Regional tissue oxygenation in asymptomatic neonates at high risk for neonatal abstinence syndrome and impact of non-pharmacologic interventions: A case report

1 Introduction

Given the ongoing nationwide opioid epidemic, neonatal abstinence syndrome (NAS) has become a major issue in newborn care. Sanlorenzo et al. reported an incidence of NAS in the United States of 5.63 per 1 000 hospital births in 2012, a nearly five-fold increase from 2000 [1]. The number of infants requiring special care nursery or neonatal intensive care unit (NICU) treatment for NAS increased approximately five-fold during this period [1, 2]. Between 2009 and 2012, cumulative hospital charges attributed to NAS climbed from $732 million to $1.5 billion [3].

NAS causes multisystem disturbances affecting postnatal function and requiring prolonged and expensive hospital stays [4]. Finding better ways to manage this increasingly common condition has become a critical concern. Current management is based on highly subjective NAS scoring systems, such as the modified Finnegan scoring paradigm [5]. An objective, reliable, and trendable estimate of NAS severity in neonates would represent an important advance in management.

Near-infrared spectroscopy (NIRS) is a noninvasive technique to evaluate and trend tissue oxygen saturation at the bedside. Similar to pulse oximetry (SpO₂), which reports global anticipated oxygen input to tissues via arterialized vessels, NIRS evaluates regional tissue oxygen saturation (rSO₂ = oxygenated hemoglobin/total hemoglobin) arising from all hemoglobin sources within a tissue. NIRS represents a predominantly post-capillary tissue oxygenation measure specific to the anatomic region being studied. It has been used to study cerebral and peripheral oxygen utilization. By simultaneously measuring SpO₂ and rSO₂, one can derive a trendable balance between oxygen supply (SpO₂) and individual tissue oxygen consumption (rSO₂) [6]. Commonly, SpO₂ and rSO₂ are used to calculate regional fractional tissue oxygen extraction (FTOE): FTOE = (SpO₂ –rSO₂)/SpO₂ [7–9].

In a recent review, Andersen et al. (2017) described the use of NIRS in the assessment of tissue “oxygen adequacy” given that states of oxygen deprivation, with associated increases in local tissue oxygen extraction, may now be noninvasively observed and trended at the bedside [8]. It is plausible that NAS results in heightened tissue oxygen utilization such that increased withdrawal symptoms are associated with higher tissue oxygen extraction. Thus, NIRS-based oxygenation data may provide an objective and trendable assessment of NAS severity. We therefore sought to determine whether NIRS-derived cerebral and peripheral muscle rSO₂ and FTOE demonstrate physiologically plausible changes in tissue oxygenation behavior that correlate with standard NAS scoring measures. We hypothesized that, among neonates at high risk for NAS, those with elevated modified Finnegan NAS scores (≥eight) would demonstrate ten percent lower cerebral rSO₂, indicative of increased tissue oxygen utilization, compared to similarly at-risk neonates without elevated NAS scores. We secondarily hypothesized that a direct correlation would be observed between NAS scores and cerebral and/or peripheral muscle FTOE. We finally hypothesized that nonpharmacological measures, specifically swaddling and cuddling, would be associated with a ten percent increase in rSO₂ with a proportional decrease in organ-specific FTOE. This study is an early step towards better individualized care for babies at risk for NAS.

2 Subjects and methods

3 Results

Subject recruitment and enrollment occurred between October 2018 and December 2019. Thirty neonates with mean gestational age 39 weeks and mean birth weight 3 127 grams were enrolled (Fig. 1). 22 (73%) were exposed to one opiate while eight (27%) had multi-drug exposures. 17 neonates (57%) were exposed to buprenorphine, and seven (23%) received morphine for NAS treatment.

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Fig. 1

Subject recruitment and enrollment.

Correlations between NAS scores and cerebral FTOE are presented in Table 1 and Fig. 2. The correlations between NAS scores and peripheral muscle FTOE are presented in Table 1. Neither cerebral nor peripheral muscle FTOE demonstrated significant correlation with modified Finnegan scores.

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Fig. 2

Correlations between neonatal abstinence syndrome (NAS) scores and cerebral fractional tissue oxygen extraction (FTOE) by day of life and swaddling state.

Comparisons between infants with elevated NAS scores (ever≥eight) versus never elevated NAS scores (< eight) are displayed in Table 2. There were no statistically significant effects of swaddling on cerebral or peripheral FTOE in infants of either group. When we divided the sample by exposure to buprenorphine, however, there was a statistically significant improvement in FTOE on Day Seven of life when babies exposed to buprenorphine were swaddled (p = 0.03) compared to the non-swaddled state. There were no statistically significant differences between groups or between pre-swaddling and swaddling monitoring periods when the babies were subdivided by single- vs. multi-drug exposure or when subdivided by whether morphine treatment was initiated.

Comparisons of simultaneous cerebral and peripheral muscle FTOE measurements among subjects subdivided by NAS score categorization and day of life are displayed in Table 3. There was only one statistically significant result, namely on Day of Life Five, where the average peripheral muscle FTOE in the never elevated NAS score group was significantly higher than that for the ever elevated NAS score group. Comparisons of cerebral NIRS FTOE scores and peripheral muscle FTOE scores between subjects with ever elevated NAS scores and subjects with never elevated NAS scores are shown in Table 4. Simultaneous cerebral and peripheral muscle FTOE measurements were significantly different, taking all data into account, for subjects with ever elevated NAS scores and subjects with never elevated NAS scores as well as specifically on Day of Life Three for subjects with ever elevated NAS scores and on Day of Life Five for subjects with never elevated NAS scores.

This study assessed the use of NIRS in the neonatal population at high risk for NAS. On a recent literature search, no studies evaluating tissue oxygenation monitoring in neonates at high risk for NAS were identified. Therefore, our study represents a pilot project to aid in determining whether non-invasive NIRS monitoring could assist clinical decision-making for this patient population.

NAS encompasses physiologic and neurobehavioral signs demonstrated by newborns exposed to opiates in utero. The pathophysiology of NAS is not completely understood, especially given the immaturity of neurologic development and processing in neonates and the intricate pharmacokinetics governing interactions among mother, placenta, and fetus [15]. NAS affects neurologic processing in multiple brain regions. Given the widespread nature of opioid receptors, NAS affects both central and autonomic neurologic function in addition to contributing to respiratory and gastrointestinal malfunction, with clinical effects on neonates’ postnatal adaptation [4]. These realities raise concern for both the short- and long-term effects of fetal opioid exposure and postnatal opioid treatment on the newborn brain [15].

In terms of management, while most literature recommends nonpharmacological care as first-line treatment, studies comparing the efficacy of behavioral interventions are lacking [15]. In some neonates, nonpharmacological management may reduce clinical symptoms and avoid the need for pharmacological therapy [4]. Medications such as morphine are added when supportive care is ineffective, high NAS scores remain, and/or opiate-associated diarrhea and/or vomiting leads to additional clinical concerns. While morphine’s effectiveness is well-established, it contributes to prolonged length of stay, as gradual weaning is required, in addition to uncertain effects on developmental outcomes [15].

Though our correlations between NAS scores and cerebral/peripheral FTOE were nonsignificant, they did plausibly trend in the correct direction for all but one category. These positive correlations were consistent with our hypothesis –higher NAS scores could potentially be associated with elevated cerebral FTOE such that enhanced withdrawal symptomatology could result in increased tissue oxygen utilization. With a larger sample size, it remains feasible that statistically significant correlations between NAS scores and cerebral FTOE would be observed.

Regarding peripheral NIRS monitoring, some correlations between NAS score and peripheral muscle FTOE were observed in the hypothesized direction while others occurred in a seemingly random fashion. These peripheral measures varied in slope and overall did not align with cerebral monitoring results. As discussed earlier, we included peripheral muscle monitoring as an exploratory measure to assess whether peripheral muscle monitoring could perhaps serve as a potentially easier-to-manage cerebral surrogate. Our data suggested that cerebral and peripheral muscle data are not equivalent. We believe this discrepancy can be explained by the body’s response to stress. Cerebral oxygenation should be a more stable signal owing to blood flow redistribution during periods of stress whereas peripheral muscle theoretically should demonstrate a more variable oxygen utilization signal. Our comparisons of simultaneously collected cerebral and peripheral muscle FTOE data furthered this claim –cerebral and peripheral muscle act differently, and one is not a surrogate for the other. Perhaps the higher reactivity of peripheral muscle makes it more susceptible to changes that have not yet impacted the behavior of cerebral oxygen extraction. Furthermore, an anecdotal lesson learned was that the peripheral muscle sensor was actually the less tolerated sensor of the two in general by the babies enrolled in the study. While the babies were generally content with the cerebral sensor across their forehead, more agitation was observed in response to right thigh sensor placement.

While we hypothesized that subjects with elevated NAS scores would have lower rSO₂ and therefore increased FTOE, we generally did not see significant FTOE differences when subjects were subdivided by whether they ever had an elevated NAS score. Interestingly, the statistically significant difference on Day of Life Five for peripheral muscle FTOE was the opposite of our expectation –given that this is the only statistically significant result, it appears most likely just due to random chance. It could also be proposed that, by Day of Life Five, the stress of withdrawal in the group of subjects having experienced elevated NAS scores caused a redistribution of blood flow to vital organs such that the peripheral muscle signal became less reactive to moment-to-moment changes in perfusion.

We additionally observed that babies exposed to buprenorphine had statistically lower cerebral FTOE scores when swaddled compared to pre-swaddling on Day of Life Seven. This may be explained by a later peak of withdrawal for babies exposed to buprenorphine compared to those exposed to other opioids [16]. Based on these findings, nonpharmacological measures such as swaddling and cuddling, or simply having parents room-in, for babies exposed to buprenorphine could be an additional area of inquiry, particularly later in these neonates’ clinical NAS observation period [17].

Our study’s particular strengths were its welcome reception by clinical staff members, our high consent rate, and the study team’s consistent approach to data collection. Given our high consent rate, we are confident that our enrolled subjects encompass a representative sample of babies undergoing NAS monitoring in our institution. Further, given the small size of the study team, variations in data collection were minimized, and we are thus confident of the reliability of our findings in this pilot project. A larger sample size is needed, however, to further study the NIRS monitoring approach in managing neonates at risk for NAS.

In terms of limitations, we acknowledge that our results are preliminary and require further study given our investigation took place at a single center with 30 subjects. While the inclusion of 30 subjects was determined after sample size calculations to assess for correlations as detailed earlier, we realize that this study design limits generalizability to the greater population and varying care practices. Furthermore, while each NIRS data collection period included time in the crib as well as time swaddled and held to draw comparisons, our study did not have a control group per se, again limiting our ability to draw conclusions on the impact of swaddling and holding on cerebral and peripheral muscle rSO₂. Furthermore, while the timing of 20 minutes in the crib and 10 minutes swaddled and held was kept consistent across NIRS data collection periods and subjects, it is possible that swaddling and holding for the final 10 minutes alone may not have been long enough to fully assess the impact of swaddling and holding on rSO₂. We also acknowledge that NAS severity is multifactorial, so there are other potential confounding factors that could have influenced study results and were not specifically assessed.

Tissue oxygenation monitoring demonstrates potential to provide objective and clinically useful physiologic information on infants at elevated risk for NAS. Further studies with larger sample sizes are required to best determine which subjects would benefit most from NIRS monitoring.