Hot Topics in Neonatology: A review of new technologies, concepts, and information

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Hot Topics in NeonatologyA review of new
technologies, concepts, and information

• May 2, 2006
• David E. Kanter, MD
• Division of Newborn Medicine
• Sinai Hospital of Baltimore

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Objectives

• Discuss new ideas in the nutritional management
  of the premature infant.
• Introduce and discuss the concepts surrounding
  hypothermia as a treatment for neonatal
  hypoxic-ischemic encephalopathy
• Review long term outcomes of premature infants.
• Introduce new concepts in neonatal resuscitation.

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Late at night, and without permission, Reuben
would often enter the nursery and perform
experiments in static electricity.
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Can Altering Neonatal Intestinal Flora Reduce the
Risk of Necrotizing Enterocolitis?

• Human intestine is host to many nonpathologic
  bacteria.
• Newborn intestinal tract is essentially sterile
  at birth
• Colonization occurs in the first 12-24 hours
  after birth
• First organisms are E. coli and enterococci
• Shortly thereafter anaerobes begin to predominate
• Preterm intestine tends to be colonized with
  different organisms than the term infant

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Alteration of Normal Flora

• Delay in normal colonization
• Infection control measures
• Reduced exposure to maternal bacterial milieu
• Sterile feeds
• Incubators
• Antibiotics
• Used frequently
• May predispose to development of resistant gut
  flora

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Necrotizing Enterocolitis (NEC)

• NEC is the most common GI emergency in preterm
  infants
• Some reports with gt 10 incidence in infants less
  than 1500 grams
• Mortality ranges from 25-30 with long term
  morbidity of up to 25 in survivors
• Complex etiology with interactions between
  bacterial milieu, enteral feedings and intestinal
  blood supply

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Probiotics !!!

• Probiotic bacteria are live microbial supplements
  that colonize the intestine and provide benefit
  to the host.
• Bifidobacterium
• Lactobacilli
• Saccharomyces

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Probiotic Effects

• Normalization of gut flora
• Protection against colonization by pathogens
• Decrease in proinflammatory cytokines
• Increase in anti-inflammatory cytokines
• Reduction in sepsis secondary to reduced
  bacterial translocation
• Improved tolerance to enteral nutrition

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Clinical Effects

• Several studies have shown that colonization of
  the premature intestine with non-pathogenic
  microorganisms is possible.
• Many studies of preterm infants at risk for NEC
  show benefit from probiotic supplementation.
• Reduction in incidence and severity of NEC
• Improved weight gain
• Improved feeding tolerance
• Decreased gastric aspirates

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Probiotics and NEC
Your amazing newborn, Hot topics in Neonatology
presentation slide by Dr. Klaus 2005
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Is it safe?

• Potential complications
• Sepsis
• Meningitis
• Soft tissue infection
• Endocarditis
• Bowel inflammation
• Gastric distension
• Gas / Flatulence

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Is it safe?

• Supplementation of infants with probiotics began
  in the 1950s
• No adverse side effects have been documented to
  date in preterm subjects
• 143 human clinical trials from 1961-1998
• Concerns for sepsis occurred in only the severely
  immunocompromised

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Clinical Unknowns

• Timing
• When to start?
• How often to give?
• Dose
• How much to give at each time?
• Bacterial Mix
• How many species and in what proportions?
• Additions to supplements
• Prebiotics unabsorbable, nondigestible food
  ingredients that act as a substrate for probiotics

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Hypothermia for Neonates with Hypoxic-Ischemic
Encephalopathy

• Whole Body Hypothermia
• vs.
• Selective Head Cooling

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Hypoxic-Ischemic Encephalopathy (HIE)

• Defined as a neonatal encephalopathy due to
  hypoxic-ischemic brain injury.
• 1-2 cases in 1000 births
• Many causes
• Different severity levels
• Moderate encephalopathy carries a 10 mortality
  and 30 risk of severe disability for survivors
• Severe encephalopathy carries a 60 mortality
  with nearly 100 severe neurological morbidity in
  survivors

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Hypothermia as a Treatment for HIE

• Studies have shown that hypoxic ischemic injury
  can be reduced by brain cooling.
• Favorable effect on many of the pathways
  contributing to brain injury
• Excitatory amino acids
• Cerebral energy state
• Cerebral blood flow and metabolism
• Nitric oxide production
• Apoptosis

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Mechanism of Action
Hypothermia modulates all these areas in the
cascade of neuronal damage and death
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Selective Head Cooling

• CoolCap Study
• 234 term infants with moderate to severe neonatal
  encephalopathy and abnormal EEG
• Randomized within 6 hours of birth to treatment
  or control
• Head cooling group kept at 34-35o C for 72 hours
  with cooling cap on head and mild systemic
  hypothermia controlled by radiant warmer.
• Analysis of subgroups within study group also
  done (i.e. moderate vs. severe encephalopathy)

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Whole-Body Hypothermia

• NICHD Neonatal Research Network Study
• 208 infants meeting criteria randomized within 6
  hours after birth.
• Infants in hypothermia group placed on 2 cooling
  blankets and esophageal temperatures were kept at
  33.5o C for 72 hours.
• Primary outcome measures were death or disability
  by 18 to 22 months of age.
• 44 of infants in hypothermia group died or had
  moderate to severe disability
• 63 of infants in the control group died or had
  moderate to severe disability

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More on Hypothermia

• Brain can be cooled by cooling the body or the
  head selectively
• Whole body cooling provides homogeneous cooling
  of all brain structures both peripheral and
  central.
• Selective head cooling provides greater cooling
  to the periphery of the brain
• Most effective when applied and restricted to
  secondary phase of HI injury
• Animals studies show rebound effect if cooling is
  terminated at either 24 or 48 hours.
• No rebound noted after 72 hours
• Critical duration of cooling unknown.

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Is It Safe?

• No significant differences in adverse events
  between control and hypothermic infants in either
  large trial.
• More studies need to be conducted before
  widespread applicability and safety can be
  ascertained.

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So should we be using it?

• The Committee on Fetus and Newborn concluded
  that
• Therapeutic hypothermia should be considered
  investigational until the short-term safety and
  efficacy have been confirmed. Long-term safety
  and efficacy remain to be defined.
• Additional trials are needed that would define
  the most effective cooling strategies.
• Registries of infants with perinatal
  encephalopathies should be established to
  facilitate data collection regarding diagnoses,
  treatments, and outcomes.
• Longer-term follow-up at least through early
  school age is essential

PEDIATRICS Vol. 117 No. 3 March 2006, pp. 942-948
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Therapies Needing Further Evaluation

• Used singly or in combination with hypothermia
• Glutamate antagonists
• Calcium channel antagonists
• Drugs that limit intracellular calcium release
• NMDA receptor blockade
• Xanthine oxidase inhibitors
• Free radical scavengers

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Long Term Outcomes

• Only a few longitudinal studies have examined
  VLBW infants and ELBW infants for gt 20 years
• Major recent studies from US, Europe and Canada
  have significantly different outcomes
• Socioeconomic class
• Access to health care
• Parental education
• Long term disability or chronic illness

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Outcomes in Young Adulthood for VLBW Infants

• 242 survivors born between 1977-1979 weighing
  less than 1500 grams with a mean gestational age
  of 29.7 weeks.
• Inner city population in Cleveland
• Group initially studied at 8 years
• Current study extends the follow up to 20 years
• 233 normal term controls born in the same period
  with similar demographics.

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Hack M, et al N Engl J Med, Vol. 346, No.3
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• Educational attainment
• Fewer VLBW participants had achieved GED or high
  school graduation than controls
• 74 vs. 83 (p0.04)
• VLBW participants had repeated a grade more
  frequently
• 40 vs. 27 (p0.003)
• Fewer VLBW men enrolled in post-secondary
  education
• 16 vs. 44 (p0.001)

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Hack M, et al N Engl J Med, Vol. 346, No.3

• VLBW participants had significant lower IQ scores
  and lower scores on subtests of academic
  achievement.
• 51 vs. 67 had an IQ score in the normal range

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Hack M, et al N Engl J Med, Vol. 346, No.3

• VLBW participants reported significantly lower
  rates of risk taking behaviors.
• Lower rates of alcohol and illicit drug use
• Lower rates of intercourse, pregnancy and births

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Adult Outcomes of ELBW Infants

• 166 long term survivors born between 1977-1982 at
  501-1000g birth weight.
• Born in central west Ontario
• Mean age at study assessment was 23.3 years
• 145 normal birth weight (NBW) controls recruited
  at 8 years of age
• Matched for age, sex and sociodemographic
  variables

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Transition to Adulthood

• Markers
• Educational attainment
• Employment
• Marriage
• Parenthood
• Study describes differences in attainment of
  these progressive markers in ELBW and control
  groups

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Results

• No significant differences found between the
  groups in education
• 15 ELBW vs. 11 NBW had lt high school education
• 32 ELBW vs. 33 NBW were still pursuing
  post-secondary education
• Half of both cohorts had permanent employment
• Significant difference in the characteristics of
  those unemployed
• 47 ELBW vs. 7 NBW had chronic
  illness/disabilities

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Results

• A similar proportion of the cohorts were married
  and/or parents.
• 23 vs. 25 were married
• 11 vs. 14 were parents
• Age of attainment of these markers were similar
  for both these groups

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Conclusion

• Socio-demographic group has a tremendous effect
  on outcome of VLBW and ELBW infants as they grow
  to adulthood and attain the socially accepted
  norms of transition to adulthood.

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Changes to the NRP

• Oxygen use in neonatal resuscitation
• Meconium suctioning at perineum
• Devices for assisting ventilation
• Use of CO2 detectors
• Laryngeal mask airway
• Epinephrine dosage
• Temperature control

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Changes to the NRP

• Use of oxygen during neonatal resuscitation
• Term infants
• Guidelines recommend use of 100 O2 if infant is
  cyanotic or requiring positive pressure
  ventilation.
• Research suggests that less than 100 may be just
  as successful.
• If resuscitation is started with less than 100
  then 90 seconds should be given to assess
  improvement. If no improvement, then 100 should
  be given.

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Changes to the NRP

• Use of oxygen during neonatal resuscitation
• Preterm infants
• Use of an oxygen blender and pulse oximeter is
  now recommended for every premature delivery.
• Positive pressure ventilation can be started with
  an oxygen concentration less than 100.
• Oxygen should be titrated based on saturations to
  keep pulse oximeter readings around 90. O2
  should be weaned if saturations rise above 95.
• If a facility does not have blenders or pulse
  oximeters and there is not time to transfer the
  mother to another facility, 100 oxygen may be
  used.

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Meconium Suctioning

• No longer recommended that all meconium stained
  infants routinely receive intrapartum suctioning.
• Large randomized controlled trial with 2514
  babies of at least 37 weeks gestation
• No benefit to routine suctioning before delivery
  of shoulders
• Suctioning does not prevent meconium aspiration
  syndrome

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Devices for Assisting Ventilation

• T-piece CPAP delivery devices now recognized as
  another method of delivering effective
  ventilation during resuscitation
• Cardin valve
• NeoPuff
• Anesthesia and self inflating bags still primary
  mode of resuscitation
• CPAP devices do not work if newborn is apneic

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Themoregulation

• Modest hypothermia in at risk term newborn
• Those at high risk for hypoxic injury may benefit
  from decreased warming during resuscitation.
• Premature infants need more than radiant warmers
  provide
• Mounting evidence supports wrapping of infants
  less than 30 weeks to prevent rapid loss of body
  heat.

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There is always more to come!Thank you