Clin Perinatol 31 (2004) 545 553

Neonatal polycythemia: is partial exchange transfusion justified?

Michael S. Schimmel, MDa,b,*, Ruben Bromiker, MDa,b, Roger F. Soll, MDc
Department of Neonatology, Shaare Zedek Medical Center, Jerusalem 91031, Israel b Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel c Department of Pediatrics, University of Vermont College of Medicine, Burlington, VT, USA
a

Neonatal hyperviscosity has been implicated as a cause of long-term neurologic delay and damage in the growing child [1,2]. As such, neonatologists have developed treatment protocols in the hope of minimizing this central nervous system (CNS) morbidity. In clinical practice, neonatal polycythemia has been used as a marker for neonatal hyperviscosity, and clinicians have focused on the newborn infants hematocrit (Hct) level as the criterion for therapeutic intervention. Partial exchange transfusion (PET) is traditionally used as the method to lower the Hct and treat hyperviscosity; however, it is unclear whether this is an effective approach in preventing the long-term neurologic consequences. This article re-evaluates this clinical approach to the diagnosis and treatment of neonatal polycythemia and suggests that this controversial therapy needs re-evaluation.

Viscosity and flow Poiseuilles equation provides a useful model to explain the physical properties that influence blood flow. The equation can be used to extrapolate the impact of polycythemia on tissue blood flow. Poiseuilles equation relates flow (F), difference in pressure (DP), the radius of the tube (r), viscosity (g), and the length of the tube (L) as follows: (F a DP.r4 / g.L). Nevertheless, one must remember that the equation was formulated for long straight tubes, a newtonian fluid (eg, water), and a steady laminar flow.

* Corresponding author. Department of Neonatology, Shaare Zedek Medical Center, Jerusalem 91031, Israel. E-mail address: schimmel@szmc.org.il (M.S. Schimmel). 0095-5108/04/$ see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2004.04.020

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Many factors may contribute to increased blood viscosity. Whole blood viscosity is influenced primarily by three factors: red blood cell number, plasma proteins, and erythrocyte deformity [3,4], with the number of red blood cells the major variable. In addition, blood flow is affected not only by the radius of the vessels but also by the endothelial characteristics, blood pressure, and end capillary pressure. In infants with hyperviscosity, increased internal friction of blood results in increased resistance to blood flow. Decreased blood flow rates, particularly in the microcirculation of vital organs, lead to decreased oxygen delivery and a symptom complex that includes abnormalities of CNS function, hypoglycemia, decreased renal function, cardiorespiratory distress including cyanosis, and coagulation disorders. Most importantly, hyperviscosity has been reported to be associated with long-term motor and cognitive neurodevelopmental disorders [1,2].

Measurement of viscosity The gold standard for the measurement of viscosity is a whole blood viscometer that can accurately measure the viscosity of blood at the low shear rates that occur naturally in the capillary circulation. Unfortunately, whole blood viscometers are not universally available in the clinical setting. Because the erythrocyte number is the most important factor affecting viscosity, measurement of the neonatal Hct has been suggested as the best clinical screening test for identifying infants with presumed hyperviscosity [4]. Traditionally, polycythemia has been defined as a venous Hct over 65%. This cutoff has been chosen based on the observation that blood viscosity exponentially increases above a Hct of 65% (Fig. 1) [5]. Nevertheless, it is unclear whether this is an appropriate clinical threshold, and whether it should be used as a justification for instituting treatment. Gross et al measured whole blood viscosity in 102 normal and 18 symptomatic infants [4]. All of the symptomatic infants had hyperviscosity, and the Hct of these infants ranged from 63% to 77%. In contrast, Drew et al reported that only 47% of infants with a Hct over 65% had hyperviscosity, and 23% of the hyperviscous infants were polycythemic [2]. These findings emphasize the fact that factors other than the erythrocyte number determine the degree of blood viscosity and demonstrate the problematic nature of deciding on therapy based on red blood cell count alone.

Polycythemia The reported incidence of neonatal polycythemia in term newborns ranges from 0.4% to 12% [6 8]. This wide variation may result from different screening techniques, different sampling sites (capillary versus peripheral or central venous), varied patient populations, the mode of delivery and methodology of

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Viscosity at 37C
80 70 60 50 40 30 20 10 0 30 40 50 60 70 80 90 100

Hematocrit
Fig. 1. Relationship of blood viscosity and Hct. (Modified from Nelson NM. Respiration and circulation before birth. In: Smith CA, Nelson NM, editors. Physiology of the newborn infant. 4th edition. Springfield (IL): Charles C. Thomas; 1976. p. 17; with permission.)

measuring (Coulter counter or centrifuged capillary blood), and the sampling time. The sampling time is the most important source of this variation. Shohat et al demonstrated that the Hct normally rises after birth, reaching a peak 2 hours postpartum and then slowly decreasing over the next 12 hours [8]. At 2 hours of life, the upper limit (2 standard deviations [SD]) of a normal capillary Hct was 71%. Simply defining polycythemia as a hematocrit over 65% may not be justified statistically. The causes of hyperviscosity or polycythemia in the neonate are varied. The entity called polycythemia can be subdivided based on underlying etiology: Increased red cell mass and plasma volume secondary to blood transfusion (delay cord clamping, twin-to-twin, or maternofetal transfusion) or maternal diabetes Increased red cell mass and normal plasma volume associated with a congenital syndrome (eg, trisomy 13, 18, 21) Increased red cell mass associated with normal or decreased plasma volume secondary to intrauterine growth retardation, placental insufficiency, maternal hypertension, or smoking [9]

Treatment of polycythemia Currently, hemodilution by PET is the recommended therapy for the polycythemic infant. PET has been shown to reduce pulmonary vascular resistance

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[10] and increase cerebral blood flow velocity [11,12]. Bada et al [13] have documented that PET normalizes cerebral hemodynamics and improves the clinical status of infants with polycythemia. PET is a relatively simple procedure but has numerous potential complications. Unfortunately, there are no data regarding the incidence of complications of PET; one can only extrapolate from the data on full-exchange transfusions performed for neonatal hyperbilirubinemia. Reported complications for whole blood exchange include infections, cardiac arrhythmia, thrombosis, emboli, vessel perforation, necrotizing enterocolitis, accidental hemorrhage, air embolus, hypothermia, a reduction in blood pressure, and cerebral blood flow fluctuation and even death [14]. Full-exchange transfusion is expected to have a higher incidence of complications than PET, because the amount of blood exchanged is almost nine times higher, and the product used for the exchange is donor blood. Most of these complications can be avoided by performing the procedure carefully while monitoring vital signs and adjusting to a standard protocol; however, the relevance of these data in calculating the magnitude of the risk of performing PET is unclear. The following statement [15] of the Committee of the Fetus and Newborn of the American Academy of Pediatrics regarding the treatment of neonatal polycythemia with PET reflects the concern and uncertainty regarding this mode of treatment,The accepted treatment of polycythemia is partial exchange transfusion (PET). However there is no evidence that exchange transfusion affects the long term outcome. Universal screening for polycythemia fails to meet the methodology and treatment criteria and also, possibly the natural history criterion. Despite this ambivalent statement, the standard practice in many neonatal units continues to be the performance of PET in symptomatic infants with a Hct greater than 65% and in asymptomatic infants with a Hct greater than 70% [16,17].

Review of the literature Given the uncertainty for the justification of continuing with such routine treatment protocols, the discussion herein systematically reviews the existing published literature. The objective of this review is to evaluate the efficacy of PET in preventing neurodevelopmental problems and other associated complications in infants with neonatal polycythemia. Only randomized or quasi randomized trials are reviewed; the subjects are term or near-term infants with neonatal polycythemia (defined as a Hct 65%). Only studies performing PET using crystalloid or colloid solutions are analyzed. Outcome measures that are evaluated are as follows: (1) primary outcomes, that is, the neurodevelopmental status until 2 years of age and neurodevelopmental and cognitive status at school age; and (2) secondary outcomes, that is, neonatal hypoglycemia, thrombocytopenia, hyperbilirubinemia, respiratory distress, infection, necrotizing enterocolitis, seizures, and thrombotic complications (Box 1).

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Box 1. Symptoms associated with neonatal polycythemia Hypoglycemia Thrombocytopenia Hyperbilirubinemia Respiratory distress Cyanosis Necrotizing enterocolitis CNS depression (poor suck or Moro reflex, hypotonia, lethargy) Seizure activity Thrombotic complications (CNS, renal)

A search strategy using PubMed was performed. All articles indexed with the key words polycythemia, hyperviscosity, and partial exchange transfusion and limited to neonates, clinical trials, review articles, and practice guidelines were sought.

Review results A search for the term hyperviscosity yielded 90 articles, whereas a search for the term polycythemia yielded 416 articles. The relevant articles could be categorized as 55 review articles, two practice guidelines, and 11 controlled clinical trials of PET. Careful reading of the articles revealed major differences and inconsistencies in the methodology used by different investigators. Differences were found in the definition of polycythemia, the populations studied, the age that the Hct was drawn, the duration of follow-up, and the definition of sequelae. As a result, it is impossible to provide a meta-analysis of the subject or even a systematic comparative statistical overview of the studies. The following section presents the results from the individual randomized controlled trials that met inclusion criteria. Malan and de V Heese [18] studied 49 term infants in whom the central venous Hct was 65% or above who were hyperviscous. The infants were randomized into two groups receiving either PET or supportive care. In addition, the two groups were compared with 30 nonpolycythemic nonhyperviscous normal infants. At 10 days, the two groups with hyperviscosity were less alert and more irritable than the control normal group. Infants in the PET group had an even poorer behavioral examination score when compared with the infants with hyperviscosity who did not undergo PET. One infant in the PET group had necrotizing enterocolitis. At 8 months, there was no statistical difference in the development scores in the three groups. Goldberg et al [19] observed 20 newborns with a central venous Hct of 64% or greater and a blood viscosity greater than 2 SD above the mean [4]. These infants were matched with 10 normal nonhyperviscous newborns. The hyper-

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viscous newborns were randomized into a PET treatment or no treatment group. At 8 hours of age, both of the hyperviscous groups and the control group underwent the neonatal Brazelton behavior assessment scale (NBAS). The control group had a statistically significant higher NBAS score than both hyperviscous groups. There was no statistically significant difference in the hyperviscous infants who underwent PET when compared with the nontreated groups, although there was a trend toward a higher score in the treated group. The PET-treated group had improved motor maturity and fewer tremors and startles, oriented better to inanimate auditory stimuli, and were more alert and active than infants who did not undergo PET. Nevertheless, at 8 months, the number of hyperviscous infants with an abnormal neurologic examination did not differ in the PET and no treatment groups. These results should be reviewed cautiously because of the groups small size and the 40% loss for follow-up. Black et al [20] studied 93 infants with polycythemia, defined as a venous Hct of 65% or greater, and hyperviscosity, defined as a viscosity measurement more than 2 SD above the mean. The infants were randomized into two groupsthose who underwent PET and those who had supportive care, including therapy for hypoglycemia if needed. These two groups were compared with a control group of 90 infants with a normal Hct and viscosity. At 1 year of age, speech abnormalities and fine-motor abnormalities were significantly more common among the infants in the two hyperviscous groups in a comparison with controls. Motor delays and neurologic diagnoses were more common in the hyperviscous groups but did not reach statistical significance. Most importantly, there was no difference between the PET and the non-PET polycythemic/hyperviscous groups. At 2 years of age, the two groups of infants who had hyperviscosity had a statistically significant increase in motor delays, speech delays, fine-motor abnormalities, and abnormal neurologic findings when compared with the control infants. Infants who underwent PET had fewer neurologic abnormalities and finemotor delays when compared with infants who received only supportive care. A follow-up study of these same infants was performed at 7 years of age [1]. The control group scored higher on tests of arithmetic and spelling skills and had better gross motor function. A comparison of hyperviscous infants who underwent PET with hyperviscous infants who did not undergo PET noted only limited benefits of the treatment, expressed as better left hand performance and higher school grade level. In a small but well-designed study, Bada et al evaluated the effect of PET or supportive care in four groups of infants [13]. Polycythemia was defined as an arterial Hct of 63% or greater and hyperviscosity as an increase in viscosity of 13 centipoises (CPS) or greater at a shear rate of 11.2 seconds-1 [13]. Four groups of infants were compared. Group 1 (n = 17) included hyperviscous symptomatic infants who were assessed to have clinical manifestations consistent with polycythemia/hyperviscosity syndrome. All of these infants underwent PET. Groups 2 and 3 included hyperviscous asymptomatic infants who were randomized to PET (n = 14) or non-PET (n = 14). Group 4 (n = 26) included infants with normal viscosity, of whom 5 had a Hct of 63% to 68% and 21 a Hct less than 63%.

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Multiple regression analysis revealed that viscosity, race, and perinatal risk were correlated to the mental development index and intelligence quotient (IQ). Bada et al emphasized that the clinical improvement seen in the symptomatic hyperviscous patients who had PET was noted in the immediate neonatal period only and did not extend to any long-term outcome. Long-term outcomes did not differ in the infants with symptomatic hyperviscosity and those with asymptomatic hyperviscosity, nor in those treated with PET and those only observed. Ratrisawadi et al [21] examined 47 polycythemic and 21 control infants and performed follow-up at the age of 1.5 to 2 years. The number of infants with an abnormal developmental quotient (DQ) was higher in the group of polycythemic infants when compared with the control group. There was no difference in the developmental test in the symptomatic and asymptomatic patients. In asymptomatic infants, no benefit of partial plasma exchange transfusion on developmental outcome was noted. Black et al [22] noted that polycythemic newborns had a higher rate of meconium staining of the amniotic fluid and lower glucose levels at birth when compared with a matched control group. They raised the possibility that the longterm sequelae seen in some of the polycythemic infants may be caused by a primary intrauterine hypoxemic insult. Hypoxemia followed by a cascade of increased red blood cell production, hyperviscosity, and low cerebral blood flow may amplify the primary intrauterine hypoxic insult; therefore, it would not be surprising that hemodilution postnatally might be of little value.

Discussion A systematic search of the literature for reports of neonatal hyperviscosity and polycythemia revealed few randomized controlled studies. Half of the reviewed studies were not relevant to this discussion, because they compared the use of different solutions in PET rather than the need for and results of PET [16,23 26]. Other studies could not document any consistent results suggesting that PET affected the long-term neurodevelopmental outcome, especially in asymptomatic infants. An explanation for these findings might relate to the observation and reasoning of Black that, in symptomatic infants, the insult to the CNS occurs primarily intrauterine; therefore, PET in the neonatal period is too late to affect the outcome. Conversely, in asymptomatic infants, there is no CNS damage to treat or even to prevent by any postnatal prophylactic therapy. No less important is the difficulty of justifying an invasive procedure such as PET when there is no general agreement on the basic diagnostic criteria for defining the condition that needs to be treated. Drew et al noted that only 23.9% of the patients who had cord hyperviscosity had polycythemia, and only 47.8% of the polycythemic infants had hyperviscosity [2]; therefore, using the Hct as a criterion for presumed hyperviscosity and the need for PET is a dubious assumption at best. The authors concur with Bada [13], Delaney-Black [1], Rothenberg [27], and others who are skeptical that the minor improvement, if any, reported

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in some studies justifies the risk of PET, particularly in otherwise asymptomatic infants. Based on the results discussed herein, the authors believe the polycythemic (Hct >70%) asymptomatic infant should be treated based on the specific etiology and should not undergo routine prophylactic PET. The following recommendations can be made: 1. In an asymptomatic polycythemic infant with presumed normal or increased blood volume status, cardiorespiratory and glucose monitoring are sufficient. 2. In symptomatic infants with a Hct above 65%, a more aggressive therapeutic approach (ie, PET with normal saline) should be used to enhance the blood flow and reduce possible ongoing tissue injury. 3. If the presumption is that the polycythemia is caused by a reduced blood and plasma volume status, such as in an infant with intrauterine growth restriction, the infant should be treated with early feeding or plasma expansion with intravenous saline and dextrose as necessary. 4. Consider PET in asymptomatic polycythemic infants with presumed normal blood and plasma volume only if repeated measurements of the venous hematocrit are over 75%. There is an urgent need for systematic studies comparing the short- and longterm outcome after PET compared with expectant management in polycythemic asymptomatic and symptomatic newborns stratified by postnatal age, red blood cell mass, and blood volume. Ideally, these studies should include measurement of blood viscosity so that objective criteria can be developed for the use of PET in the newborn period. Until these studies are performed, PET should be reserved for the symptomatic polycythemic infant or when venous Hct is over 75%.

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