BOOK
Neonatal Hyperbilirubinemia in Preterm Neonates, An Issue of Clinics in Perinatology, E-Book
David K. Stevenson | Vinod K. Bhutani
(2016)
Additional Information
Book Details
Abstract
Preterm neonates remain at increased risk for adverse bilirubin-related outcomes, including acute bilirubin encephalopathy relative to term infants. Yet, most vulnerable neonates are likely to benefit from the potent anti-oxidant properties of bilirubin. Evidence-based guidelines for the management of hyperbilirubinemia in preterm infants, however, are lacking. High concentrations of unconjugated bilirubin can cause permanent neurologic damage in infants, evident through magnetic resonance imaging of chronic bilirubin encephalopathy or kernicterus. There is a growing concern that exposures to even moderate concentrations of bilirubin may lead to subtle but permanent neurodevelopmental impairment referred to as bilirubin-induced neurologic dysfunction. Our current use of phototherapy to decrease bilirubin loads and its potential photo-oxidant properties is a biological conundrum that has been questioned in the use of phototherapy for very low birth weight neonates. In this issue of Clinics in Perinatology, we provide updates on the current understanding of the biology, mechanisms of increasing bilirubin load due to hemolysis, decreased bilirubin binding capacity and glucose-6-phosphate dehydrogenase deficiency, as well as clinical strategies to operationalize the thresholds for hyperbilirubinemia interventions in preterm infants.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | Cover | ||
| NeonatalHyperbilirubinemia inPreterm Neonates | i | ||
| Copyright\r | ii | ||
| Contributors | iii | ||
| CONSULTING EDITOR | iii | ||
| EDITORS | iii | ||
| AUTHORS | iii | ||
| Contents | vii | ||
| Foreword: Why the Premature Brain Is More Prone to Bilirubin-induced Injury\t\r | vii | ||
| Preface: Preterm Neonates: Beyond the Guidelines for Neonatal Hyperbilirubinemia\r | vii | ||
| Hyperbilirubinemia in Preterm Neonates\r | vii | ||
| Hemolysis in Preterm Neonates\r | vii | ||
| Bilirubin Binding Capacity in the Preterm Neonate\r | vii | ||
| A Pharmacologic View of Phototherapy\r | viii | ||
| Biology of Bilirubin Photoisomers\r | viii | ||
| Phototherapy and the Risk of Photo-Oxidative Injury in Extremely Low Birth Weight Infants\r | viii | ||
| Bilirubin-Induced Neurotoxicity in the Preterm Neonate \r | viii | ||
| Bilirubin-Induced Audiologic Injury in Preterm Infants\r | ix | ||
| The Preterm Infant: A High-Risk Situation for Neonatal Hyperbilirubinemia Due to Glucose-6-Phosphate Dehydrogenase Deficien\r | ix | ||
| Glucose-6-Phosphate Dehydrogenase Deficiency and the Need for a Novel Treatment to Prevent Kernicterus\r | ix | ||
| Cholestasis in Preterm Infants\r | ix | ||
| Development of a Web-Based Decision Support Tool to Operationalize and Optimize Management of Hyperbilirubinemia in Preterm \r | x | ||
| CME Accreditation Page | xi | ||
| PROGRAM OBJECTIVE | xi | ||
| TARGET AUDIENCE | xi | ||
| LEARNING OBJECTIVES | xi | ||
| ACCREDITATION | xi | ||
| DISCLOSURE OF CONFLICTS OF INTEREST | xi | ||
| UNAPPROVED/OFF-LABEL USE DISCLOSURE | xi | ||
| TO ENROLL | xi | ||
| METHOD OF PARTICIPATION | xi | ||
| CME INQUIRIES/SPECIAL NEEDS | xii | ||
| Foreword:\rWhy the Premature Brain Is More Prone to Bilirubin-induced Injury | xv | ||
| REFERENCES | xvi | ||
| Preface:\rPreterm Neonates: Beyond the Guidelines for Neonatal Hyperbilirubinemia | xvii | ||
| REFERENCES | xviii | ||
| Hyperbilirubinemia in Preterm Neonates | 215 | ||
| Key points | 215 | ||
| INTRODUCTION | 215 | ||
| NATURAL BILIRUBIN PROFILE IN PRETERM NEONATES | 217 | ||
| Prevalence and Incidence | 217 | ||
| Bilirubin Burden | 218 | ||
| CLINICAL PROFILE OF SUBTLE POSTICTERIC SEQUELAE | 219 | ||
| Auditory Dysfunction | 219 | ||
| Visuocortical Dysfunction | 220 | ||
| Integrity of Brainstem Function and Structure | 220 | ||
| BENEFICIAL ROLE OF BILIRUBIN | 221 | ||
| BENCH EVIDENCE OF BILIRUBIN NEUROTOXICITY IN PRETERM NEONATES | 221 | ||
| MARGINS OF CLINICAL SAFETY | 222 | ||
| CLINICAL CARE STRATEGIES | 223 | ||
| Timing of Interventions to Reduce Excessive Bilirubin Load | 223 | ||
| Triage for a Jaundiced Preterm Newborn with Suspicious Clinical Neurologic Signs | 224 | ||
| Emergency Interventions for Rapid Reduction of Bilirubin Concentrations | 224 | ||
| Albumin Infusion | 226 | ||
| Intravenous Gamma Immunoglobulin | 226 | ||
| Phenobarbital | 226 | ||
| Metalloporphyrins | 226 | ||
| FOLLOW-UP OF PRETERM INFANTS AT RISK FOR BILIRUBIN-INDUCED NEUROLOGIC DYSFUNCTION | 227 | ||
| SUMMARY | 227 | ||
| REFERENCES | 228 | ||
| Hemolysis in Preterm Neonates | 233 | ||
| Key points | 233 | ||
| WHAT IS HEMOLYSIS? | 233 | ||
| HOW IS HEMOLYSIS RECOGNIZED IN A JAUNDICED PRETERM INFANT? | 234 | ||
| WHAT IS THE RISK TO A PRETERM INFANT IN WHOM A DONOR RED BLOOD CELL TRANSFUSION WILL RESULT IN A RISE IN TOTAL SERUM/PLASMA ... | 235 | ||
| AFTER IDENTIFICATION OF HEMOLYSIS IN A JAUNDICED PRETERM INFANT, HOW IS EXACT CAUSE FOUND? | 238 | ||
| SUMMARY | 239 | ||
| REFERENCES | 239 | ||
| Bilirubin Binding Capacity in the Preterm Neonate | 241 | ||
| Key points | 241 | ||
| INTRODUCTION | 241 | ||
| Bilirubin–Albumin Biochemical Structure and Binding | 242 | ||
| Bilirubin–Albumin Binding Capacity and Affinity | 242 | ||
| Bilirubin–Albumin Binding as a Function of Gestational Age and Postnatal Age | 244 | ||
| Clinical Risk Factors and Bilirubin–Albumin Binding | 244 | ||
| Phototherapy and Bilirubin–Albumin Binding | 245 | ||
| Exogenous Drugs and Bilirubin–Albumin Binding | 245 | ||
| Intralipid and Bilirubin–Albumin Binding | 246 | ||
| Bilirubin:Albumin Molar Ratio and Risk for Bilirubin-Induced Neurotoxicity | 247 | ||
| Bilirubin–Albumin Binding and Neurodevelopmental Outcomes in Premature Infants | 248 | ||
| SUMMARY | 251 | ||
| REFERENCES | 252 | ||
| A Pharmacologic View of Phototherapy | 259 | ||
| Key points | 259 | ||
| INTRODUCTION | 259 | ||
| Light, Photons, Light Absorption, and Photochemistry: Photons as Drug Units | 260 | ||
| Management of Unconjugated Neonatal Hyperbilirubinemia: Indications for Phototherapy | 262 | ||
| Body burden of bilirubin | 262 | ||
| Bilirubin/albumin binding status | 262 | ||
| Measures of phototherapy efficacy | 263 | ||
| Optical Properties of Neonatal Skin: Action Spectrum and Hematocrit Dependence of Phototherapy | 263 | ||
| Skin optics | 263 | ||
| Action spectrum | 264 | ||
| Hematocrit dependence | 265 | ||
| Bilirubin: Structure, Properties, and Photochemistry | 266 | ||
| 4Z,15Z-bilirubin | 266 | ||
| Configurational isomers (E isomers) | 266 | ||
| Lumirubin | 268 | ||
| Photo-oxidation products | 268 | ||
| Excretion Rates of Photoproducts: Relative Roles in Phototherapy | 268 | ||
| Z,E-bilirubin excretion | 268 | ||
| Lumirubin excretion | 269 | ||
| Configurational versus structural isomerization | 269 | ||
| Other Factors in the Optimization of Phototherapy | 270 | ||
| Is there a limiting irradiance for phototherapy? | 270 | ||
| Continuous versus cycled (intermittent) phototherapy | 270 | ||
| Is the production of photoproducts beneficial without excretion? | 271 | ||
| High-risk, very low gestational age, and low body weight infants | 271 | ||
| Oxidative stress | 272 | ||
| Optimum phototherapy light source | 272 | ||
| RESEARCH GAPS | 273 | ||
| REFERENCES | 274 | ||
| Biology of Bilirubin Photoisomers | 277 | ||
| Key points | 277 | ||
| INTRODUCTION | 277 | ||
| BILIRUBIN TOXICITY | 278 | ||
| TYPES OF BILIRUBIN PHOTOPRODUCTS | 279 | ||
| BINDING OF BILIRUBIN ISOMERS | 279 | ||
| IN VIVO MODELS OF MEMBRANE PASSAGE | 280 | ||
| IN VITRO TOXICITY STUDIES | 282 | ||
| CLINICAL IMPLICATIONS | 285 | ||
| SUMMARY | 285 | ||
| REFERENCES | 287 | ||
| Phototherapy and the Risk of Photo-Oxidative Injury in Extremely Low Birth Weight Infants | 291 | ||
| Key points | 291 | ||
| INTRODUCTION | 291 | ||
| PHOTOTHERAPY USE IN EXTREMELY LOW BIRTH WEIGHT INFANTS | 292 | ||
| VULNERABILITY OF EXTREMELY LOW BIRTH WEIGHT INFANTS | 292 | ||
| SUMMARY/DISCUSSION | 294 | ||
| REFERENCES | 294 | ||
| Bilirubin-Induced Neurotoxicity in the Preterm Neonate | 297 | ||
| Key points | 297 | ||
| INTRODUCTION | 297 | ||
| NEUROPATHOLOGY OF KERNICTERUS | 298 | ||
| NEUROIMAGING OF KERNICTERUS | 298 | ||
| MOLECULAR AND CELLULAR MECHANISMS OF BILIRUBIN NEUROTOXICITY | 299 | ||
| Bilirubin and Membranes | 299 | ||
| Excitotoxicity | 299 | ||
| Neuroinflammation | 301 | ||
| Oxidative Stress | 302 | ||
| Bilirubin and Intracellular Calcium Homeostasis | 302 | ||
| Perturbed Cell Cycle Kinetics, Cell Cycle Arrest, Altered Neurogenesis | 302 | ||
| Central Nervous System Immaturity | 303 | ||
| Future Basic Research Efforts | 304 | ||
| Clinical Manifestations of Bilirubin-Induced Central Nervous System Injury in the Preterm Neonate | 304 | ||
| Acute bilirubin encephalopathy | 304 | ||
| Chronic bilirubin encephalopathy | 305 | ||
| Auditory-predominant kernicterus | 305 | ||
| Low-Bilirubin Kernicterus | 305 | ||
| Hypoalbuminemia | 307 | ||
| Subtle kernicterus (bilirubin-induced neurologic dysfunction) | 307 | ||
| REFERENCES | 308 | ||
| Bilirubin-Induced Audiologic Injury in Preterm Infants | 313 | ||
| Key points | 313 | ||
| INTRODUCTION | 313 | ||
| MECHANISMS OF BILIRUBIN-INDUCED NEUROLOGIC DAMAGE | 314 | ||
| PRETERM INFANTS ARE PARTICULARLY VULNERABLE TO BILIRUBIN-INDUCED NEUROLOGIC DAMAGE | 315 | ||
| BILIRUBIN-INDUCED NEUROLOGIC DAMAGE AND THE AUDITORY BRAINSTEM RESPONSE | 315 | ||
| AUDITORY NEUROPATHY SPECTRUM DISORDER | 316 | ||
| SPEECH AND LANGUAGE DISORDERS | 316 | ||
| THE UTILITY OF TOTAL SERUM/PLASMA BILIRUBIN LEVELS IN SCREENING FOR BILIRUBIN-INDUCED NEUROLOGIC DAMAGE | 317 | ||
| BENEFITS AND DRAWBACKS OF NEWBORN HEARING SCREENING | 317 | ||
| IS BILIRUBIN-INDUCED NEUROLOGIC DAMAGE AUDITORY DAMAGE REVERSIBLE? | 318 | ||
| SUMMARY | 318 | ||
| REFERENCES | 319 | ||
| The Preterm Infant | 325 | ||
| Key points | 325 | ||
| INTRODUCTION | 326 | ||
| Glucose-6-Phosphate Dehydrogenase Deficiency and Prematurity as Coexisting Risk Factors for Neonatal Hyperbilirubinemia | 326 | ||
| Glucose-6-phosphate dehydrogenase deficiency: the scope of the problem | 326 | ||
| Medical complications associated with glucose-6-phosphate dehydrogenase deficiency | 326 | ||
| Favism and acute hemolytic episodes | 326 | ||
| Extreme neonatal hyperbilirubinemia | 327 | ||
| Moderate neonatal hyperbilirubinemia | 327 | ||
| Prematurity: added risk for neonatal hyperbilirubinemia | 327 | ||
| Glucose-6-phosphate dehydrogenase deficiency and prematurity: a synergistic, potentially dangerous, combination | 328 | ||
| Glucose-6-phosphate dehydrogenase deficiency, prematurity, and uridine diphosphate-glucuronosyltransferase 1A1 (TA)7 gene p ... | 328 | ||
| IMBALANCE BETWEEN BILIRUBIN PRODUCTION AND ELIMINATION: THE BASIS OF NEONATAL HYPERBILIRUBINEMIA | 329 | ||
| Imbalance Between Bilirubin Production and Conjugation Demonstrated Mathematically | 329 | ||
| Production-conjugation index in glucose-6-phosphate dehydrogenase-normal newborns | 329 | ||
| The production-conjugation index in glucose-6-phosphate dehydrogenase-deficient neonates | 329 | ||
| The greater risk of glucose-6-phosphate dehydrogenase-deficient premature newborns demonstrated mathematically | 330 | ||
| CLINICAL REPORTS OF HYPERBILIRUBINEMIA IN GLUCOSE-6-PHOSPHATE DEHYDROGENASE-DEFICIENT PRETERM NEWBORNS | 330 | ||
| Clinical Series | 330 | ||
| Case Reports | 331 | ||
| DIAGNOSIS OF GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY IN PREMATURE INFANTS | 333 | ||
| Glucose-6-Phosphate Dehydrogenase-Adequate Premature Infants | 333 | ||
| Glucose-6-Phosphate Dehydrogenase-Deficient Premature Infants | 334 | ||
| PREVENTION AND TREATMENT OF HYPERBILIRUBINEMIA IN PRETERM, GLUCOSE-6-PHOSPHATE DEHYDROGENASE-DEFICIENT NEWBORNS | 334 | ||
| Prevention | 334 | ||
| Treatment | 334 | ||
| Extreme hyperbilirubinemia | 334 | ||
| Moderate hyperbilirubinemia | 334 | ||
| Neonatal Screening for Glucose-6-Phosphate Dehydrogenase Deficiency | 334 | ||
| PRETERM INFANTS REQUIRING BLOOD OR EXCHANGE TRANSFUSION | 335 | ||
| Should Preterm Infants Receive Only Glucose-6-Phosphate Dehydrogenase-Normal Blood? | 336 | ||
| SUMMARY AND BEST PRACTICES | 336 | ||
| REFERENCES | 336 | ||
| Glucose-6-Phosphate Dehydrogenase Deficiency and the Need for a Novel Treatment to Prevent Kernicterus | 341 | ||
| Key points | 341 | ||
| INTRODUCTION | 341 | ||
| HYPERBILIRUBINEMIA AND KERNICTERUS | 342 | ||
| GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY | 342 | ||
| GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY INCREASES THE RISK OF NEONATAL HYPERBILIRUBINEMIA AND KERNICTERUS | 343 | ||
| HOW DOES GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY CONTRIBUTE TO KERNICTERUS? | 343 | ||
| HOW TO PREVENT KERNICTERUS? | 346 | ||
| Strategies to Reduce Total Bilirubin Levels | 347 | ||
| Treatment with Antioxidants | 347 | ||
| Restoring Endogenous Glutathione: Activating Glucose-6-Phosphate Dehydrogenase | 347 | ||
| REFERENCES | 350 | ||
| Cholestasis in Preterm Infants | 355 | ||
| Key points | 355 | ||
| INTRODUCTION | 355 | ||
| INCIDENCE | 356 | ||
| ETIOLOGY AND PATHOPHYSIOLOGY | 356 | ||
| Anatomic and Functional Immaturity | 356 | ||
| Parenteral Nutrition | 357 | ||
| Intestinal Injury | 357 | ||
| Sepsis | 358 | ||
| Medications | 359 | ||
| Other Specific Diseases | 359 | ||
| CLINICAL EVALUATION | 361 | ||
| Laboratory | 361 | ||
| Radiologic | 363 | ||
| Liver Biopsy | 363 | ||
| MANAGEMENT | 363 | ||
| Medical | 363 | ||
| Ursodeoxycholic acid | 363 | ||
| Cholecystokinin | 364 | ||
| Erythromycin | 364 | ||
| Nutritional | 364 | ||
| Enteral nutrition | 364 | ||
| Cycling parenteral nutrition | 364 | ||
| Lipid dose reduction | 365 | ||
| Alternative parenteral lipids | 365 | ||
| Enteral fish oil | 365 | ||
| Vitamin E | 366 | ||
| Catheter Locks | 366 | ||
| Multidisciplinary Rehabilitation | 366 | ||
| Organ Transplantation | 367 | ||
| SUMMARY AND DISCUSSION | 368 | ||
| REFERENCES | 368 | ||
| Development of a Web-Based Decision Support Tool to Operationalize and Optimize Management of Hyperbilirubinemia in Preterm ... | 375 | ||
| Key points | 375 | ||
| INTRODUCTION | 375 | ||
| DEVELOPMENT OF THE CLINICAL DECISION SUPPORT TOOL | 376 | ||
| Operationalizing Consensus-Based Recommendations | 376 | ||
| The Clinical Decision Support Tool: “Premie BiliRecs” | 377 | ||
| Process for Electronic Medical Record Integration | 378 | ||
| Limitations | 381 | ||
| GENERATION OF NEW KNOWLEDGE | 381 | ||
| SUMMARY | 382 | ||
| ACKNOWLEDGMENTS | 382 | ||
| REFERENCES | 382 | ||
| Index | 385 |