Seminars in Fetal & Neonatal Medicine (2008) 13, 248e255

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Neonatal and hyperviscosity

Shikha Sarkar, Ted S. Rosenkrantz*

Department of , Division of NeonatalePerinatal Medicine, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA

KEYWORDS Summary Neonatal polycythemia and hyperviscosity are defined as a hematocrit 65% and Hyperviscosity; a viscosity value >2 standard deviations greater than the norm. Although polycythemia can re- Organ blood flow; flect normal fetal adaptation, it has been thought to be responsible for abnormalities in the Partial exchange neonate. Polycythemia and hyperviscosity are associated with blood-flow changes in some or- transfusion; gans, which alter their function. Partial exchange transfusion (PET) has been used to treat both Polycythemia symptomatic and asymptomatic patients. At present, no data support the use of PET in asymp- tomatic infants; the potential benefit in symptomatic infants depends on the symptoms. Stud- ies 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. ª 2008 Elsevier Ltd. All rights reserved.

Introduction The following is a review of the alterations in physiology and organ function in newborn infants with polycythemia Polycythemia of the neonate was first mentioned in the Bible and hyperviscosity, clinical correlations, and recommenda- (Genesis 25:25). In the 1970s, there were a number of case tions about potential therapies for these infants. reports and small series of infants with symptoms that were thought to be secondary to an elevated hematocrit and blood Incidence viscosity.1e3 This was followed by clinical studies of larger populations of infants, with the emphasis on polycythemia The incidence of polycythemia and hyperviscosity at sea and cerebral function. In the 1980s, several investigators ex- level is 1e2%, whereas at 1600 ft (430 m) it has been shown amined the relationship between polycythemia, hyperviscos- to be 5%.4 Infants who experience chronic or acute fetal ity, and organ system dysfunction, which helped delineate have a higher incidence. Premature infants less the changes in organ function as a result of increases in he- than 34 weeks’ gestation rarely have polycythemia or matocrit, viscosity, and arterial content. 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. * Corresponding author. Tel.: þ18606793105;fax:þ1 860 679 Samples of blood from a free-flowing or central source will 1403. yield a true value. They are also affected by the timing at E-mail address: [email protected] (T.S. Rosenkrantz). which it is drawn after birth. Finally, the hematocrit is

1744-165X/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2008.02.003 Neonatal polycythemia and hyperviscosity 249 affected by the technique used for analysis, spun is higher but more accurate than automated.

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 he- matocrit 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 Figure 1 The shaded area represents the viscosity of cord vein values, which were higher than the umbilical vein blood, at shear rates from 2 to 212 s1, for 102 healthy, full- values. term AGA infants (mean 2 standard deviations). Viscosity Polycythemia occurs as a result of increased red cell for 18 ‘symptomatic’ infants is plotted at shear rates of mass, with a decreased, normal, or increased plasma 11 s1 and 106 s1. Hematocrit (Hct) values for each group 7 e volume. The hematocrit peaks at 4 6 h of life, then drops are indicated. Note that the viscosity values increase with e slowly over the next 12 18 h and, by 24 h, it has become higher hematocrit values and with lower shear rates (from similar to the value at birth; thereafter it stays relatively Ref. 6, with permission). 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 Hematocrit in the newborn infant.9 Viscosity, as defined by Poiseuille, is the ratio of shear stress to shear rate: The hematocrit has a logarithmic relationship with blood viscosity at different shear rates. The most significant ðp p0Þr 4p shear stress hZ Z changes take place at the lowest shear rates and at 8lQ shear rate hematocrits that exceed 65% (see Fig. 1). where h Z is blood viscosity (dynes/s per square centime- ter or poise), (p p0) Z pressure gradient across the blood Plasma proteins vessel, r Z radius, l Z length of the blood vessel, and Q Z blood flow. Plasma viscosity (1.0e1.5 centipoise (cP)) is similar to that The shear stress represents the pressure gradient of water and could be considered a Newtonian fluid under along the blood vessel expressed in dynes.10 The shear normal conditions. It does not contribute significantly to rate represents the velocity between the two fluid planes the blood viscosity of the newborn. It may be a problem divided by the distance between them, expressed as per in adults with hyperproteinemic states such as Walden- second (s1). In homogeneous, or Newtonian fluids viscos- strom’s macroglobulinemia. ity remains constant even as shear stress and shear rate change. Blood, being a suspension of particles, does not Red blood cell deformability behave as a Newtonian fluid. The viscosity of blood does not remain constant with variations in the shear RBCs contribute significantly to blood viscosity, both be- stress and shear rate (Fig. 1). The shear rates in large cause they are the most prominent particle suspended in 1 vessels, such as the aorta, are greater (100e300 s ) the blood and because of their intrinsic properties. RBCs 1 than those observed in the arterioles (11e25 s ). Thus consist of a membrane surrounding an internal body of the viscosity in the aorta would be lower than the fluid. RBCs in newborns have a greater degree of deform- arterioles. ability than adult RBCs. The viscosity of internal fluid increases with increasing cell age and also decreasing shear Factors that affect blood viscosity rate.

Although a number of factors affect the viscosity of the White blood cells blood, the hematocrit, i.e. the concentration of red blood cells (RBCs), is the primary determinant in the newborn White blood cells (WBCs) are larger than RBCs; they are also infant. less deformable. However, WBCs do not affect blood 250 S. Sarkar, T.S. Rosenkrantz viscosity unless their number significantly exceeds the This phenomenon, referred to as ‘bolus flow’, reflects high normal count, such as in congenital leukemia. hemodynamic efficiency.11 Thus, the hematocrit does not affect blood viscosity at the capillary level (Fig. 2). Fibrinogen Clinical etiologies of polycythemia Fibrinogen contributes little to blood viscosity as it is and hyperviscosity normally low in the newborn.

Platelets Erythropoiesis in the human fetus varies with the arterial oxygen content (CaO2) of the blood delivered to the kidney. Decreased oxygen delivery to the kidney results in increased Although the platelets are inflexible, under normal condi- erythropoietin production and release by the fetal kidney. tions they do not contribute much to blood viscosity. They Circulating erythropoietin stimulates the production of can affect blood viscosity in adults with conditions such as RBCs. The endpoint is sufficient oxygen-carrying capacity vaso-occlusive disease, as platelet aggregates will increase and delivery to keep the fetus well oxygenated. The three blood viscosity in small or narrow vessels. common mechanisms of polycythemia are reviewed below. Blood pH Chronic fetal hypoxia Blood viscosity increases with acidosis. At a blood pH < 7 A host of fetal and intrauterine factors can lead to chronic fluid enters the RBCs and alters their shape. This phenom- fetal hypoxia, and in turn result in increased fetal eryth- enon might play an important role in increasing the viscos- ropoiesis, RBC mass, hematocrit, and blood viscosity. The ity in neonates with birth asphyxia. increase in RBC mass compensates for the low partial pressure of oxygen (P O ) of the fetus resulting in a normal Blood vessel size a 2 CaO2 and tissue oxygenation. -related conditions associated with chronic fetal hypoxia include maternal dia- In large blood vessels like the aorta, the blood flow and the betes, pregnancy-induced hypertension, fetal hyperthy- 1 shear rate (100e300 s ) are high compared with the arteri- roidism, and maternal smoking. 1 oles (11e25 s ). Thus, the viscosity in the aorta is lower Maternal diabetes is associated with an increased risk of than the arterioles. This does not apply to capillaries ranging intrauterine hypoxia. These neonates have a high preva- in diameter from 3 to 5 mm. Fahraeus and Lindqvist showed lence of polycythemia, elevated erythropoietin levels, and that viscosity decreases with decreasing size of capillaries. decreased iron and ferritin levels. Hod et al. showed an increased prevalence of polycythemia in infants of diabetic mothers (13.3%) versus controls (4.9%).12 However, hypoxia and polycythemia can be prevented with good maternal glycemic control. Fetal hyperthyroidism is associated with increase in the fetal metabolic rate and results in chronic hypoxia and polycythemia in the newborn. Maternal smok- ing leads to increased levels of , which crosses the and competes with oxygen for fetal hemoglobin-binding sites.

Acute fetal hypoxia

Perinatal asphyxia and acute fetal hypoxia remain signifi- cant causes of polycythemia. Acute intrauterine hypoxia results in a shift of blood from the placental compartment to the fetus.13 Philip et al. examined placental residual vol- umes and neonatal outcomes.14 Fetal distress and low Ap- gar scores were associated with low residual placental volumes. There is a correlation between duration of hyp- oxia and the volume of blood shifted into the fetal compart- ment. The data also suggest that fetal vasodilatation associated with acute fetal hypoxia is responsible for this shift in blood volume.

Delayed cord clamping and stripping of the

Figure 2 Blood viscosity in small capillaries (from Ref. 11, Stripping the umbilical cord towards the neonate leads to with permission). a significant placental transfusion, polycythemia, increased Neonatal polycythemia and hyperviscosity 251 blood volume, and increased RBC mass, especially if the accompanied by expanded blood volume, as with delayed neonate is being held below the level of the placenta. clamping of the umbilical cord, then the glomerular filtration Saigal and Usher raised the first concern regarding delayed rate and urine output are normal.22 In summary, the renal cord clamping contributing to polycythemia in 1977.15 More function is dependent on both hematocrit and blood volume. recent randomized studies have confirmed higher hema- tocrits in both preterm and term infants with late cord Gastrointestinal tract clamping as opposed to early cord clamping (30 s).16 Linderkamp et al. demonstrated a marked rise in the cord Nowicki et al. have demonstrated decreased intestinal 17 blood viscosity of infants with delayed cord clamping. blood flow, oxygen extraction, and uptake in both the Polycythemia is often seen in BeckwitheWeiderman unfed and fed state.23 Human studies have shown an ele- syndrome and with trisomies 13, 18, and 21. The etiologies vated bile concentration in serum and a low lipase and tryp- are unknown. sin activity in the duodenum on the first day of life.24 Partial exchange transfusion did normalize the bile and li- Altered hemodynamics pase levels but increased the risk of necrotizing enterocoli- tis (NEC), especially if the fluid used for PET was fresh 25 Polycythemia and hyperviscosity are associated with alter- frozen plasma (FFP). ations in organ blood flow. In general, there is a decrease in organ blood flow due to changes in red cell mass, CaO2, Metabolic and/or viscosity. Neonates with polycythemia are at risk for hypoglycemia. The brain 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 Polycythemia and blood hyperviscosity were presumed to have a reduced plasma volume, the whole blood glucose cause brain hypoxia and ischemia due to a reduction in the concentration might be significantly reduced even when brain blood flow resulting from sludging of RBC within small the plasma concentration is normal. Studies in poly- blood vessels. A series of experiments performed between cythemic newborn lambs demonstrated that at low to 1980 and 1995 has clarified the changes in brain blood flow, normal plasma glucose concentration values, cerebral oxygen delivery, and utilization of glucose. Rosenkrantz glucose delivery and uptake was less than normal.26 and Oh used Doppler techniques to demonstrate a reduction These experiments also proved that it is the cerebral glu- of brain blood flow in neonates with polycythemia that cose delivery, not the glucose concentration, that is the returned to normal after partial exchange transfusion limiting factor in cerebral glucose uptake. Black et al. (PET).18 To understand the factors responsible for the re- found that concurrent hypoglycemia placed polycythemic duction in brain blood flow they performed further experi- infants at the highest risk of poor neurologic function.27 ments using newborn lambs. Data from these studies The finding of decreased cerebral glucose delivery and revealed that the changes in the brain blood flow resulted uptake associated with normoglycemia in the lamb model from an increase in the C O , a normal physiologic response a 2 leads to the speculation that this might be one reason for that correlated with an increase in the hematocrit.19 the neurologic sequelae observed in human polycythemic Therefore the decrease in cerebral blood flow in the new- neonates. born with polycythemia is a physiologic response and does not cause cerebral ischemia. Clinical features

Heart and lungs Polycythemia and hyperviscosity can affect multiple organ systems and the affected neonate can present with a variety There is a decrease in cardiac output secondary to an increase of symptoms. The neonate appears ruddy or reddish in the arterial oxygen content. Systemic oxygen transport, (rubeosis) with sluggish capillary refill and poor peripheral delivery, consumption, and blood pressure are normal.20 Pul- perfusion. The most common clinical features associated monary vascular resistance increases and pulmonary blood with polycythemia include lethargy, tachypnea, tremulous- flow decreases. This is thought to be due to changes in blood ness, irritability, jaundice, poor feeding, and vomiting. viscosity. The decreased pulmonary blood flow can cause re- Some of these features can be attributed to the associated spiratory distress and cyanosis. It can be reversed with a re- metabolic problems such as hypoglycemia (Table 1).28,29 duction in the hematocrit and blood viscosity.20 Kidneys Polycythemia and hyperviscosity are associated with both Renal function is compromised. Kotagal and Kleinman used short- and long-term effects on the central nervous system. puppies to demonstrate that polycythemia, associated with Some of the immediate symptoms include lethargy, irrita- a decreased plasma volume, did not change renal blood bility, tremulousness, and e rarely e seizures. Several flow.21 However, the renal plasma flow, the glomerular filtra- studies have looked at the long-term neurologic outcomes. tion rate, urine output, and the urine sodium and potassium A study of 20 infants by Goldberg et al. made no distinction excretion were greatly reduced. If the polycythemia is between symptomatic and asymptomatic infants and 252 S. Sarkar, T.S. Rosenkrantz

Table 1 Frequency of clinical symptoms observed in association with polycythemia and hyperviscosity (from Ref. 29, with permission) Clinical symptoms Gross et al.6 Ramamurthy and Brans5 Black et al.27 Goldberg et al.29 (n Z 18) (%) (n Z 54) (%) (n Z 111) (%) (n Z 20) (%) Cyanosis 89 17 7 Nr Plethora 83 63 Nr Nr Tremulousness/jitteriness 67 13 Nr Nr Abnormal EEG 33 Nr Nr Nr Seizures 28 0 0 Nr Respiratory distress 44 4 10 15 Cardiomegaly 17 Nr Nr 85 Lethargy/poor feeding Nr 50 þ 55 Hyperbilirubinemia 50 6 Nr 5 Abnormal blood smear 50 Nr Nr Nr Thrombocytopenia 39 Nr Nr 25 Hypoglycemia 33 Nr 27 40 Hypocalcemia 6 Nr Nr 0 þ, Greater incidence compared with the control group; EEG, electroencephalogram; Nr, not reported or examined. divided them into three groups: polycythemic infants who Cardiopulmonary were treated with PET, polycythemic infants who were 30 observed, and controls. The Bayley Scales of Infant Devel- There is no evidence of lasting cardiopulmonary complica- opment; MilanieComparetti Postural Reflex Examination; tions from neonatal polycythemia. Cyanosis, tachypnea, and medical, neurological, and physical examinations cardiomegaly, pulmonary vascular congestion, pleural effu- were performed on all three groups. Neurological abnor- sions, and are due to elevated malities were found in all three groups: polycythemia pulmonary vascular resistance and increased intrapulmo- treated (67%), polycythemia observed (50%), and controls nary shunting secondary to increased blood viscosity.32 Mur- (17%). There was also a higher incidence of spastic diplegia phy et al. demonstrated elevated right ventricular pre- 30 in the two polycythemic groups. ejection to right ventricular ejection time ratios in 19 Van der Elst et al. made no distinction between asymptomatic polycythemic infants. They also showed that symptomatic and asymptomatic infants in the 49 infants the peak rate of left ventricular emptying was lower in 10 included in their study. There was no difference between a group of polycythemic infants than in age-matched con- the observed group and the group who underwent PET in trols. These infants also had evidence of decreased stroke the Brazelton neonatal assessment scale (BNBAS) and volume and cardiac output leading to the clinical manifesta- Prechtl scores at 10 days. tions of cyanosis, tachycardia, murmurs, and signs of con- A study by Ratrisawadi et al. of 105 asymptomatic gestive .34 Most investigators have reported infants had 38% follow up at 2 years. An abnormal devel- complete resolution of respiratory symptoms with PET. opmental quotient was defined as less than 100 on the Gasel development test and was present in 11/25 treated with PET and 4/15 in controls.31 Global developmental Gastrointestinal delay at 1.5e2 years was found in infants with polycythemia. Multiple studies have reported on infants with polycythe- Bada et al. studied 28 asymptomatic infants who un- mia and poor feeding and vomiting35; some suggest an asso- derwent PET32; the infants were assessed at 24 months or ciation between neonatal polycythemia and NEC.36 Most of greater. PET did not affect long-term neurodevelopmental these infants had other risk factors for NEC, such as intra- outcome. The researchers used multivariate analysis, which uterine growth retardation, birth asphyxia, or both. In revealed that other perinatal risk factors, such as fetal dis- a randomized study, Black et al. observed that 6% of the un- tress, asphyxia, hypoglycemia, maternal pre-eclampsia, treated polycythemic infants exhibited gastrointestinal and race, were responsible for the long-term neurodevelop- symptoms, whereas 51% of those who received PET ex- mental sequelae in these infants, not the polycythemia. hibited serious gastrointestinal symptoms, including NEC. They concluded that the intrauterine events are the cause This study suggested that the most important risk factor of both polycythemia and the developmental delays. for developing NEC is PET, not polycythemia itself. Those Black et al. investigated a sample size of 93 term receiving FFP during PET were at highest risk.25 Martinez- polycythemic infants, making no distinction between symp- Tallo et al. studied a group of polycythemic term infants tomatic and asymptomatic infants.33 They followed these and showed little or no association between polycythemia infants until 2 years of age and identified a group who and NEC.37 Boehm et al. showed evidence of delayed post- had ‘mental delay’ (this term was not further defined). natal development of lipase and trypsin activity and also al- They found no neurologic benefit in patients who had tered enterohepatic circulation, which might explain the received PET. feeding intolerance observed in these infants.24 Neonatal polycythemia and hyperviscosity 253

Renal regarding the treatment of neonatal polycythemia with PET, especially in those without symptoms. The statement re- 42 Neonates present with a decreased urine output and reduced flects the uncertainty regarding this modality of treatment : 21 excretion of sodium and potassium. In polycythemic infants The accepted treatment of polycythemia is PET. How- with normal blood volume, these renal changes are thought ever, there is no evidence that exchange transfusion to be due to decreased plasma volume, renal plasma flow, 22 affects long-term outcome. Universal screening for poly- and the glomerular filtration rate. PET will improve renal cythemia fails to meet the methodology and treatment function in these infants. Urine analysis sometimes shows criteria and also, possibly the natural criterion. proteinuria and elevated levels of urinary N-acetyl-b-D- glucosaminidase, which signify renal tubular damage.38 Despite this ambivalent statement, the standard of care in many neonatal intensive care units continues to be PET for Endocrine and metabolic symptomatic infants with hematocrits >65% and asymp- tomatic infants with hematocrits >70%.43 The two common metabolic abnormalities encountered in Dempsey and Barrington performed a systematic review evaluating short- and long-term outcomes following PET in these infants are hypoglycemia and hypocalcemia. Hypo- 44 glycemia occurs in 12e40% of infants, after correcting for polycythemic infants. Their objective was to determine factors such as intrauterine growth restriction (IUGR).31 Al- whether PET is associated with improved short- and long- though there has been speculation about the mechanism, term outcomes. The outcome measures included the decreased production versus increased uptake, there is no following: definite consensus.39 Saggese et al. postulated that hypocalcemia was the The proportion of infants with neurological diagnosis, result of increased levels of calcitonin gene-related peptide developmental delay, and or motor delay at 18 months (CGRP).40 In a clinical study of 43 polycythemic infants and or older. 20 controls, CGRP values were significantly elevated in the Short-term neurological and behavioral assessment scores. polycythemic group, both at birth and at 16e36 h after Short-term resolution of clinical symptoms attributed birth. Lower levels of 1,25-cholecalciferol and 24,25-chole- to polycythemia. calciferol were found in polycythemic infants when com- Adverse effects. pared with controls. Alkalay et al. proposed that the hyperviscosity interfered with the ability of the kidneys to The five randomized, controlled trials that the authors in- convert 25-hydroxyvitamin D to its active dihydroxyl 10 41 cluded in their meta-analysis were: Van der Elst et al., metabolites. Goldberg et al.,30 Ratrisawadi et al.,31 Bada et al.,32 and Black et al.33 The main results from the meta-analysis sug- Treatment gested that there is no evidence for an improvement in long-term neurological outcome (mental developmental in- Therapy for polycythemia and hyperviscosity is fraught with dex, incidence of mental delay, and incidence of neurologi- controversy. The recommended therapy for symptomatic cal diagnoses) after PET in symptomatic or asymptomatic infants is hemodilution by PET. Before considering PET the infants. Also, there was no evidence of improvement in early infant should be evaluated for other causes of the observed neurobehavioral assessment (BNBAS). Partial exchange problems. PET has been shown to decrease pulmonary transfusion might be associated with an early improvement vascular resistance, increase cerebral blood flow,18 correct in some of the clinical symptoms associated with polycythe- hypoglycemia, and improve renal function. It does not cor- mia and hyperviscosity but the data were insufficient to de- rect neurologic abnormalities in the newborn period or pre- rive any conclusions. The incidence of NEC was increased, vent long-term neurologic dysfunction. Complications of but this was more often associated with the use of FFP as PET are thought to be similar to a single or double volume the exchange fluid. The long-term outcome is most likely to exchange transfusion. be related to the underlying cause of polycythemia. The goal of PET is to reduce the infant’s hematocrit and Schimmel et al. made the following recommendations viscosity while maintaining circulatory volume. The follow- based on the above studies45: ing formula is used to calculate the volume of blood that requires to be exchanged: In an asymptomatic polycythemic infant with presumed normal or increased blood volume: monitoring is sufficient. PETZcirculating blood volume In symptomatic patients with a hematocrit >65%: PET ðobserved hematocrit desired hematocritÞ with normal saline should be used to reduce ongoing tis- ðobserved hematocritÞ sue damage. In patients with reduced blood or plasma status, e.g. IUGR infants: treatment should be with early feeding Term infant intravascular volume Z 80e90 mL/kg or plasma expansion with intravenous fluids. Desired hematocrit Z 50e55% Consider PET in asymptomatic polycythemic infants with presumed normal plasma and blood volume only The Committee of the Fetus and Newborn of the American if repeated measurements reveal a venous hematocrit Academy of Pediatrics (AAP) issued the following statement >75%. 254 S. Sarkar, T.S. Rosenkrantz

Partial exchange transfusion: Fluid type References

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