Actigraphy: An Adjunctive Method to Measure Irritability in Opioid-Exposed Newborns.

Background and purpose: Conventional measures of withdrawal in newborns with prenatal opioid exposure (POE) rely on nursing assessments, including the subjective judgment of infant irritability. This study investigated limb movement actigraphy as a tool for providing an objective, quantifiable measure of underlying distress. Methods: Correlational analyses compared continuous physiological-detected movement actigraphy and clinical intervallic-scored symptomology (modified Finnegan system) obtained from a control cohort of 37 term neonates with POE studied in their crib in the newborn unit (1-8 days). Results: Infants spent 15% crib time in high movement activity (>100 movements/minute; index irritability) and 38% crib time in low activity (0-5 movements/minute; index calm). There was a significant positive association between actigraphy and Finnegan composite score (r = .28, P = .001) and between actigraphy and subcomponent scores (i.e., central nervous system, gastrointestinal, and metabolic-vasomotor-respiratory). Conclusion: Movement activity via actigraphy captures underlying distress and calm not measured by conventional assessments. Such objective, quantifiable measures can serve to promote equitable assessment and treatment of hospitalized newborns with POE.

Efficacy of a Vibrating Crib Mattress to Reduce Pharmacologic Treatment in Opioid-Exposed Newborns: A Randomized Clinical Trial.

Importance: Pharmacologic agents are often used to treat newborns with prenatal opioid exposure (POE) despite known adverse effects on neurodevelopment. Alternative nonpharmacological interventions are needed. Objective: To examine efficacy of a vibrating crib mattress for treating newborns with POE. Design, Setting, and Participants: In this dual-site randomized clinical trial, 208 term newborns with POE, enrolled from March 9, 2017, to March 10, 2020, were studied at their bedside throughout hospitalization. Interventions: Half the cohort received treatment as usual (TAU) and half received standard care plus low-level stochastic (random) vibrotactile stimulation (SVS) using a uniquely constructed crib mattress with a 3-hour on-off cycle. Study initiated in the newborn unit where newborns were randomized to TAU or SVS within 48 hours of birth. All infants whose symptoms met clinical criteria for pharmacologic treatment received morphine in the neonatal intensive care unit per standard care. Main Outcomes and Measures: The a priori primary outcomes analyzed were pharmacotherapy (administration of morphine treatment [AMT], first-line medication at both study sites [number of infants treated], and cumulative morphine dose) and hospital length of stay. Intention-to-treat analysis was conducted. Results: Analyses were performed on 181 newborns who completed hospitalization at the study sites (mean [SD] gestational age, 39.0 [1.2] weeks; mean [SD] birth weight, 3076 (489) g; 100 [55.2%] were female). Of the 181 analyzed infants, 121 (66.9%) were discharged without medication and 60 (33.1%) were transferred to the NICU for morphine treatment (31 [51.7%] TAU and 29 [48.3%] SVS). Treatment rate was not significantly different in the 2 groups: 35.6% (31 of 87 infants who received TAU) and 30.9% (29 of 94 infants who received SVS) (P = .60). Adjusting for site, sex, birth weight, opioid exposure, and feed type, infant duration on the vibrating mattress in the newborn unit was associated with reduction in AMT (adjusted odds ratio, 0.88 hours per day; 95% CI, 0.81-0.93 hours per day). This translated to a 50% relative reduction in AMT for infants who received SVS on average 6 hours per day. Among 32 infants transferred to the neonatal intensive care unit for morphine treatment who completed treatment within 3 weeks, those assigned to SVS finished treatment nearly twice as fast (hazard ratio, 1.96; 95% CI, 1.01-3.81), resulting in 3.18 fewer treatment days (95% CI, -0.47 to -0.04 days) and receiving a mean 1.76 mg/kg less morphine (95% CI, -3.02 to -0.50 mg/kg) than the TAU cohort. No effects of condition were observed among infants treated for more than 3 weeks (n = 28). Conclusions and Relevance: The findings of this clinical trial suggest that SVS may serve as a complementary nonpharmacologic intervention for newborns with POE. Reducing pharmacotherapy with SVS has implications for reduced hospitalization stays and costs, and possibly improved infant outcomes given the known adverse effects of morphine on neurodevelopment. Trial Registration: ClinicalTrials.gov Identifier: NCT02801331.

Assessment of a hearing protection device on infant sleep in the neonatal intensive care unit.

Premature infants often require prolonged hospitalisation in the neonatal intensive care unit (NICU) where they are exposed to adverse noise that may disrupt sleep and further compromise recovery and developmental outcomes. This single-session trial assessed the effects of a novel circumaural hearing protection device (DREAMIES®; NEATCAP Medical LLC) on sleep in 10 premature infants (mean 34.1 weeks GA) in a Level III NICU. Using polysomnography (PSG), the infant's sleep was compared between three interfeed periods throughout which DREAMIES® was ON or OFF. Each infant received the same condition order, OFF1-ON-OFF2. The PSG 30 s epochs were scored by a rater masked to the condition as Quiet Sleep, Active Sleep, Indeterminate Sleep, and Wake. There was a 14.1% increase in sleep from OFF1 to ON (p = 0.05) and an 18.4% decrease in sleep from ON to OFF2 (p = 0.02); an analogous inverse effect was observed for wake (χ2  = 5.03, p = 0.08). There was a main effect of DREAMIES on active sleep (χ2  = 7.4, p = 0.025) due to more active sleep for ON1 (46%) compared with OFF2 (32%; p = 0.074). No significant effect was observed for quiet sleep or indeterminate sleep. On average, the sound level was 51 dBA (range 36-113 dBA) and did not differ significantly among the three periods. The strongest relationship between the minute-by-minute maximum sound level and movement actigraphy was observed for the OFF1 condition (ρ0.301, p < 0.001). These findings suggest that DREAMIES® may augment sleep in premature infants by reducing acute episodes of adverse noise in the NICU.

Physiologic dysregulation in newborns with prenatal opioid exposure: Cardiac, respiratory and movement activity.

BACKGROUND: Newborns with prenatal opioid exposure (POE) are commonly diagnosed with neonatal abstinence/opioid-withdrawal syndromes due to characteristic symptoms and overt behaviors. However, little is known about the underlying physiology of opioid-exposed newborns. OBJECTIVE: Cardiac, respiratory and movement activity were measured to identify physiologic dysregulation and quantify pathophysiologic instabilities of the central and autonomic nervous systems in POE newborns. METHODS: In this pilot study, 30 hospitalized POE newborns (>35 wks gestational age) participated in one of two study phases wherein physiologic activity was measured for an 8-10 h session. In Phase 1, 17 infants received usual treatment to provide a general assessment of physiologic activity. In Phase 2, 13 infants participated in an interventional study (NCT02768844) using a prototype mattress that delivered stochastic vibratory stimulation (SVS). Changes in physiologic activity were compared for device on (N) and off (F) for three interfeed periods (FNF or NFN). RESULTS: Phase 1 showed that although infants' heart rate was on average within normal newborn range (mean 137 bpm, SD 7), infants were tachycardic 16% of the study period and tachypneic (mean 74 breaths/min, SD 13) 62% of the period. Infants moved 33% of the period; 17% were durations >30 s. In Phase 2, heart rate, respiratory rate, movement duration and frequency were each reduced for SVS N compared to SVS F in the FNF protocol (P < 0.05). CONCLUSION: Findings support that physiologic measures can identify dysregulation not captured with current withdrawal scoring assessments. Larger studies are warranted to assess if mattress SVS helps regulate pathophysiologic instabilities in infants with POE.

Actigraphy: Metrics reveal it is not a valid tool for determining sleep in neonates.

Study of emerging sleep-wake patterns in neonates is important for promptly identifying and treating abnormal sleep behaviours to ensure healthy infant development and neurobehavioral outcomes. Current methods to assess sleep are costly, labour intensive, and particularly difficult to implement in fragile, hospitalised infants requiring intensive medical care. The aim of the present study was to assess the validity of actigraphy as a tool for detecting sleep in preterm infants, using polysomnography (PSG) as the "gold standard". A total of 10 neonates (mean [SD] 35.8 [1.2] weeks post-menstrual age; five female) hospitalised since birth for prematurity each participated in one 8-10 hr session during which PSG and actigraphy were recorded simultaneously. Inter-feed minute-by-minute PSG Sleep-Wake scores were compared to concurrent actigraph epochs categorised as either "Sleep" or "Wake" using three separate movement-per-minute thresholds (≤20, ≤40, ≤80). Tool validity was assessed using five metrics. A key finding was that for each of the movement thresholds there was high agreement rate, sensitivity, and predictive value of sleep (85.2%-97.2%), whereas specificity and predictive value of wake remained low (12%-46%). Receiver operating characteristic curve analysis also revealed low discriminatory power of actigraphy for estimating sleep (area under the curve = 0.636; Youden's Index J = 0.2173). Lack of sufficient minutes of autonomous wake periods among infants was identified as a key limitation in actigraphy. Findings from the present study suggest actigraphy cannot be validated for Sleep/Wake discrimination in preterm infants and that proper validation requires sufficient data from periods of both Sleep and Wake.

A pilot study to assess the safety, efficacy and ease of use of a novel hearing protection device for hospitalized neonates.

BACKGROUND: Loud noises in the neonatal intensive care unit (NICU) exacerbate patient cardiac and respiratory activity, disrupt sleep, and may contribute to hearing deficits, speech and language disorders, and neurodevelopmental delays among NICU graduates. AIMS: This study evaluated infant-patient tolerance and nurse ease of use of a novel frequency-selective hearing protection device, DREAMIES (NEATCap Medical, LLC). STUDY DESIGN AND SUBJECTS: Fifty neonates receiving care in a Level III NICU participated in a 2-phase prospective study. In Phase 1, 25 infants (mean 36.6 wks GA) wore DREAMIES for two consecutive 30-min periods. In Phase 2, 25 infants (mean 34.8 wks GA) wore DREAMIES between care and feeding times during an 8-h Device-On period followed by an 8-h Device-Off period for three consecutive days. OUTCOME MEASURES: Subject tolerance was defined by device-related skin irritation, vital sign measurements, and behavioral state. Device fit and ease of use were also evaluated by NICU nurses. RESULTS: No skin breakdown was reported in any infant in either phase. Only transient skin erythema was observed. Periods when infants wore DREAMIES resulted in lower heart and respiratory rates and increased sleep (P < 0.001). Nurses reported little to no difficulty in applying or removing the device. CONCLUSION: Findings suggest DREAMIES are a safe, easy to use, and effective device that reduces exposure to NICU noise, and may improve cardio-respiratory activity and promote sleep among neonatal patients. Further studies are warranted to examine longer term use and potential benefits of DREAMIES for improving outcomes in infants receiving NICU care. This trial is registered on clinicaltrials.govNCT02744066.

Study design and rationale for a randomized controlled trial to assess effectiveness of stochastic vibrotactile mattress stimulation versus standard non-oscillating crib mattress for treating hospitalized opioid-exposed newborns.

The incidence of Neonatal Abstinence Syndrome (NAS) continues to rise and there remains a critical need to develop non-pharmacological interventions for managing opioid withdrawal in newborns. Objective physiologic markers of opioid withdrawal in the newborn remain elusive. Optimal treatment strategies for improving short-term clinical outcomes and promoting healthy neurobehavioral development have yet to be defined. This dual-site randomized controlled trial (NCT02801331) is designed to evaluate the therapeutic efficacy of stochastic vibrotactile stimulation (SVS) for reducing withdrawal symptoms, pharmacological treatment, and length of hospitalization, and for improving developmental outcomes in opioid-exposed neonates. Hospitalized newborns (n = 230) receiving standard clinical care for prenatal opioid exposure will be randomly assigned within 48-hours of birth to a crib with either: 1) Intervention (SVS) mattress: specially-constructed SVS crib mattress that delivers gentle vibrations (30-60 Hz, ~12 µm RMS surface displacement) at 3-hr intervals; or 2) Control mattress (treatment as usual; TAU): non-oscillating hospital-crib mattress. Infants will be studied throughout their hospitalization and post discharge to 14-months of age. The study will compare clinical measures (i.e., withdrawal scores, cumulative dose and duration of medications, velocity of weight gain) and characteristic progression of physiologic activity (i.e., limb movement, cardio-respiratory, temperature, blood-oxygenation) throughout hospitalization between opioid-exposed infants who receive SVS and those who receive TAU. Developmental outcomes (i.e., physical, social, emotional and cognitive) within the first year of life will be evaluated between the two study groups. Findings from this randomized controlled trial will determine whether SVS reduces in-hospital severity of NAS, improves physiologic function, and promotes healthy development.

Salivary cortisol levels as a biomarker for severity of withdrawal in opioid-exposed newborns.

BACKGROUND: Scoring tools used to quantify withdrawal in infants with neonatal abstinence syndrome (NAS) are often confounded by subjective measurements. This study assessed salivary cortisol as an objective biomarker of withdrawal severity in opioid-exposed newborns. METHODS: A prospective study was conducted in 25 full-term opioid-exposed newborns monitored for NAS. Morning and evening salivary cortisol levels were collected starting within 48 h post birth until initiation of pharmacologic treatment for withdrawal (Pre-Treatment) or when the infant was discharged without pharmacotherapy (No Treatment). RESULTS: Cortisol levels in the Pre-Treatment group (n = 11) were significantly higher within the first week of life (median 1.74 µg/dl) than in the No Treatment group (n = 11; median 0.72 µg/dl; P = 0.003); three infants had inadequate saliva volume for cortisol assay. Cortisol significantly decreased after 72 h post birth among infants discharged without pharmacotherapy (≤72 h median 1.25 µg/dl; ≥72 h median 0.58 µg/dl; P = 0.022), whereas cortisol remained elevated for infants subsequently treated for severity of withdrawal. No cortisol circadian rhythm was observed for either group. CONCLUSIONS: Salivary cortisol in opioid-exposed newborns may provide an index of stress and help identify infants who will have more severe clinical presentation of NAS. Such a biomarker would allow risk stratification for early treatment and discharge decisions.

A Quality Improvement Initiative to Increase Scoring Consistency and Accuracy of the Finnegan Tool: Challenges in Obtaining Reliable Assessments of Drug Withdrawal in Neonatal Abstinence Syndrome.

BACKGROUND: Current practice for diagnosing neonatal abstinence syndrome and guiding pharmacological management of neonatal drug withdrawal is dependent on nursing assessments and repeated evaluation of clinical signs. PURPOSE: This single-center quality improvement initiative was designed to improve accuracy and consistency of Finnegan scores among neonatal nurses. METHODS: One-hundred seventy neonatal nurses participated in a single-session withdrawal-assessment program that incorporated education, scoring guidelines, and a restructured Finnegan scale. Nurses scored a standardized video-recorded infant presenting with opioid withdrawal before and after training. RESULTS: Nearly twice as many nurses scored at target (Finnegan score of 8) posttraining (34.7%; mean error = 0.559, SD = 1.4) compared with pretraining (18.8%; mean error = 1.31, SD = 1.95; Wilcoxon, P < .001). Finnegan scores were significantly higher than the target score pretraining (mean = 9.31, SD = 1.95) compared with posttraining (mean = 8.56, SD = 1.40, Wilcoxon P < .001); follow-up assessments reverted to pretraining levels (mean = 9.16, SD = 1.8). Score dispersion was greater pretraining (variance 3.80) compared with posttraining (variance 1.96; Kendall's Coefficient, P < .001) largely due to score disparity among central nervous system symptomology. IMPLICATIONS FOR PRACTICE: Education, clinical guidelines, and a restructured scoring tool increased consistency and accuracy of infant withdrawal-assessments among neonatal nurses. However, more than 60% of nurses did not assess withdrawal to the target score immediately following the training period and improvements did not persist over time. IMPLICATIONS FOR RESEARCH: This study highlights the need for more objective tools to quantify withdrawal severity given that assessments are the primary driver of pharmacological management in neonatal drug withdrawal.Video Abstract available at https://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx.

Vibrotactile stimulation: A non-pharmacological intervention for opioid-exposed newborns.

OBJECTIVE: To examine the therapeutic potential of stochastic vibrotactile stimulation (SVS) as a complementary non-pharmacological intervention for withdrawal in opioid-exposed newborns. STUDY DESIGN: A prospective, within-subjects single-center study was conducted in 26 opioid-exposed newborns (>37 weeks; 16 male) hospitalized since birth and treated pharmacologically for Neonatal Abstinence Syndrome. A specially-constructed mattress delivered low-level SVS (30-60Hz, 10-12µm RMS), alternated in 30-min intervals between continuous vibration (ON) and no vibration (OFF) over a 6-8 hr session. Movement activity, heart rate, respiratory rate, axillary temperature and blood-oxygen saturation were calculated separately for ON and OFF. RESULTS: There was a 35% reduction in movement activity with SVS (p<0.001), with significantly fewer movement periods >30 sec duration for ON than OFF (p = 0.003). Incidents of tachypneic breaths and tachycardic heart beats were each significantly reduced with SVS, whereas incidents of eupneic breaths and eucardic heart beats each significantly increased with SVS (p<0.03). Infants maintained body temperature and arterial-blood oxygen level independent of stimulation condition. CONCLUSIONS: SVS reduced hyperirritability and pathophysiological instabilities commonly observed in pharmacologically-managed opioid-exposed newborns. SVS may provide an effective complementary therapeutic intervention for improving autonomic function in newborns with Neonatal Abstinence Syndrome.

Kangaroo care: cardio-respiratory relationships between the infant and caregiver.

BACKGROUND: Kangaroo care, i.e., skin-to-skin cohabitation (SSC) between an infant and caregiver, is often used in neonatal intensive care units to promote bonding, breastfeeding and infant growth. The direct salutary effects of SSC on cardio-respiratory control in preterm infants remain equivocal; some reports suggest improved breathing stability, others indicate worsening of apnea, bradycardia and hypoxemia. AIM: The purpose of this study was to investigate physiological relationships between the infant and caregiver during SSC. We hypothesized that respiratory stability of the premature infant is influenced by the caregiver's heartbeat. DESIGN: A prospective study was performed in eleven preterm infants (6 female; mean PCA 32 wks). SSC was compared to a preceding incubator-control period (CTL) matched for time from feed and condition duration. Abdominal respiratory movement, electrocardiogram, skin temperature and blood-oxygen levels were recorded from the infant and the caregiver. RESULTS: During CTL, infant interbreath interval variance (IBIv; respiratory instability) was directly related to its own heart rate variance (HRv; rho=0.770, p=0.009). During SSC, infant IBIv and apnea incidence were each related to caregiver HRv (rho 0.764, p=0.006; rho 0.677, p=0.022, respectively). Infant cardio-respiratory coupling was also enhanced during SSC compared to CTL in the eupneic frequency range (0.7-1.5 Hz, p=0.018) and reduced for slower frequencies (0.15-0.45 Hz; p=0.036). CONCLUSION: These findings suggest that during SSC, respiratory control of the premature infant is influenced by the caregiver's cardiac rhythm. We propose that the caregiver's heartbeat causes sensory perturbations of the infant via somatic or other afferents, revealing a novel cohabitation-induced feed-back mechanism of respiratory control in the neonate.

Assessment of cardio-respiratory interactions in preterm infants by bivariate autoregressive modeling and surrogate data analysis.

BACKGROUND: Cardio-respiratory interactions are weak at the earliest stages of human development, suggesting that assessment of their presence and integrity may be an important indicator of development in infants. Despite the valuable research devoted to infant development, there is still a need for specifically targeted standards and methods to assess cardiopulmonary functions in the early stages of life. We present a new methodological framework for the analysis of cardiovascular variables in preterm infants. Our approach is based on a set of mathematical tools that have been successful in quantifying important cardiovascular control mechanisms in adult humans, here specifically adapted to reflect the physiology of the developing cardiovascular system. METHODS: We applied our methodology in a study of cardio-respiratory responses for 11 preterm infants. We quantified cardio-respiratory interactions using specifically tailored multivariate autoregressive analysis and calculated the coherence as well as gain using causal approaches. The significance of the interactions in each subject was determined by surrogate data analysis. The method was tested in control conditions as well as in two different experimental conditions; with and without use of mild mechanosensory intervention. RESULTS: Our multivariate analysis revealed a significantly higher coherence, as confirmed by surrogate data analysis, in the frequency range associated with eupneic breathing compared to the other ranges. CONCLUSIONS: Our analysis validates the models behind our new approaches, and our results confirm the presence of cardio-respiratory coupling in early stages of development, particularly during periods of mild mechanosensory intervention, thus encouraging further application of our approach.

Heritability of apnea of prematurity: a retrospective twin study.

BACKGROUND: Apnea of prematurity (AOP) is a disturbance in respiratory rhythm defined by idiopathic pauses in breathing that reduce blood oxygen levels and/or heart rate. It is a major clinical problem among preterm infants. OBJECTIVES: The primary goal of this study was to estimate the genetic susceptibility to AOP in a cohort of preterm twins. A secondary aim was to identify risk factors associated with AOP in this cohort. METHODS: A single-center, retrospective study (2000-2008) was performed by using data from 317 premature twin pairs (<36 weeks' gestational age). Heritability estimates were determined by comparing intrapair AOP concordance between 56 monozygotic and 161 dizygotic twin pairs by using structural equation modeling. Risk factors of AOP among a cohort of 543 premature twins were assessed by using mixed-effects logistic regression. RESULTS: The heritability of AOP was 87% (95% confidence interval [CI]: 0.64-0.97) among same-gender twins. A gender-dependent model revealed that genetic factors accounted for 99% of the variance in male twins (95% CI: 0.89-1.00) and 78% of the variance in female twins (95% CI: 0.49-0.94). Significant risk factors for AOP were low gestational age (P<.001), cesarean delivery (P=.017), and conception through assisted reproductive technologies (P=.008). CONCLUSIONS: These findings suggest that AOP has an important genetic basis underlying this developmental-related disorder of respiratory control. Future genomic studies may provide information on pathophysiological mechanisms that underlie AOP.

Stabilizing immature breathing patterns of preterm infants using stochastic mechanosensory stimulation.

Breathing patterns in preterm infants consist of highly variable interbreath intervals (IBIs) that might originate from nonlinear properties of the respiratory oscillator and its input-output responses to peripheral and central signals. Here, we explore a property of nonlinear control, the potential for large improvement in the stability of breathing using low-level exogenous stochastic stimulation. Stimulation was administered to 10 preterm infants (postconceptional age: mean 33.3 wk, SD 1.7) using a mattress with embedded actuators that delivered small stochastic displacements (0.021 mm root mean square, 0.090 mm maximum, 30-60 Hz); this stimulus was subthreshold for causing arousal from sleep to wakefulness or other detectable changes in the behavioral state evaluated with polysomnography. We used a test-retest protocol with multiple 10-min intervals of stimulation, each paired with 10-min intervals of no stimulation. Stimulation induced an approximately 50% reduction (P = 0.003) in the variance of IBIs and an approximately 50% reduction (P = 0.002) in the incidence of IBIs > 5 s. The improved stability of eupneic breathing was associated with an approximately 65% reduction (P = 0.04) in the duration of O(2) desaturation. Our findings suggest that nonlinear properties of the immature respiratory control system can be harnessed using afferent stimuli to stabilize eupneic breathing, thereby potentially reducing the incidence of apnea and hypoxia.