Early recognition of neonatal hyperbilirubinemia and its emergent management

Transcription

1 Seminars in Fetal & Neonatal Medicine (26) 11, 214e224 available at journal homepage: Early recognition of neonatal hyperbilirubinemia and its emergent management Hannah Smitherman a, *, Ann R. Stark b, Vinod K. Bhutani c a Department of Pediatrics, Section of Emergency Medicine, Baylor College of Medicine, Houston, TX, USA b Section of Neonatology, Baylor College of Medicine, Houston, TX, USA c Division of Neonatal and Developmental Medicine, Lucile Packard Children s Hospital and Stanford University, Stanford, CA, USA KEYWORDS Acute bilirubin encephalopathy; Bilirubin-induced neurologic dysfunction; Neonatal emergencies; Neonatal hyperbilirubinemia; Newborn jaundice Summary Hyperbilirubinemia and kernicterus are re-emerging as prominent clinical concerns and have been hypothesized to be secondary to increased breast-feeding rates, early hospital discharges and overall lack of concern for the potential impact of severe hyperbilirubinemia on healthy term newborns. Although the clinical symptoms can be non-specific and vague, they could be early, insidious and heralding signs of acute bilirubin encephalopathy (ABE) or acute stage kernicterus. Because it is highly prevalent, evaluation of a jaundiced neonate requires detailed questions about specific signs, review of birth and postnatal histories, evaluation of predischarge data, and possibly an emergency clinical evaluation of the neurological status of the infant. Medical urgency to evaluate, investigate and monitor such a newborn ensues from the possibility of rapid progression that might lead to permanent sequelae of bilirubin-induced neurologic dysfunction (BIND). Early recognition of the urgency and rapid transition to treatment seem to be the major barriers leading to delay in therapy. However, because there is a well-established and relatively safe treatment for neonatal jaundice, there should be zero tolerance for kernicterus, and BIND prevention has become a national priority in the USA. This paper reviews the clinical signs and epidemiology of ABE and BIND and presents a system-based strategy for preventing their occurrence, focusing particularly on the transition from recognition of clinical jaundice to actual treatment. A novel emergency-room-based protocol is presented as an example of how to expedite and facilitate rapid progression to treatment. ª 26 Elsevier Ltd. All rights reserved. Introduction * Corresponding author. Baylor College of Medicine, 6621 Fannin St. MC , Houston, TX 773, USA. Tel.: C address: hfsmithe@texaschildrenshospital.org (H. Smitherman). The majority of otherwise healthy newborns have clinical jaundice associated with increased concentration of total serum bilirubin (TSB). Although the outcome for the majority is benign, infants with untreated, extremely X/$ - see front matter ª 26 Elsevier Ltd. All rights reserved. doi:1.116/j.siny

2 Early recognition of neonatal hyperbilirubinemia 215 high TSB levels can develop signs of acute bilirubin encephalopathy (ABE). If not treated immediately, they might go on to develop kernicterus, a chronic, neurologically devastating condition resulting from bilirubin toxicity. The past focus has been on inpatient systems-based approaches that include detection of early-onset jaundice, predischarge assessment of risk for the development of subsequent hyperbilirubinemia, and early follow-up. 1e5 Ideally, these efforts would avoid delayed detection of excessive levels of TSB and limit the associated risk of neurologic injury, thus promoting a safe transition from the birth hospital to home. 6 However, recent changes in healthcare practices, including early discharge of newborns, have transformed the management of neonatal jaundice into an outpatient problem. 7,8 Despite its high prevalence in newborns, an elevated TSB concentration, because of its potential toxicity (especially when associated with signs of encephalopathy), is considered a neonatal emergency and must be addressed urgently. Epidemiology: scope of the problem More than 6% of otherwise healthy newborns develop hyperbilirubinemia during the first week of life, and most are discharged from their birth hospital before the usual peak of TSB (age 72e12 h). Hyperbilirubinemia typically resolves by 7e1 days of age and the outcome is usually benign. However, severe hyperbilirubinemia, defined as TSB above the 95th percentile for age in hours (highrisk zone), occurs in 8e9% of infants during the first week, with approximately 4% affected after 72 h. 9,1 Without appropriate intervention, progressive increase in hyperbilirubinemia to values >25 or 3 mg/dl (greater than 99th percentile for age in hours) places otherwise healthy babies at risk of bilirubin-related brain damage (kernicterus). The precise incidence of extremely high levels of hyperbilirubinemia and bilirubin neurotoxicity is not known because routine surveillance has been unavailable. Although, in a preliminary report, 82 cases of kernicterus were identified in New Jersey from 1992 to 21, resulting in an estimated rate of 7.5 cases per 1, live births, the estimated incidence is about 1 in 3, infants discharged from well baby nurseries 2 (Table 1). Pathophysiology Unconjugated bilirubin is fat soluble; it crosses cell membranes and is potentially neurotoxic. However, toxicity is generally avoided because most unconjugated bilirubin is bound to albumin. Hyperbilirubinemia develops when the rate of bilirubin production via the breakdown of heme by the reticuloendothelial system exceeds the rate of elimination, primarily by conjugation. Various genetic, environmental, and racial factors affect the equilibrium between these processes. For example, albumin binding capacity is reduced by acidosis, immaturity, and competitive binding of substances such as salicylates, sulfonamides, and free fatty acids. From a management perspective, it is useful to categorize severe hyperbilirubinemia according to its time of onset, early or late, regardless of its specific etiology (Fig. 1). In general, early-onset severe hyperbilirubinemia is associated with increased bilirubin production, while late-onset hyperbilirubinemia is often associated with delayed bilirubin elimination with or without increased bilirubin production. 11e13 Early-onset hyperbilirubinemia (TSB values >75th percentile prior to 72 h of age) is a high-risk condition because it often presents with an acute and rapid rise in TSB values, which might reach levels above the 95th percentile within the first 12 h of life. Affected infants are typically identified by visual recognition of jaundice by nurses and subsequent testing of transcutaneous or serum bilirubin concentration. The etiology in the majority of these cases is hemolysis from ABO incompatibility, although this might not always be confirmed. 2,11,12 Although early-onset hyperbilirubinemia might be identified at the birth hospital, depending on the timing of hospital discharge, both early and late onset hyperbilirubinemia can occur at home. Late-onset hyperbilirubinemia (TSB values >95th percentile after 72 h of age) can usually be predicted by predischarge bilirubin screening. 4 Late-onset hyperbilirubinemia often results from decreased bilirubin elimination. Inadequate breast-feeding with consequent dehydration and increased enterohepatic circulation of bilirubin is frequently a contributing factor. Other risk factors include familial or ethnic risk factors (siblings with jaundice, east Asian or Mediterranean descent, Gilbert s syndrome, and as yet unrecognized genetic polymorphisms of the glucoronyl transferase gene). Of note, glucose 6-phospho-dehydrogenase (G6PD) deficiency might be present in as many as 12.8% of AfricaneAmerican males. 14 Acute bilirubin encephalopathy The initial neurotoxicity of extremely elevated bilirubin levels results in acute bilirubin encephalopathy (ABE), which might progress to chronic conditions, including kernicterus. There is no evidence that neurotoxicity occurs at a specific bilirubin concentration. The critical level in Table 1 Incidence of severe hyperbilirubinemia in term and near-term infants Severe hyperbilirubinemia Incidence TSB level >95th percentile >17 mg/dl 8.1e1% 1 in 9 TSB level >98th percentile TSB level >2 mg/dl 1e2% 1 in 5 TSB level >99.9th percentile TSB level >25 mg/dl.16% 1 in 7 TSB level >99.99th percentile TSB level >3 mg/dl e.32% 1 in 1, Adapted from Bhutani et al. 11 based on the following references. 52e56

3 216 H. Smitherman et al. Early onset hyperbilirubinemia (age < 72 h) Late onset hyperbilirubinemia (age > 72 h and < 2weeks) First 24 hours of life First week of life > 1 week of life Direct Coombs positive: isoimmune erythroblastosis fetalis: rhesus disease minor blood group incompatibilities ABO (often the direct Coombs is negative) Direct Coombs negative: G6PD deficiency intrinsic red blood cell defect spherocytosis elliptocytosis hemoglobinopathies Benign idiopathic jaundice (physiologic; < 4th percentile) Sepsis (viral or bacterial) Prolonged idiopathic jaundice (breast milk jaundice; TSB < 13 mg/dl)) Sepsis (viral or bacterial) Increased enterohepatic Functional gastrointestinal circulation tract abnormality Disorders of bilirubin metabolism: UG1TA1 gene polymorphisms (delayed conjugation) Co-inheritance of UG1TA1 polymorphism with G6PD deficiciency, ABO incompatibility, spherocytosis Crigler--Naajar syndromes: I and II Gilbert syndromes others Metabolic disorders: galactosemia alpha-1-antitrypsin deficiency storage diseases others Enclosed hemorrhages: Cystic fibrosis cephalhematoma Hypothyroidism subaponeurotic hemorrhage bruising Figure 1 Differential diagnosis of neonatal hyperbilirubinemia based on pathophysiology of presentation. an otherwise healthy baby is likely influenced by postnatal age, maturity, duration of hyperbilirubinemia, and rate of TSB rise (Table 2). 13 Co-morbidities, such as near-term gestation (35 to <38 weeks gestation), hypoalbuminemia, disruption of the bloodebrain barrier (asphyxia or trauma), hemolysis (intravascular or extravascular), infection, hypoglycemia, and factors that interfere with albumin binding of bilirubin predispose newborns to ABE at lower TSB values. As noted by Poland, 15 a number of investigators have presented evidence that a more appropriate predictor of neurotoxicity is unbound or free bilirubin. 16 At present, there are no commercial assays for albumin binding reserve or unbound bilirubin in the USA. Preliminary American and Japanese studies have suggested that levels >.8 mg/dl of unbound bilirubin are associated with an increasing risk of BIND. 17e19 The risk of kernicterus increases incrementally with rising levels of TSB >19 mg/dl. 2,21 In the Pilot Kernicterus Registry, 1 the causes for kernicterus were attributed to three categories in equal proportions: hemolytic disorders Table 2 When is a bilirubin level potentially neurotoxic? Bilirubin level a Why this level can be hazardous a Any jaundiced baby with any suspicious neurological signs (clinical concern for ABE) TSB >99.9th percentile (correlate with TSB >25 mg/dl) and >72 h of age TSB >95th and <99.9th percentile with B:A ratio >7. mg/g and >72 h of age TSB >95th percentile and postnatal age less than 72 h, regardless of B:A ratio TSB >75th percentile and a rate of rise >.2 mg/dl per h Measure TSB levels. Until the results are available: all signs need to be objectively evaluated for BIND, taken seriously and intensive phototherapy initiated TSB levels might exceed the binding affinity of serum albumin and the neurotoxicity risk increases exponentially. Median serum albumin level is 4. g/dl (range 3.e4.9) for healthy term neonates. Babies with serum albumin <3.6 g/dl can be at risk with TSB level >99.9th percentile (>25 mg/dl) Low levels of albumin (<3.4 g/dl) are often seen in term newborns and are lower in near-term or bruised infants. In these babies, the binding ability of albumin for bilirubin is exceeded During the first 72 h, the binding ability of albumin is compromised and lower TSB levels are potentially neurotoxic An increase in bilirubin load at >1 mg per 5 h or w5 mg/day is likely to jump track to >95th percentile values and the baby can reach neurotoxic levels unless followed closely Adapted from Bhutani et al. 11 ABE, acute bilirubin encephalopathy; B:A ratio, bilirubin to albumin ratio; BIND, bilirubin-induced neurologic dysfunction; TSB, total serum bilirubin. a TSB levels based on hour-specific values as described on the hour-specific bilirubin nomogram. 9

4 Early recognition of neonatal hyperbilirubinemia 217 (mostly ABO isoimmunization), G6PD deficiency (associated with both hemolysis and impaired bilirubin conjugation), and idiopathic causes (presumably from delayed or impaired function of the glucoronyl transferase enzyme system), coupled with breast-feeding and inadequate nutritional intake. The presenting signs of ABE are subtle and non-specific. They can be elicited by direct questioning of the parent of a severely hyperbilirubinemic neonate. Close observation is required to assess clinical progression. The early presenting signs of ABE can be described in terms of the infant s mental status, muscle tone, and cry: feeding difficulties lethargy, with altered awakeesleep pattern irritability and fussiness, difficult to console intermittent arching. If untreated, these might progress to include increasing hypertonia, especially of extensor muscles, with retrocollis and opisthotonus, in association with varying degrees of drowsiness, poor feeding, hypotonia, and alternating tone. 21e23 (Fig. 2). Advanced signs are marked by cessation of feeding, bicycling movements, inconsolable irritability and shrill crying, possible seizures, fever, and coma. These late findings are ominous predictors of the likelihood of severe kernicteric sequelae, even with intensive treatment. To facilitate the accurate documentation of progression of ABE, a scheme for grading the severity of ABE has been described by Volpe. 23 Increasing scores are indicative of worsening BIND and might be of prognostic value (Table 3). These clinical tools can help clinicians understand the progression of BIND. 24,25 BIND abnormalities with progression to scores between 4 and 6 are often reversible. Prompt and effective intervention during the early phases of ABE can prevent chronic kernicteric sequelae. Rapid reduction of the bilirubin load by a combination of intensive phototherapy and exchange transfusion can reduce the extent of brain damage. The rate of progression of clinical signs depends on the rate of bilirubin rise, duration of hyperbilirubinemia, adequacy of albumin binding reserves, level of unbound bilirubin, host susceptibility, and presence of co-morbidities. Death from acute bilirubin Figure 2 Classic signs of acute bilirubin encephalopathy (reproduced, with permission, from Bhutani et al. 11 ). toxicity results from respiratory failure and progressive coma or intractable seizures. Chronic bilirubin-induced neurologic dysfunction Failure to reduce elevated bilirubin levels at a time when neurotoxicity might be reversible can result in substantial long-term morbidity, including choreoathetoid cerebral palsy, sensorineural hearing loss, gaze paresis, dental hypoplasia, and cognitive impairment. The mortality rate approaches approximately 1%. 2 BIND refers to a wide spectrum of disorders caused by severe hyperbilirubinemia. The common insult in all cases of BIND is an elevated TSB level that exceeds the infant s neuroprotective defenses and results in neuronal injury, primarily in the basal ganglia (but also in the hippocampus and cerebellum) and the brainstem nuclei for oculomotor function and hearing. 21e26 The physical findings of chronic, irreversible bilirubin encephalopathy have variable presentations. Typical findings include extrapyramidal movement disorders (dystonia and athetosis), gaze abnormalities, auditory disturbances (especially sensorineural hearing loss with central processing disorders and/or auditory neuropathy), and enamel dysplasia of the deciduous teeth. 21e24,26e28 Cognitive deficits are unusual but can be severe, although they might reflect inaccurate assessment of intelligence in children with hearing, communication and coordination problems. The neuromotor manifestations of extrapyramidal damage are present in almost all cases, but sometimes become apparent only with reinforcement and attempts at skilled movements. 29 Auditory disturbances are almost always present and are both central (brainstem) and peripheral (auditory nerve) in origin. They can be subtle, difficult to diagnose and variable or delayed in clinical expression, and they might be the only apparent residua of ABE. Although not yet proven, some experts believe that there might be additional neurological manifestations of BIND, including subtle basal ganglia and central processing disorders. 16,27,3e32 Clinical management The primary goal for effective and efficient management of neonatal hyperbilirubinemia is to prevent ABE and BIND. The preventive clinical strategies include implementation of the existing American Academy of Pediatrics (AAP) guidelines 6,7 and/or enhancement by a system-based approach. 11e13 All these safety recommendations are geared toward safely and cost-effectively distinguishing those babies who are most likely to have a benign experience with newborn jaundice from those in whom the course is less predictable or potentially unsafe. 12 The US Joint Commission of Accreditation of Hospital Organizations recommends that all hospital and healthcare professionals caring for newborn infants, both in the hospital and after discharge, observe these recommendations cited in the updated AAP clinical practice guidelines. 33 Prior practice parameters developed by the AAP provided useful guidelines for the management of term healthy newborns provided these are followed diligently and with concern. 1,6,7,34 However, they were based predominantly on visual recognition of jaundice and identification of

5 218 H. Smitherman et al. Table 3 Clinical progression of acute bilirubin encephalopathy Clinical evaluation Non-specific, subtle Progressive toxicity Advanced toxicity Score for a clinical sign in each column Ranges of score 1e3 4e6 7e9 Mental status Sleepy C poor feed Lethargy C irritability Semi-coma or seizures Muscle tone Slight decrease Hyper- or hypotonia depending on arousal state or mild nuchal/ truncal arching Markedly increased (opisthotonus), or decreased tone, or bicycling movements Cry High pitched Shrill Inconsolable Adapted from Bhutani et al. 11 An incremental score is assigned for each clinical sign to obtain a maximum of BIND score of 9. Infants with scores of 4e6 usually have reversible ABE. A progression to a higher score is indicative of worsening BIND. 25 As adapted by Volpe. 23 clinical and epidemiological risk factors for severe hyperbilirubinemia. Recent reports and evaluation of safety data have demonstrated that visual assessment of jaundice is unreliable and unsafe. 24,27 Non-invasive skin reflectance meters that produce a bilirubin reading in milligrams per deciliter (TcB) have been studied extensively, shown to correlate well and can act as a reliable index for estimating serum bilirubin levels (TSB) in the newborn. 35e37 Relatively simple and non-invasive, these transcutaneous bilirubinometers can help establish risk, prevent bilirubin inducing morbidity and mortality, and aid in reducing costs. They have been shown to be helpful in pigmented infants. 38e4 Bhutani et al. explored, evaluated 11e13,24,41e43 and proposed a practical, familycentered, safety-oriented, system-based strategy to prevent ABE and kernicterus, which is summarized below. Prompt recognition Clinical recognition of jaundice within the first 24 h of birth is crucial and should require immediate documentation and quantification of severity by TSB and/or transcutaneous bilirubin (TcB) measurement. 44 Institutions are encouraged to develop patient-care protocols and policies that facilitate nurse-initiated objective measurement of bilirubin. Hour-specific bilirubin nomogram A predischarge bilirubin measurement by TSB/TcB measured at the time of blood sampling for metabolic screening can be used in conjunction with an hour-specific bilirubin nomogram 9 to predict the risk of development of subsequent hyperbilirubinemia. The ability to uniformly define the intensity of hyperbilirubinemia for a corresponding age in hours and to accurately identify infants at risk of developing severe hyperbilirubinemia enables the provider to cost-effectively target infants most likely to benefit from closer clinical and laboratory follow up (or new prophylactic therapies), while avoiding the cost and potential harm of intervention for low-risk infants. On the basis of available evidence, all babies should be screened for targeted follow-up of hyperbilirubinemia that is based on an hourspecific TSB measured for risk assessment (Fig. 3). There are currently no evidence-based recommendations for how to manage infants given a specified probability of developing hyperbilirubinemia after hospital discharge and opinions will vary based on the experience of the provider, practice settings, and parental preferences. 11 Table 4 summarizes the management options that we recommend for various predischarge TSB levels. Post-discharge follow-up All babies discharged from a birthing site at less than 72 h of age should have mandatory follow-up appointments with a physician or nurse within 48 h (or within 24 h when deemed at high risk). This visit can also help promote successful breast-feeding. For those babies discharged at 4e 5 days of age (such as when maternal discharge is delayed), follow-up at 1 week of age is generally safe. Babies at high risk for subsequent development of hyperbilirubinemia should be red-flagged so that they can be followed more closely and monitored for non-compliance by follow-up staff (Table 5). Access to outpatient support Parents should have access to support services such as lactation counseling and telephone assessment services to Serum Bilirubin (mg/dl) Rate of TSB rise =.2 mg/dl/hr) High Risk Bilirubin Track (age in hrs) Low Risk BilirubinTrack (age in hrs) Rate of TSB rise =.1 mg/dl/hr) Age (hours) Figure 3 Hour-specific bilirubin nomogram for term and near-term healthy babies showing the rate of total serum bilirubin (TSB) rise, between 24 and 6 h age, for: (1) the high-risk track (95th percentile) at.2 mg/dl per h; (2) the intermediate track (75th percentile) at.15 mg/dl per h; (3) the low-risk track (4th percentile) at.1 mg/dl per h (adapted from Bhutani et al. 11 ).

6 Early recognition of neonatal hyperbilirubinemia 219 Table 4 Postdischarge and follow-up based on predischarge TSB (mg/dl) level (based on the hour-specific bilirubin nomogram) Predischarge TSB level at postnatal age (hour-specific) Discharge only if TSB level is <95th percentile Follow-up within 24 h >75th percentile 48 h <75th percentile 41e44 <12.3 >1. <1. <7.9 45e48 <12.7 >1.4 <1.4 <8.2 49e56 <13.2 >11. <11. <8.7 57e64 <14.7 >12.2 <12.2 <9.4 65e72 <15.5 >13. <13. <1.3 >72 <15.5 >14. <14. <11. TSB recheck optional (unless indicated by clinical risk factors) <4th percentile Adapted from Bhutani et al. 11 TSB, total serum bilirubin. Percentiles refer to established guidelines for healthy, term newborns. 6 address their concerns in a timely fashion. Telephone assessments should respond to parental concerns of newborn jaundice, poor feeding, lactation difficulties, and changes in behavior and activity. Further, ongoing lactation support in breast-feeding babies helps ensure adequacy of intake, especially in those who have lost more than 8% of birth weight. Aggressive transition to therapy Most importantly, clinicians should ensure aggressive transition to treatment with intensive phototherapy and/or exchange transfusion once the need is recognized to prevent severe hyperbilirubinemia. This is discussed at length below. Office-based procedures Severely jaundiced babies can be first seen at the pediatrician s office or clinic. The front office and triage staff should be trained to recognize the early signs of ABE (see above), and be familiar with the need for an urgent approach. Providers should periodically review mechanisms for rapid transfer and admission of hyperbilirubinemic infants directly to inpatient units, ideally a neonatal intensive care unit. Readmission to the birth hospital allows for reduction in delays associated with the performance of the diagnostic work-up. 45 Ideally, all attempts should be made to bypass busy emergency rooms. If travel time exceeds 2e3 min, arrangements should be made for phototherapy during transport. Phototherapy lights (Table 6) should be easily and rapidly accessible and periodically inspected and maintained to ensure proper functioning. Transports should be planned with direct communication with a responsible neonatologist so that care plans can be initiated before and during the transport interval. 11,13 Emergency department protocols Busy emergency departments where exposure to sick and ill individuals and potentially long waiting times are possible should be avoided for relatively stable yet potentially atrisk neonates. 6 Ironically, emergency department visits for neonates have increased since the initiation of early postpartum discharge. 46 For infants who are without a medical home and institutions that lack direct admission procedures, the emergency department (ED) should establish a system-based process of fast tracking. Although much attention has been placed on nursery-based protocols, there is very little information in the literature regarding written emergency-department-based protocols for jaundiced neonates. Even in well-appearing, previously healthy neonates, Table 5 Suggested interventions based on severity of hypberbilirubinemia Severe hyperbilirubinemia at >72 h of age Follow rate of TSB rise and B:A ratio Interventions TSB level >75th percentile TSB level <14 mg/dl..and <.2 mg/dl per h Nutritional support TSB level >95th percentile TSB level >17 mg/dl..and >.2 mg/dl per h Intensive phototherapy at home or in hospital TSB level >98th percentile TSB level >2 mg/dl..and B:A ratio <7. Intensive phototherapy (in hospital) TSB level >99.9th percentile TSB level >25 mg/dl..and/or B:A ratio >7. mg/g Intensive phototherapy and prepare for an exchange transfusion TSB level >99.99th percentile TSB level >3 mg/dl..and/or B:A ratio >7. mg/g Intensive phototherapy and perform an exchange transfusion Adapted from Bhutani et al. 11 B:A ratio, bilirubin to albumin ratio; TSB, total serum bilirubin.

7 22 H. Smitherman et al. Table 6 Modes of phototherapy Home-based (blanket) Hospital-based (intensive) a Source of light Fiber-optic; LED or fluorescent sources Bank of fluorescent lights; LED light source Color of light Special blue Special-blue Spectral reflectance Wide (425e475-nm range) Narrow and specific at 43 nm (425e475-nm range) Irradiance (at skin surface) At least 25 mw/cm 2 per nm 25e35 mw/cm 2 per nm Surface area (exposed) Torso is wrapped; eye patches not needed Entire body-surface (exclude eye patches and diaper area) Adapted from Bhutani et al. 11 a Can be complemented with white halogen lights to cover a wider a surface area (avoid shadows with multiple lights). hyperbilirubinemia should be considered an urgent situation, and triage protocols should reflect this. Texas Children s Hospital (TCH), a tertiary care hospital serving a large urban community, sees more than 85, patients per year. From May 24 to May 25, 289 infants 28 days or younger presented to the emergency department with a chief complaint of jaundice or hyperbilirubinemia. Of those, 114 (39.4%) were discharged home to be followed up as outpatients. Of the 175 admitted, only 22 (12.6%) attempted to bypass the emergency department with a direct admit process. Only 9 (5.1%) patients were treated in the 24-h observation unit, which was new at this time. TCH has initiated a novel protocol for the rapid evaluation and management ( fast-tracking ) of well-appearing jaundiced neonates presenting unavoidably to the emergency department. The protocol, triage algorithm, and pre-printed orders were developed collaboratively by emergency medicine, neonatology, and nursing services and based on the AAP guideline. 6,7 The overall objective is the rapid recognition of risk severity and a reduction in the time to definitive phototherapy and definitive treatment. This algorithm is also intended to triage neonates to an appropriate level of care, thereby limiting additional transfers of care and potentially limiting cost with rapid treatment and more time-efficient discharges. Transcutaneous bilirubinometers have also been widely implemented in nursery care. However, to our knowledge, there have been no reports describing the use of a bilirubinometer as a triage tool in emergency rooms to aid in rapid decision making and final disposition. Fast-tracking well-appearing jaundiced neonates All patients are screened on arrival at the TCH emergency department triage station by a registered nurse. When jaundice or hyperbilirubinemia in a neonate less than 14 days old is identified as a chief complaint or noted by the triage staff, the infant will immediately be assessed for clinical signs of ABE. If the infant appears well, the hyperbilirubinemia in an otherwise well-appearing neonate protocol will be initiated. According to preestablished protocols, the triage staff will perform a TcB reading that will be interpreted according to the infant s age in hours. An attending physician will complete a brief medical screening exam, determine any isolation needs, and verify that the neonate is otherwise asymptomatic. Then, in conjunction with the triage algorithm completed by the physician and triage nurse (Fig. 4), the neonate s disposition will be determined. For example, if the Bilichekä level is less than 12 (mg/dl) in a term (>38 weeks), well-appearing infant more than 24 h old, no phototherapy is needed; the infant can be seen less urgently. Infants with higher TcB levels who appear well, are >38 weeks gestation, and have no known risk factors for neurotoxicity (Fig. 4, left graph) will be placed into the low-risk category, can bypass the emergency department, and be fast-tracked to a 24-h observation unit immediately. Phototherapy will be initiated while confirmatory studies are drawn and registration paperwork is completed. Infants with TcB levels above 12, who are <38 weeks but have no risk factors, or who are >38 weeks gestation with risk factors, are considered to be at medium risk (Fig. 4, middle graph). These neonates are not eligible for the observation unit and will be fast-tracked to an inpatient neonatal unit. Phototherapy will be initiated immediately on arrival to the unit; confirmatory studies and registration paperwork are completed while the neonate is receiving phototherapy. Well-appearing neonates requiring phototherapy, who are <37 weeks gestation, and who have risk factors (Fig. 4, right graph) are considered to be at high risk and will likewise be triaged directly to the neonatal unit after a brief medical screening exam. Infants who need intensive phototherapy and might need an exchange transfusion should generally be admitted to an intensive care unit. Fast-tracking unstable, ill-appearing or symptomatic neonates Infants who are unstable, ill appearing, or symptomatic require urgent evaluation and treatment. Interim resuscitation efforts and procedures should not delay the commencement of phototherapy. This requires immediate availability of phototherapy equipment in the emergency department. Phototherapy lights (Phillips F-2 T12/BB) in the 425e475-nm range should be rapidly accessible and periodically inspected and maintained to ensure proper functioning. Staff in the emergency department should be continually re-educated on the signs and urgency of the treatment of neonatal jaundice and trained in the use of the phototherapy equipment. Treatment should begin even while the airway, breathing, and circulation are being assessed. An immediate transcutaneous bilirubin level should be measured and

8 Early recognition of neonatal hyperbilirubinemia 221 Triage Algorithm: Well-appearing Jaundiced Neonate Age of infant (in hours): Bilirubin level Triage Bilichek: Known total bilirubin in last 24 hours: Risk Factors 1. Was the baby born prematurely (less than 38 weeks)? Yes No (Number of weeks: ) 2. Is the history suggestive of illness? (poor feeding, fever, lethargy) Yes No 3. Does the baby show signs of bilirubin encephalopathy (high-pitched cry, arching, retrocollis)? Yes No 4. Is mom blood type O? Yes No Unknown 5. Is mom Rh negative? Yes No Unknown 6. Is the baby direct Coombs positive? Yes No Unknown 7. Does the baby have or is there a family history of G6PD deficiency? Yes No Unknown Low risk infants: > or = 38 weeks, no risk factors Medium risk infants: > or = 38 weeks + risk factors, OR 35 to 37 6/7 weeks, no risk factors High risk infants: 35 to 37 6/7 weeks, + risk factors Total Serum Bilirubin (mg/dl) Infants at lower risk ( 38wk and well) Infants at higher risk ( /7 wk + risk factors) 96 h 5 Days 6 Days 7 Days Birth 24 h 48 h 72 h 96 h 5 Days 6 Days 7 Days Age Age Birth 24 h 48 h 72 h µmol/l Total Serum Bilirubin (mg/dl) µmol/l If Bilichek < 12, triage as usual If Bilicheck > 12 but below line, order confirmatory capillary bilirubin If Bilichek above line, initiate orders for phototherapy and confirmatory labs in RTA Total Serum Bilirubin (mg/dl) Infants at medium risk ( 38wk + risk factors or /7 wk and well ) Birth 24 h 48 h 72 h 96 h 5 Days 6 Days 7 Days µmol/l If Bilichek < 12, triage as usual If Bilicheck > 12 but below line, order confirmatory capillary labs If Bilichek above line, initiate orders for phototherapy and confirmatory labs in NICU Age Patient name label Figure 4 Emergency department triage algorithm utilizing a transcutaneous bilirubinometer. a blood sample sent to the laboratory for total bilirubin, serum albumin, electrolytes, calcium, and typing and crossmatching for 17 ml/kg of blood (in anticipation of a double-volume exchange transfusion). In the presence of specific signs of ABE, an exchange transfusion is recommended regardless of the TSB level (see below). As part of the TCH protocol, once resuscitation has begun, the arrangements are immediately made to transition care to the neonatologist. Cooperation between services allows rapid transport of the unstable, critically ill neonate to the NICU and a seamless transfer of care. Quality improvement Before implementing this approach, the triage algorithm was applied retrospectively to ten patients through review of medical records. Based on subsequent outcomes, these patients would have been treated appropriately according

9 222 H. Smitherman et al. to the algorithm. In one case, a patient admitted to the intermediate neonatal care unit could have been triaged to the observation unit. As the protocol is used, we will continue to monitor waiting time, appropriateness of triage, timeliness of treatment, and length of hospital stay. Emergent therapy All neonates meeting criteria for phototherapy should be treated with intensive phototherapy (confirmed irradiance of >3 mw/cm 2 per nm) to the entire body surface area with a goal to reduce the bilirubin load by >.5 mg/dl per h. In addition to phototherapy, other measures can be undertaken emergently to reduce the bilirubin load in an effort to reduce the risk of toxic effects from elevated levels of unconjugated serum bilirubin (Table 7). The treating physician should enhance clearance of bilirubindwhether systemic and/or enteral 47e49 dand limit factors that stimulate enterohepatic circulation (allowing deconjugation by intestinal glucurondase because meconium contains 1 mg bilirubin/dl). Asphyxia, hyperosmolarity, and infection should be addressed, as these factors increase the permeability of the bloodebrain barrier and nerve cell membranes to bilirubin. Factors that reduce retention of bilirubin in the circulation should be avoided (e.g. hypoproteinemia), 5 so, before an exchange transfusion, an albumin infusion (1 g/kg) could be considered, especially if serum albumin is low (<3.4 g/dl), although this is controversial. Displacement of bilirubin from existing albumin should be avoided; states of acidosis, hypoglycemia (which increases free fatty acid concentrations), starvation, and hypothermia should be corrected, and exposure to drugs such as sulfisoxizole or moxalactam limited. Consider reduction of bilirubin production by administering immune globulin (IVIG) when the hyperbilirubinemia is attributed to ABO sensitization. 18,51 Exchange transfusions Indications for exchange transfusion in an asymptomatic newborn include: (1) TSB levels >3 mg/dl; 34 (2) failure of intensive phototherapy to produce a dramatic TSB drop of <.5 mg/dl per h or <2 mg/dl drop in 4 h; or (3) an infant with hyperbilirubinemia who has had a successful universal hearing screen and subsequently fails an automated brainstem evoked response (ABR) screen. In these cases, the risk of exchange transfusion is weighed against the risk of bilirubin neurotoxicity (Table 8). Exchange transfusion should be performed immediately in an infant with signs of ABE. Conclusion Pediatricians and other health care providers need an increased concern for newborn jaundiceda problem that is challenging because it is so common and usually benign, yet can be neurologically devastating if left untreated. Unfortunately, visual inspection of jaundice is an unreliable indicator of the severity of hyperbilirubinemia. Although term babies who are ill, preterm neonates, and infants with multiple co-morbidities constitute a group vulnerable to ABE, jaundice is to be watched and treated even in healthy infants. Hence, there have been suggestions to adjust the recommendations for interventions with phototherapy or exchange transfusions, including lower TSB thresholds in the more vulnerable population: near-term (<38 weeks gestation) infants, those at earlier postnatal ages (<72 h), and those with hypoalbuminemia or the presence of co-morbidities. In the setting of early postnatal hospital discharge and cost constraints, a system-based program of education (including parents), surveillance for risk factors and co-morbidities, universal pre-discharge TSB/TcB Table 7 Strategies to reduce the bilirubin load (>95th percentile) and manage acute bilirubin encephalopathy Treatment strategies Modes of therapy Interventions Crash-cart approach Organized team effort See text goal: prompt, rapid and timely reduction of bilirubin load Reduction by rapid systemic clearance (within 2e4h) Intensive phototherapy Blue lights (Phillips F2 T12/BB fluorescent bulbs or LED light source) at an irradiance of >3 mw/cm 2 per nm in the 425e435-nm range. Goal: decrease bilirubin level at >.5 mg/dl per h Exchange transfusion Double-volume (17 ml/kg), iso-volumic exchange conducted over 6e9 min. Goal: rapid and efficient reduction bilirubin load Reduction by enteral clearance Continue and encourage feeding (in babies with BIND score <4) Supplement with formula feeding and expressed breast milk to decrease enterohepatic circulation and increase gastrointestinal clearance of bilirubin Reduction of bilirubin production Control of hemolysis Consider immunoglobulin therapy in presence of blood group incompatibility Inhibition of production Ongoing clinical trials of heme-oxygenase inhibitors Neuroprotection for BIND Enhance albumin binding of bilirubin Consider albumin infusion at a dose of 1 g/kg before an exchange transfusion Systemic support for BIND Intravenous fluid and electrolyte support to supplement enteral nutrition. Provide respiratory support as needed for apnea and respiratory failure Adapted from Bhutani et al. 11 BIND, bilirubin-induced neurologic dysfunction.

10 Early recognition of neonatal hyperbilirubinemia 223 Table 8 Serious adverse events attributed to exchange transfusion In term and near-term infants with hyperbilirubinemia Gestational age (range) Death Resuscitation Sepsis/NEC Embolism Thrombocytopenia Arrhythmia Total (%) 35e42 weeks (n Z 26) 33e34 weeks (n Z 18) e31 weeks (n Z 13) 1 a 8 <28 weeks (n Z 16) Adapted from Bhutani et al. 11 NEC, necrotizing enterocolitis. a Infant with non-immune hydrops. measurement, and a targeted follow-up based on the hourspecific bilirubin nomogram should improve management of jaundice, minimize lapses in care, decrease the occurrence of severe hyperbilirubinemia, and prevent both acute and chronic bilirubin encephalopathy. Although the main focus has been on inpatient/nursery settings, many neonates are discharged home early and develop late-onset hyperbilirubinemia. Future protocols and system-based strategies should focus on the aggressive transition from community providers to their final dispositiondan intervention that must be made expeditiously. Emergent care should consist of rapid access to intensive phototherapy, maintenance of physiologic parameters (oxygenation, acid-base status), administration of albumin or IVIG, and the use of exchange transfusions in extreme cases. ABE and BIND are preventable if recognized early on in the disease process, and practitioners should develop an attitude of zero tolerance. References 1. Bhutani VK, Johnson LH, Shaprio SM. Kernicterus in sick and preterm infants (1999e22): a need for an effective preventive approach. Semin Perinatol October 24;28(5): 3129e5 [Review]. 2. Centers for Disease Control and Prevention. National center on birth defects and developmental disabilities: kernicterus. October 24, 22. Available at, dd/kernicterus2.htm. 3. Brown AK, Johnson L. Loss of concern about jaundice and the reemergence of Kernicterus in full-term infants in the era of managed care. In: Fanaroff AA, Klaus MH, editors. The year book of neonatal and perinatal medicine. Philadelphia: Mosby Yearbook; p. xviiexxviii. 4. A National Framework for Healthcare Quality Measurement and Reporting: A Consensus Report. National Quality Forum 5. Maisels MJ, Gifford KL. Normal serum bilirubin level in the newborn and the effect of breastfeeding. Pediatrics 1986;78: 837e American Academy of Pediatrics Practice Guidelines. Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 weeks or more of gestation. Pediatrics 24;114(1):297e American Academy of Pediatrics Practice Parameter. Management of hyperbilirubinemia in the healthy term newborns. Pediatrics 1994;94:558e Mollen TJ, Scarfone R, Harris MC. Acute severe bilirubin encephalopathy in a newborn. Pediatric Emergency Care September 24;2(9):599e Bhutani VK, Johnson L, Sivieri EM. Predictive ability of predischarge hour-specific bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999;13:6e Stevenson DK, Fanaroff A, Maisels J, et al. Prediction of hyperbilirubinemia in term and near-term newborn infants. Pediatrics 21;18:31e Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in the term neonate: for a safer first week. Pediatr Clin North Am August 24;51(4):843e61, vii. 12. Bhutani VK, Johnson LH, Maisels MJ, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol 24;24(1): Bhutani VK, Johnson LH, Koren R. Treating acute bilirubin encephalopathydbefore its too late. Contemp Pedso 25; 22: Kaplan M, Hercshel M, Hammerman C, Hoyer JD, Stevenson DK. Hyperbilirubinemia among African American, glucose-6-phosphate dehydrogenase deficient neonates. Pediatrics August 24;114(2):e213e Poland RL. Preventing kernicterus: almost there. J Pediatr April 22;14(4):396e Bhutani VK. Neonatal hyperbilirubinemia and the potential risk of subtle neurological dysfunction. Pediatr Res 21;5: Nakamura H, Yonetani M, Uetani Y, Funato M, Lee Y. Determination of serum unbound bilirubin for prediction of kernicterus in low birth weight infants. Acta Paediatr Jpn 1992;34: 642e Funato M, Teraoka S, Tamai H, Shimada S, Nakamura H. Followup study of auditory brainstem evoked responses in hyperbilirubinemic newborns treated with exchange transfusion. Acta Paediatr Jpn 1996;38:17e Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. J Pediatr 1994;93:488e Mollison PL, Cutbush M. Diagnosis and treatment of hemolytic disease in the newborn. Concours Med 18 April 1953;75(16): Jones MH, Sands R, Hyman CB, Sturgeon P, Koch FP. Longitudinal study of the incidence of central nervous system damage following erythroblastosis fetalis. Pediatrics 1954;14: Van Pragh R. Diagnosis of kernicterus in the neonatal period. Pediatrics 1961;28:87e Volpe JJ. Bilirubin and brain injury. In: Neurology of the newborn. 4th ed. Philadelphia: WB Saunders; Johnson L, Brown AK, Bhutani VK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 22;93:488e Johnson L, Brown AK, Bhutani VK. BIND e a clinical score for bilirubin induced neurologic dysfunction in newborns. Pediatrics Suppl 1999;14: Perlstein M. Neurologic sequelae of erythroblastosis fetalis. Am J Dis Child 195;79:65e Soorani-Lunsing I, Woltil A, Hadders-Algra M. Are moderate degrees of hyperbilirubinemia in healthy term neonates really safe for the brain? Pediatr Res 21;5:71e Forrester RM, Miller J. The dental changes associates with kernicterus. Arch Dis Child 1953;3:224e31.

11 224 H. Smitherman et al. 29. Byers RK, Paine RS, Crothers B. Extra pyramidal cerebral palsy with hearing loss following erythroblastosis. Pediatrics 1955; 15:248e Ohlsson A, editor. Neonatal jaundice: continuing concern and need for research. Pediatr Res 21;5: Maisels MD, Newman TB. Bilirubin and neurologic dysfunction e do we need to change what we are doing? Pediatr Res 21;5: Hintz S, Stevenson DK. Just when you thought is was safe. Pediatr Res 21;5:675e Joint Commission on Accreditation of Healthcare Organizations. Sentinel Event Alert 18: Kernicterus Threatens Healthy Newborns; May 2, 21, < newscletters/sentinelceventcalert/sea-18.htm>. 34. AAP Subcommittee on Neonatal Hyperbilirubinemia. Neonatal jaundice and kernicterus. Pediatrics 21;18:763e Bhutani VK, Gourley G, Kreamer BL, Dalin C, Adler SA, Johnson L. Non-invasive measurement of total serum bilirubin in a multi-racial pre-discharge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics 2; 16(2):e Rubaltelli FF, Gourley GR, Loskamp N, et al. Transcutaneous bilirubin measurement: a multicenter evaluation of a new device. Pediatrics 21;17:1264e Ebbeson F, Rasmussen LM, Wimberly PD. A new transcutaneous bilirubinometer, Bilichek, used in the neonatal intensive care unit and the maternity ward. Acta Paediatr 22;91:23e Slusher TM, Angyo IA, Bode-Thomas F, Akor F, Pam SD, Adetunii AA, et al. Transcutaneous bilirubin measurements and serum total bilirubin levels in indigenous African infants. Pediatrics June 24;113(6):1636e Engle WD, Jackson GL, Sendelbach D, Manning D, Frawley WH. Assessment of a transcutaneous device in the evaluation of neonatal hyperbilirubinemia in a primarily Hispanic population. Pediatrics 22;11:61e7. 4. Bhutani VK, Gourley GR, Adler S, Kreamer B, Dalin C, Johnson LH. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics 2; 16:E Johnson L, Bhutani VK. Guidelines for management of the jaundiced term and near-term infant. Clin Perinatol September 1998;25(3):555e Bhutani VK, Johnson LH. Jaundice technologies: prediction of hyperbilirubinemia in term and near-term newborns. J Perinatal 21;21(Suppl. 1):S76e Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics January 1999;13(1):6e Bhutani VK, Johnson LH. Jaundice technologies: prediction of hyperbilirubinemia in term and near-term newborns. J Perinatol 21;21:S76e Garland JS, Alex C, Deacon JS, Raab K. Treatment of infants with indirect Hyperbilirubinemia. Readmission to birth hospital vs nonbirth hospital. Arch Pediatr Adolesc Med 1994;148(12): 1317e Brown AK, Damus K, Kim MH, King K, et al. Factors relating to readmission of term and near-term neonates in the first two weeks of life. Early Discharge Survey Group of the Health Professional Advisory Board of the Greater New York Chapter of the March of Dimes. J Perinat Med 1999;27(4):263e Suresh GK, Clark RE. Cost effectiveness of strategies that are intended to prevent kernicterus in newborn infants. Pediatrics 24;114(4):917e Gourley GR, Kreamer B, Cohnen M, Kosorok MR. Neonatal jaundice and diet. Arch Pediatr Adolesc Med February 1999;153(2): 184e Hansen TWR. Acute management of extreme neonatal jaundice e the potential benefits of intensified phototherapy and interruption of enterohepatic circulation. Acta Pediatr 1997; 86:843e6. 5. Johnson LH, Dalin C, Abbasi S, Weis C, Gerdes JS, Bhutani VK. The importance of measuring serum albumin in excessively hyperbilirubinemic infants. Pediatr Res 2;47:44A. 51. Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev 22;3:CD Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a pre-discharge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics January 1999;13(1):6e Stevenson DK, Fanaroff A, Maisels J, et al. Prediction of hyperbilirubinemia in term and near-term newborn infants. Pediatrics 21;18:31e Martinez JC, Garcia HO, Otheguy LE, Drummond GS, Kappas A. Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. Pediatrics January 1999;13(1):1e Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med 2;154:114e Newman TB, Klebanoff M. Neonatal hyperbilirubinemia and long-term outcome: Another look at the collaborative perinatal project. Pediatrics 1993;92:651e7.