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Slide 1-

Advances in Neonatal Care Thomas Raffay, MD, FAAP Assistant Professor Department of Pediatrics, Division of Neonatology Rainbow Babies and Children’s Hospital Case Western Reserve University Cleveland, Ohio I have no financial interests to disclose
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Objectives: Review the benefits and complications of delayed cord clamping in the delivery room Discuss the role of therapeutic hypothermia in neonatal encephalopathy Review the benefits of exogenous surfactant for respiratory distress syndrome and modes of administration Review non-invasive ventilation strategies in the neonate Discuss the current practices of analgesia and sedation in the neonate
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When available the published meta-analysis of related randomized-controlled, quasi-randomized controlled, or cluster trials were used to arrive at primary and secondary results and include the reviewers’ final conclusions The Cochrane Database of Systematic Reviews was the primary source of meta-analyses presented in this talk or a comparable meta-analysis using search, selection criteria, and reports of bias similar to Cochrane analyses
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Neonatology: Historical Perspectives 1995: 1st Cochrane Review Widespread Antenatal Steroid Use 1989: Commercial Surfactant 1960: Positive Pressure Ventilators 1971: CPAP & HFOV 1973: IMV 1999: iNO Approved by FDA 1986: Triggered Ventilation In Newborn 1975: First Neonatal ECMO Survivor 1967: Northway Describes BPD %Survival to Discharge
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Delayed Cord Clamping
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Delayed Cord Clamping A large volume of blood remains in the umbilical cord and placenta at birth 75 – 120 mL of fetal blood Delaying cord clamping (30 seconds or more) results in an autologous transfusion of baby’s blood and a higher circulating blood volume Alternative: “milking” or “stripping” of the cord
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Delayed Cord Clamping: Historical Aristotle, “It often happens that the child appears to have been born dead when it is merely weak, and when before the umbilical cord has been ligatured, the blood has run out into the cord and its surroundings. But experienced midwives have been known to squeeze back the blood into the child's body from the cord, and immediately the child that a moment before was bloodless came back to life again.”
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Delayed Cord Clamping: Delivery Room Management (AAP/NRP & ACOG) For vigorous term and preterm infants, cord clamping should be delayed for 30 – 60 seconds Infant placed skin-to-skin, wrapped, and warmed – begin initial steps of newborn care Contraindications: bleeding from placental abruption /previa or cord avulsion Unclear benefits in multiple gestations, IUGR, abnormal placentation, and nonvigorous newborn Delivery plan made with OB and Neonatal teams
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Delayed Cord Clamping: Term Neonate Benefits: Increased hemoglobin and birth weights Decreased risk of developing iron-deficiency anemia during infancy No beneficial nor adverse maternal outcomes No improvements in mortality, NICU admission, or childhood neurodevelopmental outcomes
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Delayed Cord Clamping: Preterm Neonate Benefits: Fewer post-natal transfusions for anemia Higher mean blood pressures and less need for inotropic drugs Decreased risk for intraventricular hemorrhage (IVH, all grades) Decreased risk for necrotizing enterocolitis (NEC) No clear changes in mortality, Respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), or neurodevelopmental outcomes
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Delayed Cord Clamping: Complications Risks (both term and preterm) Increased circulating blood resulting in polycythemia Increased bilirubin levels and risk for hyperbilirubinemia and need for phototherapy Potential delay in resuscitation – although no differences reported in preterm cord gas pH, APGARs, intubation/surfactant, or hypothermia
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Delayed Cord Clamping: Future Directions Further evaluation of optimal duration and circumstance (multiples, IUGR, fetal distress) Cord “milking” in the nonvigorous newborn Timing of uterotonic agents after birth Long-term outcomes (including immunity)
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Delayed Cord Clamping: Summary ACOG and AAP recommendations for 30 – 60 second delay in all vigorous infants More clear benefits of delayed cord clamping in the preterm population Monitor for hyperbilirubinemia Before birth, establish a plan for the timing and immediate resuscitation with obstetric and newborn provider
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Therapeutic Hypothermia
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Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy Peripartum asphyxia occurs in 4-5 per 1000 live births, a quarter of these newborns have subsequent signs of moderate or severe neonatal encephalopathy (1.5 per 1000) Note: the cause and timing is typically not clear – only 20% of hypoxic-ischemic injury was directly identified to an antepartum insult In clinical trials, rates of death or disability may be as high as 65%
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Therapeutic Hypothermia: Pathophysiology of Hypoxia Ischemia Complex bi-phasic biochemical cascade initiated with hypoxia-ischemia leading to neuronal necrosis or apoptosis Hypothermia targets the secondary phase of energy failure, attenuating delayed neuronal death Fanaroff & Martin’s Neonatal-Perinatal Medicine, 10th ed
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Therapeutic Hypothermia: 11 Trials Population (>1500 infants): Infants >35wk gestation Peripartum asphyxia (acidosis, low 10 min APGAR, PPV at 10 min) and moderate/severe neonatal encephalopathy or seizure Hypothermia Intervention: Initiated in first 6 hours of life Whole body or head cooling (32.5-35.4° C) 48 – 72 hours in duration
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Therapeutic Hypothermia: Outcomes Decreased mortality (number needed to benefit 11) Decreased major neurodevelopmental disability at 18 months in survivors (NNTB 8) Less likely to have abnormal MRI findings The most benefit in neurodevelopmental disability was observed in patients with moderate encephalopathy At 6 to 7 years of age, decreased mortality remained significant but neurodevelopmental impairments were no longer statistically different
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Therapeutic Hypothermia: Safety Potential Risks Sinus bradycardia/arrhythmias Thrombocytopenia Leukopenia Subcutaneous fat necrosis Pulmonary hypertension
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Therapeutic Hypothermia: Remaining Questions/Dilemmas Strict entry criteria: timing, GA, pH, APGARs, resuscitation, neuro exam Benefits in mild neuroencephalopathy? Caution: “Clinical creep” leading to therapy ineffectiveness or harms Limited to first 6 hours of life Passive or active cooling at referring community hospital or in transport
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Therapeutic Hypothermia: Future Directions Late Cooling (initiated 6-24 hours of life) Optimized Cooling (longer and/or lower) Cooling in Preterm Infants (32–35 wks GA) Cooling with ECMO Cooling for Metabolic Encephalopathy
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Therapeutic Hypothermia: Summary Has become the standard of care for neonatal encephalopathy Improves mortality and neuro-disability (NNT 7) Early referral (w/in 6 hours of life) to tertiary center for concerns for hypoxia-ischemia and encephalopathy Ongoing trials to expand therapy and test adjunct therapies
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Exogenous Surfactant
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Respiratory Distress Syndrome Previously known as “Hyaline Membrane Disease” Results from insufficiency of the pulmonary surfactant system → low compliance and alveolar collapse
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RDS Epidemiology Most common cause of morbidity and mortality in preterm infants Incidence at 23wk is ~100% Incidence at 29wk is 60% Incidence at 39wk near 0% Incidence of RDS by gestational age (A) and birth weight (B)
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What is surfactant? “Surface Active” protein Synthesized/processed/packed/secreted/recycled by Alveolar Type II Cells Composed of 90% lipids and 10% proteins Made in the Endoplasmic Reticulum and Golgi Bodies Stored in Lamellar bodies Secreted and form tubular myelin reservoir Tubular myelin forms a multilayer film at air-liquid interface Recycled in Alveolar Type II cell or cleared by Alveolar Macrophage Alveolar Space Surfactant Lamellar Body Alveolar Type II Cell Alveolar Type I Cell Alveolar Macrophage Lipid Vesicle Monolayer-Multilayer Film Turnover Recycling Clearance M Hallman. NEJM 2004 Adsorption Secretion Tubular Myelin Air Liquid Golgi Complex Endoplasmic Reticulum
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LaPlace Formula What is surfactant? “Surface Active” protein: predominantly phosphatidylcholine Decreases surface tension of the alveolus
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Exogenous Surfactant: Benefits Widely available and used since the 1990’s Synthetic or animal-derived Greatest benefit with antenatal corticosteroids and if delivered early in RDS course Improves lung compliance, oxygenation, and FRC Reduces the severity and mortality of RDS Reduced mortality in LBW infants (unresolved if it changes BPD incidence alone) Reduces the incidence of air leak syndromes Does not inhibit endogenous surfactant synthesis
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Exogenous Surfactant: Complications Common: Desaturation Bradycardia Apnea Less Common: Pulmonary hemorrhage Pneumothorax Hypotension
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Exogenous Surfactant: Comparing Types Bovine derived: Lung Lavage vs Minced No differences in mortality or incidence of chronic lung disease Minced Bovine (beractant) vs Minced Porcine (poractant alpha) Porcine: Decreased mortality before discharge Porcine: Decreased risk of death or oxygen requirement at 36 weeks CGA (BPD) Porcine: less need for second surfactant dose and less treatment for patent ductus arteriosus (PDA) Comparative trials showing superiority used a higher initial dose of poractant No differences in trials of bovine lavage vs minced porcine
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Exogenous Surfactant: Comparing Types Animal derived vs Protein-free Synthetic Animal: greater improvement in weaning early ventilator support and decreased risk of pneumothorax Animal: decreased risk of mortality or chronic lung disease Animal: increased risk of necrotizing enterocolitis (NEC) and intraventricular hemorrhage (IVH, all grades)
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Exogenous Surfactant: Modes of Delivery Mode of delivery in placebo trials: intubation for RDS and instillation of fluid suspension via ETT Early surfactant (<2-3 hours) shows improved outcomes Yet, even several large volume/high pressure PPV breaths may damage the immature lung and result in BPD INSURE: Intubate-SURfactant-Extubate LISA: Less Invasive Surfactant Administration MIST: Minimally Invasive Surfactant Therapy LMA: Laryngeal Masked Airway administration Nebulization: aerosolized surfactant
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Exogenous Surfactant: INSURE Delivery Prophylactic INSURE vs CPAP infants were intubated, received surfactant, and immediately extubated to minimize mechanical ventilation, if necessary sedation would be reversed No benefits (death and/or BPD) of early prophylactic surfactant with INSURE vs CPAP and rescue surfactant >60% of infants failed to extubate after INSURE leading to longer duration of mechanical ventilation Conclusion: Routine stabilization on CPAP demonstrated a decrease in the risk of death or BPD in infants successfully stabilized on CPAP. Practical: Better to start with CPAP support in DR if possible and intubate and administer surfactant only to infants with signs of RDS/worsening respiratory failure (within first 2-3 hours of life)
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Exogenous Surfactant: LISA/MIST Delivery LISA In an infant on CPAP, a thin catheter is placed between the vocal cords with the aid of Magill forceps under direct laryngoscopy; surfactant is administered during spontaneous breathing Improved oxygenation and end-expiratory volume MIST A rigid vascular catheter is placed between the vocal cords without the use of Magill forceps; surfactant is similarly administered during spontaneous breathing Similar results to LISA
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Exogenous Surfactant: LISA/MIST Delivery LISA/MIST vs Intubation and surfactant Significant reduction in death and/or BPD Decreased risk of intraventricular hemorrhage (IVH, Grades 3&4) More likely to remain extubated at 72 hours Less need for mechanical ventilation during duration of hospitalization LISA/MIST vs CPAP alone Significant reduction in death and/or BPD Decreased risk of air leaks Some controversy over pre-medication: use of premedication increased need for PPV and intubation potentially diminishing positive effects of LISA/MIST
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Exogenous Surfactant: LMA Delivery The laryngeal mask airway (LMA) is a supraglottic device that is usually used to apply positive pressure ventilation for a short time
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Exogenous Surfactant: LMA Delivery Small trials of LMA delivery of surfactant LMA surfactant shown to improve oxygenation Compared to INSURE, infants less likely to require subsequent mechanical ventilation (likely due to INSURE pre-medication) LMA used as a guide for MIST catheter placement LMA placement has not yet been proven feasible in the smallest of infants (<1 kg) who would benefit most from less invasive surfactant administration methods
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Exogenous Surfactant: Nebulization Studies using jet nebulizers in the late 90’s had very low surfactant deposition (<1%) and thus did not show convincing evidence in treatment of RDS More recent studies have utilized vibrating perforated membrane nebulizers (>14% lung deposition) which have shown improved oxygenation in a RDS feasibility pilot study Vibrating Perforated Membrane Pillow & Minocchieri. Neonatology. 2012;101(4):337-44.
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Exogenous Surfactant: Nebulization Powdered surfactant protein aerosolizers are also being developed to deliver concentrated recombinant surfactant protein (SP-C) Not currently recommended, but ongoing controlled-trials of surfactant nebulization may soon provide additional evidence in RDS
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Exogenous Surfactant: Delivery Summary Niemarkt, et al. Neonatology 2017;111(4):408-414
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Exogenous Surfactant: Summary CPAP ventilation (with or without exogenous surfactant) may reduce the need for intubation, decrease risk for death and/or BPD An exogenous surfactant bolus (animal or synthetic) is most effective if given early and in the setting of antenatal steroids The least invasive mode of “effective” surfactant delivery should be utilized, minimizing need/duration of PPV or IMV
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Non-invasive Ventilation
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Non-invasive Ventilation 1960’s - Neonatal intermittent PPV via ETT Many newborn lives saved by mechanical ventilation but its adverse effects are well documented Instability during intubation ETT airway trauma and infections Volutrauma, barotrauma, and shear stress 1971 – George Gregory and colleagues described neonatal CPAP in infants <1500g via an ETT and pressurized head chambers Multiple iterations: negative thoracic pressure vests, cut-down ETT, face masks/bags, nasal masks, nasal prongs (single and double lumen)
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Non-invasive Ventilation Numerous neonatal trials comparing use of non-invasive respiratory support Objective: compare meta-analyses of head-to-head trails on immediate outcomes, complications, incidence of chronic lung disease, and extubation success
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Non-invasive Ventilation: CPAP Nasal CPAP is a noninvasive method for applying a constant distending pressure to the lungs via the nostrils CPAP preserves spontaneous breathing, does not require endotracheal intubation, and thus may result in less lung injury than mechanical ventilation
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Non-invasive Ventilation: CPAP CPAP vs Mechanical Ventilation (+/-surfactant) in RDS CPAP: Reduced incidence of death or BPD CPAP: Decreased need for mechanical ventilation and the use of surfactant Prophylactic CPAP vs supportive care (<32wk GA) CPAP: Reduced treatment failure (defined as: recurrent apnea, hypercarbia, or hypoxemia requiring rescue CPAP or mechanical ventilation) No significant reductions in death, BPD, or other secondary outcomes
Slide 47-

Non-invasive Ventilation: CPAP CPAP after extubation in preterm infants Compared to oxygen hood, CPAP reduced incidence of apnea, respiratory acidosis, and hypoxemia Did not effect rate of endotracheal reintubation when comparing initial vs rescue CPAP Interpretation: CPAP can be used to prevent respiratory instability following extubation in preterm infants, but cannot rescue an infant from needing reintubation
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Non-invasive Ventilation: Modes of CPAP Continuous flow (single level), bubble flow, bi-level/biphasic flow Bubble CPAP BiPhasic CPAP
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Non-invasive Ventilation: Modes of CPAP Meta-analysis reviews have not found convincing evidence of superiority or inferiority of modalities on failure rates in management of respiratory distress, mortality, chronic lung disease, or post-extubation failure Conventional flow CPAP vs Bubble CPAP post-extubation resulted in reduced overall duration of CPAP support BiPhasic CPAP for RDS resulted in shorter duration of CPAP support and supplemental oxygen BiPhasic CPAP post-extubation showed no differences in 7 day success rates Of note, bubble CPAP is a low-cost system available in resource-limited countries that compares favorably with higher-cost systems
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Non-invasive ventilation: High Flow Nasal Cannula High flow nasal cannulae (HFNC) are small, thin, tapered binasal tubes that deliver oxygen or blended oxygen/air at gas flows of more than 1 L/min in preterm infants Heated/humidified gas delivery is preferable Functions by O2 delivery and CO2 “wash-out” in pharynx, but HFNC systems are capable of creating distending pressure (CPAP equivalent) Possibility of unmeasured and variable PEEP
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Non-invasive ventilation: High Flow Nasal Cannula HFNC vs CPAP in initial management of RDS No differences in rates of death or BPD Rates of intubation within 1st week were not significantly different HFNC vs CPAP after extubation in preterm infants No differences in rates of death or BPD No differences in rate of treatment failure/reintubation HFNC: reduced nasal trauma and pneumothorax
Slide 52-

Nasal Intermittent Positive Pressure Ventilation (NIPPV) and Intermittent Mechanical Ventilation (NIMV) Noninvasive ventilation during which patients are exposed intermittently to higher levels of airway pressure, along with NCPAP through the same nasal device Limitations of ventilator flow sensor do not allow for accurate synchronization of high pressure “breaths” In the Vermont Oxford Network, NICU’s use of NIPPV has increased from 10% in 2006 to 33% in 2015
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NIPPV/NIMV NIPPV vs CPAP for initial management of RDS NIPPV decreased rates of respiratory failure and need for intubation No observed change in risk for death or BPD No evidence of harm reported NIPPV vs BiPhasic CPAP for RDS (2 center RCT) No differences found in failure/reintubation or duration of support No differences in death or BPD, IVH, pneumothorax, or other secondary outcomes
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NIPPV/NIMV NIPPV vs CPAP after extubation of preterm infant NIPPV: Reduced extubation failure and reintubation at 48 hours and 7 days post-extubation NIPPV: Decreased incidence of air leaks No difference in incidence of death or BPD
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Synchronized NIPPV Sub-group analysis of synchronized vs non-synchronized NIPPV for initial RDS management Increased risk of respiratory failure and intubation if synchronized No differences between mortality, BPD, and air leaks Sub-group analysis of synchronized vs non-synchronized NIPPV after extubation Reduced risk of BPD and air leaks if synchronized Is synchronization important? Likely underpowered and were not true head-to-head comparisons
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Synchronized and High-Frequency NIPPV Number of synchronization methods: nasal flow synchronized, abdominal impedance sensor or band, and neurally adjusted ventilatory assist (NAVA) sensor at level of diaphragm High-Frequency NIPPV eliminates of the need for synchrony by delivering high-frequency small tidal volume respirations
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Neurally Adjusted Ventilatory Assist (NAVA) Electrodes embedded within a specialized catheter are positioned in the esophagus detecting the timing and magnitude of the electrical activity of the diaphragm Potential to synchronize initiation, size, and termination of NIPPV with each patient breath
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Non-invasive Ventilation: Summary Nasal CPAP has been extensively studied and remains the gold-standard of noninvasive ventilatory support for the premature newborn Reasonable to manage very premature infants on NCPAP from delivery Reduces mortality and/or BPD compared to mechanical ventilation Reduces respiratory instability and need for extra support after extubation NIPPV likely augments the benefits of NCPAP HFNC may be equivalent to NCPAP
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Analgesia and Sedation in the NICU
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Analgesia and Sedation in the NICU Only since the early 80’s has it become widely accepted that infants, particularly premature infants, are readily capable of experiencing pain – and treatment of pain improves outcomes Recurrent neonatal pain alters brain neurophysiology/chemistry and reduces brain maturation Related to impaired postnatal growth, permanently higher cortisol levels, poorer motor and cognitive development
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Analgesia and Sedation in the NICU Nociception (“tissue injury”) neurons are present early in gestation Neurophysiological afferent pain pathways reach the cortex between 20 and 26 wk GA Simons and Tibboel. Sem in F etal and Neo Med. 11(4) 2006. 227-31
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Analgesia and Sedation in the NICU By 24 wk GA somatosensory cortex responses are observed in response to heel-stick, and these magnitudes increases with age NICU audits estimate that neonates undergo an average of 4-16 painful exposures/day that may benefit from analgesia (observational audits describe ~50% accompanied by some form of pain-relieving intervention)
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Non-pharmacological Treatment Skin-to-skin – decreases pain measures in both term and preterm infants during painful procedures (also effective with non-mother provider) Breast-feeding – lower pain response to needle puncture in term infants Breast milk – via pacifier or syringe as effective as pharmacologic sucrose solution Sensorial stimulation – when all 4 elements used (tactile, gustatory, auditory, visual) more effective than pharmacologic sucrose solution
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Pharmacological Treatment Sucrose – safe and effective for reducing pain from single events in infants as low as 22 wk GA. Greatest efficacy if given 2 min prior to event with effects lasting approximately 4 mins. Non-opioids – Paracetamol (acetaminophen) when used for postoperative pain control reduced the overall need of opioids Opioids – most common agent for persistent or surgical pain, recommended for elective intubations Benzodiazipines – limited evidence of efficacy with concerns for potential harm (increased mortality, length of stay, poor neurological outcomes) Other agents (ketamine, propofol, methadone, clonidine, and dexmedetomidine) – limited or no evidence of efficacy or safety in neonates
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Pharmacological Treatment for Elective/Non-emergent Intubation Tracheal intubation significantly raises arterial blood pressure, decreases oxygenation and heart rate, and increases intracranial pressure – premedication attenuates these adverse physiologic responses Premedication reduces the time and number of attempts to complete intubation, while minimizing the potential for airway injury
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Pharmacological Treatment for Elective/Non-emergent Intubation In 2010 the American Academy of Pediatrics recommended premedication for all nonemergency neonatal intubations A short-acting analgesic agent plus a vagolytic and rapid-onset muscle relaxant More studies are needed to determine the optimal pharmaceutical agents and combinations
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Pharmacological Treatment for Neonates on Mechanical Ventilation Opioid analgesics in mechanically ventilated preterm infants Reduced Premature Infant Pain Profile scores No difference in mortality, duration of mechanical ventilation, or neurodevelopmental outcomes Increased feeding intolerance and hypotension Morphine vs Midazolam Both reduced pain scores, but an increase in poor neurologic outcomes were reported with midazolam Clonidine added to fentanyl and/or versed gtt if >4 days of MV No difference in mortality or duration of mechanical ventilation Conclusion: Insufficient evidence for routine use, but should consider morphine over midazolam when clinically indicated
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Adverse Effects of Opioids Respiratory depression Potential to increase duration of mechanical ventilation Hypotension Dependence, tolerance, and withdrawl Urinary and stool retention/constipation Feeding intolerance Prospective cohort of very premature neonates reported that a 10-fold increase in morphine exposure was associated with a decrease in cerebellar volume at term and poorer motor and cognitive outcomes at 18 months
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Analgesia and Sedation: Summary Infants experience pain, and repeated painful procedures have the potential for short and long-term adverse consequences Assessment of neonatal pain is necessary Consider non-pharmacological strategies (+/- sucrose) for short-term, mild-moderate procedures Opioids and/or paracetamol treatment are indicated for procedural pain relief Premedication improves intubation success and attenuates physiologic instability Selective (not routine) opioid use in mechanically ventilated neonates can be used as determined by clinical assessment More data is needed on efficacy and safety of other analgosedatives in neonates
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Advances in Neonatal Care – Take-Away’s Delayed Cord Clamping – Good! (particularly for premies) Therapeutic Hypothermia – Great! (restrictive qualifications but NNT 7) Surfactant – Great! (“Greatest” if you can avoid intubation/PPV) Non-invasive Ventilation – Good and getting better! (CPAP/HFNC/NIPPV > intubated on SIMV) Pain – Bad! Analgesia – Good! (Better recognition and use of non-pharm)
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Advances in Neonatal Care Thank you!
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References Klaus and Fanaroff’s Care of the High-Risk Neonate. 6th ed. 2013: Fig 19-1 Fanaroff & Martin’s Neonatal-Perinatal Medicine, 10th ed Bennet L. The art of cord clamping: sparing the linen or sparing the child? J Physiol. 2013;591(Pt 8):2021–2022. Evid Based Child Health. 2014 Jun;9(2):303-97 – Cochrane update Cochrane Database Syst Rev. 2012 Aug 15 Cochrane Database Syst Rev. 2013 Jan 31;(1): Volpe. Neurology of the Newborn 5th ed Cochrane Database Syst Rev. 2013 Jan 31;(1): 11 Cochrane Database Syst Rev. 2015 Dec 21;(12 Cochrane Database Syst Rev. 2015 Aug 24;8: Neonatology. 2017;111(4):408-414 Cochrane Database Syst Rev. 2012 Mar 14;(3): BMC Pediatr. 2014 Jun 19;14:155. Isayama JAMA. 2016;316(6):611-624 Arch Dis Child Fetal Neonatal Ed. 2017 Jan;102(1):F17-F23 Cochrane Database Syst Rev. 2011 Jul 6;(7):CD008309. Pinheiro JM J Perinatol. 2016 Mar;36(3):196-201. Vannozzi J Matern Fetal Neonatal Med. 2017 Oct;30(19):2375-2377. Cochrane Database Syst Rev. 2012 Oct 17;10 Pillow JJ Neonatology. 2012;101(4):337-44. Finer N. J Aerosol Med Pulm Drug Deliv 2010; 23: 303–309. Pohlmann GJ Aerosol Med Pulm Drug Deliv. 2013 Dec;26(6):370-9. Subramaniam P1, Ho JJ, Davis PG. Cochrane Database Syst Rev. 2016 Jun 14;(6):CD001243 Davis PG1, Henderson-Smart DJ. Cochrane Database Syst Rev. 2003;(2): Ho JJ1, Subramaniam P, Davis PG Cochrane Database Syst Rev. 2015 Jul 4;(7): De Paoli AG1, Davis PG, Faber B, Morley CJ Cochrane Database Syst Rev. 2008 Jan 23;(1):CD002977 Agarwal S1, Maria A2, Roy MK3, Verma A3 J Clin Diagn Res. 2016 Sep;10(9):SC09-SC12 Martin S1, Duke T2, Davis P3 Arch Dis Child Fetal Neonatal Ed. 2014 Nov;99(6):F495-504 J Pediatr. 2009 May;154(5):645-50 Lista G1, Castoldi F, Arch Dis Child Fetal Neonatal Ed. 2010 Mar;95(2):F85-9 O'Brien, C. Campbell, L. Brown BMC Pediatr, 12 (2012), p. 43 Wilkinson D1, Andersen C, O'Donnell CP, De Paoli AG, Manley BJ Cochrane Database Syst Rev. 2016 Feb 22;2:CD006405 Lemyre B1 Cochrane Database Syst Rev. 2016 Dec 15;12:CD005384 Li W Pediatr Pulmonol. 2015 Apr;50(4):402-9. Salvo V1 Pediatrics. 2015 Mar;135(3):444-51 Lemyre B Cochrane Database Syst Rev. 2017 Feb 1;2:CD003212 Firestone NeoReviews 2017;18;e413 Simons and Tibboel. Sem in F etal and Neo Med. 11(4) 2006. 227-31 Lim Y1, Godambe S2. Arch Dis Child Educ Pract Ed. 2017 Jul 19. Stevens B1, Yamada J, Ohlsson A, Haliburton S, Shorkey A. Cochrane Database Syst Rev. 2016 Jul 16;7:CD001069. Ohlsson A, Shah PS. Cochrane Database Syst Rev. 2016 Oct 7;10:CD011219 Ng E1, Taddio A2, Ohlsson A3 Cochrane Database Syst Rev. 2017 Jan 31;1:CD002052 Kimberly A. Allen Adv Neonatal Care. 2012 Apr; 12(2): 107–111 Kumar P Pediatrics. 2010 Mar;125(3):608-15. Bellù R1 Arch Dis Child Fetal Neonatal Ed. 2010 Jul;95(4):F241-51 Bellù R1 Cochrane Database Syst Rev. 2008 Jan 23;(1):CD004212. Romantsik O. Cochrane Database Syst Rev. 2017 May 10;5:CD012468. Zwicker JG1 J Pediatr. 2016 May;172:81-87.e2