45:
In an asymptomatic polycythemic infant with presumed
normal or increased blood volume: monitoring is
sufficient.
In symptomatic patients with a hematocrit >65%: PET
with normal saline should be used to reduce ongoing tissue damage.
In patients with reduced blood or plasma status, e.g.
IUGR infants: treatment should be with early feeding
or plasma expansion with intravenous fluids.
Consider PET in asymptomatic polycythemic infants
with presumed normal plasma and blood volume only
if repeated measurements reveal a venous hematocrit
>75%.
254
References
1. Wood JL. Plethora in the newborn infant associated with cyanosis and convulsions. J Pediatr 1952;54:143e51.
2. Michael AF, Mauer AM. Maternalefetal transfusion as a cause of
plethora in the neonatal period. Pediatrics 1961;28:458e61.
3. Danks DM, Stevens LH. Neonatal respiratory distress with a high
hematocrit. Lancet 1964;2:499e500.
4. Stevens K, Wirth FH. Incidence of neonatal hyperviscosity at
sea level. J Pediatr 1980;97(1):118e9.
5. Ramamurthy RS, Brans YW. Neonatal polycythemia. I. Criteria
for diagnosis and treatment. Pediatrics 1981;68:168e74.
6. Gross GP, Hathaway WE, McGaughey HR. Hyperviscosity in the
neonate. J Pediatr 1973;82:1004e12.
7. Brans YW, Shannon DL, Ramamurthy RS. Neonatal polycythemia. II. Plasma, blood and red cell volume estimates in relation
to hematocrit levels and quality of intrauterine growth. Pediatrics 1981;68:175.
8. Shohat M, Merlob P, Reisner SH. Neonatal polycythemia. I.
Early diagnosis and incidence relating to time of sampling. Pediatrics 1984;73:7.
9. Linderkamp O, Versomld HT, Riegel KP, et al. Contribution of
red cells and plasma to blood viscosity in preterm and fullterm infants and adults. Pediatrics 1984;74:45.
10. Van der Elst CW, Malan AF, De van Heese H. Blood viscosity in
modern medicine. S Afr Med J 1977;52:526e8.
11. Fahraeus R, Lindqvist T. The viscosity of blood in narrow capillary tubes. Am J Physiol 1931;96:562e8.
12. Hod M, Merlob P, Friedman S. Prevalence of congenital anomalies and neonatal complications in the offspring of diabetic
mothers in Israel. Isr J Med Sci 1991;27:498e502.
13. Oh W, Omari K, Emmanouilides GC, Phelps DI. Placenta to lamb
fetus transfusion in utero during acute hypoxia. Am J Obstet
Gynecol 1975;122:316e21.
14. Philip AGS, Yee AB, Rosy M, et al. Placental transfusion as an
intrauterine phenomenon in deliveries complicated by fetal
distress. BMJ 1969;2:11e3.
15. Saigal S, Usher R. Symptomatic neonatal plethora. Biol Neonate 1977;32:62e72.
16. Mercer JS. Current best evidence: a review of literature on umbilical cord clamping. J Midwifery Womens Health 2001;46(6):
402e14.
17. Linderkamp O, Nelle M, Kraus M, Zilow EP. The effects of early
and late cord-clamping on blood viscosity and other hematological parameters in full-term neonates. Acta Paediatr 1992;
81:745e50.
18. Rosenkrantz TS, Oh W. Cerebral blood flow velocity in infants
with polycythemia and hyperviscosity: effects of partial exchange transfusion with plasmanate. J Pediatr 1982;101:94e8.
19. Rosenkrantz TS, Stonestreet BS, Hansen NB. Cerebral blood
flow in the newborn lamb with polycythemia and hyperviscosity. J Pediatr 1984;104:276e80.
20. Fouron JC, Hebert F. The circulatory effects of hematocrit variations in normovolemic newborn lambs. J Pediatr 1973;82:
995e1003.
21. Kotagal VR, Kleinman LI. Effect of acute polycythemia on newborn renal hemodynamics and function. Pediatr Res 1982;16:
148e51.
22. Oh W, Oh MA, Lind J. Renal function and blood volume in newborn infants related to placental transfusion. Acta Paediatr
Scand 1966;56:197e210.
23. Nowicki P, Oh W, Yao A, et al. Effect of polycythemia on gastrointestinal flow and oxygenation in piglets. Am J Physiol 1984;
247(Gastrointest. Liver Physiol. 10):G220e5.
24. Boehm G, Delitzsch AK, Senger H, et al. Postnatal development
of liver and exocrine pancreas in polycythemic newborn infants. J Pediatr Gastroenterol Nutr 1992;15:310e4.
Summary
Polycythemia and hyperviscosity are common in the newborn. Some of the clinical findings in such infants are
attributable to the increased hematocrit and blood viscosity, and PET might improve these problems. However, PET
does not appear to prevent or reverse neurologic abnormalities found in this population.
Practice points
Diagnosis of polycythemia is affected by sampling
site, timing, and the technique used for analysis.
Polycythemia, hyperviscosity, and their associated
complications are the end results of acute or
chronic intrauterine hypoxia.
PET is the recommended treatment for symptomatic infants.
There are no clear, long-term neurological benefits from PET.
Crystalloids are as effective as colloids and have
the advantages of being cheaper, easily available,
and not conferring risk of infections or
anaphylaxis.
Research agenda
To decide which infants should be treated.
To determine optimal treatment.
To search for interventions to improve short- and
long-term outcomes.
255
39. Creswell JS, Warburton D, Susa JB, et al. Hyperviscosity in the
newborn lambs produces perturbation in glucose homeostasis.
Pediatrics 1981;15:1348e50.
40. Saggese G, Bertelloni S, Baroncelli GI, et al. Elevated calcitonin gene related peptide in polycythemic newborn infants.
Acta Pediatr 1992;81:966e8.
41. Alkalay A, Pomerance JJ, Prause J, et al. Cholecalciferol metabolites in polycythemic newborns. Isr J Med Sci 1985;21:
95e7.
42. American Academy of Pediatrics Committee on Fetus and Newborn. Routine evaluation of blood pressure, hematocrit and
glucose in newborns. Pediatrics 1993;92:474e6.
43. Acunas B, Celtik C, Vatansever U, et al. Thrombocytopenia: an
important indicator for the application of partial exchange in
polycythemic newborn infants? Pediatr Int 2000;42:343e403.
44. Dempsey EM, Barrington K. Short and long term outcomes following partial exchange transfusion in the polycythemic newborn: a systematic review. Arch Dis Child Fetal Neonatal Ed
2006;91(1):F2e6. Epub 2005, Sept. 20.
45. Schimmel MS, Bromiker R, Soll RF. Neonatal polycythemia: is
partial exchange transfusion justified? Clin Perinatol 2004;
31:545e53.
46. De Waal KA, Baerts W, Offringa M. Systematic review of the optimal fluid for dilutional exchange transfusion in neonatal polycythemia. Arch Dis Child Fetal Neonatal Ed 2006;91:7e10.
47. Dempsey EM, Barrington K. Crystalloid or colloid for partial exchange transfusion in neonatal polycythemia: a systematic review and meta-analysis. Acta Paediatr 2005;94(11):1650e5.
48. Deorari AK, Paul VK, Shreshta L, Singh M. Symptomatic neonatal polycythemia: comparison of partial exchange transfusion
with saline versus plasma. Indian Pediatr 1995;32:1167e71.
49. Rothmaier A, Arlettaz R, Bauer K, et al. Randomized controlled
trial of Ringer solution versus serum for partial exchange transfusion in neonatal polycythemia. Eur J Pediatr 1995;154:53e6.
50. Wong W, Fok TF, Lee CH, et al. Randomized controlled trial:
comparison of colloid or crystalloid for partial exchange transfusion for treatment of neonatal polycythemia. Arch Dis Child
Fetal Neonatal Ed 1997;77:F115e8.
51. Krishnan L, Rahim A. Neonatal polycythemia. Indian J Pediatr
1997;64:541e6.