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Blood Exchange Transfusion for Infants with Severe Neonatal Hyperbilirubinemia
Blood Exchange Transfusion for Infants with Severe Neonatal Hyperbilirubinemia Srinivas Murki, MD, DM,* and Praveen Kumar, MD, DM† Blood exchange transfusion has become a rare event in most developed countries. As a result, many pediatricians may not have performed or even seen one. However, it remains a frequent emergency rescue procedure for severe neonatal hyperbilirubinemia in many underdeveloped regions of the world. Conventionally, exchange transfusion has been performed via a central umbilical venous catheter by pull-push cycle method and recently peripheral artery/peripheral vein has emerged as an alternative, isovolumetric route. Continuous arterio-venous exchange is possibly more effective though its automation has not been successful. Concerns for procedural and operator related adverse events have been raised in the context of declining indications. A required continued expertise for this life-saving intervention, in the face of rare but critical hyperbilirubinemia and/or unrecognized hemolytic diseases, deserves adaptation of newer technologies to make neonatal exchange transfusion a safer and more effective procedure. Technological innovations and simulation technologies are urgently needed. Semin Perinatol 35:175-184 © 2011 Elsevier Inc. All rights reserved. KEYWORDS acute bilirubin encephalopathy, adverse events, blood exchange transfusion, exchange transfusion, hyperbilirubinemia, infant, jaundice, kernicterus, newborn
B
lood exchange transfusion (BET) was introduced in the late 1940s to decrease the mortality attributable to rhesus hemolytic disease of the newborn and to prevent kernicterus in surviving infants.1 The use of this procedure was subsequently expanded to hyperbilirubinemia, other hemolytic diseases of the newborn, neonatal sepsis, disseminated intravascular coagulation, metabolic disorders (such as aminoaciduria with associated hyperammonemia), severe fluid or electrolyte imbalance, polycythemia, and severe anemia. Intervention for severe neonatal hyperbilirubinemia, especially hemolytic diseases, remains the most frequent indication. The primary goal of the procedure is to remove circulating antibody coated red blood cells and/or products of hemolysis in various immune (eg, rhesus and ABO isoimmunization) or nonimmune hemolytic anemias (eg, glucose 6-phospho dehydrogenase deficiency [G-6-PD deficiency] and other red cell enzyme deficiencies). The corollary benefits include re-
*Consultant Neonatologist, Fernandez Hosp, Hyderabad, India. †Additional Professor, Neonatal Unit, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Address reprint requests to Dr Praveen Kumar, MD, DM, Additional Professor, Neonatal Unit, Dept of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh-160012, India. E-mail: [email protected]
0146-0005/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2011.02.013
duction in excessive unconjugated bilirubin and possibly enhanced bilirubin-albumin binding. The procedure involves incremental removal of the infant’s blood having high bilirubin levels and/or antibody-coated red blood cells and simultaneous replacement with fresh donor blood providing fresh albumin with binding sites for bilirubin. Development and widespread use of Rh-immunoglobulin, improvements in diagnostic prenatal ultrasound, intensive phototherapy, and revised American Academy of Pediatrics (AAP) guidelines for hyperbilirubinemia have resulted in a worldwide decrease in the need for BET during the last 2 to 3 decades.2-4 This has also resulted in decreasingly available expertise for BET in the developed world. Limited technological breakthroughs or simulation technologies have emerged to improve the safety of this life-saving procedure that often needs to be conducted at level II regional centers of the developing world. Among many nations and regions with poorly developed health infrastructure, BET still remains a frequent rescue procedure because of absence of communitybased use of phototherapy, late referrals, suboptimal or ineffective phototherapy devices, delayed recognition of excessive bilirubin levels,5 and higher prevalence of G-6-PD deficiency.6 Currently, the estimated use of exchange transfusion in United States, if an exchange transfusion is performed in any 175
S. Murki and P. Kumar
176 infant with serum total bilirubin (STB) ⬎30 mg/dL (510 mol/L), is at approximately 3/100,000 live births7. In this review article, we share our perspectives based the experiences of a region that performs approximately 150 exchange transfusions annually for both inborn and outborn infants. We also review the current procedural technologies that have not changed significantly during the past 2-3 decades. However, on the basis of the adverse events encountered in an era of decreasing technical skills, technological solutions are needed for a safer and rarer use of neonatal exchange transfusion.
Table 1 Choice of Blood Group for Donor Blood (ABO and Rh typing) Maternal Group
Infant Group
O A or B or AB
O or A or B or AB O or A or B or AB
Rh negative
Rh positive or negative
Donor Glood Group O Baby blood group or O group Rh negative
Choice and Use of Donor Blood
Current Indications for BET For infants ⬎34 weeks’ of gestation, the current AAP guidelines published in 2004 are now the most widely followed in India.8 Originally, Cockington nomograms9 were the most popular birth weight-specific charts for the treatment of hemolytic jaundice in neonates. Current AAP guidelines represent a consensus of the committee that reviewed and updated the previous guideline and is based on a careful review of the evidence, including a comprehensive literature review by the New England Medical Center Evidence-Based Practice Center.10 National Institute for Health and Clinical Excellence of UK commissioned separate guidelines for phototherapy and exchange transfusion in term and preterm infants.11 For preterm and low birth weight infants, the need for exchange is determined by the birth-weight or gestation and sickness as well as a medical judgment of a neonatal expert.12 Because of the increased incidence of intrauterine growth restriction, lower serum albumin levels, greater incidence of birth asphyxia, geographic prevalence of G-6-PD deficiency, and possible risk of acute bilirubin encephalopathy (ABE) at lower serum bilirubin levels,13 some centers in India prefer to follow our institutional recommendation to use the medium and high risk thresholds for intervention illustrated in AAP nomograms for all infants.14 Rh hemolytic disease is often encountered in our practice; for these infants, BET has been recommended soon after birth in the presence of hydrops fetalis (initially only partial exchange may be done to increase hematocrit if baby cannot tolerate double volume BET), in a baby born with pallor, hepato-splenomegaly and positive direct antiglobulin test with history of previous sibs requiring BET, decreasing hematocrit and increasing STB despite intensive phototherapy.
Review of Technical Procedures An exchange transfusion is always done with informed parental consent. A written informed consent is obtained from the parent/s before initiating the procedure of BET. Benefits and risks of the procedure as well as the risks of not doing the procedure in an infant with critical hyperbilirubinemia are explained in simple, understandable verbal and written communication. Indications for the procedure are often urgent in nature and direct communication with parents is vital.
The medical decision to select donor blood type is dependent on the mother and infant’s blood and Rh grouping (Table 1). In case of Rh incompatibility, if the blood is arranged before birth, it should be O Rh negative that has been cross-matched against the mother. If donor blood is being arranged after birth, it should be Rh negative of baby’s ABO group cross-matched against both the infant and mother’s blood sample. For infants with ABO incompatibility, Rh matched O group cross-matched with mother is recommended. For infants with nonhemolytic causes of severe hyperbilirubinemia, the donor blood should be cross matched against both infant and mother to ensure detection of unrecognized minor blood group incompatibilities. In view of a high prevalence of G-6-PD deficiency in our donor population, we are often concerned about both donor and recipient’s G-6-PD status. Our preference is to use as fresh donor blood as is possible. To avoid the risk of neonatal hyperkalemia, we designate “fresh” donor blood that was collected ⬍5 days before the procedure. To ensure an optimal hematocrit for the donor blood, we reconstitute packed red blood cells and fresh frozen plasma in a ratio of 3:1. When BET is planned with O Rh-negative blood, one should ask for O Rh-negative packed red blood cells suspended in AB plasma to minimize the anti-A and anti-B titres. The reconstitution is conducted in the blood bank and ideally performed with a closed system. Saline wash if available can reduce the risk of hyperkalemia and also reduce the antigen load on the red blood cells. The donor blood is also tested for infections, such as hepatitis, cytomegalovirus, human immune deficiency, malaria and others based on regional blood bank procedures. In areas with high prevalence of G-6-PD deficiency, we recommend that the donor blood should undergo screening.15 Ideally, we irradiate the donor blood within 24 hours before transfusion to prevent graft versus host disease.16 Before the procedure, the blood should be warmed to body temperature using either a water bath or by wrapping the container in a warmed towel. Rapid rewarming by placing it under the radiant warmer, massaging between hands or placing under running hot water is to be avoided to minimize preprocedure hemolysis of the donor blood. Infusion warmers are usually not effective because of the high flow rates at which the blood is drawn from the bag.
BET and severe neonatal hyperbilirubinemia
177
Choice of Routes and Techniques for the Exchange
French size 5 or 8 prefilled with saline and attached to a 10-mL syringe is gently inserted into the umbilical vein. The venous catheter is advanced to the desired location as described above. The umbilical venous catheter is connected to 2 three-way stopcocks or 1 four-way stopcock. The 4 channels of connection to the umbilical catheter should, respectively (and in sequence), connect to the umbilical catheter, catheter draining the withdrawn blood, donor blood, and a saline prefilled syringe (Fig. 1). All the connections should be prefilled with saline to exclude an air cavitation reaching the umbilical catheter. The catheter or the connections should never be left open to the atmosphere to prevent any air embolism. The first aliquot of blood drawn from the neonate can be used for laboratory tests. During the procedure, the size of each aliquot should be approximately 5%-8% of infant’s estimated blood volume (smaller aliquots for smaller and sicker infants). In a term infant with a body weight appropriate for gestational age, usually 15- to 20-mL aliquots may be withdrawn or infused at a rate of 5 ml/kg/min. For low-birthweight and preterm infants, it is a general practice to be cautious and withdrawal/infusion should be limited to approximately 5 mL/kg. It is important to note that as the aliquot volume decreases, the proportion of dead space volume would increase making the BET less effective. Thus, aliquot volumes ⬍2 mL are not recommended. The entire procedure should ideally be completed within 60-90 minutes with about 30-35 cycles of completed isovolumetric infusion and withdrawals. Meticulous records for withdrawals and infusions are maintained to avoid net blood loss or overtransfusion. Larger aliquots (⬎8% of blood volume) and rapid transfusions have been associated with altered hemodynamics sometimes compromising the gut circulation.17,18 Air embolism is a major risk; thus, the syringe should be held vertical during infusion and air cavitation should be avoided during withdrawal phase. Infusion of blood with consistent hematocrit requires frequent mixing (gentle shaking or kneading) of the donor blood bag every 5-10 cycles. Use of citrate anticoagulants in donor blood may lead to decrease in the infant’s serum calcium consequent to changes in calcitonin.19,20
BET may be performed with (a) a single catheter in the umbilical vein which reaches inferior vena cava below its junction with right atrium, (b) a catheter each in umbilical vein and umbilical artery, or (c) a substitute catheter placed in either a peripheral artery (usually radial artery) and/or a large sized peripheral vein. Usually a large peripheral or brachial vein is enough. Rarely, one may have to cannulate jugular or femoral vein if the infant is severely dehydrated and peripheral veins are collapsed. Technical Procedures for Use of Umbilical Route Single-Catheter Pull Push Technique. In this “central” technique, BET is usually performed through a catheter passed via the umbilical vein that has been placed in the inferior vena cava below its junction with the right atrium. If one is able to advance the catheter to about 8 cm in preterm and 11 cm in term without resistance, its tip will usually lie in the inferior vena cava. If resistance is encountered, the catheter can be withdrawn to about 3 cm in preterm and 5 cm in term. This will place the tip proximal to the portal sinus and the procedure can be accomplished. Aliquots of donor blood (at 5%-8% of estimated infant blood volume) are exchanged with infant blood till a desired cumulative volume of exchange (2-fold the estimated infant blood volume) is reached. Asepsis, temperature regulation, correct position of the catheter and standard precautions related to blood transfusion must be adhered to (Table 2). The procedure is performed with continuous monitoring of vital signs and by placing the infant on the radiant warmer/flat incubator mattress. Soothing techniques, sucrose solutions, and gentle restraints are often needed to minimize discomfort and to allow a sterile field. Use of anesthesia or sedation is not necessary. Oral feeds are withheld before the procedure and the stomach should be emptied with a gastric tube if an infant has been fed within 2-3 hours previously. Diapers should be used for hygiene. Periumbilical area is cleaned as for a surgical procedure using Betadine or chlorhexidine skin preparation. The operational area should be covered with sterile surgical drapes. A loose purse string should be placed around the base of the cord for hemostasis. An umbilical venous catheter of
Table 2 Complications Because of Donor Blood Donor Blood
Infant Complication
Old blood (high Kⴙ, low platelets) Citrate blood
Hyperkalemia, thrombocytopenia Hypocalcemia and hypomagnesemia
Cold High glucose
Hypothermia Rebound hypoglycemia
G-6-PD deficient
Increased hemolysis, rebound hyperbilirubinemia
Prevention or Treatment Use blood less than 5 days old. Monitor ECG during and after procedure. Watch for signs of bleeding. Consider 1-2 mL kgⴚ1 of calcium gluconate after 50-100 mL of blood exchange in sick infants. Monitor serum calcium 2 h after an exchange. In case of unexplained arrhythmia use 2 ml/kg of 10% calcium gluconate infusion. Prewarm the blood. Check blood glucose 2 h after BET. Initiate early enteral feeds. In endemic areas screen for G-6-PD status of donor blood
BET, blood exchange transfusion; ECG, electrocardiogram; G-6-PD, glucose 6-phospho dehydrogenase.
S. Murki and P. Kumar
178
Figure 1 Schematic diagram for performing a single-catheter pull push BET through the umbilical vein.
However, significant or symptomatic decreases in serum calcium levels are rare; use of calcium infusions may be associated with fluctuation in heart rate, bradycardia, and even cardiac arrest. Thus, routine administration of calcium gluconate during BET is not recommended.21 Calcium may be used in presence of electrocardiogram changes or in small and sick neonates, in a dose of 10% calcium gluconate 1-2 mL/kg after every 50-100-mL blood exchange under continuously electronic cardiac monitoring. During the procedure, the infant should be attached to a vital signs monitor for continuous observation of temperature, heart rate, respiratory rate, oxygen saturations and electrocardiogram. During the procedure, the operator must call out the volume “out” and “in” with each withdrawal and infusion (eg, “ten in—ten out”). A trained individual should maintain a timed running record of each cycle of BET on a structured data sheet. Each infusion, withdrawal and cumulative volumes should be recorded accurately so the volumes infused and withdrawn are verified to be equal. A sample of blood (from the last aliquot) can be preserved for repeat cross match, if repeat BET or simple transfusions are required. After removing the umbilical catheter, homeostasis is achieved by holding the umbilical stump and tying the purse string at the base. Decisions for remedication are generally considered before the procedure. In our practice, we administer vitamin K after procedure in infants with severe Rh isoimmunization because of the severe
liver involvement and coagulation failure.22 If the infant is on antibiotics or anticonvulsants, their dose is often repeated to ensure therapeutic concentrations. However, the amount of drug eliminated by the process of BET is variable ranging from as low as 3% to 32% depending on several factors like the number of doses received prior and dosing interval.23-25 In addition to continued surveillance of vital signs, the infant should be checked for any bleeding from the umbilical stump, rebound hypoglycemia and biochemical/hematological adverse events. If the infant remains stable, enteral feeding may be reinitiated within 2 hours.26 A prior study from our institution supports that routine use of antibiotics post BET is not necessary in our population.27 Double-Catheter Pull Push Technique. In this technique, both umbilical vein and artery are catheterized. Blood is withdrawn from the umbilical artery and simultaneously equal volume is replaced through the umbilical vein. Additional personnel are needed to operate each catheter and monitor their synchronization. Advantages include a timely completion of the procedure and perceived value to achieve an isovolumetric infusion and withdrawal. Technical Procedures for Use of Peripheral Route Umbilical vessels are often not accessible and a peripheral technique may be used. Use of peripheral arteries and veins may reduce the risks of infection, central vessel complica-
BET and severe neonatal hyperbilirubinemia tions, and reduce the time to initiate an emergency procedure. Removal and replacement of blood takes place simultaneously and may thus minimize the hemodynamic changes caused by fluctuations in circulatory volume. Throughout the procedure, only the limbs need to be exposed and restrained; hence, temperature regulation may be easier. Because gastrointestinal complications are unlikely, fasting of the infants before and after the procedure may not be necessary. Unlike the umbilical route, the peripheral route can be used in infants of any age, including those in whom the umbilical cord has fallen and dried up or in whom umbilical vessel cannulation has failed.28,29 Success in carrying out peripheral vessel exchange transfusions depends largely on successful placement and maintenance of the peripheral arterial catheter, which may be technically difficult especially in vigorous term infants. Also, smaller caliber of peripheral catheters may result in their occlusion. Pull Push Via Peripheral Artery and Peripheral Vein. A peripheral artery (radial or posterior tibial) is catheterized using a 24-gauge catheter under aseptic conditions. Before cannulation, modified Allen’s test should be performed to confirm the adequacy of collateral circulation. The artery can be located either by palpation or by transillumination with a fiberoptic light source. The catheter is connected to a syringe and three-way stopcock so that blood can be withdrawn and discarded intermittently. A 22-gauge or 24-gauge catheter is inserted aseptically into a superficial vein of another limb and connected to a three-way stopcock in a similar manner, for the infusion of donor blood. Two different operators carry out withdrawal and replacement of blood simultaneously at a rate of 5-10 mL/min. To prevent occlusion, the arterial catheter may need to be flushed intermittently with measured volumes of heparinized saline. Disadvantages. Fast and irregular rates of withdrawal and infusion in pull-push method could cause volatile disturbances in the hemodynamic state of the newborn. Rapid pushes may elevate systemic and intracranial pressures.30 Rapid withdrawal may lead to local ischemia in the limb and may be associated with pain and discomfort. The catheter has a tendency to become occluded frequently because of the negative suction applied during pull. Continuous Arterio-venous Exchange via Peripheral Artery and Peripheral vein. To overcome the disadvantages of the pull-push method described previously, continuous ateriovenous exchange (CAVE)31 may be used as an option. This technique is an economical alternative to automated mechanical pumps and allows the blood to flow out and in continuously at a more regular rate than the intermittent and irregular flows achieved by pull push. A peripheral vein is cannulated and connected to a syringe pump or pediatric drip set containing donor blood. The volume of fluid is calculated as exchange volume plus the dead space of the tubing plus another 5 mL as a buffer. A 24-gauge cannula is inserted in the radial artery of the opposite limb after modified Allen’s test. The arterial cannula is attached to standard intravenous tubing set, which has been cut exactly into half and flushed
179 with heparinized saline. Blood is allowed to let out through the arterial line and the time required to a prefixed volume (4.0 mL) of the half cut intravenous tubing is noted. From this, the rate of blood coming out per minute is calculated and the rate of intravenous infusion adjusted to the same. The volumes coming out and going in are continuously monitored along with the vitals. Continuous monitoring is required to match the volume infused to the volume exchanged.
Technologies to Automate BET Several methods for automated BET using a peristaltic pump or a micropump were attempted but did not become popular because of technical difficulties.32,33 Goldman and Tu34 and Funato et al35 successfully automated the BET process by simultaneous withdrawal and replacement using 2 volumetric infusion pumps, one withdrawing infant’s arterial blood, the other replacing equal volumes of donor blood in synchrony. The efficacy of exchange was shown to be superior with the automated method compared with the conventional pull push method35. In addition, because of the continuous regulated flow, automated techniques would offer similar benefits as the CAVE technique mentioned above. Further studies are needed to compare the safety, efficacy, and skill requirements of the newer automated technologies with the traditional methodologies. Currently, no automated system for BET is available commercially.
Assessment of Infant Blood Volume to Design BET A key component to assess the efficacy of an exchange transfusion is to assess the infant’s total circulating blood volume. Traditionally, the estimate for a term newborn’s blood volume has been 80-90 ml/kg. Procedures that use 80-90 ml/kg of donor blood have been termed as singlevolume blood exchange transfusion (SVBET), those that use of 160-180 mL/kg are termed as double-volume blood exchange transfusion (DVBET). On the basis of the time constant of the exchange (conducted in a timely manner), an SVBET is likely to exchange 63% of the infant’s blood whereas DVBET exchanges 86%. However, because of tissue to intravascular dynamics, more bilirubin is removed from the infant than the blood volume exchanged during BET. Forfar et al36 measured the bilirubin mass removed during exchange transfusion and correlated this with the volume of exchange in infants with Rh disease. The bilirubin removed was 45% higher than the fall in serum bilirubin. The bilirubin removed correlated with the volume of exchange during a single volume exchange. An additional 20%-70% of bilirubin removed was noticed with the double volume exchange. An exchange volume of 160-180 mL/kg resulted in a maximal removal of bilirubin. Further increase in exchange volume did remove more bilirubin, but to a much lesser extent.
S. Murki and P. Kumar
180 Table 3 Adverse Events After Blood Exchange Transfusion Author, Type of Study, Year of Publication Odel,49
No and Type of Study Population
Weldon and retrospective observational study, Pediatrics 1968 Keenan et al,46 retrospective observational study, Pediatrics 1985
Two hundred thirty-two infants and 351 BETs in: 6 years’ duration
Jackson,47 retrospective observational study, Pediatrics 1997
One-hundred six infants (81 healthy and 25 sick)
Badiee,50 retrospective observational study, Sing Medical Journal 2007
Sixty-eight infants
Steiner et al,2 retrospective observational study, Pediatrics 2007
One-hundred seven infants and 141 BETs
Chacham S et al, personal communication, prospective observational study, 2010
One hundred forty-one infants (80 healthy and 61 sick) underwent 182 BETs
One-hundred ninety infants underwent 331 BETs
The authors of a smaller randomized controlled trial compared SVBET with DVBET in infants with hemolytic jaundice because of ABO incompatibility.37 They noted no significant difference in the short-term outcomes (de-
Adverse Events Mortality was 1 in 148 vigorous infants and in 10 of the 84 sick infants. No difference in mortality between low birth weight and normal birth weight 22 (6.7%) had adverse events related to exchange transfusion. The adverse events were bradycardia (n ⴝ 8), cyanosis (n ⴝ 3), vasopasm (n ⴝ 2), thrombosis (n ⴝ 2) and apnea (n ⴝ 7). The mortality was 0.53 per 100patients or 0.3 per 100 procedures. All the deaths were in critically ill patients 2% died because of BET (both sick) One healthy neonate had severe NEC Three sick infants (12%) had serious complications Fourteen healthy infants (17%) had apnea or bradycardia with cyanosis requiring resuscitation (n ⴝ 5), hypocalcemia associated with electrocardiographic abnormalities, marked jitteriness, or pedal spasm (n ⴝ 3), rectal bleeding (n ⴝ 2), and one each had, surgery for removal of knotted femoral vein catheter guidewire, hypertension and hematuria associated with umbilical artery catheter, transient bacteremia, and petechial rash from thrombocytopenia. Four additional sick infants had rectal bleeding associated with thrombocytopenia from exchange transfusion, bleeding from umbilical stump requiring platelet transfusion, severe apnea and bradycardia with cyanosis requiring resuscitation and jitteriness associated with hypocalcemia One infant died (1.5%) BET-related complications in 14 infants (21%) Complications included thrombocytopenia (n ⴝ 4), hypocalcemia (n ⴝ 2), one each with seizure, NEC, hypoglycemia, bradycardia, hypoxia, limb color change, ALE, suspected DIC. Hypocalcemia and thrombocytopenia in 53 procedures each (38%). 11% had other complications, such as bradycardia (4%), catheter malfunction (3%), seizures (2%), NEC (1%), apnea (1%), and hyperkalemia (1%) 68% of infants had one or more AE resulting in 112 AEs per 100 BETs. Most common adverse events were biochemical (BAE) and hematological (HAE). Most common BAE was asymptomatic hypocalcemia. All AEs were significantly greater among sick neonates when compared with healthy ones. Also the incidence of overall AE was greater among preterm neonates and those with lower birth weights. Incidence of serious adverse events was 12.6 per 100 ET. Death occurred in 6.4% (n ⴝ 9) of the infants who underwent BET. All the neonates who died were sick. None died in the “healthy” group.
crease in bilirubin and anemia at 10 days) between SVBET with DVBET. Immediate postexchange platelet levels were greater in the SVBET group, but hemoglobin levels were greater in the DVBET group. No interventions were re-
BET and severe neonatal hyperbilirubinemia quired to correct this, and at 10 days after exchange, no statistically significant difference was noted. The follow-up of study infants was only for 3 months, and neurodevelopmental outcomes were not studied. Currently, there is insufficient evidence to support any change in the common practice of performing double volume exchange rather than single volume exchange.38
Use of Albumin Fortified Exchange Transfusion Rapid reduction in unbound bilirubin levels may theoretically prevent bilirubin encephalopathy. Bilirubin is bound to albumin as the dianion with a primary binding site that has a capacity of binding of one molecule of bilirubin. A molar ratio of 1.0 indicates that approximately 8.3 mg bilirubin is bound to each 1 g of albumin. From a therapeutic viewpoint, albumin infusion before BET may be advantageous, because an increased reserve of albumin may be protective against bilirubin toxicity by providing more binding sites, thereby reducing the levels of unbound bilirubin. Odell,39 in 1959, verified the hypothesis that vascular bilirubin-albumin binding would cause a shift of bilirubin from the extravascular to intravascular compartment after the administration of albumin. Subsequent studies showed that albumin administration improved the efficiency of exchange transfusion, by up to 40% in the bilirubin removed, though this did not translate to measurements in postexchange serum bilirubin level.40 A recent study showed that if 20% albumin in the dose of 1 g/kg was administered 1 hour before the exchange, the STB levels at 6 and 12 hours after procedure as well as the duration of phototherapy were significantly lower.41 However, the study did not measure the amount of bilirubin removed. Because the STB does not correlate well with the total body bilirubin and the improvement noted with albumin administration has not been deemed to be too beneficial compared with the potential risks of albumin infusion, its routine clinical use is still not justified.42
Concomitant Use of Intravenous Immunoglobulins Intravenous immunoglobulin (IVIG) has been used sporadically in the treatment of hemolytic disease to prevent exchange transfusion since the early 1990s. The exact mechanism of action is unknown, but it is thought to inhibit hemolysis by blocking antibody receptors on red blood cells: IVIG occupies the Fc receptor sites thus competing with anti-D sensitized neonatal erythrocytes and preventing further hemolysis. The 2004 AAP guidelines for hyperbilirubinemia, recommend that in isoimmune hemolytic disease, IVIG (0.5-1 g/kg over 2 h) could be administered if the STB is increasing despite intensive phototherapy or the STB level is within 34-51 mol/L (2-3 mg/dL) of the exchange level. If necessary, this dose can be
181 repeated in 12 hours. The authors of a Cochrane review suggest a statistically significant reduction in the need for exchange transfusion using IVIG.43 However, in patients with ABO hemolytic disease, there was no significant difference between the use of IVIG and intensive blue light phototherapy.44 The current evidence supports IVIG as a relatively safe and effective means of reducing the need for exchange transfusion in hemolytic diseases,43 although concerns about side effects need to be weighed against those for an exchange transfusion.
Technologies to Ascertain Adverse Events Adverse events may be related to the severity of illness, the procedure, the catheter placements, the blood product, or the operator. Mortality rates attributable to exchange transfusion ranged from 0.65% to 3.2% in studies performed in the 1960s and from 0.4% to 3.2% during the 1970s and 1980s. The causes of death ascribed to exchange transfusion included cardiovascular collapse during the transfusion and the subsequent complications of necrotizing enterocolitis, bacterial sepsis, and pulmonary hemorrhage. The most frequently cited review of adverse events from exchange transfusion is from the 1974-1976 prospective National Institute of Child Health and Human Development phototherapy study.45 Keenan et al46 reported that 190 infants underwent 331 exchange transfusions. Adverse clinical problems were observed in 6.7% of the exchange transfusions, and the observed rate of serious morbidity was 5.2%. On the basis of 1 death attributed to the procedure, they calculated mortality rate to be 0.53 per 100 patients and 0.3 per 100 procedures. Only 2 of the 14 serious adverse events occurred in infants defined as being in good condition at the initiation of the exchange transfusion (Table 3). In a publication by Jackson et al,47 the incidence of mortality or serious permanent sequelae was ⬍1% in healthy neonates whereas the incidence of procedure-related complications leading to death was 8% and the rate of severe complications (death or permanent serious sequelae) was 12% in ill infants. The other common morbidities included symptomatic hypocalcemia, bleeding associated with thrombocytopenia, catheter-related complications, apnea and bradycardia with cyanosis requiring resuscitation. Five percent of healthy infants in this study developed symptomatic hypocalcemia. Nearly 10% of healthy infants had platelet counts ⬍50,000/L. In addition to the complications reported in the study by Jackson et al other reported complications are hypothermia, hyperkalemia, acidosis and hypoglycemia. Steiner et al2 reported that 38% of neonates who received BET developed hypocalcemia. Some studies have reported that BET via the peripheral arteries for withdrawal and peripheral vein for infusion of blood is associated with fewer complications. In a study from Taiwan,48 123 exchange-transfusion procedures were performed in 102 neonates in a 12-year
S. Murki and P. Kumar
182 Table 4 AE Rates Among “Healthy” Neonates Undergoing BET
Birth wt in g
n
<1000 1000-1499 1500-1999 2000-2500 >2500 Total
6 5 12 24 33 80
No of AEs per No Neonates with AEs Total No 100 of (%) of AEs BETs BETs 8 6 15 29 38 96
6 (100) 4 (80) 6 (50) 15 (62.5) 17 (51.5) 48 (60)
15 7 9 30 28 89
188 117 60 103 74 92.7
P ⴝ .013, 2 test for Trends was used for comparison among the 5 groups (Chacham et al, personal communication).
study period: 24 were performed via the umbilical vein method and 99 via the peripheral vessels method. A total of 87 procedures were performed in 75 stable neonates and 36 in 27 unstable neonates. Eight neonates died before discharge, but none of the deaths was attributable to the exchange transfusion procedure. Severe adverse events occurred more commonly in the umbilical vein group than the peripheral artery/vein group in the stable neonates. Most of the studies reporting adverse events after BET are retrospective in nature, have defined adverse events varyingly, and scrutinized the records for a varying length of time after BET.49,50 A prospective study from India involving 182 BETs in 141 neonates reported 112 adverse events per 100 BETs. All neonates undergoing BET in this study were investigated for clinical, biochemical, hematological and intracranial adverse events and followed up for 2 weeks. The definitions used were more liberal compared with previous studies. Hypocalcemia was defined as ionized calcium ⬍1 mol/L or decrease of ⬎0.3 mol/L fall from the pre-BET value. Similarly, thrombocytopenia was defined as a platelet count ⬍ 100,000/cu.mm or a decrease of ⬎2% from pre-BET value. The most common events were biochemical closely followed by hematological adverse events. All events were significantly higher among sick neonates when compared with healthy ones and increased with decreasing birth weights (Table 4; Chacham S, Kumar P, Dutta S, personal communication). We report a checklist (Table 5) that is based on our current practice to minimize adverse events and promote a multidisciplinary team approach.
rangements are made for BET (see algorithm in Fig. 2). Because of delayed referrals, infants are likely to be dehydrated and correction with intravenous fluid supplementation is often necessary. In a randomized controlled trial from northern India, it was shown that 73% of term neonates presenting to the emergency with severe hyperbilirubinemia had high serum osmolality, without the usual overt clinical signs of dehydration. In this study, use of intravenous fluids over the first 8 hours of admission decreased the need for an exchange transfusion by 70% without any long-term adverse effects.51 In summary, although the use of an exchange transfusion has become less frequent in the developing nations, it still remains the only rescue therapy to prevent neonatal brain injury in infants who have limited access to optimal primary care at birthing. In the absence of evidence-based studies from these “front-lines” of primary care, the technologies to perform safe and successful exchange transfusions have often remained antiquated. In our opinion and experience, emphasis for prevention of severe neonatal hyperbilirubinemia at Table 5 Checklist Before the Initiation of Neonatal Exchange Transfusion* Steps 1 2 3 4 5 6 7
8
9
10
Crash Cart Approach to Manage Acute Bilirubin Encephalopathy or Critical Hyperbilirubinemia A neonate presenting with severe jaundice should be urgently evaluated for signs of ABE and severity of hyperbilirubinemia should be immediately verified by transcutaneous bilirubinometry and/or STB. Those with ABE or bilirubin levels near thresholds for an exchange zone should be immediately (crash-cart approach) started on intensive phototherapy to the maximum possible body surface area while ar-
11 12
Procedures in a Neonatal Intensive Care Unit Identify patient, consent and indication for the procedure Verify continuous monitoring of vital signs Use nasogastric tube for gastric decompression Confirm placement and security of exchange catheter(s) Verify donor blood identification, blood type, collection date and hematocrit estimation Use safe warming and intermittent “mixing” techniques Determine and decide aliquot for each phase of cycle (⬃5 mL/kg/infused and equal amount withdrawn). Determine exchange rate: total cycle duration in ⬃3 min, both infusion plus withdrawal (about 30-35 cycles) Assign individual to document events and vital signs, monitor synchronization/cycle and verify iso-volumetric completion of a cycle. Continue phototherapy during and after procedure Consider remedications, as needed Send last aliquot blood sample for: biochemistry, hematology and blood bank (repeat cross-matching).
*At least 3 individuals at the bedside are required to conduct the procedure: (i) credentialed and experienced clinician to operate exchange cycles (a standby assistant may be needed); (ii) a second clinician/nurse to monitor and handle the infant as well as administer medications. This individual must have direct and immediate access to an alerted neonatal resuscitation team; (iii) a third individual with clinical background to accurately record, monitor, verify and document events.
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Figure 2 Algorithm for crash-cart management of neonatal jaundice as a pediatric emergency. ABE, acute bilirubin encephalopathy; IVF, intravenous fluids; PT, phototherapy; STB, serum total bilirubin; TcB, transcutaneous bilirubin.
the primary care level to make the exchange transfusion a rare event, needs to be coupled with evidence-based technological advancements to conduct the procedure with expertise, efficiency and safety.
References 1. Diamond LK: Erythroblastosis foetalis or haemolytic disease of the newborn. Proc R Soc Med 40:546, 1947 2. Steiner LA, Bizzaro MJ, Ehrenkranz RA, et al: A decline in the frequency of neonatal exchange transfusions and its effect on exchange related morbidity and mortality. Pediatrics 120:27-32, 2007 3. Stockman JA, De Alacron PA: Overview of the state of the art of Rh disease: History, current clinical management and recent progress. J Pediatr Hematol/Oncol 23:885-893, 2001 4. Dennery PA, Seidman DS, Stevenson DK: Neonatal hyperbilirubinemia. N Engl J Med 344:581-590, 2001 5. Setia S, Villaveces A, Dhillon P, et al: Neonatal jaundice in Asian, white, and mixed-race infants. Arch Pediatr Adolesc Med 156:276-279, 2002 6. Murki S, Dutta S, Narang A, et al: A randomized, triple-blind, placebocontrolled trial of prophylactic oral phenobarbital to reduce the need for phototherapy in G6PD-deficient neonates. J Perinatol 25:325-330, 2005 7. Mah MP, Clark SL, Akhigbe E, et al: Reduction of severe hyperbilirubinemia after institution of predischarge bilirubin screening. Pediatrics 125:e1143-e1148, 2010 8. American Academy of Pediatrics: Subcommittee on hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 114:297-316, 2004
9. Cockington RA: A guide to the use of phototherapy in the management of neonatal hyperbilirubinemia. J Pediatr 95:281-285, 1979 10. Ip S, Chung M, Kulig J, et al: An evidence-based review of important issues concerning neonatal hyperbilirubinemia. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Pediatrics 114:e130e153, 2004 11. Rennie J, Burman-Roy S, Murphy MS, et al: Neonatal jaundice: Summary of NICE guidance. BMJ 340:c2409, 2010 12. Maisels MJ, Watchko JF: Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonat Ed 88:F459-F463, 2003 13. Dhaded SM, Kumar P, Narang A: Safe bilirubin level for term babies with non-hemolytic jaundice. Indian Pediatr 33:1059-1060, 1996 14. Murki S, Kumar P, Majumdar S, et al: Risk factors for kernicterus in term babies with non-hemolytic jaundice. Indian Pediatr 38:757-762, 2001 15. Samanta S, Kumar P, Kishore SS, et al: Donor blood glucose 6-phosphate dehydrogenase deficiency reduces the efficacy of exchange transfusion in neonatal hyperbilirubinemia. Pediatrics 123:e96-e100, 2009 16. Dwyer DM, Holland PV: Transfusion-associated graft-versus-host disease. Vox Sang 95:85-93, 2008 17. Aranda JV, Sweet AY: Alterations in blood pressure during exchange transfusion. Arch Dis Child 52:545-548, 1977 18. Farquhar JW, Smith H: Clinical and biochemical changes during exchange transfusion. Arch Dis Child 33:142-159, 1958 19. Nelson N, Finnström O: Blood exchange transfusions in newborns, the effect on serum ionized calcium. Early Hum Dev 18:157-164, 1988 20. Dincsoy MY, Tsang RC, Laskarzewski P, et al: Serum calcitonin response to administration of calcium in newborn infants during exchange blood transfusion. J Pediatr 100:782-786, 1982
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184 21. Locham KK, Kaur K, Tandon R, et al: Exchange blood transfusion in neonatal hyperbilirubinemia-role of calcium. Indian Pediatr 39:657659, 2002 22. Hey E, Jones P: Coagulation failure in babies with rhesus isoimmunization. Br J Haematol 42:441-454, 1979 23. Yakatan GJ, Smith RB, Leff RD, et al: Pharmacokinetic considerations in exchange transfusion in neonates. Clin Pharmacol Ther 24:90-94, 1978 24. Bertino JS Jr, Kliegman RM, Myers CM, et al: Alterations in gentamicin pharmacokinetics during neonatal exchange transfusion. Dev Pharmacol Ther 4:205-215, 1982 25. Fuquay D, Koup J, Epstein MF, et al: Effect of exchange transfusion on serum gentamicin concentrations. Dev Pharmacol Ther 3:214-221, 1981 26. Cser A: Metabolic and hormonal changes during and after exchange transfusion with heparinized or ACD blood. Arch Dis Child 49:940945, 1974 27. Fok TF, So LY, Leung KW, et al: Use of peripheral vessels for exchange transfusion. Arch Dis Child 65:676-678, 1990 28. Sarkar S, Narang A, Roy P, et al: Bacteremia after exchange transfusion in neonates. Pediatr Infect Dis J 12:777-779, 1993 29. Campbell N, Stewart I: Exchange transfusion in ill newborn infants using peripheral arteries and veins. J Pediatr 94:820-822, 1979 30. Butt WW, Gow R, Whyte H, et al: Complications resulting from use of arterial catheters: retrograde flow and rapid elevation in blood pressure. Pediatrics 76:250-254, 1985 31. Shah R, Kumar P: Continuous Arterio-venous Exchange (CAVE)—A low cost new Technique of Partial Exchange Transfusion, in Proceedings of XXIX Annual Convention of National Neonatology Forum (Neocon2009) at Ahmedabad, India 2009 32. Valentine CH: Exchange-transfusion apparatus. Lancet 2:1466, 1966 33. Philpott MC, Banerjee A: Automated method for exchange transfusion. Arch Dis Child 47:815, 1972 34. Goldman SL, Tu HC: Automated method for exchange transfusion: A new modification. J Pediatr 102:119, 1983 35. Funato M, Shimada S, Tamai H, et al: Automated exchange transfusion and exchange rate. Acta Paediatr Jpn 31:572-577, 1989 36. Forfar JO, Keay AJ, Elliott WD, et al: Exchange transfusion in neonatal hyperbilirubinaemia. Lancet 2:1131-1137, 1958 37. Amato M, Blumberg A, Hermann U Jr: Effectiveness of single versus
38.
39. 40.
41.
42.
43.
44.
45.
46. 47. 48.
49. 50. 51.
double volume exchange transfusion in newborn infants with AB0 hemolytic disease. Helv Paediatr Acta 43:177-186, 1988 Thayyil S, Milligan DW: Single versus double volume exchange transfusion in jaundiced newborn infants. Cochrane Database Syst Rev 4:CD004592, 2006 Odell GB: The dissociation of bilirubin from albumin and its clinical implications. J Pediatr 55:268-279, 1959 Odell GB, Cohen SN, Gordes EH: Administration of albumin in the management of hyperbilirubinemia by exchange transfusions. Pediatrics 30:613-621, 1962 Shahian M, Moslehi MA: Effect of albumin administration prior to exchange transfusion in term neonates with hyperbilirubinemia—a randomized controlled trial. Indian Pediatr 47:241-244, 2010 Ahlfors CE: Pre exchange transfusion administration of albumin: An overlooked adjunct in the treatment of severe neonatal jaundice? Indian Pediatr 47:231-232, 2010 Alcock GS, Liley H: Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev 3:CD003313, 2002 Nasseri F, Mamouri GA, Babaei H: Intravenous immunoglobulin in ABO and Rh hemolytic diseases of newborn. Saudi Med J 27:18271830, 2006 Scheidt PC, Bryla DA, Nelson KB, et al: Phototherapy for neonatal hyperbilirubinemia: Six-year follow-up of the National Institute of Child Health and Human Development clinical trial. Pediatrics 85:455463, 1990 Keenan WJ, Novak KK, Sutherland Jm, et al: Morbidity and mortality associated with exchange transfusion. Pediatrics 75:417-421, 1985 Jackson JC: Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics 99:E7, 1997 Chen HN, Lee ML, Tsao LY: Exchange transfusion using peripheral vessels is safe and effective in newborn infants. Pediatrics 122:e905e910, 2008 Weldon VV, Odel GB: Mortality risk of exchange transfusion. Pediatrics 41:797-801, 1968 Badiee Z: Exchange transfusion in neonatal hyperbilirubinaemia: Experience in Isfahan, Iran. Singapore Med J 48:421-423, 2007 Mehta S, Kumar P, Narang A: A randomized controlled trial of fluid supplementation in term neonates with severe hyperbilirubinemia. J Pediatr 147:781-785, 2005
B
lood exchange transfusion (BET) was introduced in the late 1940s to decrease the mortality attributable to rhesus hemolytic disease of the newborn and to prevent kernicterus in surviving infants.1 The use of this procedure was subsequently expanded to hyperbilirubinemia, other hemolytic diseases of the newborn, neonatal sepsis, disseminated intravascular coagulation, metabolic disorders (such as aminoaciduria with associated hyperammonemia), severe fluid or electrolyte imbalance, polycythemia, and severe anemia. Intervention for severe neonatal hyperbilirubinemia, especially hemolytic diseases, remains the most frequent indication. The primary goal of the procedure is to remove circulating antibody coated red blood cells and/or products of hemolysis in various immune (eg, rhesus and ABO isoimmunization) or nonimmune hemolytic anemias (eg, glucose 6-phospho dehydrogenase deficiency [G-6-PD deficiency] and other red cell enzyme deficiencies). The corollary benefits include re-
*Consultant Neonatologist, Fernandez Hosp, Hyderabad, India. †Additional Professor, Neonatal Unit, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Address reprint requests to Dr Praveen Kumar, MD, DM, Additional Professor, Neonatal Unit, Dept of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh-160012, India. E-mail: [email protected]
0146-0005/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2011.02.013
duction in excessive unconjugated bilirubin and possibly enhanced bilirubin-albumin binding. The procedure involves incremental removal of the infant’s blood having high bilirubin levels and/or antibody-coated red blood cells and simultaneous replacement with fresh donor blood providing fresh albumin with binding sites for bilirubin. Development and widespread use of Rh-immunoglobulin, improvements in diagnostic prenatal ultrasound, intensive phototherapy, and revised American Academy of Pediatrics (AAP) guidelines for hyperbilirubinemia have resulted in a worldwide decrease in the need for BET during the last 2 to 3 decades.2-4 This has also resulted in decreasingly available expertise for BET in the developed world. Limited technological breakthroughs or simulation technologies have emerged to improve the safety of this life-saving procedure that often needs to be conducted at level II regional centers of the developing world. Among many nations and regions with poorly developed health infrastructure, BET still remains a frequent rescue procedure because of absence of communitybased use of phototherapy, late referrals, suboptimal or ineffective phototherapy devices, delayed recognition of excessive bilirubin levels,5 and higher prevalence of G-6-PD deficiency.6 Currently, the estimated use of exchange transfusion in United States, if an exchange transfusion is performed in any 175
S. Murki and P. Kumar
176 infant with serum total bilirubin (STB) ⬎30 mg/dL (510 mol/L), is at approximately 3/100,000 live births7. In this review article, we share our perspectives based the experiences of a region that performs approximately 150 exchange transfusions annually for both inborn and outborn infants. We also review the current procedural technologies that have not changed significantly during the past 2-3 decades. However, on the basis of the adverse events encountered in an era of decreasing technical skills, technological solutions are needed for a safer and rarer use of neonatal exchange transfusion.
Table 1 Choice of Blood Group for Donor Blood (ABO and Rh typing) Maternal Group
Infant Group
O A or B or AB
O or A or B or AB O or A or B or AB
Rh negative
Rh positive or negative
Donor Glood Group O Baby blood group or O group Rh negative
Choice and Use of Donor Blood
Current Indications for BET For infants ⬎34 weeks’ of gestation, the current AAP guidelines published in 2004 are now the most widely followed in India.8 Originally, Cockington nomograms9 were the most popular birth weight-specific charts for the treatment of hemolytic jaundice in neonates. Current AAP guidelines represent a consensus of the committee that reviewed and updated the previous guideline and is based on a careful review of the evidence, including a comprehensive literature review by the New England Medical Center Evidence-Based Practice Center.10 National Institute for Health and Clinical Excellence of UK commissioned separate guidelines for phototherapy and exchange transfusion in term and preterm infants.11 For preterm and low birth weight infants, the need for exchange is determined by the birth-weight or gestation and sickness as well as a medical judgment of a neonatal expert.12 Because of the increased incidence of intrauterine growth restriction, lower serum albumin levels, greater incidence of birth asphyxia, geographic prevalence of G-6-PD deficiency, and possible risk of acute bilirubin encephalopathy (ABE) at lower serum bilirubin levels,13 some centers in India prefer to follow our institutional recommendation to use the medium and high risk thresholds for intervention illustrated in AAP nomograms for all infants.14 Rh hemolytic disease is often encountered in our practice; for these infants, BET has been recommended soon after birth in the presence of hydrops fetalis (initially only partial exchange may be done to increase hematocrit if baby cannot tolerate double volume BET), in a baby born with pallor, hepato-splenomegaly and positive direct antiglobulin test with history of previous sibs requiring BET, decreasing hematocrit and increasing STB despite intensive phototherapy.
Review of Technical Procedures An exchange transfusion is always done with informed parental consent. A written informed consent is obtained from the parent/s before initiating the procedure of BET. Benefits and risks of the procedure as well as the risks of not doing the procedure in an infant with critical hyperbilirubinemia are explained in simple, understandable verbal and written communication. Indications for the procedure are often urgent in nature and direct communication with parents is vital.
The medical decision to select donor blood type is dependent on the mother and infant’s blood and Rh grouping (Table 1). In case of Rh incompatibility, if the blood is arranged before birth, it should be O Rh negative that has been cross-matched against the mother. If donor blood is being arranged after birth, it should be Rh negative of baby’s ABO group cross-matched against both the infant and mother’s blood sample. For infants with ABO incompatibility, Rh matched O group cross-matched with mother is recommended. For infants with nonhemolytic causes of severe hyperbilirubinemia, the donor blood should be cross matched against both infant and mother to ensure detection of unrecognized minor blood group incompatibilities. In view of a high prevalence of G-6-PD deficiency in our donor population, we are often concerned about both donor and recipient’s G-6-PD status. Our preference is to use as fresh donor blood as is possible. To avoid the risk of neonatal hyperkalemia, we designate “fresh” donor blood that was collected ⬍5 days before the procedure. To ensure an optimal hematocrit for the donor blood, we reconstitute packed red blood cells and fresh frozen plasma in a ratio of 3:1. When BET is planned with O Rh-negative blood, one should ask for O Rh-negative packed red blood cells suspended in AB plasma to minimize the anti-A and anti-B titres. The reconstitution is conducted in the blood bank and ideally performed with a closed system. Saline wash if available can reduce the risk of hyperkalemia and also reduce the antigen load on the red blood cells. The donor blood is also tested for infections, such as hepatitis, cytomegalovirus, human immune deficiency, malaria and others based on regional blood bank procedures. In areas with high prevalence of G-6-PD deficiency, we recommend that the donor blood should undergo screening.15 Ideally, we irradiate the donor blood within 24 hours before transfusion to prevent graft versus host disease.16 Before the procedure, the blood should be warmed to body temperature using either a water bath or by wrapping the container in a warmed towel. Rapid rewarming by placing it under the radiant warmer, massaging between hands or placing under running hot water is to be avoided to minimize preprocedure hemolysis of the donor blood. Infusion warmers are usually not effective because of the high flow rates at which the blood is drawn from the bag.
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Choice of Routes and Techniques for the Exchange
French size 5 or 8 prefilled with saline and attached to a 10-mL syringe is gently inserted into the umbilical vein. The venous catheter is advanced to the desired location as described above. The umbilical venous catheter is connected to 2 three-way stopcocks or 1 four-way stopcock. The 4 channels of connection to the umbilical catheter should, respectively (and in sequence), connect to the umbilical catheter, catheter draining the withdrawn blood, donor blood, and a saline prefilled syringe (Fig. 1). All the connections should be prefilled with saline to exclude an air cavitation reaching the umbilical catheter. The catheter or the connections should never be left open to the atmosphere to prevent any air embolism. The first aliquot of blood drawn from the neonate can be used for laboratory tests. During the procedure, the size of each aliquot should be approximately 5%-8% of infant’s estimated blood volume (smaller aliquots for smaller and sicker infants). In a term infant with a body weight appropriate for gestational age, usually 15- to 20-mL aliquots may be withdrawn or infused at a rate of 5 ml/kg/min. For low-birthweight and preterm infants, it is a general practice to be cautious and withdrawal/infusion should be limited to approximately 5 mL/kg. It is important to note that as the aliquot volume decreases, the proportion of dead space volume would increase making the BET less effective. Thus, aliquot volumes ⬍2 mL are not recommended. The entire procedure should ideally be completed within 60-90 minutes with about 30-35 cycles of completed isovolumetric infusion and withdrawals. Meticulous records for withdrawals and infusions are maintained to avoid net blood loss or overtransfusion. Larger aliquots (⬎8% of blood volume) and rapid transfusions have been associated with altered hemodynamics sometimes compromising the gut circulation.17,18 Air embolism is a major risk; thus, the syringe should be held vertical during infusion and air cavitation should be avoided during withdrawal phase. Infusion of blood with consistent hematocrit requires frequent mixing (gentle shaking or kneading) of the donor blood bag every 5-10 cycles. Use of citrate anticoagulants in donor blood may lead to decrease in the infant’s serum calcium consequent to changes in calcitonin.19,20
BET may be performed with (a) a single catheter in the umbilical vein which reaches inferior vena cava below its junction with right atrium, (b) a catheter each in umbilical vein and umbilical artery, or (c) a substitute catheter placed in either a peripheral artery (usually radial artery) and/or a large sized peripheral vein. Usually a large peripheral or brachial vein is enough. Rarely, one may have to cannulate jugular or femoral vein if the infant is severely dehydrated and peripheral veins are collapsed. Technical Procedures for Use of Umbilical Route Single-Catheter Pull Push Technique. In this “central” technique, BET is usually performed through a catheter passed via the umbilical vein that has been placed in the inferior vena cava below its junction with the right atrium. If one is able to advance the catheter to about 8 cm in preterm and 11 cm in term without resistance, its tip will usually lie in the inferior vena cava. If resistance is encountered, the catheter can be withdrawn to about 3 cm in preterm and 5 cm in term. This will place the tip proximal to the portal sinus and the procedure can be accomplished. Aliquots of donor blood (at 5%-8% of estimated infant blood volume) are exchanged with infant blood till a desired cumulative volume of exchange (2-fold the estimated infant blood volume) is reached. Asepsis, temperature regulation, correct position of the catheter and standard precautions related to blood transfusion must be adhered to (Table 2). The procedure is performed with continuous monitoring of vital signs and by placing the infant on the radiant warmer/flat incubator mattress. Soothing techniques, sucrose solutions, and gentle restraints are often needed to minimize discomfort and to allow a sterile field. Use of anesthesia or sedation is not necessary. Oral feeds are withheld before the procedure and the stomach should be emptied with a gastric tube if an infant has been fed within 2-3 hours previously. Diapers should be used for hygiene. Periumbilical area is cleaned as for a surgical procedure using Betadine or chlorhexidine skin preparation. The operational area should be covered with sterile surgical drapes. A loose purse string should be placed around the base of the cord for hemostasis. An umbilical venous catheter of
Table 2 Complications Because of Donor Blood Donor Blood
Infant Complication
Old blood (high Kⴙ, low platelets) Citrate blood
Hyperkalemia, thrombocytopenia Hypocalcemia and hypomagnesemia
Cold High glucose
Hypothermia Rebound hypoglycemia
G-6-PD deficient
Increased hemolysis, rebound hyperbilirubinemia
Prevention or Treatment Use blood less than 5 days old. Monitor ECG during and after procedure. Watch for signs of bleeding. Consider 1-2 mL kgⴚ1 of calcium gluconate after 50-100 mL of blood exchange in sick infants. Monitor serum calcium 2 h after an exchange. In case of unexplained arrhythmia use 2 ml/kg of 10% calcium gluconate infusion. Prewarm the blood. Check blood glucose 2 h after BET. Initiate early enteral feeds. In endemic areas screen for G-6-PD status of donor blood
BET, blood exchange transfusion; ECG, electrocardiogram; G-6-PD, glucose 6-phospho dehydrogenase.
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Figure 1 Schematic diagram for performing a single-catheter pull push BET through the umbilical vein.
However, significant or symptomatic decreases in serum calcium levels are rare; use of calcium infusions may be associated with fluctuation in heart rate, bradycardia, and even cardiac arrest. Thus, routine administration of calcium gluconate during BET is not recommended.21 Calcium may be used in presence of electrocardiogram changes or in small and sick neonates, in a dose of 10% calcium gluconate 1-2 mL/kg after every 50-100-mL blood exchange under continuously electronic cardiac monitoring. During the procedure, the infant should be attached to a vital signs monitor for continuous observation of temperature, heart rate, respiratory rate, oxygen saturations and electrocardiogram. During the procedure, the operator must call out the volume “out” and “in” with each withdrawal and infusion (eg, “ten in—ten out”). A trained individual should maintain a timed running record of each cycle of BET on a structured data sheet. Each infusion, withdrawal and cumulative volumes should be recorded accurately so the volumes infused and withdrawn are verified to be equal. A sample of blood (from the last aliquot) can be preserved for repeat cross match, if repeat BET or simple transfusions are required. After removing the umbilical catheter, homeostasis is achieved by holding the umbilical stump and tying the purse string at the base. Decisions for remedication are generally considered before the procedure. In our practice, we administer vitamin K after procedure in infants with severe Rh isoimmunization because of the severe
liver involvement and coagulation failure.22 If the infant is on antibiotics or anticonvulsants, their dose is often repeated to ensure therapeutic concentrations. However, the amount of drug eliminated by the process of BET is variable ranging from as low as 3% to 32% depending on several factors like the number of doses received prior and dosing interval.23-25 In addition to continued surveillance of vital signs, the infant should be checked for any bleeding from the umbilical stump, rebound hypoglycemia and biochemical/hematological adverse events. If the infant remains stable, enteral feeding may be reinitiated within 2 hours.26 A prior study from our institution supports that routine use of antibiotics post BET is not necessary in our population.27 Double-Catheter Pull Push Technique. In this technique, both umbilical vein and artery are catheterized. Blood is withdrawn from the umbilical artery and simultaneously equal volume is replaced through the umbilical vein. Additional personnel are needed to operate each catheter and monitor their synchronization. Advantages include a timely completion of the procedure and perceived value to achieve an isovolumetric infusion and withdrawal. Technical Procedures for Use of Peripheral Route Umbilical vessels are often not accessible and a peripheral technique may be used. Use of peripheral arteries and veins may reduce the risks of infection, central vessel complica-
BET and severe neonatal hyperbilirubinemia tions, and reduce the time to initiate an emergency procedure. Removal and replacement of blood takes place simultaneously and may thus minimize the hemodynamic changes caused by fluctuations in circulatory volume. Throughout the procedure, only the limbs need to be exposed and restrained; hence, temperature regulation may be easier. Because gastrointestinal complications are unlikely, fasting of the infants before and after the procedure may not be necessary. Unlike the umbilical route, the peripheral route can be used in infants of any age, including those in whom the umbilical cord has fallen and dried up or in whom umbilical vessel cannulation has failed.28,29 Success in carrying out peripheral vessel exchange transfusions depends largely on successful placement and maintenance of the peripheral arterial catheter, which may be technically difficult especially in vigorous term infants. Also, smaller caliber of peripheral catheters may result in their occlusion. Pull Push Via Peripheral Artery and Peripheral Vein. A peripheral artery (radial or posterior tibial) is catheterized using a 24-gauge catheter under aseptic conditions. Before cannulation, modified Allen’s test should be performed to confirm the adequacy of collateral circulation. The artery can be located either by palpation or by transillumination with a fiberoptic light source. The catheter is connected to a syringe and three-way stopcock so that blood can be withdrawn and discarded intermittently. A 22-gauge or 24-gauge catheter is inserted aseptically into a superficial vein of another limb and connected to a three-way stopcock in a similar manner, for the infusion of donor blood. Two different operators carry out withdrawal and replacement of blood simultaneously at a rate of 5-10 mL/min. To prevent occlusion, the arterial catheter may need to be flushed intermittently with measured volumes of heparinized saline. Disadvantages. Fast and irregular rates of withdrawal and infusion in pull-push method could cause volatile disturbances in the hemodynamic state of the newborn. Rapid pushes may elevate systemic and intracranial pressures.30 Rapid withdrawal may lead to local ischemia in the limb and may be associated with pain and discomfort. The catheter has a tendency to become occluded frequently because of the negative suction applied during pull. Continuous Arterio-venous Exchange via Peripheral Artery and Peripheral vein. To overcome the disadvantages of the pull-push method described previously, continuous ateriovenous exchange (CAVE)31 may be used as an option. This technique is an economical alternative to automated mechanical pumps and allows the blood to flow out and in continuously at a more regular rate than the intermittent and irregular flows achieved by pull push. A peripheral vein is cannulated and connected to a syringe pump or pediatric drip set containing donor blood. The volume of fluid is calculated as exchange volume plus the dead space of the tubing plus another 5 mL as a buffer. A 24-gauge cannula is inserted in the radial artery of the opposite limb after modified Allen’s test. The arterial cannula is attached to standard intravenous tubing set, which has been cut exactly into half and flushed
179 with heparinized saline. Blood is allowed to let out through the arterial line and the time required to a prefixed volume (4.0 mL) of the half cut intravenous tubing is noted. From this, the rate of blood coming out per minute is calculated and the rate of intravenous infusion adjusted to the same. The volumes coming out and going in are continuously monitored along with the vitals. Continuous monitoring is required to match the volume infused to the volume exchanged.
Technologies to Automate BET Several methods for automated BET using a peristaltic pump or a micropump were attempted but did not become popular because of technical difficulties.32,33 Goldman and Tu34 and Funato et al35 successfully automated the BET process by simultaneous withdrawal and replacement using 2 volumetric infusion pumps, one withdrawing infant’s arterial blood, the other replacing equal volumes of donor blood in synchrony. The efficacy of exchange was shown to be superior with the automated method compared with the conventional pull push method35. In addition, because of the continuous regulated flow, automated techniques would offer similar benefits as the CAVE technique mentioned above. Further studies are needed to compare the safety, efficacy, and skill requirements of the newer automated technologies with the traditional methodologies. Currently, no automated system for BET is available commercially.
Assessment of Infant Blood Volume to Design BET A key component to assess the efficacy of an exchange transfusion is to assess the infant’s total circulating blood volume. Traditionally, the estimate for a term newborn’s blood volume has been 80-90 ml/kg. Procedures that use 80-90 ml/kg of donor blood have been termed as singlevolume blood exchange transfusion (SVBET), those that use of 160-180 mL/kg are termed as double-volume blood exchange transfusion (DVBET). On the basis of the time constant of the exchange (conducted in a timely manner), an SVBET is likely to exchange 63% of the infant’s blood whereas DVBET exchanges 86%. However, because of tissue to intravascular dynamics, more bilirubin is removed from the infant than the blood volume exchanged during BET. Forfar et al36 measured the bilirubin mass removed during exchange transfusion and correlated this with the volume of exchange in infants with Rh disease. The bilirubin removed was 45% higher than the fall in serum bilirubin. The bilirubin removed correlated with the volume of exchange during a single volume exchange. An additional 20%-70% of bilirubin removed was noticed with the double volume exchange. An exchange volume of 160-180 mL/kg resulted in a maximal removal of bilirubin. Further increase in exchange volume did remove more bilirubin, but to a much lesser extent.
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180 Table 3 Adverse Events After Blood Exchange Transfusion Author, Type of Study, Year of Publication Odel,49
No and Type of Study Population
Weldon and retrospective observational study, Pediatrics 1968 Keenan et al,46 retrospective observational study, Pediatrics 1985
Two hundred thirty-two infants and 351 BETs in: 6 years’ duration
Jackson,47 retrospective observational study, Pediatrics 1997
One-hundred six infants (81 healthy and 25 sick)
Badiee,50 retrospective observational study, Sing Medical Journal 2007
Sixty-eight infants
Steiner et al,2 retrospective observational study, Pediatrics 2007
One-hundred seven infants and 141 BETs
Chacham S et al, personal communication, prospective observational study, 2010
One hundred forty-one infants (80 healthy and 61 sick) underwent 182 BETs
One-hundred ninety infants underwent 331 BETs
The authors of a smaller randomized controlled trial compared SVBET with DVBET in infants with hemolytic jaundice because of ABO incompatibility.37 They noted no significant difference in the short-term outcomes (de-
Adverse Events Mortality was 1 in 148 vigorous infants and in 10 of the 84 sick infants. No difference in mortality between low birth weight and normal birth weight 22 (6.7%) had adverse events related to exchange transfusion. The adverse events were bradycardia (n ⴝ 8), cyanosis (n ⴝ 3), vasopasm (n ⴝ 2), thrombosis (n ⴝ 2) and apnea (n ⴝ 7). The mortality was 0.53 per 100patients or 0.3 per 100 procedures. All the deaths were in critically ill patients 2% died because of BET (both sick) One healthy neonate had severe NEC Three sick infants (12%) had serious complications Fourteen healthy infants (17%) had apnea or bradycardia with cyanosis requiring resuscitation (n ⴝ 5), hypocalcemia associated with electrocardiographic abnormalities, marked jitteriness, or pedal spasm (n ⴝ 3), rectal bleeding (n ⴝ 2), and one each had, surgery for removal of knotted femoral vein catheter guidewire, hypertension and hematuria associated with umbilical artery catheter, transient bacteremia, and petechial rash from thrombocytopenia. Four additional sick infants had rectal bleeding associated with thrombocytopenia from exchange transfusion, bleeding from umbilical stump requiring platelet transfusion, severe apnea and bradycardia with cyanosis requiring resuscitation and jitteriness associated with hypocalcemia One infant died (1.5%) BET-related complications in 14 infants (21%) Complications included thrombocytopenia (n ⴝ 4), hypocalcemia (n ⴝ 2), one each with seizure, NEC, hypoglycemia, bradycardia, hypoxia, limb color change, ALE, suspected DIC. Hypocalcemia and thrombocytopenia in 53 procedures each (38%). 11% had other complications, such as bradycardia (4%), catheter malfunction (3%), seizures (2%), NEC (1%), apnea (1%), and hyperkalemia (1%) 68% of infants had one or more AE resulting in 112 AEs per 100 BETs. Most common adverse events were biochemical (BAE) and hematological (HAE). Most common BAE was asymptomatic hypocalcemia. All AEs were significantly greater among sick neonates when compared with healthy ones. Also the incidence of overall AE was greater among preterm neonates and those with lower birth weights. Incidence of serious adverse events was 12.6 per 100 ET. Death occurred in 6.4% (n ⴝ 9) of the infants who underwent BET. All the neonates who died were sick. None died in the “healthy” group.
crease in bilirubin and anemia at 10 days) between SVBET with DVBET. Immediate postexchange platelet levels were greater in the SVBET group, but hemoglobin levels were greater in the DVBET group. No interventions were re-
BET and severe neonatal hyperbilirubinemia quired to correct this, and at 10 days after exchange, no statistically significant difference was noted. The follow-up of study infants was only for 3 months, and neurodevelopmental outcomes were not studied. Currently, there is insufficient evidence to support any change in the common practice of performing double volume exchange rather than single volume exchange.38
Use of Albumin Fortified Exchange Transfusion Rapid reduction in unbound bilirubin levels may theoretically prevent bilirubin encephalopathy. Bilirubin is bound to albumin as the dianion with a primary binding site that has a capacity of binding of one molecule of bilirubin. A molar ratio of 1.0 indicates that approximately 8.3 mg bilirubin is bound to each 1 g of albumin. From a therapeutic viewpoint, albumin infusion before BET may be advantageous, because an increased reserve of albumin may be protective against bilirubin toxicity by providing more binding sites, thereby reducing the levels of unbound bilirubin. Odell,39 in 1959, verified the hypothesis that vascular bilirubin-albumin binding would cause a shift of bilirubin from the extravascular to intravascular compartment after the administration of albumin. Subsequent studies showed that albumin administration improved the efficiency of exchange transfusion, by up to 40% in the bilirubin removed, though this did not translate to measurements in postexchange serum bilirubin level.40 A recent study showed that if 20% albumin in the dose of 1 g/kg was administered 1 hour before the exchange, the STB levels at 6 and 12 hours after procedure as well as the duration of phototherapy were significantly lower.41 However, the study did not measure the amount of bilirubin removed. Because the STB does not correlate well with the total body bilirubin and the improvement noted with albumin administration has not been deemed to be too beneficial compared with the potential risks of albumin infusion, its routine clinical use is still not justified.42
Concomitant Use of Intravenous Immunoglobulins Intravenous immunoglobulin (IVIG) has been used sporadically in the treatment of hemolytic disease to prevent exchange transfusion since the early 1990s. The exact mechanism of action is unknown, but it is thought to inhibit hemolysis by blocking antibody receptors on red blood cells: IVIG occupies the Fc receptor sites thus competing with anti-D sensitized neonatal erythrocytes and preventing further hemolysis. The 2004 AAP guidelines for hyperbilirubinemia, recommend that in isoimmune hemolytic disease, IVIG (0.5-1 g/kg over 2 h) could be administered if the STB is increasing despite intensive phototherapy or the STB level is within 34-51 mol/L (2-3 mg/dL) of the exchange level. If necessary, this dose can be
181 repeated in 12 hours. The authors of a Cochrane review suggest a statistically significant reduction in the need for exchange transfusion using IVIG.43 However, in patients with ABO hemolytic disease, there was no significant difference between the use of IVIG and intensive blue light phototherapy.44 The current evidence supports IVIG as a relatively safe and effective means of reducing the need for exchange transfusion in hemolytic diseases,43 although concerns about side effects need to be weighed against those for an exchange transfusion.
Technologies to Ascertain Adverse Events Adverse events may be related to the severity of illness, the procedure, the catheter placements, the blood product, or the operator. Mortality rates attributable to exchange transfusion ranged from 0.65% to 3.2% in studies performed in the 1960s and from 0.4% to 3.2% during the 1970s and 1980s. The causes of death ascribed to exchange transfusion included cardiovascular collapse during the transfusion and the subsequent complications of necrotizing enterocolitis, bacterial sepsis, and pulmonary hemorrhage. The most frequently cited review of adverse events from exchange transfusion is from the 1974-1976 prospective National Institute of Child Health and Human Development phototherapy study.45 Keenan et al46 reported that 190 infants underwent 331 exchange transfusions. Adverse clinical problems were observed in 6.7% of the exchange transfusions, and the observed rate of serious morbidity was 5.2%. On the basis of 1 death attributed to the procedure, they calculated mortality rate to be 0.53 per 100 patients and 0.3 per 100 procedures. Only 2 of the 14 serious adverse events occurred in infants defined as being in good condition at the initiation of the exchange transfusion (Table 3). In a publication by Jackson et al,47 the incidence of mortality or serious permanent sequelae was ⬍1% in healthy neonates whereas the incidence of procedure-related complications leading to death was 8% and the rate of severe complications (death or permanent serious sequelae) was 12% in ill infants. The other common morbidities included symptomatic hypocalcemia, bleeding associated with thrombocytopenia, catheter-related complications, apnea and bradycardia with cyanosis requiring resuscitation. Five percent of healthy infants in this study developed symptomatic hypocalcemia. Nearly 10% of healthy infants had platelet counts ⬍50,000/L. In addition to the complications reported in the study by Jackson et al other reported complications are hypothermia, hyperkalemia, acidosis and hypoglycemia. Steiner et al2 reported that 38% of neonates who received BET developed hypocalcemia. Some studies have reported that BET via the peripheral arteries for withdrawal and peripheral vein for infusion of blood is associated with fewer complications. In a study from Taiwan,48 123 exchange-transfusion procedures were performed in 102 neonates in a 12-year
S. Murki and P. Kumar
182 Table 4 AE Rates Among “Healthy” Neonates Undergoing BET
Birth wt in g
n
<1000 1000-1499 1500-1999 2000-2500 >2500 Total
6 5 12 24 33 80
No of AEs per No Neonates with AEs Total No 100 of (%) of AEs BETs BETs 8 6 15 29 38 96
6 (100) 4 (80) 6 (50) 15 (62.5) 17 (51.5) 48 (60)
15 7 9 30 28 89
188 117 60 103 74 92.7
P ⴝ .013, 2 test for Trends was used for comparison among the 5 groups (Chacham et al, personal communication).
study period: 24 were performed via the umbilical vein method and 99 via the peripheral vessels method. A total of 87 procedures were performed in 75 stable neonates and 36 in 27 unstable neonates. Eight neonates died before discharge, but none of the deaths was attributable to the exchange transfusion procedure. Severe adverse events occurred more commonly in the umbilical vein group than the peripheral artery/vein group in the stable neonates. Most of the studies reporting adverse events after BET are retrospective in nature, have defined adverse events varyingly, and scrutinized the records for a varying length of time after BET.49,50 A prospective study from India involving 182 BETs in 141 neonates reported 112 adverse events per 100 BETs. All neonates undergoing BET in this study were investigated for clinical, biochemical, hematological and intracranial adverse events and followed up for 2 weeks. The definitions used were more liberal compared with previous studies. Hypocalcemia was defined as ionized calcium ⬍1 mol/L or decrease of ⬎0.3 mol/L fall from the pre-BET value. Similarly, thrombocytopenia was defined as a platelet count ⬍ 100,000/cu.mm or a decrease of ⬎2% from pre-BET value. The most common events were biochemical closely followed by hematological adverse events. All events were significantly higher among sick neonates when compared with healthy ones and increased with decreasing birth weights (Table 4; Chacham S, Kumar P, Dutta S, personal communication). We report a checklist (Table 5) that is based on our current practice to minimize adverse events and promote a multidisciplinary team approach.
rangements are made for BET (see algorithm in Fig. 2). Because of delayed referrals, infants are likely to be dehydrated and correction with intravenous fluid supplementation is often necessary. In a randomized controlled trial from northern India, it was shown that 73% of term neonates presenting to the emergency with severe hyperbilirubinemia had high serum osmolality, without the usual overt clinical signs of dehydration. In this study, use of intravenous fluids over the first 8 hours of admission decreased the need for an exchange transfusion by 70% without any long-term adverse effects.51 In summary, although the use of an exchange transfusion has become less frequent in the developing nations, it still remains the only rescue therapy to prevent neonatal brain injury in infants who have limited access to optimal primary care at birthing. In the absence of evidence-based studies from these “front-lines” of primary care, the technologies to perform safe and successful exchange transfusions have often remained antiquated. In our opinion and experience, emphasis for prevention of severe neonatal hyperbilirubinemia at Table 5 Checklist Before the Initiation of Neonatal Exchange Transfusion* Steps 1 2 3 4 5 6 7
8
9
10
Crash Cart Approach to Manage Acute Bilirubin Encephalopathy or Critical Hyperbilirubinemia A neonate presenting with severe jaundice should be urgently evaluated for signs of ABE and severity of hyperbilirubinemia should be immediately verified by transcutaneous bilirubinometry and/or STB. Those with ABE or bilirubin levels near thresholds for an exchange zone should be immediately (crash-cart approach) started on intensive phototherapy to the maximum possible body surface area while ar-
11 12
Procedures in a Neonatal Intensive Care Unit Identify patient, consent and indication for the procedure Verify continuous monitoring of vital signs Use nasogastric tube for gastric decompression Confirm placement and security of exchange catheter(s) Verify donor blood identification, blood type, collection date and hematocrit estimation Use safe warming and intermittent “mixing” techniques Determine and decide aliquot for each phase of cycle (⬃5 mL/kg/infused and equal amount withdrawn). Determine exchange rate: total cycle duration in ⬃3 min, both infusion plus withdrawal (about 30-35 cycles) Assign individual to document events and vital signs, monitor synchronization/cycle and verify iso-volumetric completion of a cycle. Continue phototherapy during and after procedure Consider remedications, as needed Send last aliquot blood sample for: biochemistry, hematology and blood bank (repeat cross-matching).
*At least 3 individuals at the bedside are required to conduct the procedure: (i) credentialed and experienced clinician to operate exchange cycles (a standby assistant may be needed); (ii) a second clinician/nurse to monitor and handle the infant as well as administer medications. This individual must have direct and immediate access to an alerted neonatal resuscitation team; (iii) a third individual with clinical background to accurately record, monitor, verify and document events.
BET and severe neonatal hyperbilirubinemia
183
Figure 2 Algorithm for crash-cart management of neonatal jaundice as a pediatric emergency. ABE, acute bilirubin encephalopathy; IVF, intravenous fluids; PT, phototherapy; STB, serum total bilirubin; TcB, transcutaneous bilirubin.
the primary care level to make the exchange transfusion a rare event, needs to be coupled with evidence-based technological advancements to conduct the procedure with expertise, efficiency and safety.
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