INTRODUCTION — Nearly all newborn infants develop elevated bilirubin levels (ie, total serum or plasma bilirubin [TSB] >1 mg/dL [17 micromol/L], which is the upper limit of normal for adults). As TSB levels increase, the newborn may develop visible jaundice. Neonates with severe hyperbilirubinemia (defined as TSB >25 mg/dL [428 micromol/L] in term and late preterm newborns [gestational age (GA) ≥35 weeks]) are at risk for developing bilirubin-induced neurologic disorders (BIND).
The management of term and late preterm newborn infants who require escalation of care and/or exchange transfusion for treatment of unconjugated hyperbilirubinemia is reviewed here. Initial management of unconjugated hyperbilirubinemia, including management of phototherapy, is discussed separately.
The management of term and late preterm newborn infants who require escalation of care and/or exchange transfusion for treatment of unconjugated hyperbilirubinemia is reviewed here. Initial management of unconjugated hyperbilirubinemia, including management of phototherapy, is discussed separately. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns".)
Other related issues are discussed separately:
●Pathogenesis and etiology of neonatal hyperbilirubinemia (see "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia")
●Risk factors, clinical manifestations, and neurologic complications of neonatal hyperbilirubinemia (see "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia")
●Screening for hyperbilirubinemia in term and late preterm newborns (see "Screening for hyperbilirubinemia in term and late preterm newborn infants")
●Hyperbilirubinemia in preterm infants (GA <35 weeks) (see "Unconjugated hyperbilirubinemia in preterm infants <35 weeks gestation")
●Conjugated (direct) hyperbilirubinemia in newborns (see "Causes of cholestasis in neonates and young infants")
DEFINITIONS — The following terms are used throughout this topic:
●Benign neonatal hyperbilirubinemia is a transient and normal increase in bilirubin levels occurring in nearly all newborn infants. It was previously referred to as "physiologic jaundice."
●Severe neonatal hyperbilirubinemia is defined as a total serum or plasma bilirubin (TSB) >25 mg/dL (428 micromol/L). It is associated with an increased risk for developing bilirubin-induced neurotoxicity.
●Extreme neonatal hyperbilirubinemia is defined as a TSB >30 mg/dL (513 micromol/L). It is associated with a higher risk for developing bilirubin-induced neurotoxicity, including irreversible chronic encephalopathy.
●Bilirubin-induced neurologic disorders (BIND) results from selective brain damage from free (unbound) bilirubin crossing the blood-brain barrier and binding to brain tissue. The spectrum of neurotoxic injury, including acute and chronic bilirubin encephalopathy (ABE and CBE, respectively), is collectively referred to as BIND. The manifestations of BIND, ABE, and CBE are described separately. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Consequences of severe hyperbilirubinemia'.)
Assessment of neonatal hyperbilirubinemia is based upon total bilirubin rather than unconjugated bilirubin levels alone because neonatal hyperbilirubinemia is mostly due to increased bilirubin production, resulting primarily in unconjugated bilirubin. Cholestasis, which presents with primarily elevated conjugated (direct) bilirubin, is a rare cause of neonatal hyperbilirubinemia. (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia" and "Causes of cholestasis in neonates and young infants".)
GOALS — Escalation of care for neonatal hyperbilirubinemia based upon the criteria discussed below is a medical emergency. The goals are to prevent acute bilirubin encephalopathy (ABE) and/or the need for exchange transfusion.
The decision of when to initiate and escalate therapy are based upon the newborn's risk of developing severe hyperbilirubinemia and bilirubin-induced neurologic disorders (BIND). The most important risk factor for BIND is the severity and duration of bilirubin exposure. Additional risk factors are summarized in the tables (table 1 and table 2) and discussed separately. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Risk factors for neurotoxicity'.)
Our approach is generally consistent with guidance from the American Academy of Pediatrics (AAP) [1]. Links to this and other society guidelines are provided separately. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Society guideline links'.)
CRITERIA FOR ESCALATING CARE — Escalating care is appropriate for newborns with any of the following (algorithm 1):
●Elevated total serum or plasma bilirubin (TSB) levels in association with signs of acute bilirubin encephalopathy. These include lethargy, hyper- or hypotonia, poor suck, high-pitched cry, recurrent apnea, opisthotonos, retrocollis, seizures (table 3).
●Rapidly rising TSB levels (ie, increasing by ≥0.3 mg/dL [5 micromol/L] per hour in the first 24 hours or ≥0.2 mg/dL [3 micromol/L] per hour thereafter) despite intensive phototherapy.
●TSB levels that are at or close to the exchange transfusion threshold (ie, within 2 mg/dL [34 micromol/L] of the thresholds (figure 1A-B).
Of note, while these criteria are similar to those for exchange transfusion, they are intentionally less stringent. Thus, some neonates will meet criteria for escalation of care but will not ultimately require exchange transfusion. (See 'Criteria for exchange transfusion' below.)
This was demonstrated in a study from the California Perinatal Quality Care Collaborative that included data on nearly 3,000,000 live-born term and late preterm newborns from 2007 to 2012, of whom 0.1 percent required admission to a neonatal intensive care unit (NICU) for management of hyperbilirubinemia [2]. Among newborns admitted to the NICU, 19 percent developed severe hyperbilirubinemia (ie, TSB ≥25 mg/dL [428 micromol/L]), yet only 3 percent required exchange transfusion.
SETTING OF CARE — Newborns who meet the criteria for escalating care should be managed for in an intensive care unit setting (depending on local resources, this may be a neonatal intensive care unit [NICU] or pediatric intensive care unit [PICU]). For patients being seen in the outpatient setting, it is preferable to directly admit to the NICU, if feasible, so that treatment can begin promptly. However, if this cannot be arranged, the patient should be referred to the emergency department at a facility where phototherapy is available. If the newborn cannot be promptly admitted to a NICU, the clinical team caring for the newborn should consult with a neonatologist to help guide management.
LABORATORY EVALUATION
Tests to perform — The following laboratory tests should be obtained in all neonates requiring escalation of care for hyperbilirubinemia [1]:
●Total serum or plasma bilirubin (TSB) and direct (or conjugated) serum bilirubin
●Complete blood count and reticulocyte count
●Direct antiglobulin test (DAT), if not already performed
●Serum albumin
●Serum electrolytes, blood urea nitrogen (BUN), and creatinine
●Type and crossmatch
●Glucose-6-phosphate-dehydrogenase (G6PD) enzyme activity, if not already measured
B/A ratio — The bilirubin/albumin (B/A) ratio can be used as an additional factor in determining the need for exchange transfusion; it should not be used alone, but in conjunction with TSB values and other risk factors [1,3].
●Calculation – The B/A mass ratio (in mg/g) is calculated as follows:
•Using conventional units – Divide the TSB (in mg/dL) by the serum albumin (in g/dL). For example, a newborn with a TSB of 21 mg/dL and a serum albumin of 3 g/dL would have a B/A mass ratio of 7.
•Using Système International (SI) units – Divide the TSB (in micromol/L) by the serum albumin (in g/L) and then multiply by a factor of 0.585. For example, a newborn with a TSB of 359 micromol/L and a serum albumin of 30 g/L would have a B/A mass ratio of 7.
The B/A ratio can also be expressed as a molar ratio. To convert the mass ratio to molar ratio, use the following conversions:
•Bilirubin in mg/dL × 17.1 = bilirubin in micromol/L
•Albumin in g/dL × 152 = albumin in micromol/L
Thus, a newborn with a TSB of 21 mg/dL (359 micromol/L) and serum albumin of 3 mg/dL (30 g/L) would have a B/A molar ratio of 0.79.
●Interpretation – The B/A ratio is used to assess how much of the TSB is bound to albumin. Elevated B/A ratios indicate that most binding sites on albumin are occupied. Further increases in bilirubin can lead to elevated levels of free (unbound) bilirubin, which can cross the blood-brain barrier resulting in neurotoxicity (figure 2) [4]. The B/A ratio at which this occurs differs depending on gestational age (GA; and other risk factors for neurotoxicity) (table 2). In addition, certain medications (eg, ceftriaxone) can displace bilirubin from albumin. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Risk factors for neurotoxicity'.)
In neonates who require escalation of care for hyperbilirubinemia the following B/A ratios are used as thresholds for performing exchange transfusion (table 4) [1]:
•B/A mass ratio ≥8.0 (molar ratio 0.9) for newborns with GA ≥38 weeks and no neurotoxicity risk factors
•B/A mass ratio ≥7.2 (molar ratio 0.81) for newborns with GA ≥38 weeks and at least one neurotoxicity risk factor
•B/A mass ratio ≥7.2 (molar ratio 0.81) for newborns with GA 35 through 37 weeks and no neurotoxicity risk factors
•B/A mass ratio ≥6.8 (molar ratio 0.77) for newborns with GA 35 through 37 weeks and at least one neurotoxicity risk factor
INITIAL MEASURES — Initial measures for neonates who require escalation of care include phototherapy, intravenous (IV) hydration, and, in newborns with alloimmune hemolytic disease, intravenous immune globulin (IVIG) (algorithm 1) [1]. These interventions should be started while preparations are made for possible exchange transfusion. In some cases, phototherapy and IV hydration may effectively reduce total serum or plasma bilirubin (TSB) levels such that exchange transfusion can be avoided.
Phototherapy — If the newborn is not yet receiving phototherapy, phototherapy should be started immediately. If the newborn is already receiving phototherapy, efforts should be made to optimize its delivery (eg, maximizing skin exposure, using light sources from above and below the newborn, eliminating any interruptions to phototherapy). Additional details regarding phototherapy are provided separately. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Initial intervention (phototherapy)'.)
IV hydration — For all newborns who meet criteria for escalation of care, we suggest IV hydration. IV hydration is provided with crystalloid fluid (typically 10 percent dextrose with one-quarter normal saline) at a maintenance rate (ie, approximately 80 mL/kg per day for newborns <48 hours old; 80 to 100 mL/kg per day for those ≥48 hours old). Subsequent adjustments are based on measurement of serum electrolytes. We suggest not using colloid infusions such 5 or 25 percent albumin. (See "Fluid and electrolyte therapy in newborns".)
Limited clinical trial evidence suggests that IV hydration in addition to phototherapy lowers TSB levels faster and may reduce the need for exchange transfusion [5,6]. In a meta-analysis of seven trials involving 462 newborns with hyperbilirubinemia who were randomly assigned to supplemental IV hydration or no IV hydration, TSB levels at 12 hours were modestly lower in the IV hydration group (mean difference 0.6 mg/dL [10 micromol/L]) [5]. Exchange transfusion rates were also lower in the IV hydration group (6 versus 15 percent; relative risk [RR] 0.39, 95% CI 0.21-0.71). No newborns in either group developed acute bilirubin encephalopathy (ABE). The trials included in the meta-analysis had important methodologic limitations, including small numbers, lack of blinding, selective reporting, and limited follow-up. In addition, many of these trials were performed prior to the introduction of blue light-emitting diode-based phototherapy, which is not associated with increased fluid losses. The use of fluorescent- or halogen-based phototherapy devices, which can cause overheating and fluid loss, in these trials may have confounded their results. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Light sources and devices'.)
Based on the available trial data, the certainty that IV hydration hastens resolution of hyperbilirubinemia relative to phototherapy alone is low. Nevertheless, the potential benefits likely outweigh the downsides in this setting. Importantly, the decision to perform exchange transfusion is independent of the use of IV fluids. (See 'Criteria for exchange transfusion' below.)
Selective use of IVIG — For newborns with hyperbilirubinemia due to alloimmune hemolytic disease of the newborn (HDN), treatment with IVIG is suggested, as discussed separately. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Immune globulin therapy'.)
HDN may be suspected based upon maternal/infant Rh or ABO incompatibility and/or positive direct antiglobulin test (DAT). However, a negative DAT does not exclude the diagnosis of HDN, particularly in the setting of ABO incompatibility. This is discussed separately. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Diagnosis'.)
Central line placement — If exchange transfusion is anticipated, central venous access should be obtained, typically with an umbilical venous catheter. In addition, a peripheral or umbilical arterial catheter should be placed to facilitate drawing blood and for invasive hemodynamic monitoring during the procedure. (See "Vascular (venous) access for pediatric resuscitation and other pediatric emergencies", section on 'Umbilical vein access'.)
MONITORING — Appropriate monitoring for newborns requiring escalation of care for hyperbilirubinemia includes the following:
●Continuous cardiorespiratory and pulse oximetry monitoring
●Frequent blood pressure measurements
●Careful monitoring of fluid intake and output
●Total serum bilirubin (TSB) measurement every two hours
●Monitoring for signs of acute bilirubin encephalopathy (ABE) (table 3)
For newborns who require exchange transfusion, additional monitoring is performed during and after the procedure, as discussed below. (See 'Procedure' below.)
EXCHANGE TRANSFUSION — Exchange transfusion is the most effective and immediate method for rapidly removing bilirubin in newborns who are at risk for developing bilirubin-induced neurologic disorders (BIND).
Exchange transfusion involves removing some of the newborn's own blood and replacing it with allogenic blood, thereby lowering the total serum or plasma bilirubin (TSB) concentration. In patients with allogenic hemolytic disease due to ABO or Rh incompatibility, exchange transfusion also decreases hemolysis by removing antibody-coated neonatal red blood cells (RBCs) and unbound maternal antibody. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Exchange transfusion'.)
Criteria for exchange transfusion — Criteria for exchange transfusion include any of the following (algorithm 1) [1]:
●Signs of acute bilirubin encephalopathy (ABE) – For patients with elevated TSB levels in association with signs of ABE (eg, lethargy, hyper- or hypotonia, poor suck, high-pitched cry, recurrent apnea, opisthotonos, retrocollis, or seizures (table 3)), exchange transfusion is warranted even if the TSB is not above the treatment threshold. However, newborns with signs of encephalopathy in the setting of TSB levels that are well below the exchange should undergo evaluation for other etiologies since ABE is unlikely at TSB levels <20 mg/dL (342 micromol/L); most reported cases of ABE have occurred at TSB levels ≥30 mg/dL (513 micromol/L). (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Investigations' and "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Acute bilirubin encephalopathy (ABE)'.)
For newborns with subtle neurologic findings, measuring the brainstem auditory evoked response (BAER) may be helpful to assess for ABE since an abnormal BAER is highly suggestive of ABE [7]. However, BAER testing may not be readily available in many settings and this assessment should not delay treatment. (See "Screening the newborn for hearing loss", section on 'Automated auditory brainstem response' and "Hearing loss in children: Screening and evaluation", section on 'Brainstem response'.)
●TSB at or above the hour-specific exchange transfusion threshold – The TSB thresholds used to guide therapy differ depending upon gestational age (GA) and whether the newborn has risk factors for neurotoxicity (table 2):
•For newborns without neurotoxicity risk factors (figure 1A)
•For newborns with risk factors for neurotoxicity, lower thresholds are used for exchange transfusion (figure 1B)
●Bilirubin/albumin (B/A) ratio at or above exchange transfusion threshold – The B/A thresholds used to guide therapy differ depending upon GA and whether the newborn has risk factors for neurotoxicity, as summarized in the table (table 4). (See 'B/A ratio' above.)
Newborns who meet one or more of these criteria should undergo exchange transfusion.
If the TSB level and B/A ratio are below the exchange transfusion thresholds and signs of ABE are absent, exchange transfusion may be deferred. Intensive phototherapy and intravenous (IV) hydration should be continued, and TSB should be checked every two hours until the TSB is >2 mg/dL (34 micromol/L) below the hour-specific exchange transfusion threshold. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'De-escalating therapy'.)
Support for these exchange transfusion TSB thresholds comes from a study involving >500,000 newborns born between 1995 and 2011 at a healthcare system in California [8]. Of the 1833 newborns who were exposed to TSB levels at or above the exchange transfusion threshold, 0.4 percent (n=7) later developed cerebral palsy (CP); whereas among newborns without exposure to such high TSB levels, 0.1 percent (86 of 104,716) developed CP (relative risk 4.7; 95% CI 2.2-10.0]). Of the 93 patients with CP in this study, three had a pattern consistent with chronic bilirubin encephalopathy (CBE, previously called kernicterus), all of whom had neonatal TSB levels that exceeded the exchange transfusion threshold by >5 mg/dL (86 micromol/L).
These TSB threshold values serve as guidelines and they do not guarantee that adverse sequelae will be averted. Clinicians should be aware that the risk of developing bilirubin neurotoxicity is infant-specific. The decision to perform exchange transfusion requires clinical judgement, taking into consideration the TSB trajectory, progression of clinical signs, and identification of known neurotoxicity risk factors. Often, consultation with an experienced neonatologist at a tertiary center is warranted.
Procedure — Exchange transfusion for neonatal hyperbilirubinemia consists of double-volume isovolumetric exchange. The procedure should be performed only by trained personnel in a neonatal or pediatric intensive care unit (NICU/PICU) equipped with full monitoring and resuscitation capabilities.
●Calculating the blood volume – The volume needed for double exchange transfusion is 160 mL/kg. This replaces approximately 85 percent of the infant's circulating red blood cells (RBCs).
If the neonate does not tolerate double exchange (eg, due to hemodynamic instability) or if there are technical challenges (eg, difficulty withdrawing sufficient blood), it is acceptable to perform a single-volume exchange with a blood volume of 80 mL/kg. This replaces approximately 60 percent of the infant's circulating RBCs.
●Blood products to use – Exchange transfusion is performed with appropriately cross-matched reconstituted blood using washed RBCs and fresh frozen plasma (FFP) with a hematocrit of approximately 40 to 45 percent. Irradiated and cytomegalovirus-safe blood products are used, as discussed separately. (See "Red blood cell transfusions in the newborn".)
RBCs should be reconstituted with FFP rather than saline because the albumin content in FFP ensures adequate bilirubin binding. An RBC product alone is inadequate and may potentiate ongoing bilirubin toxicity due to its reduced intravascular bilirubin-binding capacity [9].
In our center, we do not administer albumin prior to exchange transfusion. It has been suggested that infusion of albumin one to two hours before the procedure might theoretically allow for removal of more bilirubin by shifting more extravascular bilirubin into the circulation. However, this has not been shown to decrease the need for repeat exchange transfusion or enhance TSB decline and it carries an additional risk of volume overload which may compound the hemodynamic challenges of the exchange transfusion itself.
●Performing the exchange – Neonatal exchange transfusion is ideally performed manually. Some centers may use reliable infusion pumps. However, we generally discourage use of such devices unless the team is proficient with using them in this setting since device malfunctions or mishaps could contribute to increased risk of adverse sequalae from the procedure.
After obtaining central venous access, reconstituted blood is administered in aliquots of approximately 8 to 10 percent of the total blood volume (6 to 8 mL/kg per aliquot). For term neonates, aliquots of 20 mL are adequate and safe. This is done by simultaneously withdrawing blood from one catheter or access port while replacing blood through a separate catheter or access port (eg, withdrawing from the arterial line while transfusing through the umbilical venous catheter). This is repeated until the total volume has been exchanged.
Phototherapy is continued during the procedure. Central venous and arterial catheters should be removed as soon as possible after the procedure once it is confirmed that the TSB level has declined and repeat exchange transfusion is not required.
●Monitoring during the procedure – Appropriate monitoring for newborns undergoing exchange transfusion includes the following:
•Continuous cardiorespiratory and pulse oximetry monitoring
•Blood pressure (BP) monitoring with either continuous invasive BP measurement or noninvasive BP measurements every 15 minutes during the procedure
•Measurement of serum electrolytes and ionized calcium before, during, and after the procedure
•Complete blood count before and after the procedure
•Measurement of coagulation studies (eg, prothrombin time [PT], activated partial thromboplastin time [aPTT]) before and after the procedure
If abnormalities are noted on laboratory monitoring (eg, electrolyte abnormalities, coagulopathy, thrombocytopenia), corrective intervention may be required (eg, calcium repletion, factor replacement, platelet transfusion). (See "Neonatal hypocalcemia", section on 'Acute therapy' and "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management", section on 'Platelet transfusion'.)
Efficacy — The efficacy of exchange transfusion for neonatal hyperbilirubinemia is supported by observational studies demonstrating that exchange transfusion dramatically reduces TSB levels [10,11]. Most of these studies were carried out in the 1960s to 1980s when management of neonatal hyperbilirubinemia differed considerably from the modern era. Limited data suggest that exchange transfusion may improve indirect measures of brain function (ie, brainstem auditory evoked response) [12-15].
Complications — The risks of exchange transfusion include risks attributable to placing central venous and arterial catheters, risks associated with exposure to blood products, and risks directly from the procedure itself. (See "Vascular (venous) access for pediatric resuscitation and other pediatric emergencies", section on 'Complications' and "Red blood cell transfusion in infants and children: Administration and complications".)
Potential complications include:
●Hemodynamic instability
●Thrombotic complications, including portal vein thrombosis
●Air embolus
●Cardiac arrhythmias
●Life-threatening electrolyte abnormalities (eg, hypocalcemia and hyperkalemia)
●Fluid overload
●Anemia from excessive blood withdrawal with concurrent hemolysis
●Central catheter-related vascular complications
●Blood-borne infections
●Thrombocytopenia and coagulopathy
●Necrotizing enterocolitis
●Graft versus host disease
In the modern era, exchange transfusions are rarely performed. Thus, it is difficult to assess the current risks of morbidity and mortality associated with this procedure. Studies published in the 1980s reported mortality rates of 0.3 percent associated with the procedure [10,16]; serious complications occurred in 1 percent of procedures [10]. Subsequent studies are limited by the number of patients, but still suggest a significant risk of morbidity and mortality especially in critically ill neonates [9,17-21].
POST-PROCEDURE MANAGEMENT — Management following exchange transfusion includes:
●Resuming phototherapy – Phototherapy should be restarted if it was interrupted for the procedure. Ideally, phototherapy should be continued at the same therapeutic dose throughout the procedure.
●Monitoring total serum or plasma bilirubin (TSB) levels – TSB level should be measured at the end of the procedure with a repeat level two hours later. Immediately after a successful double-volume exchange transfusion, TSB levels are typically reduced by approximately 50 to 85 percent compared with pre-exchange values [22]. TSB levels subsequently increase to approximately two-thirds the pre-exchange concentrations because of re-equilibration between extravascular and vascular bilirubin.
●De-escalation of phototherapy – Subsequent management decisions are based upon TSB levels. The approach to de-escalating phototherapy is discussed in detail separately. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'De-escalating therapy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neonatal jaundice".)
SUMMARY AND RECOMMENDATIONS
●Importance and goals of care – Neonates with severe hyperbilirubinemia are at risk for developing bilirubin-induced neurologic disorders (BIND) if treatment to lower the total serum or plasma bilirubin (TSB) levels is not provided in a timely manner. The goals of escalating care are to prevent acute bilirubin encephalopathy (ABE) and/or the need for exchange transfusion. (See 'Goals' above.)
●Criteria for escalating care – Escalation of care is appropriate for newborns with any of the following (algorithm 1) (see 'Criteria for escalating care' above):
•Elevated TSB in association with signs of ABE (ie, lethargy, hyper- or hypotonia, poor suck, high-pitched cry, recurrent apnea, opisthotonos, retrocollis, seizures (table 3))
•Rapidly rising TSB levels (ie, increasing by ≥0.3 mg/dL [5 micromol/L] per hour in the first 24 hours or ≥0.2 mg/dL [3 micromol/L] per hour thereafter) despite intensive phototherapy
•TSB levels that are within 2 mg/dL [34 micromol/L] of the exchange transfusion thresholds (figure 1A-B)
Some neonates will meet criteria for escalation of care but will not ultimately require exchange transfusion.
●Setting of care – Newborns who meet criteria for escalating care should be cared for in an intensive care unit setting (depending on local resources, this may be a neonatal intensive care unit [NICU] or pediatric intensive care unit [PICU]). For patients being seen in the outpatient setting, it is preferable to directly admit to the NICU, if feasible, so that treatment can begin promptly. (See 'Setting of care' above.)
●Laboratory evaluation – The following tests should be obtained in all newborns who require escalation of care (see 'Laboratory evaluation' above):
•Total and direct serum bilirubin
•Complete blood count (CBC) and reticulocyte count
•Direct antiglobulin test (DAT), if not already performed
•Serum albumin
•Serum electrolytes, blood urea nitrogen (BUN), and creatinine
•Type and crossmatch
•Glucose-6-phosphate-dehydrogenase (G6PD) enzyme activity, if not already measured
●Initial measures – Initial measures for neonates who require escalation of care include (see 'Initial measures' above):
•Phototherapy – Phototherapy should be provided immediately if not already started, and its delivery should be optimized (eg, maximize skin exposure, use light sources from above and below, eliminate interruptions). (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Initial intervention (phototherapy)'.)
•Intravenous (IV) hydration – For all newborns who require escalation of care, we suggest IV hydration (Grade 2C). This consists of a crystalloid solution (typically 10 percent dextrose with one-quarter normal saline) at a maintenance rate (ie, approximately 80 mL/kg per day for newborns <48 hours old; 80 to 100 mL/kg per day for those ≥48 hours old). Limited clinical trial evidence suggests that IV hydration in addition to phototherapy lowers TSB levels faster and may reduce the need for exchange transfusion. (See 'IV hydration' above.)
•Intravenous immunoglobulin (IVIG) – For newborns with hyperbilirubinemia due to alloimmune hemolytic disease, treatment with IVIG is suggested, as discussed separately. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Immune globulin therapy'.)
●Monitoring – Appropriate monitoring for newborns requiring escalation of care includes the following (see 'Monitoring' above):
•Continuous cardiorespiratory and pulse oximetry monitoring
•Frequent blood pressure measurements
•Careful monitoring of fluid intake and output
•TSB measurement every two hours
•Monitoring for signs of ABE (table 3)
●Exchange transfusion – For newborns with signs of ABE (table 3), we recommend exchange transfusion (Grade 1C). We also suggest exchange transfusion for asymptomatic newborns with TSB levels at or above the hour-specific TSB threshold for exchange transfusion (figure 1A-B) and/or bilirubin/albumin (B/A) ratio at or above the exchange transfusion threshold (table 4) (Grade 2C). (See 'Exchange transfusion' above.)
If the TSB and B/A ratio are below the exchange transfusion thresholds and signs of ABE are absent, intensive phototherapy and IV hydration should be continued, and TSB should be checked every two hours until the TSB is >2 mg/dL (34 micromol/L) below the hour-specific exchange transfusion threshold. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'De-escalating therapy'.)
