Management of comfort and sedation in neonates with neonatal encephalopathy treated with therapeutic hypothermia

Abstract

Ensuring comfort for neonates undergoing therapeutic hypothermia (TH) after neonatal encephalopathy (NE) exemplifies a vital facet of neonatal neurocritical care. Physiologic markers of stress are frequently present in these neonates. Non-pharmacologic comfort measures form the foundation of care, benefitting both the neonate and parents. Pharmacological sedatives may also be indicated, yet have the potential to both mitigate and intensify the neurotoxicity of a hypoxic-ischemic insult. Morphine represents current standard of care with a history of utilization and extensive pharmacokinetic data to guide safe and effective dosing. Dexmedetomidine, as an alternative to morphine, has several appealing characteristics, including neuroprotective effects in animal models; robust pharmacokinetic studies in neonates with NE treated with TH are required to ensure a safe and effective standard dosing approach. Future studies in neonates treated with TH must address comfort, adverse events, and long-term outcomes in the context of specific sedation practices.

1. Introduction

Neonatal encephalopathy (NE) leads to brain injury and neurodevelopmental impairment with serious long-term impact for the child, family, and society. Management of neonates with NE has been revolutionized by advances in neonatal neurocritical care. Early treatment with therapeutic hypothermia (TH), during which the neonate is cooled to 33.5 °C for 72 h, forms the foundation for current practice.

In the setting of moderate or severe NE, therapeutic hypothermia must be started within 6 h of birth for benefit, with a number needed to treat of 7 to prevent death or moderate-severe neurodevelopmental impairment in one neonate. Even with the standard use of TH, the rate of mortality and neurodevelopmental morbidity in moderate-severe NE ranges from 45% in initial trials to 29% in more recent trials [1,2]. It is critical to recognize that TH, while a key component of neurocritical care in neonates with NE, is but one facet of care that also involves providing appropriate analgesia and sedation, detecting and managing seizures, correcting metabolic derangements, avoiding hypocapnia, hypoxemia and hypotension, and providing appropriate nutrition [3]. As such, TH for NE is not a single “treatment” but rather part of a bundle of neonatal neurocritical care that extends beyond the first three days after birth [4].

The management of sedation in the term neonate with NE undergoing TH is an important element of optimal neonatal neurocritical care. Yet, the management of sedation is highly variable in these neonates. The appropriate use of sedation is important in order to provide compassionate care and to prevent stress and shivering that occurs at the temperatures required for effective neuroprotection. Preventing stress can be seen as a component to limit further injury in a vulnerable brain [5, 6]; however, it is also important to recognize that medications commonly used for sedation have the potential to profoundly alter the developing brain in critically ill neonates with NE.

In this chapter, we will review the indications for appropriate sedation in the term neonate with NE undergoing TH, including potential clinical practice approaches. As a foundation to addressing this issue, we will describe the pathophysiology of stress during TH. Within the context of pharmacological approaches to managing stress, it is imperative to consider non-pharmacologic strategies of providing comfort during TH. This is critical given the potential impact of pharmacologic sedatives on the neonatal brain exposed to hypoxia-ischemia (HI). This review is informed by recent evidence in other populations of critically ill neonates. We will specifically address the use of the most common sedatives in neonates with NE during TH. Neonates undergoing TH are a challenging population from a drug dosing standpoint due to the impact of hypoxic-ischemic multi-organ injury and cooling on pharmacokinetics. We will conclude by presenting potential clinical practice approaches for treatment, including drug dosing, and outlining key knowledge gaps for future investigations. Ultimately, the neonatal neurocritical care clinician has an important opportunity to promote optimal brain development and health through the effective use of sedation in the term neonate with NE undergoing TH.

1.1. Pathophysiology of stress during therapeutic hypothermia

Most mammals who do not hibernate, including humans, are homoeothermic, or warm-blooded, which means that core temperature of the body is tightly regulated and can be maintained above environmental temperatures. Chemical and physiological processes of the body are optimized for a certain temperature (37.0 °C for humans). Receptors involved in temperature regulation are distributed throughout the body with receptor signaling processed in the hypothalamus. The skin surface, deep abdominal and thoracic tissues, spinal cord, and non-hypothalamic portions of the brain each contribute roughly 20% to the control of autonomic thermoregulatory defenses. Thermoregulatory defenses are effective in adults in most environments; body temperature rarely deviates more than a few tenths of a degree. Lowering of the body temperature alters physiologic homeostasis and occurs by external influences such as immersion in cold water or anesthesia. At gradual lowering of the body temperature, vasoconstriction occurs first, followed by non-shivering thermogenesis and finally shivering in adults and older children.

Specific to neonatal hypothermia, vasoconstriction, bradycardia, and a consequent decrease in cardiac output (7% per °C) occur, alongside a decrease in metabolic rate (5–8% per °C) and changes in blood gas values due to reduced CO₂ production and higher CO₂ dissolution in the blood [7]. These changes may affect cerebral blood flow, which is already reduced by decreased cardiac output [8]. Hypothermia has also been shown to reduce the time spent in deep sleep (quiet sleep) [9]. Additionally, gastrointestinal, hepatic, and renal effects may alter pharmacokinetics and pharmacodynamics (discussed in detail later in this review).

Human neonates rely primarily on brown fat thermogenesis to generate body heat during induced hypothermia, and rarely shiver. Therefore, pharmacologic muscle relaxation, required for maintenance of target temperatures during TH in adults, is not standard of care in neonatal TH, and should be avoided in the absence of compelling indications to maintain the ability to complete neurologic examinations [10]. However, TH in neonatal sheep models, mammals who also rely on brown fat thermogenesis early in life, produces significant physiologic stress evidenced by a persistent elevation of circulating cortisol levels after asphyxia [11]. Approximately 10% of newborns undergoing TH show moderate-to-severe stress on the COMFORTNeo-scale, a validated clinical scale using alertness, calmness, respiratory response or crying, movement, facial tension and muscle tone as markers of stress and comfort, despite the common use of morphine (96%) and midazolam (74%) in this cohort [12]. However, evidence suggests traditional subjective markers of stress may be unreliable in the infant with NE during TH. For example, a case report utilizing skin conductance algesimetry found frequent signs of pain or stress during TH, corresponding with increases in heart rate and blood pressure but not pain scale scores [13].

Increased mortality and morbidity, including neurodevelopmental impairment, have been repeatedly associated with stress in preterm human infants [14]. However, limited data address these outcomes in the context of stress in term neonates with NE. Additional studies are clearly required to identify valid subjective and/or objective assessment tools to measure stress in term human neonates with NE requiring TH, as well as their association with long-term outcome. Thus, when considering the management of stress during TH, clinicians must first consider approaches for providing comfort that have the most favorable risk profile.

1.2. Non-pharmacologic approaches to provide comfort during therapeutic hypothermia

Existing data on the treatment of discomfort and shivering during TH center on the pharmacologic approaches described later in this article. To date, no studies have systematically evaluated non-pharmacologic treatment for discomfort during TH. However, family-centered developmental care strategies represent standard of care in critically ill neonates, and warrant consideration in neonates with NE requiring TH. Non-nutritive sucking and/or facilitated tucking (defined as a containment strategy that uses the placement of the caregiver’s hands on the head and lower limbs) are effective for single and repeat exposures to painful procedures (i.e., heel lance) in other neonatal populations, and should be considered in the standard bundle of non-pharmacologic care for minor painful procedures in neonates with NE receiving TH [15]. Preliminary data also suggest potential benefits of parental presence and of the odor of mother’s milk in reducing pain response [16,17]. Animal studies have shown the neuropeptide oxytocin plays an important role in pain mitigation as well as parent-infant bonding, providing a plausible link between family-centered developmental care and pain mitigation [18].

Recent data specific to NE have highlighted the trauma and stress parents experience when their infant undergoes TH. In a cohort of 31 parents, 41% report concerns over their infant’s pain/distress, including a perception that TH is uncomfortable [19]. Barriers that inhibit closeness, such as the cooling mattress and other medical equipment, impede bonding and contribute to parents’ traumatic experiences [20]. The inability to hold their infant has been described as “one of the most emotional issues” for parents [21]. In other populations such as preterm infants, parental separation is a stressor to both the parent and infant that can lead to adverse effects on parent-infant interactions and neurocognitive outcomes [18].

Involving parents in their neonate’s care, including incorporation of parental holding in the setting of clinical stability, can be successfully accomplished during TH [22]. While skin-to-skin care is not feasible, holding while on the cooling mattress is an alternative strategy without adverse effects on cardiorespiratory stability or temperature regulation [23]. No studies have evaluated holding in the context of cooling method, but servo-controlled whole-body cooling most optimally maintains target temperature for neonatal TH [24]. Thus, it is likely this method of cooling is also optimal for temperature regulation during holding. Additional family-centered care strategies such as oral care with mother’s milk, reading to their infant, and involvement in care (diaper changes, etc.) may also be incorporated alongside parental holding. Provision of minimal enteral nutrition during therapeutic hypothermia, ideally with mother’s milk, has emerged in many units [25]. Potential benefits include improving structural and functional integrity of the gut, reducing systemic inflammation, promoting gastrointestinal microbial diversity, reaching full feeds earlier, providing comfort, and empowering the mother. The feasibility of these developmental care interventions highlight the vital importance of their incorporation into TH protocols to benefit neonates and parents, although further research on this topic and standardization of practice are clearly urgently needed.

1.3. Potential impact of pharmacologic sedatives on the neonatal brain after hypoxia-ischemia

The ability to maintain a neonate’s comfort during TH is of major importance in modern neonatal neurocritical care. In addition to using sedation as a component of compassionate critical care, recent experimental studies in newborn piglets suggest that TH is not neuroprotective in the absence of sedation, suggesting the stress of hypothermia and shivering may interfere with the neuroprotective benefits of TH [26]. Yet, these observations are concurrent with mounting experimental evidence in rodents and non-human primates that exposure to sedatives, analgesics, and/or anesthetics have long term deleterious effects on the developing brain [27].

From the seminal experimental studies of Ikonomidou et al., we recognize that blockade of N-methyl-D-aspartate (NMDA) glutamate receptors in the developing rodent brain, even for only a few hours during late fetal or early neonatal life, triggers widespread apoptotic neurodegeneration [28]. These studies highlight the critical role of NMDA-mediated glutamate excitatory neurotransmission in regulating survival of developing neurons, and the need for caution in modulating these pathways in clinical practice [28]. Subsequently, other investigators observed that in seven-day old rat pups, a 6 h exposure to drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) led to widespread apoptotic neurodegeneration, deficits in hippocampal synaptic function, and memory impairments persisting to adulthood [29]. In fact, experimental studies indicate that sedatives (e.g., benzodiazepines) and anesthetics (e.g., ketamine, propofol), which inhibit NMDA receptor-mediated excitation and/or enhance gamma-aminobutyric acid (GABA)-mediated action, have negative impacts beyond neuronal apoptosis and have been linked to degeneration of oligodendroglia, suppression of neurogenesis, and inhibition of synaptic development [27]. These changes in the brain have long-lasting effects on subsequent cognition and behaviour [27]. Beyond the cerebrum, a 24-h infusion of the intravenous opioid fentanyl increased apoptosis in the internal granular cell layer in the cerebellum of healthy newborn pigs [30]. These laboratory investigations are consistent with recent human epidemiological studies that link general anesthesia for surgery and long-term cognitive outcomes in young children [27]. Yet, these studies are not supported by a recent clinical trial in which slightly less than 1 h of general anesthesia in early infancy does not alter neurodevelopmental outcome at five years of age, highlighting the vital links between duration, degree, and setting of exposure [31].

Clinical studies specifically addressing the impact of the most commonly used sedative medications in the term neonate with NE undergoing TH on brain injury and development are lacking. Yet, studies in preterm neonates highlight the importance of everyday clinical practices for brain maturation. In this context, exposure to pain during neonatal intensive care is a central factor that predicts maturation of the brain from early-life to term-equivalent age, particularly of the thalamus [32]. This association is most evident in preterm neonates born at the youngest gestational ages, such that the relevance of these observations to the full term neonate with NE is unknown [32]. Preterm neonates often spend months in the NICU, where they are treated with many painful procedures that are essential to life-saving care. Recent reports suggest that some medications regularly used for sedation in the NICU are linked to impaired brain maturation with some regional specificity: midazolam-hippocampus, morphine and fentanyl-cerebellum [14]. Furthermore, recent experimental data in non-human primates suggest that hypothermia decreases anesthesia-induced neuronal and oligodendroglial apoptosis, but only within a narrow temperature window (35–36.5 °C) [33]. As this benefit was lost below 35 °C, the applicability of hypothermic protection for sedation in human neonates requires further attention [33]. In concert, the above data highlight the complex interplay between pharmacologic sedation, stress, TH, and brain injury/development, prompting careful consideration of available preclinical and clinical data regarding specific agents in this setting.

1.4. Impact of therapeutic hypothermia on pharmacokinetics

Neonates with NE treated with TH represent a challenging population from a drug dosing standpoint. In addition to established predictors of drug pharmacokinetics including weight and organ maturation (often estimated using gestational age, post-menstrual age, and/or post-natal age), additional unique processes that can potentially have a large impact on drug pharmacokinetics and drug dose needs are present in this population, namely multi-organ injury and TH.

In NE, injury to the brain is only part of the spectrum, and the global hypoxic-ischemic insult frequently results in multi-organ injury and failure. Acute liver and kidney injury have been reported in up to 60% and 40% of neonates with NE, respectively [3]. The liver and kidney both play vital roles in the metabolism and elimination of drugs. Several clinical studies in neonates with perinatal asphyxia prior to the era of hypothermia have demonstrated marked alterations in the pharmacokinetics of drugs metabolized by the liver (phenobarbital, theophylline) and/or eliminated by the kidney (gentamicin) with 44–53% lower drug clearance compared to non-asphyxiated neonates of similar gestational age [34]. These studies clearly highlight the large impact multi-organ injury has on drug pharmacokinetics in this population.

More recent clinical studies in the era of hypothermia have further advanced and deepened our pharmacokinetic understanding of several drugs used in neonates with NE during hypothermia [34–36]. The most consistent and clinically relevant finding has been a reduction in clearance and a subsequent need for lower doses to achieve similar drug exposures compared to neonates without NE. The reduction in clearance has been found for drugs metabolized in the liver and eliminated unchanged by the kidney. However, the extent and magnitude of effect is variable and drug specific. Another frequent finding in studies to date was the presence of large variation between neonates in clearance for a given drug. This variation likely reflects in part the varying degrees of hepatic and/or renal injury in an individual neonate. For example, one study found neonates with the highest serum creatinine levels on the second day after birth had the lowest clearance of gentamicin, a renally eliminated drug [37]. Similarly, neonates with the most severe hepatic injury, based on liver enzyme elevations, had lower clearance and higher concentrations of the hepatically metabolized drugs morphine and midazolam [34]. Lastly, pharmacokinetics are not static and the dynamic nature of neonates in general, and specifically those with NE, will need to be considered. Hepatic metabolism and renal clearance of medications mature rapidly in the first weeks after birth in term neonates [38]. Additionally, drug clearance often improves as recovery of organ function occurs in neonates with NE over the first days after birth [36]. Like the injury itself, though, the trajectory of recovery varies between patients and those most severely ill often having ongoing organ dysfunction and reduced drug clearance.

Hypothermia is predicted to reduce drug clearance due to the temperature dependence of metabolic processes involved in clearance pathways and/or changes in organ blood flow. However, the independent effect of hypothermia on drug pharmacokinetics in neonates with NE is challenging to isolate since in most clinical pharmacokinetic studies performed all neonates received hypothermia within standard of care. Without a control normothermic NE population, disentangling the effect of hypothermia and rewarming from organ injury and recovery is problematic given the anticipated collinearity of these two clinical factors. With this limitation in mind, studies have attempted to isolate the effect of hypothermia for several drugs applying advanced population pharmacokinetic modeling and simulation techniques. The effect of hypothermia was variable, from no identifiable impact to small-to-moderate reductions in clearance [35,36]. Importantly, for drugs in which an effect of hypothermia was found, the magnitude of impact was not as large as that due to the underlying liver or kidney injury and subsequent recovery that occurs in neonates. There is some suggestion that the impact of hypothermia is dependent on the metabolic and elimination pathway of the drug. For example, an effect of hypothermia may be minimal for drugs eliminated via the kidney (e.g., gentamicin, amoxicillin, morphine-6-gluronide metabolite) or drugs metabolized in the liver with a high hepatic clearance (e.g., lidocaine) [36]. Further studies are needed to confirm the impact of hypothermia on individual drugs before generalized predictions about common metabolic and elimination pathways can be applied. In this setting, pharmacokinetic studies of specific medications are essential to guide dosing strategies and promote the safe and effective use of drugs in this population of newborns.

1.5. Preclinical data regarding pharmacologic sedation during therapeutic hypothermia

The Rice-Vannucci model, a neonatal rodent model, is one of the animal models that has been used extensively to study the effects of perinatal HI and neuroprotection. Following unilateral carotid ligation under halothane or isoflurane anesthesia and a brief recovery period, HI is induced in rats by decreasing the fraction of inspired oxygen for a certain period of time. To date, the impact of specific sedative agents have not been evaluated during TH experiments in rats [39]. To study physiological changes in addition to neuroprotection, larger mammals have been used as models of (near) term perinatal HI. Most experiments in these animals have been performed with anesthesia during the hypoxic-ischemic insult. In piglets, carotid clamping combined with a reduction in fraction of inspired oxygen, or only a reduction of oxygen, were applied [40]. Experimental TH demonstrated profound benefit in several studies in which the piglets were sedated with propofol (a potent GABA agonist) and fentanyl or nitrous oxide, oxygen, and isoflurane for the whole period of TH [40,41]. In one experiment, piglets were not sedated during TH, and started shivering [26]. In this experiment, the neuroprotective effect of TH was eliminated, suggesting that the stress of hypothermia increased cerebral metabolic demands.

Extensive experiments have been performed in fetal sheep. Fetuses were exteriorized following maternal anesthesia and received halothane during surgery. After a 24 h baseline period, HI was induced by inflating carotid cuffs. Thereafter, TH was applied by cooling the head through a cooling cap. During hypothermia in this model, no sedation was provided, and the benefits of TH persisted [42].

These preclinical experiments, along with the clear adverse impacts of some sedatives, may explain the absence of standing sedation protocols from the majority of human clinical trials of TH. Specifically, GABA agonists including propofol and benzodiazepines cannot be considered for continuous sedation due to an unacceptable incidence of associated hypotension [43]. The frequency of acute adverse effects must also be considered in the context of highly concerning long-term impact (see previous section). However, the utilization of an opioid in the piglet model presented above has been extrapolated to clinical practice and a trial of TH in human neonates.

1.6. Clinical data regarding opioids during therapeutic hypothermia

Opioids have been utilized extensively in neonatal care and have clear benefits on morbidity and mortality in the setting of severe, acute pain [14]. Opioids exert their action through G-protein-coupled μ-opioid receptors, present in the human fetal brain by mid-gestation. Of all natural and synthetic opioids, morphine and fentanyl have been used most in neonatal care.

Although extensive human studies have focused on the safety and efficacy of TH, many of these studies did not describe the use of sedatives, nor has the stress of being cooled been described in much detail in neonates not receiving sedation. Although likely a component of standard care, the majority of clinical trials of TH did not describe a specific approach to sedation in publication. In contrast, the clinical trial by Eicher et al. utilized morphine for analgesia at the attending physician’s discretion, or fentanyl if cardiovascular compromise was significant [44]. In the TOBY trial, neonates received sedation with morphine infusion or chloral hydrate if they appeared to be distressed [45]. Unfortunately, to date, the requirement for patient-specific, open-label analgesia or sedation have not been reported from these trials.

The neo.nEURO.network trial is the only TH trial that included continuous or scheduled opioid as standard care for comfort. All neonates in the hypothermia and control groups received sedation to reduce discomfort attributable to encephalopathy and TH and to counteract the stress response: 0.1 mg/kg morphine every 4 h, or an equivalent dose as a continuous infusion, or fentanyl at an equivalent dose [46]. Of interest, this trial documented a larger effect size for reducing neurodevelopmental impairments or death (32% absolute risk reduction [ARR] of death or severe disability, number needed to treat [NNT] = 3) compared to historic trials of TH (ARR = 15%, NNT = 7). However, caution should be exercised regarding both the efficacy and safety of pre-emptive opioid therapy for comfort during TH. A recent secondary analysis of the observational Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE) study found no protective effect of open-label morphine infusion (N = 141) on magnetic resonance imaging at one week of age or neurodevelopmental testing at 22 months of age, compared to similar neonates (N = 28) who did not receive morphine infusion [47]. Neonates who received morphine infusion were more likely to be hypotensive (49% vs. 25%, p = 0.02) and had a longer hospital stay (12 days vs. 9 days, p = 0.009).

These data highlight the common side effects of opioids including hypoventilation, hypotension, urinary retention, and decreased intestinal motility. Additionally, these data highlight the vital nature of considering morphine dosing in the context of NE and TH. The majority of neonates who received pre-emptive morphine in the MARBLE study were at a dose of 10–20 mcg/kg/hour by 24 h after birth [47]. Extensive subsequent pharmacokinetic/pharmacodynamic studies have the potential to improve safety and efficacy by modifying the standard dosing approach to morphine in TH. It was only after the introduction of TH as standard care that the pharmacokinetics of opioids during TH were completely characterized. Morphine undergoes metabolism in the liver and the predominant metabolite is morphine-3-glucuronide, which is non-sedative. The less abundant metabolite morphine-6-glucuronide is pharmacologically active with sedative and analgesic effects [48]. Both metabolites are eliminated through the kidneys. The largest pharmacokinetic studies of morphine in neonates with NE treated with hypothermia from two separate groups report similar findings [49,50]. The concentration of the active metabolite morphine-6-glucuronide rose over the first 12–24 h of treatment with greater accumulation in those with more severe kidney dysfunction. Morphine clearance was 50% lower compared to prior reports in normothermic non-asphyxiated term neonates. Based on the pharmacokinetic understanding gained, an ‘optimized’ loading dose of 50 μg/kg followed by a continuous infusion of 5 μg/kg/h, or 0.04–0.05 mg/kg every 6 h, was suggested. These dosing strategies were predicted to achieve morphine concentrations believed to be effective for analgesia in neonates (10–40 ng/mL), while minimizing the risk of extremely high concentrations associated with toxicity. However, dose individualization for a neonate is still needed given the variation between neonates in pharmacokinetics and exposures needed for analgesia and comfort. In addition, although morphine-6-glucuronide was measured in both studies, concentrations needed for analgesia/sedation and algorithms utilizing pharmacokinetic models to account for this metabolite in dosing strategies are not currently known. Studies describing the short-term and long-term outcomes of neonates with NE who receive morphine utilizing this updated dosing approach are urgently needed.

1.7. Preclinical and clinical data regarding dexmedetomidine during therapeutic hypothermia

Alpha-2-adrenergic agonists may represent ideal medications for achievement of both comfort and optimal long-term outcome in neonates exposed to HI. Dexmedetomidine, a potent alpha-2 agonist, provides analgesia, anxiolysis, and sedation via reduction in sympathetic outflow from the locus coeruleus and release of substance P from the dorsal horn of the spinal cord. In addition to direct sedative effects, alpha-2 agonists directly inhibit brown adipose and shivering thermogenesis via medullary premotor neurons in the rostral raphe pallidus. Potentially due to these mechanisms, these agents augment decreases in cranial temperature during TH [51]. Endogenous neuroprotection during the latent phase of NE relies on suppression of brain activity via activation of central alpha-2-adrenergic receptors. Exogenous blockade of central alpha-2 receptors results in a significant increase in epileptiform electroencephalographic transients, apoptosis, and neuronal loss in the hippocampus; in addition, low-dose infusion of an exogenous alpha-2 agonist results in a significant increase in surviving neurons after recovery from umbilical cord occlusion in fetal sheep [52]. Dexmedetomidine also inhibits inflammatory cytokines, including interleukin-6, produced in response to brain injury and associated with death or moderate/severe injury on magnetic resonance imaging [53]. Additionally, dexmedetomidine, as an imidazole compound, stimulates the expression of phosphorylated extracellular signal-regulated kinases in the hippocampus and brain derived neurotrophic factor by astrocytes, offering both direct and indirect pathways of neuronal and synaptic protection [54].

Preclinical data highlight the potential influence of these molecular mechanisms on outcome. Rat pups exposed to HI (but not hypothermia) using the Rice-Vannucci model experienced reduced loss of brain matter and improved neuromotor function at 30 and 40 days after treatment with dexmedetomidine [55]. However, dexmedetomidine did not offer additive short-term neuromotor benefits when combined with TH after induced cerebral ischemia in a rodent model, although a trend toward greater survival of hippocampal neurons with the combination suggests the potential for long-term neurologic benefit [56].

Human data regarding dexmedetomidine in neonates with NE during TH are less robust. In clinical studies to date, dexmedetomidine was found to lower the shivering threshold to a similar degree as general anesthetics in adult humans [57]. However, a lower level of sedation was needed compared to general anesthetics for efficacy with no associated respiratory depression. Dexmedetomidine has been evaluated retrospectively in term neonates with NE receiving TH (N = 19). At a dose of 0.3 μg/kg/hour (range 0.2–0.5 μg/kg/hour), dexmedetomidine eliminated the need for open label boluses of opioid for pain/agitation perceived by the bedside clinician, shivering, or tachycardia [58]. Two patients received dexmedetomidine as monotherapy; of seventeen neonates receiving fentanyl infusion at initiation of dexmedetomidine, thirteen (76%) of the opioid infusions were discontinued within 4 h. Eleven of fourteen neonates (79%) who required mechanical ventilation after birth were extubated on dexmedetomidine infusion; none of the five neonates spontaneously breathing at dexmedetomidine initiation required intubation. One neonate experienced bradycardia during dexmedetomidine infusion, which resolved after decreasing the concurrent fentanyl infusion without alteration of the dexmedetomidine dose. No neonates experienced hypotension during therapy. Enteral feedings were initiated at a mean of three days after birth, and full enteral feedings were achieved at a mean of six days after birth, two days before historic controls treated with fentanyl infusion. These results are consistent with a larger, retrospective comparison (N = 70) documenting less frequent breakthrough analgesia/sedation with continuous dexmedetomidine (0.27 ± 0.15 mcg/kg/hour) compared to intermittent scheduled morphine (0.1 mg/kg/dose every 4 h) [59]. There were no differences in hemodynamic variables or enteral feeding outcomes (although enteral feeding was not initiated during TH in this study). Approximately half of the study patients in each group required invasive mechanical ventilation, with increased ventilator support from baseline confined exclusively to morphine treated patients (0% vs. 32%, p = 0.02). The latter finding should be interpreted in the context of the dosing of morphine in this cohort compared to the pharmacokinetic studies discussed earlier in this review.

These results require additional validation, given the potential pitfalls of dexmedetomidine administration in neonates with NE treated with TH. Pediatric patients undergoing TH for traumatic brain injury have experienced clinically significant bradycardia during dexmedetomidine infusion [60]. Importantly, dexmedetomidine was utilized in conjunction with remifentanil in these cases. Additionally, bradycardia in these pediatric patients occurred 18–22 h after increasing the infusion rate from 0.5 μg/kg/hour to 0.7–1 μg/kg/hour. These data highlight the importance of judicious dosing and careful monitoring for adverse effects.

Like morphine, dexmedetomidine is hepatically metabolized and renally eliminated, and pharmacokinetics are altered by HI and TH. In contrast to morphine, the pharmacokinetics of dexmedetomidine for sedation in neonates with NE treated with TH are less well characterized [61]. In animal models, dexmedetomidine clearance is reduced by 56% following experimental HI and by an additional 33% during TH [62]. The pharmacokinetics of dexmedetomidine have been evaluated in only seven human neonates with moderate/severe NE treated with TH [61]. The maximum dexmedetomidine dose evaluated in this study was 0.4 μg/kg/hour, and no firm conclusions regarding safe and effective dosing can be made at this time. The emerging reports describing dexmedetomidine use in clinical practice highlight the urgent need for robust pharmacokinetic studies.

1.8. Potential approaches in clinical practice

Non-pharmacologic approaches form the foundation of providing comfort to mitigate stress in neonates with NE receiving TH and should include holding, parental presence and involvement in care, and oral care with mother’s milk. The role of pharmacologic sedation in neonates with NE remains controversial. The majority of clinical trials of TH in human neonates utilized an intermittent “as indicated” approach to analgesia and sedation; however, this approach may result in under treatment of stress given the unclear validity of subjective scoring tools in neonates with NE treated with TH. Additionally, intermittent boluses of sedation result in greater fluctuations in drug concentration, potentially increasing the risk for adverse effects including hypotension, bradycardia, and respiratory depression. Considering the balance of available evidence, both “as indicated” and preemptive approaches to sedation during TH are valid. A recent survey documented pre-emptive opioid infusion as standard care during TH in ventilated neonates in 86% of centers in the United Kingdom and 50% of centers in the United States and Canada; 40% and 44%, respectively, used pre-emptive morphine during TH in non-ventilated neonates [63]. When designing a clinical approach, providers must consider unit-specific factors as well as emerging evidence regarding safety, efficacy, and pharmacokinetics to ensure optimal and compassionate care. Furthermore, the multidisciplinary team must understand the potential impact of pharmacologic sedation on accurate neurologic assessments and interpretation of amplitude-integrated electroencephalography readings [47]. Benzodiazepines should be avoided for sedation, due to a high risk for hemodynamic adverse effects and the potential to augment aberrant neuronal and synaptic development in the setting of hypoxic injury. Morphine currently represents the approach to pharmacologic sedation with the strongest evidence base, although clinical trials focusing on safety, efficacy, and long-term outcome are urgently needed. A loading dose of 50 μg/kg should be followed by a continuous infusion of 5 μg/kg/hour [49,50]. Acute agitation or shivering may be managed with conservative bolus dosing (generally 25 μg/kg); titration of the continuous infusion should be cautious, in increments of no more than 2.5 μg/kg/hour and generally not exceeding 10 μg/kg/hour. In the absence of additional clinical complications, morphine infusions may be discontinued without weaning at any point during rewarming. The use of low-dose dexmedetomidine infusion (0.2–0.5 mcg/kg/hour) has recently been raised as an alternative to morphine infusion in the setting of appropriate monitoring for bradycardia. Potential acute benefits (i.e., lack of respiratory depression and impact on gastrointestinal motility) and long-term advantages (i.e., preclinical data suggesting neuroprotection) should be carefully considered in the setting of outstanding research questions including limited pharmacokinetic data. If utilized, dexmedetomidine may be weaned during rewarming by 0.1 mcg/kg/hour every 6 h to a minimum dose of 0.2 mcg/kg/hour before discontinuation.

1.9. Research directions

Determining the optimal strategy for sedation in term neonates with NE undergoing TH is of paramount importance, as the data reviewed above raise several concerns with routine sedation. Observational studies are necessary to identify and evaluate objective markers of stress in neonates with varying degrees of NE receiving TH. On the basis of these data, subjective assessment tools must be validated and/or designed to allow bedside evaluation of stress in this population. Since randomized controlled trials of each pharmacologic agent are limited by feasibility and costs, leveraging opportunities to compare clinical strategies and outcomes across centers is warranted. For example, the Canadian Neonatal Network successfully leveraged variation in outcomes across sites to identify better NICU practices for preterm neonates (e.g., to reduce infection) [64]. To inform clinical practices, robust pharmacokinetic and pharmacodynamic studies of morphine, dexmedetomidine, and potentially other sedatives must be undertaken in neonates with NE receiving TH. Studies of morphine must focus on available subjective and objective pharmacodynamic endpoints to inform therapeutic concentrations of morphine and morphine-6-glucuronide needed for sedation. Studies of dexmedetomidine must elucidate the impacts of both NE and TH on drug pharmacokinetics, the dynamic impact of alterations in clearance and volume of distribution, and the impact on long-term neurodevelopmental outcome. Centers utilizing dexmedetomidine in the absence of robust pharmacokinetic data must carefully record, analyze, and publish both safety and efficacy endpoints. Robust clinical and pharmacokinetic data have the potential to inform the prospective trials necessary to confirm the acute benefit:risk profile of dexmedetomidine in TH and evaluate long-term neurodevelopmental outcomes [65].

1.10. Practice points

• Non-pharmacologic approaches form the foundation for providing comfort for neonates with NE receiving TH

• Benzodiazepines should be avoided for sedation

• Morphine 50μg/kg followed by a continuous infusion of 5 μg/kg/ hour currently represents the approach to pharmacologic sedation with the strongest basis in evidence

• Low-dose dexmedetomidine infusion may be considered as an alternative to morphine infusion in the setting of appropriate monitoring for bradycardia

1.11. Research directions

• Identify and evaluate objective and subjective markers of stress in neonates with varying degrees of NE receiving TH and develop improved scoring systems for discomfort adjusted for NE and TH

• Leverage opportunities to compare clinical strategies of sedation and long-term outcomes across centers

• Advance the pharmacokinetic and pharmacodynamic understanding of morphine and dexmedetomidine

• Prospective studies of the safety, efficacy, and long-term outcomes of neonates with NE treated with morphine or dexmedetomidine