PDA with Left-To-Right Shunt ▪ Elevated Venous Pressure from Tension Pneumothorax Or Excessive Ventilator Pressures

Alphabet Soup of Preemie Problems… Developmental Care, IVH, PVL

Tanya Hatfield, MSN, RNC-NIC 2 Objectives

Upon completion of this presentation the participant will be able to:

▪ Identify developmental and physiological differences between the term and premature infant ▪ Identify various stressors experienced by the preemie in the ICN and discuss evidence based methods to reduce them ▪ Describe evidence based nursing interventions designed to enhance the normal development of the preterm and term ill neonate

3 Brain Development

(Giedd, 1999) Brain Development

▪ Brain development is activity-dependent • experiences and stimuli "shape" the way the connections are made. • different beginnings foster different end points • Interventions can increase cell maturation, such as environmental enrichment So why is developmental care crucial?

6 This is what we are working with…

7 Developmental care Goal is to optimize -Early life exposure development by providing predicts future outcomes an environment and later in life experiences that support -Neurons that fire physiologic stability and together wire together allow for brain -THRIVE not just survive development and growth of the extremely low birth reduce morbidities as weight infant much as possible

8 “Everything Matters” Dr. Heidelise Als Normal newborn behavior and development

▪ Regulation/State Cycling ▪ Posture ▪ Movement Patterns ▪ Attention

10 Premature Infants‐ Developmental Consequences Evolution of developmental delay is evident by term equivalent • Compared to full term infants: • Poor orientation (p<.001) • Poor tolerance of handling (p<.001) • Poor self regulation (p<.001) • More sub-optimal reflexes (p<.001) • More stress (p<.001) • More hypertonicity (p<.001) • More hypotonia (p<.001) • More excitability (p=.007)

Pineda, Bobbi. "Neurobehavioral Assessment Of High-Risk Infants In The NICU". (2016): n. pag. Web. 11 Five Subsystems of Behavioral Organization

1. Autonomic or Physiologic 2. Motor 3. State a. Attention or Interactional b. Self-regulation

12 13 Neurobehavioral Organization and Facilitation- Autonomic

Signs of stress- tachypnea, irregular breathing, gasping, pallor, cyanosis, sneezing, yawns, hiccups, straining with defecation, tremors, twitches of extremities

Signs of stability- smooth, regular breathing, stable pink color, no twitching or tremors

Interventions- Reduce light, noise and activity, hand containment, slowly awaken, pace feeds, minimize sleep disruptions, position appropriately, manage pain

14 (Verklan and Walden, 2015) Neurobehavioral Organization and Facilitation- Motor

Signs of stress- hyper or hypotonia, unable to maintain flexed, aligned posture, stiff extension of extremities, frequent squirming or flailing movement to little to no movement Signs of stability- consistent reliable tone for PMA, improving or well-maintained posture, less self-stimulating motor arousals, hands to mouth, activity consistent with environment Interventions- support rest/sleep, minimize stress, provide boundaries/positioning aids/containment, encourage skin-to- skin

15 (Verklan and Walden, 2015) Neurobehavioral Organization and Facilitation- Sleep State

Signs of stress- Restlessness, movement, responsive to environment

Signs of stability- quiet restful sleep, less movement, less responsive to environment

Interventions- ▪ Age appropriate positioning that promotes comfort ▪ Quiet dim environment without interruption ▪ Position with hands to face/mouth

16 (Verklan and Walden, 2015) Neurobehavioral Organization and Facilitation- Awake State (attention/interaction)

Signs of stress- low level arousal, hyperalert, prolonged awake periods, difficult to console

Signs of stability- alert, eyes that can focus on object/person. Robust crying, but able to be consoled with intervention

Interventions- ▪ Encourage parent holding, STS ▪ May be ready for eye contact at 30-32 weeks ▪ Support awake moments with age appropriate activity

17 (Verklan and Walden, 2015) Neurobehavioral Organization and Facilitation- Self-Regulation

Without self-regulation- Little attempt to flex or tuck body, few attempts to push against boundaries, sucking a pacifier may be stressful

Strategies for self-regulation- foot boundaries, hands grasped together, hand to mouth/face, grasping blanket, position changes Interventions- ▪ Swaddle exams, have another person for support ▪ Swaddle & provide boundaries, hands to mouth ▪ Provide pacifier when awake and at times other than exams/procedures

18 (Verklan and Walden, 2015) Neurobehavioral Organization and Facilitation- State Transitions

Signs of stress- Rapid state transitions, unable to move to drowsy when stressed

Signs of stability- Transitions smoothly from high arousal to quiet alert or sleep, focused attention, maintains quiet alert without stress

Interventions- ▪ Encourage parenting to support skill, cue recognition ▪ Avoid rapid disruption of state behavior ▪ Assist return to sleep ▪ Provide auditory and visual stimulation*

19 (Verklan and Walden, 2015) In what state is it most appropriate to interact with an infant?

1. Active alert 2. Quiet Alert 3. Drowsy transitional 4. Light sleep

20 Watson, R. (2007). Core review for neonatal intensive care nursing. Philadelphia, Pa.: Elsevier Saunders. Developmental Assessment & Response

Cues Clues

Physical & behavioral Reasons for response? stability vs stress Stress cues?

Consider Response

Nursing Intervention or facilitation

Connect Patterns of Behavior

Cues that happen every exam & weight

Communicate Developmental Plan

1. Containment during exams and weights

21 (Verklan and Walden, 2015) Core Measures of Developmental Care

Protected Sleep

Assessment and Management of Stress and Pain

Developmentally Supportive Daily Living Activities

Family-Centered Care

Healing Environment

22 (Verklan and Walden, 2015) Impact of NICU Environment - Physical

▪ Healthy environments for NICU design • Single-patient rooms • Social Impact ▪ Skin and development • First sense to develop • Interface for development

23 (Verklan and Walden, 2015) Impact of NICU Environment - Sound

▪ Sound vs NOISE ▪ AAP recommends ambient noise to be less that 45-dB ▪ Ototoxic meds and noisy environment may both contribute to hearing loss ▪ Potential for atypical development of auditory pathways

24 (Verklan and Walden, 2015) Source Sound Level (dB) Potential Effects Sound in the ICN Airplane engine 130 Pain/ hearing loss

RockFindings music show that many high120 amplitude levels (70 dB or above) are related to staff activities Heavy traffic 80-90 ▪ Closing drawers Snapping isolette portholes 110!!! shut▪ Trash can lids Placing▪ Incubator hard objects ports andon top drawers 77-84 Prolonged exposure at this of isolette level can cause hearing ▪ Laughter and conversation loss MedAAP pump has alarms recommended NICU77-84 noise should not exceed 45 dB

Overhead pages 79

3 people talking at the 73-84 Interrupts sleep patterns same time

Water in vent tubing 62

25 Impact of NICU Environment - Light

▪ Vision is the last sense to develop ▪ Early light leads to • Interference with auditory discrimination pathways • Problems with peripheral vision, motor coordination, disconjugate gaze & visual processing disorders

▪ Mismatch in sensory input may alter neuronal connections and organization ▪ Negatively influence later development Developmental Care Practices

▪ Care necessitates a collaborative team with family participation ▪ Positioning interventions depend on infant’s needs • Flexion, containment midline alignment regardless of position • Use of aids to support ▪ Utilize slow transfer with flexion and containment ▪ Utilize infant feeding cues to determine feeding readiness Positioning

▪ Therapeutic positioning can influence normal alignment & neuromotor control

▪ Limited intrauterine space promotes “physiologic flexion”

▪ Correct and incorrect positioning affects the neurobehavioral organization, musculoskeletal development and neuromotor functioning Positioning Goals ▪ Decrease the effects of gravity ▪ Prevent musculoskeletal deformity ▪ Promote sensory motor development ▪ Provide boundaries & postural support ▪ Enhance self-regulatory behavior through good positioning ▪ Promote skin integrity ▪ Nurturing to promote long-term development ▪ Neutral or ▪ Elbow flexion slightly flexed neck ▪ Hands to face or midline ▪ Gently rounded shoulders ▪ Hips partially flexed and ▪ Trunk slightly adducted and rounded with knee flexion pelvic tilt ▪ Secure boundaries for foot bracing

30 Outcomes of Poor Positioning

▪ Skull flattening on sides of the head ▪ Decreased depth of rib cage ▪ Hip external rotation and abduction (frog legs) ▪ Retraction and abduction of shoulders (W) ▪ External tibial torsion ▪ Increased neck extension with head preference

Prone ▪ Facilitates flexion and head control ▪ Improves oxygenation ▪ Keep hips and knees flexed ▪ Knees under hips • Flexed and close to the body ▪ Hands near mouth ▪ Head to side Prone

Yes!

No! Prone Supine

▪ Time on back will decrease severity of head molding

▪ Keep shoulders flexed with hands on chest or abdomen

▪ Hips and knees flexed

▪ Symmetry throughout • No hip rotation Supine Do’s Supine “Don’ts” Side Lying

▪ Chin tucked with head to midline, arms forward with hands to face or mouth, hips and knees flexed Side Lying 41 (Morris, 2016) Anatomy!! ▪ Ventricles ▪ Intraventricular Foramen ▪ Cerebral aqueduct ▪ Choroid plexus ▪ Germinal matrix

Introductory sentence Arial – 21pt font 42 Anatomy!!

Introductory sentence Arial – 21pt font 43 Germinal Matrix ▪ Highly vascularized and poorly supported • Involutes over time ‒ 23-24 weeks 2.5 mm width ‒ 32 weeks 1.4 mm width ‒ 36 weeks involute

44 IVH Pathogenesis

Thought to be caused by capillary bleeding. ▪ Major factors: • Intra-vascular factors ‒ Loss of cerebral autoregulation ‒ Abrupt alterations in cerebral blood flow and pressure • Vascular factors ‒ Germinal matrix-vulnerable to hypoxia ‒ Reperfusion injury • Extravascular factors ‒ Poor vascular support in cerebral tissue

45 IVH Risk Factors

Abrupt changes in cerebral circulation ▪ Rapid changes in PaCO2 ▪ Rapid changes in aortic pressure • Rapid infusion of volume expander • Excessive increase in vasopressor infusion • Noxious procedures ‒ suctioning, PIV insertion, CT insertion, loud noises, aggressive handling ▪ Large PDA with left-to-right shunt ▪ Elevated venous pressure from tension pneumothorax or excessive ventilator pressures

46 IVH Timing and Progression

▪ May begin in utero, but usually begins after birth ▪ Hemorrhages may be small at first, then progress to larger hemorrhages later ▪ Most large or progressive IVH’s begin in the first week of life

47 Surveillance for Intracranial Hemorrhage in ELBW Infant ▪ Stable neonate • HUS at end of the first week of life • If HUS normal repeat at 1 month of age • Repeat HUS sooner if infant has a predisposing event or deteriorates ‒ Weekly head circumference measurements

48 Symptoms of IVH

▪ Majority are asymptomatic • Dx is cranial ultrasound ‒ 4th day 90% detected ‒ Serial ultrasounds ▪ Symptomatic (common) • Changes in LOC, movement, tone, respirations, • Symptomatic (uncommon) catastrophic deterioration • Coma, posturing, seizures, bulging fontanelle/split sutures, hematocrit drop, bradycardia, hypotension, temperature instability, hypoglycemia, metabolic acidosis

49 IVH ▪ Diagnostic: • Cranial ultrasound (serial) – Papile Classification (1988): ‒ Grade I: Subependymal hemorrhage in the periventricular germinal matrix. ‒ Grade II: Partial filling of the lateral ventricles without ventricular dilation. ‒ Grade III: Intraventricular hemorrhage with dilation ‒ Grade IV: Intraventricular hemorrhage with parenchymal involvement or extension of blood into the cerebral tissue • LP to rule out septic shock or meningitis

50 Grade I IVH

http://www.slideshare.net/PediatricHomeService/brain-injury-in-preterm-infants

51 Grade II IVH

http://www.slideshare.net/PediatricHomeService/brain-injury-in-preterm-infants

52 Grade II IVH

http://pediatriceducation.org/2005/03/14/

53 Grade III IVH

http://www.slideshare.net/PediatricHomeService/brain-injury-in-preterm-infants

54 Grade III IVH

http://pediatriceducation.org/2005/03/14/

55 Grade IV IVH

http://www.slideshare.net/PediatricHomeService/brain-injury-in-preterm-infants http://www.nrdaddy.com/lectures/ivh_pvl/ivhgrad_4a.htm 56 Grade IV IVH

http://www.slideshare.net/PediatricHomeService/brain-injury-in-preterm-infants http://www.nrdaddy.com/lectures/ivh_pvl/ivhgrad_4a.htm 57 http://www.slideshare.net/PediatricHomeService/brain-injury-in-preterm-infants http://www.nrdaddy.com/lectures/ivh_pvl/ivhgrad_4a.htm 58 Periventricular Leukomalacia

http://www.armobgyn.com/en/Neurosonography.htm

59 Periventricular Leukomalacia

http://www.armobgyn.com/en/Neurosonography.htm

60 Kidokoro, H., Anderson, P., Doyle, L., Woodward, L., Neil, J., & Inder, T. (2014). Brain Injury 61 and Altered Brain Growth in Preterm Infants: Predictors and Prognosis. PEDIATRICS, 134(2), e444-e453. http://dx.doi.org/10.1542/peds.2013-2336 IVH Outcomes

▪ Small (Grade I) • Neurodevelopmental disability similar to premature infants without IVH ▪ Moderate (Grade II-III) • Neurodevelopmental disability in 40% • Mortality 10% • Progressive hydrocephalus in 20% ▪ Severe (Grade PVHI) • Major neurodevelopmental disability in 80% • Mortality rate 50-60% • Hydrocephalus common in survivors

Introductory sentence Arial – 21pt font 62 Intracerebellar Hemorrhage ▪ Diagnostic: • Cranial ultrasound • CT to define the hemorrhage • MRI for definitive diagnosis ▪ Outcome: • More favorable in term than preterm infants • Probable neurologic deficits

http://www.mrineonatalbrain.com/ch04-

63 09.php Periventricular Leukomalacia (PVL)

▪ Ischemic, necrotic periventricular white matter lesions of arterial origin ▪ Risk factors: systemic hypotension, recurrent apnea with bradycardia ▪ Pathophysiology ▪ Incidence

64 PVL

▪ Clinical presentation: • Acute phase: hypotension and lethargy • 6 to 10 weeks later: ‒ Irritable ‒ Hypertonic ‒ Increased arm flexion and leg extension ‒ Frequent tremors ‒ Abnormal Moro reflex

65 PVL

▪ Diagnostic: • Cranial ultrasound • CT • MRI

• Initial presentation: PV echodensities • Later: PV cystic changes

66 Periventricular Leukomalacia

http://www.armobgyn.com/en/Neurosonography.htm

67 PVL

▪ Outcome: • Based on location and extent of the injury • Major motor deficits • Significant upper arm involvement is associated with intellectual deficits • Visual impairment • Lower limb weakness

68 PVL Outcome

http://www.nrdaddy.com/lectures/ivh_pvl/prog4.htm http://www.perinatal.nhs.uk/reviews/cp/cp_causes.ht m69 Posthemorrhagic Hydrocephalus

▪ Progressive dilation of the ventricles after IVH caused by injury to the periventricular white matter; inhibition of CSF flow ▪ Two types: • Acute • Chronic (subacute) ▪ Incidence: • Acute dilation in up to 50% of infants with IVH (generally resolves) • Slightly more than 50% of severe cases will result in progressive ventricle dilation

70 Post Hemorrhagic Hydrocephalus

▪ Frequent complication of GM-IVH • Clot obstructing CSF flow at the level of the aquaduct of Sylvius

71 Hydrocephalus

▪ Clinical presentation: • Rapid increase in head size • Episodic apnea and bradycardia • Lethargy • Increased ICP • Tense, bulging anterior fontanel • Separated cranial sutures • Ocular movement abnormalities

72 Hydrocephalus

▪ Diagnostic: • Measure weekly OFC • CT • Cranial ultrasound • MRI ▪ Outcome: • Poor outcomes if decompression is not successful with shunt placement • Motor and cognitive deficits

73 Post Hemorrhage Ventricle Device External Ventricular Drain/Reservoir/Shunt/

▪ EVD ▪ Ommaya reservoir ▪ Ventriculoperitoneal (VP) shunt

Willows Vision Appeal,. (2015). Willow's Story. Retrieved 10 November 2015, from http://www.willowsvisionappeal.com/willows-story.html Mskcc.org,. (2015). About Your Ommaya Reservoir Placement Surgery for Pediatric Patients | Memorial Sloan Kettering Cancer Center. Retrieved 10 November 2015, from https://www.mskcc.org/cancer-care/patient-education/about-your-ommaya-reservoir-placement-surgery 74 Seattlechildrens.org,. (2015). Hydrocephalus Treatment | Seattle Children’s Hospital. Retrieved 10 November 2015, from http://www.seattlechildrens.org/medical-conditions/brain-nervous-system-mental-conditions/hydrocephalus-treatment/ Patient Care and Management

▪ Prevent preterm birth ▪ Promote in utero transport ▪ Promote a non stressful intrapartum course ▪ Provide efficient resuscitation with expedient intubation ▪ Cluster care activities and promote appropriate handling ▪ Minimize noxious stimuli ▪ Avoid events associated with wide swings in arterial and venous pressures (i.e.: seizures, apnea, etc.). ▪ Prevent blood pressure swings – slow volume replacement

75 Potentially Better Practices to Prevent Brain Injury

1. Antenatal steroids & magnesium 2. Optimize management and delivery at center with a NICU 3. Early management by a Neonatologist/NNP 4. Minimize pain and stress 1. Avoid pain and stress 2. Developmental Care 5. Optimal positioning (midline) 6. Treat hypotension 7. Judicious indomethacin use 8. Optimize respiratory management 9. Limit sodium bicarbonate use 10. Use post-natal dexamethasone judiciously

76 McLendon et al. Pediatrics, 2003; Carteaux, et al, Pediatrics, 2003 IVH Bundles

77 Delayed Cord Clamping (DCC)

• ACOG Committee Opinion, Number 684, January 2017 • DCC in vigorous term and preterm infants for at least 30-60 seconds after birth • DCC increases hemoglobin levels at birth and improves iron stores • Improves transitional circulation • Decreases need for pRBC transfusion • Lowers incidence of NEC and IVH • Does not increase risk of postpartum hemorrhage • What is done in your center?

http://www.acog.org/Resources-And-Publications/Committee- 78 Opinions/Committee-on-Obstetric-Practice/Timing-of-Umbilical-Cord-Clamping- After-Birth The “Golden” Hour (Delivery Room Toolkit) ▪ Based on principles from cardiovascular and emergency medicine ▪ First hour of life is a time of critical transition and adaptation ▪ Management has been show to impact long term outcomes ▪ Structured focus on thermoregulation, minimizing energy consumption, and respiratory support ▪ Measurable data points include: time to admission, admission temperature, admission glucose, initiation of IV fluids with glucose and amino acids ▪ What does your “Golden” hour look like?

Castrodale, V. and Rinehart, S. (2014). The Golden Hour: improving the stabilization 79of the very low birth-weight infant. Advances in Neonatal Care, 14(1):9-14. Neutral Head Positioning ▪ First studied in adults in the 1980s ▪ Infants less than 32 weeks are positioned in neutral midline position with the head of the bed tilted upward for 72 hours ▪ Goal: to reduce alterations in cerebral blood flow associated with turning of the head from side to side in efforts to reduce the incidence of IVH ▪ Thoughts? ▪ Key stakeholders? Equipment needs? ▪ How is this audited?

80 Cerebral blood flow ▪ELBWs have impaired cerebral autoregulation

▪Everyday ICN tasks that affect Cerebral Blood Flow (CBF) •Diaper changes •Suctioning •Blood sampling

▪Can we prevent harm to our patients?

Schulz, G., Keller, E., Haensse, D., Arlettaz, R., Bucher, H., & Fauchere, J. (2003). Slow Blood Sampling From an Umbilical Artery Catheter Prevents a Decrease in 81 Cerebral Oxygenation in the Preterm Newborn. PEDIATRICS, 111(1), e73-e76. http://dx.doi.org/10.1542/peds.111.1.e73 Blood Sampling

▪Evidence has shown blood sampling techniques from UACs affect cerebral blood flow and oxygenation ▪20 second vs. 40 second push- pull

Schulz, G., Keller, E., Haensse, D., Arlettaz, R., Bucher, H., & Fauchere, J. (2003). Slow Blood Sampling From 82 an Umbilical Artery Catheter Prevents a Decrease in Cerebral Oxygenation in the Preterm Newborn. PEDIATRICS, 111(1), e73-e76. http://dx.doi.org/10.1542/peds.111.1.e73 Permissive hypotension

▪ Current practice ▪ Preterm infants with a MAP

Ahn, S., Kim, E., Kim, J., Shin, J., Sung, S., & Jung, J. et al. (2012). Permissive Hypotension in Extremely Low Birth Weight Infants (≤1000 gm). Yonsei Medical Journal, 53(4), 765. http://dx.doi.org/10.3349/ymj.2012.53.4.765 83 Offsetting stress with POSITIVE experiences

▪ Stressful experiences in NICU are inevitable ▪ How do we provide positive experiences? • Tactile • Vestibular • Gustatory • Olfactory • Auditory • Visual ▪ How do we document this?

84 Take care of this brain

[email protected]

85 QUESTIONS??

References

▪ Altimier, L., Warner, B., Kenner, C. & Amlung, S. (1999). Value Study. Neonatal Network, 18(4), 35-38. ▪ Chang, E.F. & Merzenich, M.M. (2003). Environmental noise retards auditory cortical development. Science, 300: 498–502 ▪ Fucile, S. & Gisel, E. (2010). Sensorimotor Interventions Improve Growth and Motor Function in Preterm Infants. Neonatal Network. VOL. 29, NO. 6, November/December 2010 ▪ Graven, S. & Browne, J.V. (2008). Sleep and Brain Development The Critical Role of Sleep in Fetal and Early Neonatal Brain Development. Newborn and Infant Nursing Reviews, December 2008 References

▪ Liu, W.F. , Laudert, S., Perkins, B., MacMillan-York, E., Martin, S. & Graven, S. (2007). The development of potentially better practices to support the neurodevelopment of infants in the NICU. Journal of Perinatology (2007) 27, S48–S74; doi:10.1038/sj.jp.7211844 ▪ Lutes, L. M., Graves, C. D. & Jorgensen, K. M. (2004). The NICU experience and its relationship to sensory integration. In: C.Kenner & J. M.McGrath (Eds), Developmental care of newborns & infants. A guide for health professionals (1st edn, pp. 157–182). Philadelphia, PA: Elsevier ▪ Murdoch, D.R. & Darlow, B.A. (1984). Handling during neonatal intensive care. Archives of Diseases of Childhood, 59, 957-961 References

▪ Report of the Seventh Consensus Conference on Newborn ICU Design February 1, 2007. Recommended Standards for Newborn ICU Design. ▪ Stephen B.E. & Vohr B.R. (2009). Neurodevelopmental Outcome of the Premature Infant. Pediatr Clin N Am. 56:631 ▪ Vandenberg, K.A. (2007). Individualized developmental care for high risk newborns in the NICU: A practice guideline. Early Human Development (2007) 83, 433–442

90 Alphabet Soup of Preemie Problems… PDA

Amber Mason, BSN, CCRN Objectives

▪Describe normal cardiac physiology and development

▪Understand the unique physiologic needs of the preterm infant with a PDA

▪Define the implications prematurity presents with the cardiac system

92 Normal Cardiovascular Function: Review

Uptodate.com,. (2015). Identifying newborns with critical congenital heart disease. Retrieved 22 October 2015, 93 from http://www.uptodate.com/contents/identifying-newborns-with-critical-congenital-heart- disease?source=search_result&search=congenital+heart+disease&selectedTitle=1~150 Review of FETAL SHUNTS The PDA and the Fetus

The ductus arteriosus serves to divert blood away from the fluid-filled lungs toward the descending aorta and placenta In the Full Term Neonate…

▪Profound ductal wall hypoxia

• Inhibits local production of PGE2 and NO

• Produces smooth muscle apoptosis

• Induces local production of growth factors ‒TGF- β Transforming growth factor-β ‒VEGF vascular endothelial growth factor

96 In the Preterm Neonate…

▪Ductus frequently remains open for many days after birth

▪Even with constriction the premature ductus frequently fails to develop profound hypoxemia

• Vessel does not undergo anatomic remodeling

‒Susceptible to vessel reopening

97 Ductal Constriction and the Preterm Infant

▪ Intrinsic tone of the extremely immature ductus is <70% compared to term infant

▪ ↑ Sensitivity to the vasodilating effects of

PGE2 and NO

98 In the Preterm Neonate…

A PDA is normal on DOL 3 and may remain open through the first week of life in 50% of preterm infants

99 In the Preterm Neonate…

▪The presence of a hemodynamically significant PDA with a large left-to-right shunt is a common cause of morbidity in the extremely premature neonate

100 Redistribution of Systemic Blood Flow

Even with a small PDA blood is shunted away from the: • Skin • Bone • Muscle • GI tract • Kidneys

101 A Hemodynamically Significant PDA May Increase the Risk of… ▪ Intraventricular hemorrhage ▪ Pulmonary edema/hemorrhage ▪ Necrotizing enterocolitis ▪ BPD/ventilator dependence ▪ Retinopathy of prematurity ▪ Surgical intervention ▪ Death

102 How Does a PDA Present?

Actual Monitor of Preemie with Significant PDA

103 PDA Presentation ▪Usually asymptomatic when ductus is small ▪Bounding pulses ▪Palmar pulses ▪Active precordium ▪Wide swings in oxygen saturation ▪Murmur ▪Widening pulse pressure (>20mm Hg) ▪Low diastolic pressure ▪ ↑ Vascular markings on CXR ▪ ↑ Heart size is a late sign ▪ Apnea or worsening respiratory status ▪ Prolonged capillary fill time from ↓ systemic output

104 Diagnostics for Diagnosis of PDA

▪Chest x-ray ▪Echocardiogram ▪B-Type Natriuretic Peptide (BNP)

105 Chest X-ray of CHF

▪The increase in left ventricular pressure increases pulmonary venous pressure, causing pulmonary congestion ▪Cardiomegaly is a late sign

106 Echocardiographic Findings

Echocardiography is the best way to determine: • Presence of PDA • Size of PDA • Hemodynamic significance • Degree and direction of shunting

107 Laboratory Findings with PDA

▪B-Type Natriuretic Peptide (BNP) is released from the heart in response to increased wall tension. ▪Can be useful to help evaluate the left to right shunting through the ductus. ▪Normal Value • Normal <25 • >100 indicates significant left to right shunt PDA: Treatment Modalities

▪Conservative measures are employed initially: ▪ Fluid Restriction ▪ Restricted fluid administration reduces the risk of PDA and NEC and demonstrates trends towards reducing the risk of BPD, IVH, and death (Cochrane Database, 2010) ‒Total fluids on admission will be 80mL/kg/day with slow increases ▪ Diuretics (lasix) ▪ Positive end-expiratory pressure: useful in reducing left-to-right shunt via PDA PDA Treatment Modalities

▪ Pharmacologic • Indomethacin (Indocin) • Inhibits the action of prostaglandin synthetase, and thus inhibits the synthesis of the prostaglandin E series ‒Indomethacin is a potent vasoconstrictor and ↓ cerebral, gastrointestinal, and renal blood flow • Acetaminophen (Paracetamol)

110 Indomethacin IV Administration Special Considerations: ▪ Rapid infusions of intravenous indomethacin have been associated with significant reductions in cerebral blood flow. ▪ Administer by syringe infusion pump over 30 minutes ▪ Flush what is left in the tubing with 1 ml NS over 30 minutes ▪ Administer into dedicated peripheral IV ▪ Notify provider for… • Creatinine >2mg/dL, UO <1mL/kg/hr, Abdominal distension, Platelets <100k, Bilious gastric residual, Hemoccult positive stool Indomethacin Side Effects • Hypertension • Edema • Hyperkalemia • Dilutional hyponatremia • Hypoglycemia • Renal impairment • Gastrointestinal dysfunction • Abdominal distension, gastrointestinal bleeding, necrotizing enterocolitis, gastric perforation, gastric ulceration ▪ Platelet dysfunction and bleeding tendency. Contraindications to Indomethacin

▪ Suspected CHD ▪ Known GI or renal anomaly ▪ Poor renal function ▪ Bleeding disorders or thrombocytopenia ▪ Necrotizing enterocolitis ▪ Sepsis Acetaminophen Therapy

▪NSAIDs come with many risks ▪Acetaminophen is an alternative for hemodynamically significant PDA ▪IV or Oral ▪No need to stop feeds

PDA – Surgical Repair

• Ligation and division through a left posteriolateral thoracotomy without cardiopulmonary bypass • The vessel is isolated and ligated with a clip or band. • Mortality less than 1% • Complications are rare but may include: ‒ Injury to the recurrent laryngeal nerve ‒ Injury to left phrenic nerve ‒ Injury to thoracic duct ‒ Ligation of PA ‒ Infection ‒ Bleeding PDA Ligation 118 References

▪ Finer, N. N., Rich, W., Halamek, L. P., & Leone, T. A. (2012). The delivery room of the future: The fetal and neonatal resuscitation and transition suite. Clinics in Perinatology, 39(4), 931-939. ▪ Kandraju, H., Murki, S., Subramanian, S., Gaddam, P., Deorari, A., & Kumar, P. (2013). Early routine versus late selective surfactant in preterm neonates with respiratory distress syndrome on nasal continuous positive airway pressure: A randomized controlled trial. Neonatology, 103(2), 148-154. ▪ Kumar, P., Denson, S. E., Mancuso, T. J., & Committee on Fetus and Newborn, Section on Anesthesiology and Pain Medicine. (2010). Premedication for nonemergency endotracheal intubation in the neonate. Pediatrics, 125(3), 608-615. ▪ Leone, T. A., Finer, N. N., & Rich, W. (2012). Delivery room respiratory management of the term and preterm infant. Clinics in Perinatology, 39(3), 431-440. ▪ Vaucher, Y. E., Peralta-Carcelen, M., Finer, N. N., Carlo, W. A., Gantz, M. G., Walsh, M. C., et al. (2012). Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. The New England Journal of Medicine, 367(26), 2495-2504.

119 Alphabet Soup of Preemie Problems: RDS & BPD

12 0 Objectives

▪Review aspects of fetal lung development, pulmonary function and vulnerabilities of the premature infant ▪Discuss indications and updated management strategies for respiratory support of the premature infant with RDS ▪Review causes of preterm lung injury Changes in Respiratory Management of the Preterm Neonate ▪Antenatal steroids ▪Surfactant replacement therapy ▪Permissive hypercapnia ▪Gentler ventilatory modes (HFOV, PC, PS) ▪Inhaled nitric oxide ▪Non-invasive ventilation: NCPAP/SiPAP, HFNC, RAM ▪Judicious use of oxygen ▪Improved survival of preterm babies Lung Development

123 Impact of Preterm Birth on Lung Development ▪Preterm infants, especially ELBW, in middle of canalicular stage, just beginning saccular stage ▪Interruption of lung development due to •Preterm birth •Air-breathing when lung should be fluid-filled •Mechanical ventilation and oxygen therapy ▪Diminished elasticity reduces pulmonary compliance due to •Altered collagen composition •Decreased elastin concentration Respiratory Vulnerabilities

▪Newborn susceptible to respiratory distress due to limits on respiratory system: •Ribcage not well ossified •Respiratory muscles have low endurance and strength •Floppy chest wall offers little resistance to collapse •Obligate nose breathers •Tongue large, trachea and glottis small

Risk Factors for Developing Respiratory Distress Syndrome Increased risk Decreased risk ▪Premature Birth ▪Chronic intrauterine stress ▪Sex ▪PPROM ▪Infant of a Diabetic Mother ▪Maternal HTN ▪Asphyxia ▪IUGR/SGA ▪C-section without labor ▪Antenatal steroids ▪Caucasian race ▪Mat. drug use ▪Chorioamnioitis ▪Tocolytic agents ▪Hydrops RDS Pathophysiology

▪Insufficient volume of surfactant •Unstable alveoli collapse •Normal Functional Residual Capacity not established •Each breath requires increased energy output Surface Tension and Surfactant ▪Surfactant- Composed of surfactant proteins and phospholipids- oily liquid •Synthesis controlled by enzymes, regulated by hormones: glucocorticoids •Spreads easily, rapidly over lung surface

▪Surface tension •The force that arises from the interaction of molecules of a liquid •Opposes lung inflation, supports lung deflation •Smaller diameter of alveolus requires higher pressures for inflation •Surfactant coats alveolus reducing effort to inflate lungs from low volume RDS Pathophysiology ▪Death of alveolar epithelial cells/airway cells •Sloughing of cells, exudation of serum •Fibrin clots: hyaline membranes •Decreased surface area for gas exchange RDS Clinical Findings ▪Physical Exam ▪Tachypnea, grunting, flaring, retracting within minutes or hours of life ▪Pallor, cyanosis, hypotension ▪Decreased breath sounds, rales ▪CXR •Reduced lung volumes •“Ground glass” appearance: areas of atelectasis and hyperexpansion ▪Lab findings •Blood gas: hypoxemia, acidosis (respiratory, metabolic, mixed) CXR: Air bronchograms 132 RDS Prevention ▪Antenatal steroids (Betamethasone 48 hrs PTD) ▪Accelerate lung maturation ▪Single course for women between 24 and 34 wks gestation at risk for preterm delivery ▪Reduces incidence of RDS by 50% in infants < 31 wks ▪Decreases neonatal mortality by 30% ▪Decreases incidence of IVH and NEC ▪No adverse consequences identified at this dose ▪Ongoing trials evaluating use of repeated doses in undelivered moms at continued high risk Unique Needs of the ELBW Baby: It’s All About Protection ▪What we do during those first minutes, to hours can affect outcomes ▪All systems immature and vulnerable

13 4 6/27/2017 The Golden Hour ▪Definition •Taken from shock trauma medicine indicating the critical first hour as the most important for improving survival •For the extremely preterm neonate, initial steps undertaken to optimize coordination and execution of care with the goal of minimizing injury and improving outcomes GOAL: resuscitation without injury!

13 5 6/27/2017 We Are Better, Together! California Perinatal Quality Care Collaborative (CPQCC): Delivery Room Management

▪Collaborative aims: •Best practice “Bundle” to improve care at high risk deliveries addressing: ‒Teamwork with use of pre-resuscitation checklists and simulation based learning ‒Optimization of respiratory care for the preterm baby ‒Maintenance of normothermia, avoidance of hypo and hyperthermia

13 6 6/27/2017 www.cpqcc.org CPQCC Delivery Room Management Collaborative Outcomes

Measure Collaborative Individual Non Participant Before/After Before /After Before/After n 20 n 31 n 44

Rate of 39% to 21% 38% to 42% to Hypothermia 33% 34%

Rate of 53% to 40% 44% to 43% to Intubation in DR 36% 40%

Rate of 37% to 20% 19% to 18% to Surfactant Administration 12% 16% in Delivery 13Room 7 6/27/2017 RDS Treatment Strategies ▪Initial DR stabilization -California Perinatal Quality Care Collaborative (CPQCC) guidelines ▪Surfactant replacement ▪Support ventilation (lung protection is goal) ‒Non-invasive ventilation ‒Gentler mechanical ventilation ▪Fluids, electrolytes, glucose, calories, normothermia ▪Prevent complications •Infection •BPD/CLD ▪Inhaled nitric oxide Surfactant Replacement ▪Rescue decreases severity of BPD but not incidence ▪Adverse effects ▪Transient hypoxia, bradycardia ▪Acute airway obstruction ▪Transient falls in BP, CBF (cerebral blood flow) ▪Pulmonary hemorrhage ▪To intubate or not to intubate? •Stable at birth: should the patient be intubated for surfactant? Can destabilize patient & cause deterioration Surfactant Replacement ▪Prophylaxis vs Rescue Treatment • Prophylaxis: give within 15 minutes of birth • Rescue: give when babe has established RDS • Moved from a prophylactic approach to early rescue dosing ‒Indicated for intubated patients needing >30% FiO2 • No consistent criteria for when to use Surfactant Replacement ▪Dose: how many? •Most respond well to one dose •Additional dosing depends on response to first •Criteria for repeating dose unclear

‒Accepted: q 12hrs, FiO2 >40% ‒Very little data re: optimal dose, timing ▪Administration •Bolus better than slow infusion: better distribution •Use ETT with side port, HV dose into lungs •Turning side to side not used at UCSF Oxygen therapy ▪Most commonly used drug in neonatal care ▪No concentration is “safe” ▪Use blender, analyzers ▪Continuous monitoring (HR, sats) ▪Humidify, warm ▪Maintain stable delivery, concentration ▪Wean slowly with continuous monitoring

▪O2 saturation: target ranges

•Under 1000gms: 85%-92% (PaO2 45-60 torr)*** •Beyond 36wks: 90-95% Non-invasive Ventilation ▪High-Flow Nasal Cannula (HFNC) ▪Delivers higher flows (up to 8L/min) thru NC with high humidity ▪Used by many centers (64%) as primary support for RDS, apnea of prematurity, post-extub care ▪Minimal research to establish safety/efficacy ▪No direct measure of pressure, may get excessive PEEP

▪Nasal CPAP •Primary means of respiratory support in VLBW •Early use of NCPAP in VLBW assoc with decreased rates of BPD/CLD, ROP (VON study) ‒Good evidence that even VLBW/ELBW can be successfully treated with NCPAP without surfactant Noninvasive Ventilation ▪Nasal CPAP Indications ▪Spontaneous breathing, mild to moderate RDS ▪Cannot maintain PaO2 of 60 torr in 60% FiO2 ▪Support during weaning from mechanical ventilation ▪Advantages •Establishes and maintains FRC, Conserves surfactant, Decreases resistance, increases compliance, Reduces apnea, lung injury, inflammation, Conserves energy, Reduce need for mechanical ventilation ▪Disadvantages •Gaseous distension of bowel, Increased rate of pneumos, Difficulty keeping prongs in nose/mask on face, maintaining patency, Infant agitation, Labor intensive for neonatal nurse, Risk for device related pressure ulcers, scarring, disfigurement Respiratory- Functional Residual Capacity (FRC)

Movie 1 - Time-lapsed phase contrast X-ray image sequence, showing the effect intermittent positive pressure ventilation (PPV) without a positive end- expiratory pressure (PEEP), on lung aeration at birth.

http://neoreviews.aappublications.org/highwire/filestream/18026/field_highwire _adjunct_files/0/Movie1_PPV_no_PEEP.mov

Movie 2 - Time-lapsed phase contrast X-ray image sequence, showing the effect intermittent positive pressure ventilation (PPV) with 5 cmH2O of positive end-expiratory pressure (PEEP), on lung aeration at birth.

http://neoreviews.aappublications.org/highwire/filestream/18026/field_highwire _adjunct_files/1/Movie2_PPV_with_PEEP.mov

Hooper, S., te Pas, A., Lewis, R., & Morley, C. (2010). Establishing Functional Residual Capacity at Birth. Neoreviews, 11(9), e474-e483. 145 http://dx.doi.org/10.1542/neo.11-9-e474 Mechanical Ventilation & CPQCC DR Guidelines for Intubation ▪Indications • Apnea unresponsive to stimulation or hand ventilation

• High and rising PaCO2 : >60mmHg = respiratory failure

• Increasing FiO2 needs: > 60% despite NCPAP ‒ Sign of low lung volumes ‒ Indicator of severe RDS ‒ Obstructed breaths ‒ No response to CPAP ‒ Apnea UCSF Conventional Ventilation Practice

▪Principles ‒Keep tidal volumes normal (4 to 5 ml/kg) ‒Sats 88 to 92

‒PaCO2 about 45 to 60 (permissive hypercapnea) ‒ pH >7.25 ‒Extubate ASAP Desaturation Episodes: Critical Points ▪Fewer desaturations with proper positioning ▪Prone ▪Developmental positioning, nesting ▪Minimal handling during desaturation episode ▪Assess need for sedation ▪Be patient, most will recover with no intervention

▪O2 titrations used as last resort for desaturation episodes ▪Set tight sat alarms on monitor ▪Document episodes, interventions, infant’s response Bronchopulmonary Dysplasia (BPD) BPD Implications of Preterm Birth and RDS/Bronchopulmonary Dysplasia (BPD)

▪Preterm birth greatest cause of neonatal morbidity and death in US and globally ▪Immature lungs require respiratory assistance ▪Ventilation injures lungs: lung tissue inflammation leads to BPD ▪80% of infants with BPD born before 30 wks gestation ▪BPD: increases mortality, long-term implications for lung health and brain development Bronchopulmonary Dysplasia (BPD)

▪A chronic pulmonary disorder characterized by •Pulmonary fibrosis •Brochiolar metaplasia •Emphysema •Interstitial edema BPD: Definition/Description ▪NICHD definition mild BPD

•Requiring O2 for a total of at least 28 days •Acute lung injury minimized by antenatal steroids and surfactant treatment •Disrupted alveolar and vascular development: fewer, larger alveoli, pulmonary hypertension •Less inflammation and fibrosis

▪New description: significant BPD •O at 36wks postmenstrual age and for more than 28 days2

•Inability to maintain O2 sats of 90% or more in RA Current Definition of BPD:

Gestational age

<32 week ≥32 week

>28 days but <56 days postnatal 36 weeks PMA or discharge to Time point of assessment age or discharge to home, home, whichever comes first whichever comes first

Treatment with oxygen >21 percent for at least 28 days plus

Breathing room air at 36 weeks Breathing room air by 56 days Mild BPD PMA or discharge, whichever postnatal age or discharge, comes first whichever comes first

Need* for <30 percent oxygen at Need* for <30 percent oxygen at Moderate BPD 36 weeks PMA or discharge, 56 days postnatal age or whichever comes first discharge, whichever comes first

Need* for ≥30 percent oxygen Need* for ≥30 percent oxygen and/or positive pressure (PPV or and/or positive pressure (PPV or Severe BPD NCPAP) at 56 days postnatal age NCPAP) at 36 weeks PMA or or discharge, whichever comes discharge, whichever comes first (UpToDate 2017) first BPD Incidence

▪Inversely proportional to gestational age ▪Of survivors corrected to 36 weeks •85% of babies born at 22 weeks had an O2 requirement •22% of babies born at 28 weeks had an O2 requirement (Stoll et al., 2010) BPD Summary

▪Chronic lung disease ▪Inversely proportional to gestational age ▪Develops after acute pulmonary disease ▪Chronic, constant recurrent lung injury ⦿Lung injury and repair occur simultaneously with organ growth and development

▪Prolongs need for O2 , mechanical ventilation Factors that Contribute to BPD Nutritional Problems Genetics Fetal Programing Hyperoxic Injury BPD Other Increased Pulmonary Arterial Muscularization

Sex-specific Alterations in Differences Microbiome Inflammation Barotrauma BPD: Multifactoral •Lung immaturity: prematurity •Lung injury/inflammation ‒ Barotrauma/volutrauma ▪O toxicity: high or low levels, short or long term2

▪Occurs in ventilated infants without O2 •Infection ‒Chorioamnionitis ▪Inflammatory cytokines present in high levels in amniotic fluid of babes who develop BPD BPD Treatment ▪Lung protection •Extubate to nasal CPAP or SiPAP with low FiO to minimize toxicity to lung 2 •No air leak (PIE or pneumo) •Best ventilation strategy yet to be determined •Sats of 88% to 92% will provide adequate tissue oxygenation, help avoid complications of BPD •Better weight gain •Prevent development of pulmonary hypertension, right-sided heart failure •Avoid hyperoxia: ROP BPD → Pulmonary HTN

(Mourani et al. Clinic Perinatol 2015) Diagnosis of Pulmonary Hypertension

▪Cardiac catheterization – gold standard •Invasive ▪ECHO •Non-invasive •Right ventricular systolic pressure derived from tricuspid regurgitant jet velocity, or from estimated pulmonary pressures >50% of the systemic pressures •Limitations such as interobserver reliability Risk Factors for Development of Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Systemic Review and Meta-Analysis Naguib, et al. 2016

▪Inclusion Criteria: •Studies involving preterm infants with BPD and pulmonary hypertension that reported an assessment of risk factors for pulmonary hypertension ▪Exclusion Criteria: •Animal models, adult population •Further cardiovascular or lung anomalies Risk Factors for Development of Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Systemic Review and Meta-Analysis

Naguib, et al. 2016 Treatment of Pulmonary Hypertension in Bronchopulmonary Dysplasia

(Mourani & Abman, 2015) ▪No controlled trial of pulmonary hypertension treatment in BPD has been conducted ▪Aggressively treat factors contributing to lung disease: •Episodes of hypoxia •Ventilatory insufficiency •Bronchoconstriction •Chronic reflux and aspiration •Upper and lower airway obstruction ▪Immunoprophylaxis against respiratory infections Treatment of Pulmonary Hypertension in Bronchopulmonary Dysplasia (Mourani & Abman, 2015) ▪Inhaled iNO •local vasodilator •Approved for the treatment of pulmonary hypertension of the newborn •Has most safety data for preterm infants ▪Sildenafil (selective type 5 phosphodiesterase inhibitor) •Systemic vasodilator • Approved in adults, extensively used off-label for infants Inhaled Nitric Oxide: Therapeutic effects

• Improves oxygenation: optimizes ventilation/perfusion matching • Reduces lung inflammation and edema • Antioxidant effect on lung injury • Protective effects on surfactant function • Beneficial effects on pulmonary vascular/alveolar development

▪Early use in neonates to treat PPHN in term and late preterm infants •Early RCT’s in preterms ‒Improved oxygenation ‒Decreased need for mechanical ventilation ‒Improved survival without increase in IVH (>1000gms) ‒Trend toward decrease in CLD/BPD ‒Improvement in neurodevelopmental outcomes at 2 yrs of age Treatment of Pulmonary Hypertension in Bronchopulmonary Dysplasia ▪Trepostinil (Remodulin) •Vasodilator •Continuous IV or subcutaneous infusion •Can create V/Q mismatch and intrapulmonary shunts → Desaturations ▪Bosentan •Competitive antagonist of endothelin-1 (therefor blocks vasoconstriction) ▪PDA stent •RV failure ▪Supplemental oxygen •Target oxygen saturations >93% premature infants, >95% term infants ▪Diuretics •Volume overload •Spironolactone – additional benefit due to mineralcorticoid blockade in RV hypertrophy/PH, and can improve lung mechanics in BPD In Summary: Simple Lung Protection Philosophy ▪Lung protection from delivery to discharge ▪Normal lung volume is good •Over distension is bad •Atelectasis is bad ▪Stability is good ▪Working hard is bad ▪Ventilator strategy is more important than ventilator type ▪It is best to be off the ventilator 169 References

▪Cifuentes J. et al: Respiratory System Management and Complications. In Kenner C. and Lott J: Comprehensive Neonatal Nursing (3rd ed. pp 211- 217). Saunders 2003 ▪CPQCC: Delivery Room Management Quality Improvement Toolkit, revised 7/6/11 ▪Durand, D.: Ventilator Strategies in the NICU: What’s New in 2010. Presentation at 7th National Advanced Practice Neonatal Nurses Conference. Contemporary Forums, San Francisco, March 2010 ▪Farrow K., Steinhorn R.: Neonatal Respiratory Failure: Pathophysiology and Management. In Muers K. et al: ECMO Extracorporeal Cardiopulmonary Support in Critical Care (3rd ed. pp 253-265) ELSO 2005 ▪Gardes J.: Bronchopulmonary Dysplasia. In Polin R., Yoder M. eds: Workbook in Practical Neonatology (4th ed. Pp 167-184) Saunders Elsevier 2007 References

171 References

⦿ Gardner S., Goldson E.: The Neonate and the Environment: Impact on Development. In Merenstein and Gardner: Handbook of Neonatal Intensive Care (7th ed pp 285-296) Mosby Elsevier 2011 ⦿ Gardner S. et al: Respiratory Diseases. In Merenstein & Gardner: Handbook of Neonatal Intensive Care (7th ed pp 581-641) Mosby Elsevier 2011 ⦿ Gardner, S. et al: Pain and Pain Relief: . In Merenstein & Gardner: Handbook of Neonatal Intensive Care (7th ed pp 581-641) Mosby Elsevier 2011 ⦿ Inselman S. et al: Growth and Development of the Lung. Journal of Pediatrics Vol 98 #1. January 1981, pp 1-6 ⦿ Kenner C: Resuscitation and Stabilization of the Newborn. In Kenner C. and Lott J: Comprehensive Neonatal Nursing (3rd ed pp 211-217) Saunders 2003 ⦿ Miller, N.: Techniques of Early Respiratory Management of Very Low Extremely Low Birth Weigh Infants. Neonatal Network, Vol. 29, No 3, May/June 2010, pp 153-160 References

⦿ Peterson, S.: Understanding the Sequence of Pulmonary Injury in the Extremely Low Birth Weight, Surfactant-Deficient Infant. Neonatal Network, Vol. 28, No. 4, July/Aug 2009, pp 221-229 ⦿ Sosento I, Bancalari E: New Developments in the Presentation, Pathogenesis, Epidemiology and Prevention of Bronchopulmonary Dysplasia. In Bancalari E., Polin R.: The Newborn Lung: Neonatology Questions and Controversies (pp 187 -207) Saunders 2008 ⦿ Stokowski, L. A. (2005). A primer on apnea of prematurity. Advances in neonatal care, 5(3), 155-170. ⦿ UCSF Intensive Care Nursery VAP Task Force: Ventilator Associated Pneumonia Prevention Bundle. June 2007 ⦿ UCSF Intensive Care Nursery: SOP: Trial of Late Surfactant to Prevent BPD: A Study in Preterm Infants Receiving Inhaled Nitric Oxide (TOLSURF study) ⦿ UCSF Medical Center Department of Nursing: Respiratory Care of the Neonate-Intensive Care (Neonatal). Nursing Procedures Manual. Revised 8/07 Alphabet Soup of Preemie Problems… ROP

Retinopathy Of Prematurity

Tanya Hatfield, MSN, RNC-NIC Neonatal Outreach Educator UCSF Benioff Children’s Hospital Retinal Development

▪ The retina is a thin layer of tissue covering the back of the eye. ▪ Begins at the optic nerve and progresses into the periphery. ▪ Retinal vascular development begins at 15 to 18 weeks gestation. ▪ By 32-34 weeks gestation, the blood vessels in the eye are well developed. ▪ Maturation of the vessels supplying the optic nerve is not complete until term The Road to ROP-Pathophysiology

• The preterm infant is in a hypoxic environment in utero (Pa02 25 to 35 mmHg) • When babies are born premature, the blood vessels on the retina are not fully developed • The relative increase in oxygen extra utero (hyperoxia) inhibits vascular endothelial growth factor (VEGF), causing vasoconstriction of fragile, immature retinal vessels which progress to vaso-obliteration • The second phase of ROP occurs at 32-34 weeks. The vascular obliteration that occurs secondary to hypoxic stimulation up‐regulates VEGF & the retina responds by creating LOTS of vessels (vaso-proliferation) The Road to ROP-Pathophysiology

▪ This rapid growth can damage the retina ▪ Improper growth of the blood vessels on the retina and the damage caused by the growth ▪ One of leading causes of childhood blindness ▪ If the new vessels proceed to develop abnormally the capillaries may extend into the vitreous body and/or over the surface of the retina. ▪ Leakage of fluid or hemorrhage from the abnormal vessels may occur. The Road to ROP

▪ Zone • Refers to the location (I,II, III) - how far developing retinal vessels have progressed ▪ Staging • Standardized approach for describing ROP The Road to ROP Stages of ROP

• Stage 1: Mildly abnormal growth of retinal vessels. Usually gets better without any treatment and has no long-term effects

("Retinopathy of Prematurity | Pediatrics Clerkship", 2018) Stages of ROP

• Stage 2: Growth of retinal vessels is moderately abnormal. Usually gets better without any treatment and has no long-term effects

("Retinopathy of Prematurity | Pediatrics Clerkship", 2018) Stages of ROP • Stage 3: Ridge with Fibrovascular proliferation. Growth of retinal vessels is severely abnormal. Infants with Stage 3 may require treatment and have a higher risk for long-term problems

("Retinopathy of Prematurity | Pediatrics Clerkship", 2018) • Stage 4: Partial retinal detachment. Usually requires treatment and may lead to long-term vision problems or blindness • Stage 5: Complete retinal detachment. Requires treatment and may lead to long-term vision problems and blindness

("Retinopathy of Prematurity | Pediatrics Clerkship", 2018) • Plus Disease – Sign of ROP advancing quickly. • Usually requires treatment ▪ Plus disease frequently leads to vessel contraction and scar formation, which in turn, leads to macular displacement. ▪ Rush disease: Aggressive form of ROP. Develops between 3-5 weeks after delivery, may progress rapidly. Factors Associated with ROP ▪ Placental Insufficiency ▪ IVH/Seizures ▪ PREMATURITY ▪ Nutritional deficiency ▪ Supplemental oxygen ▪ Low plasma vitamin A concentrations ▪ Ventilatory Support ▪ Ethnicity ▪ Apnea and Bradycardia ▪ Exposure to bright light ▪ Hypercapnia/Hypocapnia ▪ Blilrubin/phototherapy ▪ Sepsis ▪ Steroids Prevention

• Treat Oxygen like a drug • Monitor Pa02 on ABGs – keep 50 to 70 mmHg • Even if the infant requires only room air, the Pa02 can rise to 60 to 100mmHg • Protect the eyes • Set high alarm limits on Pulse Ox The Road to ROP ▪ Surveillance ▪ Cryosurgery (rarely done) ▪ Laser Surgery ▪ Intravitreal administration of Anti-vascular endothelial growth factor agents (Avastin) ▪ Retinal Buckling for complete detachment Complications of ROP

• Varying degrees of visual impairment may require corrective lenses or surgery. ▪ Strabismus ( Crossed-eyed) ▪ Nystagmus (Rapid involuntary motion of the eyeball) ▪ Glaucoma (Abnormal high fluid pressure in the eye) ▪ Cataracts (Opacity of the lens) ▪ Amblyopia (“Lazy eye” Dimness of sight – Visual transmission not recognized properly) ▪ Macular ectopia (displacement of ocular muscles) ▪ Myopia (nearsightedness) The end References

▪ Verklan, M., & Walden, M. (2015). Core curriculum for neonatal intensive care nursing (5th ed.).

▪ Retinopathy of Prematurity | Pediatrics Clerkship. (2018). Retrieved from https://pedclerk.bsd.uchicago.edu/page/retinopathy-prematurity Alphabet Soup of Preemie Problems… MBM & NEC

Tanya Hatfield, MSN, RNC-NIC Neonatal Outreach Educator Objectives Upon completion of this presentation the participant should be able to:

▪ Differentiate between the term and preterm GI system ▪ Describe nutritional goals for the preterm infant ▪ Identify risk factors for necrotizing enterocolitis (NEC) ▪ Identify signs and symptoms of NEC ▪ Describe medical and surgical treatment plans for NEC

19 2 Embryologic GI Development ▪ Fetal gut complete by 20-22 weeks ▪ Functional development begins in utero and continues into infancy ▪ At 32 weeks the fetus begins normal gastric emptying. At 34-36 weeks suck swallow coordination occurs, along with rapid peristalsis

Medline Plus. (2017). Fetal development: MedlinePlus Medical Encyclopedia.Medlineplus.gov. Retrieved 15 April 2017, from 193 https://medlineplus.gov/ency/article/002398.htm How long are the small intestines?

19 McElroy, S. (2017). Innate Immunity and NEC. 4 Presentation, UC Davis. 19 5 Small Intestines Tight Junctions

19 6 When Good Guts Go Bad…

197 What is NEC? ▪Definition: an acquired disease that affects the GI system, particularly that of premature infants. It is characterized by inflammation of the bowel wall followed by areas of necrosis, most commonly in the terminal ileum and proximal colon, but may affect any or all of the small and large intestines.

19 Verklan, M., & Walden, M. (2015). Core curriculum for neonatal intensive care 8 nursing (5th ed.). Incidence ▪BW 501 to 750 g – 12 percent risk, 42 percent mortality with NEC ▪BW 751 to 1000 g – 9 percent risk, 29 percent mortality with NEC ▪BW 1001 to 1250 g – 6 percent risk, 21 percent mortality with NEC ▪BW 1251 to 1500 g – 3 percent risk, 16 percent mortality with NEC

19 Verklan, M., & Walden, M. (2015). Core curriculum for neonatal intensive care 9 nursing (5th ed.). What is or isn’t NEC?

20 Gordon, P. (2017). We have to redefine NEC. Presented at, UC Davis 0 NEC Pathogenesis ▪Prematurity •Propensity towards gut inflammation •Impaired intestinal barrier function •Decreased intestinal motility •Deficient mucosal enzymes, hormones, pepsin, and gastric acid •Immature autoregulation of microcirculation •Lack of amniotic fluid •Immature mucin layer

20 1 NEC Pathogenesis ▪Enteral Feeds •Formula feeding •Fortification

▪Abnormal intestinal microbiota •Decreased commensal flora •Increased pathogenic bacteria •Prolonged antibiotic therapy •Acid suppression medications

20 2 NEC Pathogenesis

▪Gut Ischemia •Abnormal gut vascular regulation •More prone to hypoxic events

▪Inflammatory response •Genetic factors? •TLR4?

20 3 NEC Pathogenesis ▪TLR4 •Toll-like receptor

20 4 Etiology

Common final pathway – the endogenous production of inflammatory mediators that precipitate intestinal injury Model of Pathogenesis

▪ Subclinical event (hypoxia, ischemia) ▪ Intestines become colonized ▪ Bacteria bind to injured mucosa ▪ Inflammatory response ▪ Increased permeability of mucosa ▪ Translocation of bacteria ▪ Inflammatory response accelerates ▪ Inflammatory mediators, reactive oxygen species further injure mucosa ▪ Maladaptive vasoconstrictive response leads to ongoing ischemia/reperfusion injury ▪ End result – cycle of feedback mechanisms ultimately causing necrosis and perforation GastrointestinalIn the adult intestine… Development

Fats = Seagulls Hypoxemia/ Hypovolemia = Natural Disaster (complacent, harmless, unhelpful) If persists can destroy the wall and overfill the bay allowing unrestricted access to the town! Bacteria = Sharks In medical terms, it can lead to damage inflammation and shock.

Commensal Biofilm = The Barges

Mucin = The Moat

Epithelium = The Wall TLR-4, Immune Cells, etc = sentries

20 Medline Plus. (2017). Fetal development: MedlinePlus Medical 7 Encyclopedia.Medlineplus.gov. Retrieved 15 April 2017, from Resthttps://medlineplus.gov/ency/article/002398.htm of the body = town GastrointestinalBreastIn the premature Milk intestine… Development • Walls aren’t as strong • Moat isn’t as wide • Lots more sentries • Not as many barges

20 Medline Plus. (2017). Fetal development: MedlinePlus Medical 8 Encyclopedia.Medlineplus.gov. Retrieved 15 April 2017, from https://medlineplus.gov/ency/article/002398.htm GastrointestinalBreast Milk DevelopmentFormula • Has growth factors to increase • Less protection against pathogen invasions mucin production • Over expressed TLR-4 (sentries) sends out • Has HMOs that distract pathogensBoth are still at alarmrisk causing for excessive inflammatory and feed commensals “natural disasters”response but (town panic & wall damage) hopefully the breast fed infant can weather the storm a little better

20 Medline Plus. (2017). Fetal development: MedlinePlus Medical 9 Encyclopedia.Medlineplus.gov. Retrieved 15 April 2017, from https://medlineplus.gov/ency/article/002398.htm Diagnosing NEC Bell’s Staging of NEC ▪ Stage 1-Suspected NEC ▪ Gastric residuals, abdominal distention, temp instability, A/B/Ds ▪ Stage 2- Proven NEC • Absent bowel sounds, abdominal tenderness, pneumatosis, portal venous gas, metabolic acidosis, ↓ Platelets ▪ Stage 3- Advanced NEC • Severely ill, marked distension, peritonitis, hypotension, disseminated intravascular coagulation (DIC) ‒Stage IIIA intact bowel, stage IIIB perforated bowel visualized as a pneumoperitoneum Presentation – clinical findings

▪ Abdominal distension ▪ Feeding residuals, often bilious ▪ Gross or occult blood in stool ▪ Abdominal tenderness ▪ Erythema or bluish discoloration of abdominal wall ▪ Absent bowel sounds ▪ Non-specific signs (temp. instability, glucose instability, lethargy, apnea/bradycardia, hypotension) Visual Exam Presentation – Laboratory Findings

▪ Glucose instability ▪ Abnormally high or low WBC ▪ Left shift of WBC (increased bands, metas) ▪ Thrombocytopenia ▪ Metabolic acidosis ▪ DIC ▪ CRP Presentation- Radiologic Findings Normal Abdominal Xray

▪ Uniform size and shape of loops ▪ Diameter approximates vertebra ▪ Gas throughout entire bowel tract ▪ Gas pattern should vary on subsequent x rays ▪ No free air in abdomen and liver is opaque Presentation – Radiographic Findings ▪ Non-specific bowel dilatation ▪ Thickening of bowel wall ▪ Fixed, dilated loop unchanged on >1 radiograph ▪ Pneumatosis intestinalis ▪ Portal venous gas ▪ Pneumoperitoneum

222 Ultrasound

▪ Used to look for bowel wall thickening ▪ Free air ▪ Portal Venous gas Management- Suspected NEC ▪ NPO ▪ Fluid/electrolyte and parenteral nutrition management ▪ Gastric decompression ▪ Labs ▪ Antibiotics (Ampicillin and Gentamicin, Vancomycin, Cefotaxime, Flagyl?) ▪ Correct metabolic acidosis ▪ Serial xrays ▪ Respiratory & Circulatory support ▪ Rule out other causes of distension ▪ Transfusions? ▪ Close monitoring Management – Definite NEC ▪ Obtain consult with surgical team ▪ Serial KUB’s ▪ NPO 7-10 days ▪ Careful I/O’s – maintain bowel perfusion, may require fluid resuscitation ▪ Circulatory support ▪ Respiratory support ▪ PT, PTT, fibrinogen, platelets ▪ Frequent abg’s, electrolytes ▪ Antibiotics 7-14 days Surgical Treatment Medical management is appropriate in most cases ▪ Operative intervention indications: • Perforation, evidence of necrotic bowel (fixed loop, metabolic acidosis, DIC, shock), or progressively worsening clinical condition despite intensive medical management ▪ Surgical Options: ▪ Peritoneal drain ▪ Exploratory laparotomy for resection of necrotic bowel Surgical Considerations ▪ Peritoneal drain +/- irrigation • Allows time for baby to stabilize • Better able to delineate viable gut when do operate • Laparotomy indicated if not improving in 24-48 hrs • Exploratory laparotomy for resection of necrotic bowel ▪ Primary Anastomoses ▪ Ostomy & Mucous Fistula

Prevention ▪ Human milk ▪ Pasteurized MBM is not as protective ▪ Intestinal priming (gut stimulation feedings) ▪ Promotes structural and functional maturation ▪ Promotes acquisition of normal flora ▪ Stimulate release of gastric hormones ▪ Slow, but not too slow, feed advancement ▪ Minimize prolonged antibiotic use ▪ Antenatal glucocorticoids for lung maturation also accelerate intestinal maturation ▪ Prebiotics, probiotics, postbiotics How can Human Milk Prevent NEC?

http://www.human- milk.com/infographic/l eaflet.html

230 Colostrum Care ▪ Oropharyngeal administration ▪ Use syringe to place directly onto the oral mucosa in the buccal cavity for absorption via the mucosa ▪ Allows for systemic absorption of the cytokines and pancreatic secretory trypsin inhibitor (PSTI) ▪ Rich source of Oligosaccharides ▪ May reduce time to full feeds Trophic feeds ▪ Improved feeding tolerance & advancement of feeds ▪ Improved weight gain ▪ Shortened duration of TPN (less central lines!) ▪ Reduction in direct bilirubin & less phototherapy ▪ Decreased length of stay ▪ Does not increase risk of NEC!

231 Enteral Nutrition

▪ Breast milk is best

▪ Donor breast when MBM not available

▪ Use of standardized feeding guideline ▪ Reduced risk of NEC ▪ Less variability ▪ Achieve full feeds earlier

232 Probiotics… The “Golden Age” of Probiotics: A Systematic Review and Meta-Analysis of Randomized and Observational Studies in Preterm Infants •Probiotics potentially prevent severe NEC and late-onset sepsis, and reduce mortality in preterm infants Prophylactic Probiotics for Preterm Infants: A Systematic Review and Meta-Analysis of Observational Studies. •Probiotic supplementation reduces the risk of NEC and mortality in preterm infants. The effect sizes are similar to findings in meta-analyses of RCTs. However, the optimal strain, dose and timing need further investigation.

23 3 Prevention - Disadvantages of NPO ▪ “The wisdom of stopping all enteral intake is counter- intuitive to the ontologic processes that started in utero” Edmund Gamma, Lyle Browne, State Univ. NV ▪ Has not uniformly provided protection, may simply delay the onset of NEC ▪ Predisposes to injury when finally fed

• Gut atrophy

• Decreased mucin production and enzyme activity

• Decreased secretion of IgA

• Increased transmural penetration of bacteria, and antigens

• Increased susceptibility to infection

• Autodigestion 235 References

▪ American Academy of Pediatrics, Section on Breastfeeding. (2005). Breastfeeding and the use of human milk. Pediatrics, 115(2), 496‐506.

▪ Bisquera JA, Cooper TR, Berseth CL. Impact of necrotizing enterocolitis on length of stay and hospital charges in very low birth weight infants. Pediatrics.2002;109(3):423-428.

▪ Cochrane Library 2001, CPQCC/CAN; McClure, 2000; Peter, et al, 2002; Ziegler, 2002; Kuzman O’Reily, 2003; Berseth Yu, et al, 2005; Tyson & Kennedy Cochrane review, 2005 ▪Dasgupta, S., Arya, S., Choudhary, S., & Jain, S. K. (2016). Amniotic fluid: Source of trophic factors for the developing intestine. World journal of gastrointestinal pathophysiology, 7(1), 38. ▪Dermyshi, E., Wang, Y., Yan, C., Hong, W., Qiu, G., Gong, X., & Zhang, T. (2017). The “Golden Age” of Probiotics: A Systematic Review and Meta-Analysis of Randomized and Observational Studies in Preterm Infants. Neonatology, 9-23. http://dx.doi.org/10.1159/000454668 ▪Gephart, S., Spitzer, A., Effken, J., Dodd, E., Halpern, M., & McGrath, J. (2014). Discrimination of GutCheckNEC: a clinical risk index for necrotizing enterocolitis. Journal Of Perinatology, 34(6), 468-475. http://dx.doi.org/10.1038/jp.2014.37

236 References

▪Morgan, J., Young, L., & McGuire, W. (2014). Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Of Systematic Reviews. http://dx.doi.org/10.1002/14651858.cd001970.pub5

▪Mulvihill, S. J., Stone, M. M., Debas, H. T., & Fonkalsrud, E. W. (1985). The role of amniotic fluid in fetal nutrition. Journal of pediatric surgery, 20(6), 668-672.

▪ Rodriguez, N., Meier, P., Groer, M., Zeller, J., Engstrom, J., & Fogg, L. (2010). A Pilot Study to Determine the Safety and Feasibility of Oropharyngeal Administration of Own Motherʼs Colostrum to Extremely Low-Birth- Weight Infants. Advances In Neonatal Care, 10(4), 206-212. http://dx.doi.org/10.1097/anc.0b013e3181e9413

▪Underwood, M. (2017). Probiotics and the Prevention of Necrotizing Enterocolitis. Presentation, UC Davis.

▪Vohr, B., Poindexter, B., Dusick, A., McKinley, L., Wright, L., Langer, J., & Poole, W. (2006). Beneficial Effects of Breast Milk in the Neonatal Intensive Care Unit on the Developmental Outcome of Extremely Low Birth Weight Infants at 18 Months of Age. PEDIATRICS, 118(1), e115-e123. http://dx.doi.org/10.1542/peds.2005- 2382

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