Oral Somatosensory Stimulation in Newborns with CCHD Dongli Song MD, PhD Associate Chief, Division of Neonatology Director, Newborn Clinical Research Director, Newborn Neuroprotection Program Santa Clara Valley Medical Center Stanford University School of Medicine (Affiliated) Department of Pediatrics, Division of Neonatal and Developmental Medicine Stanford University School of Medicine Thank you for the kind introduction, and I would like to thank the meeting organizer for giving me the opportunity to present the results from our recent multicenter RCT.

Disclosure: No personal financial disclosure Study PI - multicenter RCT of Patterned Oral Somatosensory Stimulation in Preterm Infants Funded by Innara Health, Inc. I am not a cardiologist/cardiac surgeon I am a neonatologist I have no personal financial disclosure , I will talk about an innovative approach to address neonatal feeding difficulties

Feeding Difficulties in Children with Congenital Heart Disease Malnutrition and failure to thrive are common in children with CHD post surgical repair Poor oral feeding is a major cause of imbalanced nutritional intake Nutritional/feeding issues in these infants often persist throughout the first years of life Increased rate of oral motor and speech abnormalities and poor neurodevelopmental outcomes

Oral Feeding Difficulties in Neonates with CHD The mode of feeding at time of discharge from hospital after the first stage of palliation in infants with hypoplastic left heart syndrome Less than 50% infants went home on independent oral feeding. Barbara Medoff-Cooper, Sharon Y. Irving Cardiology in the Young (2009)

Normal Feeding Development Reviewed by Bingham 2008, Costa 2008, Barlow 2009, Lau 2015 & 2016 36 30 34 32 28 PMA (weeks) 38 Breathe Swallow Suck ~18-20 weeks Increase frequency, amplitude, suck bursts, consistent rhythmic pattern ~11 30-32weeks Coordinated Suck-Swallow 26-29 weeks 1:1 Suck:Swallow 34-36 weeks Suck-Swallow-Breathing 44 The coordination of the three rhythmic movements (suck, swallow, and breathe) is essential for safe and effective independent oral feeding. These movements appear in early gestation, but become mature during late third trimester and early postnatal period. Adverse experiences during the critical period of oral feeding development lead to delayed/abnormal oral feeding abilities

Feeding Difficulties in Infants with Congenital Heart Disease Prolonged NPO and intubation -deprivation of normal oral experience Multiple invasive procedures and surgeries- obnoxious stimulation and injuries in the peripheral (laryngeal nerve injury) and CNS Cardiopulmonary instability and postoperative gastrointestinal dysfunction-poor endurance and feeding intolerance pinterest.com The normal oral feeding developmental process is interrupted in infants with CHD. They are often kept for prolonged NPO and intubation which deprive them from normal oral stimulation . Multiple invasive procedures and surgeries, which are are necessary to saving the lives, cause obnoxious stimulation and injuries in peripheral and CNS

Feeding Difficulties in Neonates with Congenital Heart Disease Infants with CHD are usually born at full term but their feeding difficulties are very similar to that of preterm infants (Pereira et al., 2015, Medoff-Cooper and Irving, 2009) Disorganized and weak suck Delayed triggering of swallowing Poor coordination in suck-swallow-breathe

Oral Somatosensory Input The Cortical Homunculus The strategy of preventing neonatal feeding difficulties is to minimize adverse stimuli and provide more positive physiological inputs to enhance normal oral feeding development The lips, tongue, and palate have very high-density sensory receptors and provide dynamic inputs to the brain During a critical developmental period the brain is highly sensitive and depends on proper external stimulation Providing a pacifier in preterm infant’s mouth during gavage feeding is a safe NNS stimulation. It has been shown to improve premature infants’ oral feeding performance and decrease their length of NICU stay. However, this type of stimulation is passive an the beneficial effects are variable among different publications. nobaproject.com The representation of somatosensory in the brain is related to the number of sensory neuronal connections, not the physical size of the body parts

Oral Somatosensory Input Non-nutritive Sucking (NNS) Suck on pacifier or recreational breastfeeding (No liquid ingestion) A safe oral somatosensory stimulation to the developing brain Improve infants’ oral feeding performance and decrease their length of NICU stay Regular pacifier stimulation: passive NNS and the beneficial effects are variable in different studies Providing a pacifier in preterm infant’s mouth is a safe NNS stimulation. It has been shown to improve premature infants’ oral feeding performance and decrease their length of NICU stay. However, this type of stimulation is passive an the beneficial effects are variable among different publications.

Patterned Oral Somatosensory Stimulation -NTrainer® Therapy Barlow SM, 2008, 2009 A repeating pattern of 6 pulses (1.8 Hertz) with 2 seconds pause The stimuli resemble the spatiotemporal features of normal infants’ NNS burst Entrains rhythmic, natural NNS Dr. Barlow has developed a bedside device to provide consistent and patterned oral somatosensory stimulation through a pulsatile pacifier. Exaggerated For viewing 275 um nipple Distortion

Patterned Oral Somatosensory Stimulation -NTrainer® Therapy Programmed, patterned, and consistent oral somatosensory stimulation improves NNS and nutritive feeding skills in preterm infants Dr. Barlow’s research team has conducted a series of studies and shown that the patterned oral stimulation is more effective than a regular pacifier.

Improvement in NNS after NTrainer Therapy Presentation Version June 2012 Improvement in NNS after NTrainer Therapy Increasing Sucks per burst Bursts per minute Suck pressure Reproducibility Here is an example of an infant's NNS during a 12 day treatment course KCBioMedix

B Govindaswami, MBBS, MPH Standardized Patterned Somatosensory Oral Stimulation in Very Preterm Infants: A Multicenter Randomized Controlled Trial D Song, MD, PhD, P Jegatheesan, MD, S Nafday MD, K Ahmad MD, J Nedrelow MD, M Wearden MD, S Nemerofsky MD, S Pooley, MD, D Thompson PhD, Z Cohen RN, T Cornejo RN, C Garrett RN, B Govindaswami, MBBS, MPH Santa Clara Valley Medical Center, San Jose, CA Children's Hospital at Montefiore-Weiler and Wakefield divisions, and Albert Einstein College of Medicine, Bronx, NY Pediatrix Medical Group, North Central Baptist Hospital Cook Children’s Medical Center, Fort Worth, TX Sponsored by: Innara Health, Inc. We have conducted a multicenter RCT to evaluate the clinical impact of this patterned oral simulation therapy in very premature infants.

Study Design Subjects: 210 preterm infants GA 260/7 - 306/7 weeks (Median GA 28.8 weeks, and BW 1.16 kg) Experimental group: - Pulsatile pacifier stimulation x 3-4/d (during tube feeding) x 10 days Initiation at 30 0/7 - 326/7weeks PMA Control group : - Sham – Non-pulsatile pacifier Primary outcome: Days from initiation to full oral feeding (FOF) Secondary outcomes: Length of hospital stay (LOS) Growth – weight gain and HC Neonatal mortality and morbidity (Breastfeeding is always given first priority!) The study enrolled 210 preterm infants born at 26-30 weeks gestation. The experimental group received NTrainer therapy 3 to 4 times a day during tube feeding for ten days. The control group received the identical study protocol with a non-pulsatile pacifier.

Study Outcomes Experimental Sham Difference P value (Mean + SD) n=109 N=101 Completed training sessions (%) 97 0.124 Days to FOF 22.94 ± 10.54 26.96 ± 14.84 -4 0.029 LOS 59.75 ± 20.21 65.78 ± 19.80 -6.03 0.034 PMA at FOF (weeks) 35.83 ± 1.70 36.42 ± 2.28 -0.58 0.042 PMA at discharge (weeks) 37.29 ± 2.09 37.92 ± 2.35 -0.63 0.046 Wt gain during intervention 18.23 ± 5.43 17.95 ± 5.07 + 28 0.708 Wt gain during NICU stay 12.63 ± 2.28 12.95 ± 2.24 +0.32 0.25 This slide summarizes the main findings of our study. The interventions are well tolerated and 97% training sessions were completed. Compared to the control group, the experimental group showed a 4 day reduction in transition to FOF and 6 day reduction in LOS. There is no difference between the two groups in mortality and morbidities, including IVH, NEC, late on set infection, CLD and ROP.

Why Oral Sensory Entrainment Reduces LOS ? A larger reduction in LOS compared to time to FOF Ntrainer entrainment promotes integration of multiple systems involved in feeding and facilitates interactions between the infant and environment – enhance overall developmental maturation required for discharge

Oral Somatosensory Input Modulates aEEG NTrainer System® BRAINZ® + = The synchronous sensory input relay in the brainstem and project to the thalamus, and subsequently relayed to orofacial regions of the sensorimotor cortex.

Summary: Patterned oral somatosensory stimulation (NTrainer®) is a effective therapy in improving oral feeding development in preterm infants Patterned oral somatosensory stimulation presents a new and exciting neurotherapeutic strategy to prevent and treat feeding disorders associated with CHD It is non-invasive and well tolerated by infants on respiratory support and thus can be used before and after surgery Feeding is important not only for nutrition, but may also have a significant impact on an infant’s speech development and long-term neurodevelopmental outcome

Improving Clinical Practice Thank you ! Feeding guidelines Evidence based practice Innovative therapies Change our practice model: More attention and resources to infant feeding Education: Feeding is important not only for nutrition, but also has a significant impact on an infant’s maturation and long-term neurodevelopmental outcome Babies and their families SCVMC NICU staff Collaborators: Children's Hospital at Montefiore-Weiler and Wakefield divisions, Albert Einstein CollegePediatrix Medical Group, North Central Baptist Hospital, Cook Children’s Medical Center. Funding: Santa Clara First Five; Innara Health, Inc.

The unique orosensory experience offered by the ‘motorized pacifier nipple’ is physiologically salient and The spectrally patterned stimuli resemble the spatiotemporal features of normal infants’ NNS burst. This form of stimulation serves to entrain the activity patterns of sensory receptors located in the lips, tongue, and jaw. The synchronous sensory input relay in the brainstem and project to the thalamus, and subsequently relayed to orofacial regions of the sensorimotor cortex. Descending neuromodulatory inputs are presumed to influence the firing patterns of facial, trigeminal, and hypoglossal motoneurons. The richness of the somatic sensory experience offered by an entraining pacifier nipple presents new and exciting neurotherapeutic applications

Improving Clinical Practice Changing our feeding practice model: Education: feeding is important not only for nutrition, but also has a significant impact on an infant’s maturation and long-term neurodevelopmental outcome Put more attention and resources to infant feeding Standardized feeding guidelines Implement evidence based practice Develop more innovative therapies

GA Subgroup Analysis (Mean + SD) Experimental Sham Difference P value Group A (GA 26-28 weeks) n-=55 n=57 Days to FOF 26.04=11.32 27.93=14.77 -1.89 0.471 LOS 73.33=15.92 72.04=14.59 +1.29 0.663 Group B (GA 29-30 weeks) n=52 n=39 19.84=9.04 25.00=15.05 -5.16 0.048 44.71=11.43 56.08=21.55 -11.37 0.002 There is no difference between the two groups in weight gain, mortality and morbidities, including IVH, NEC, late on set infection, CLD and ROP.

Timing of Intervention Post hoc analysis Timing of Intervention Intervention was initiated between 30-32 weeks PMA Post hoc analysis to determine if the timing of intervention affects outcomes: Early group (<31 weeks PMA) Late group (>31 weeks PMA)

Subgroup Analysis

Oral Somatosensory Stimulation Critical Period for Oral Somatosensory Stimulation Timing of Intervention Early Late PMA (weeks) Critical Period The timing effect of the therapy may reflect the neurophysiological maturity of the infant at the time of intervention We need to design a training regimen that targets the infant’s critical period of feeding development

Establishing Oral Feeding A Complex Developmental Process Maturation and integration of multiple systems Craniofacial - somatosensory and motor Specialized sensory systems - olfactory, gustatory, hearing and vision GI and Cardiorespiratory systems Neuromuscular system - maintain tone and position CNS – state and satiety and hunger regulation Suck-Swallow-Breathing coordination all cranial nerves Hypothalamic feedback loops of