Neonatal Pain and Stress

Key Points

Pain and discomfort in infants are common occurrences in intensive care.
Identification and management of neonatal pain remain challenging.
Many neonatal pain scoring tools assist in classifying pain, but many were not validated in clinical practice.
Neonatal pain recognition with near-infrared spectroscopy and amplitude-integrated electroencephalography does not always align with clinical manifestations of pain, raising questions about how best to define, diagnose, and treat pain.
Untreated neonatal pain can result in long-term adverse outcomes due to alterations in brain structure and hormone imbalance, resulting in abnormal childhood pain responses.
Pharmacologic treatment of pain is widely used, but nonpharmacologic interventions may be just as effective.

Background

In the 1980s, a public outcry regarding the recognition and management of pain in hospitalized patients prompted the US Department of Health and Human Services, The Joint Commission, and other professional organizations to mandate pain management practices for all patients, including neonates. An initial statement endorsing pain management for neonates undergoing surgical interventions, regardless of age and cortical immaturity, was jointly issued by the American Academy of Pediatrics Committees on Fetus and Newborn, the Committee on Drugs, the Section on Anesthesiology, the Section on Surgery as well as the American Society of Anesthesiologists. The Acute Pain Management Guideline Panel of the US Agency for Health Care Policy and Research also endorsed the need for pain management in neonates.

The subsequent conundrum was that neonatal caregivers were expected to assess and treat perceived neonatal pain and discomfort in the absence of evidence-based methods with which to base their assessment and therapy. The lack of verbal skills, immature behaviors in response to pain, and the nonspecific nature of physiologic indicators of pain in a critically ill patient all combine to make accurately assessing pain in term and preterm neonates challenging. The challenge of pain assessment is further compounded by typical NICU interventions such as mechanical ventilation, physical restraints, and pharmacologic sedation, all of which mask distress behaviors. Because the gold standard of pain assessment (self-reporting using validated scales) is not applicable to neonatal patients, providers must reply on physiologic, behavioral, and biobehavioral indicators as surrogates for self-reporting pain.

Taxonomy

Defining neonatal pain and its myriad presentations may help clinicians to recognize and therefore treat it. The proposed taxonomy includes distinctions between acute episodic pain, acute recurrent pain, prolonged pain, persistent pain, and chronic pain ( Table 22.1 ). The origin and resultant physiologic status for various painful stimuli can be quite different. Tools for assessment of neonatal pain and stress must be based on an understanding of the normal development of behavioral responses to pain and stress—an infant is not a small adult.

Table 22.1

Suggested Starting Point for Defining the Pain Terms Used for Neonatal Pain

From Anand KJS. Defining pain in newborns: need for a uniform taxonomy? Acta Paediatr . 2017;106(9):1438–1444.

Pain Term	Onset	Duration	Character *	Primary Hyperalgesia
Acute episodic	Immediate	0–120 ^† min	Sharp, well-localized	Present, mild, short-lasting
Acute recurrent	Immediate	Variable	Sharp, well-localized	Present, moderate or severe
Prolonged ^‡	Rapid, may be gradual	1 h–24 ^† h	Sharp, diffusely localized	Present, moderate or severe
Persistent ^‡	Rapid or gradual, cumulative	1–7 days	Dull/sharp, diffusely localized	Present, moderate or severe
Chronic	Usually gradual	8 days or longer	Dull, diffusely localized	May be present or absent, mild if present

Pain Term	Secondary Hyperalgesia	Allodynia	Behavioral Phenotype	Physiological Phenotype
Acute episodic	Probably absent	Probably absent	Strongly reactive and reflexive	High peak, sympathetic activation
Acute recurrent	Present, mild or moderate	Probably absent	Weakly reactive or reflexive	Prolonged peak, sympathetic activation
Prolonged ^‡	Mild or absent	Probably absent	Strongly reactive on stimulation	High plateau, sympathetic activation
Persistent ^‡	Present, mild or moderate	May be present, mild/moderate	Hyperreactive initially, later hyporeactive	Normal or low sympathetic activation
Chronic	Present, moderate, or severe	May be present, moderate/severe	Hyporeactive more often, could also be hyperreactive	Normal or suppressed sympathetic drive

* Based on descriptions in adult patients but may be discerned by a careful physical examination.

† Some infants with increased sensitivity to pain may have a slower decay of the acute pain following an invasive procedure, thus justifying some overlap in the durations of acute episodic pain and prolonged pain.

‡ Continuous pain may be characterized as either “prolonged” or “persistent.”

An international survey of experts in neonatal pain, including physicians, nurses, researchers, and parents from around the world, used the Delphi method to propose a definition of chronic pain in neonates. They put forth the following:

“Chronic pain can often not be associated with a specific cause. It has no obvious endpoint in sight and is no longer proximate to an event or procedure. Chronic pain may alter perception causing non-noxious events to be perceived as painful, leading to a chronic pain response. It depletes stress hormones, increases energy consumption, and therefore interferes with growth. As a consequence, chronic pain may likely prolong hospitalization and add to existing neonatal morbidities.”

The optimal approach to neonatal pain management relies on a concerted, mindful practice that involves:

Reducing the frequency of painful procedures
Decreasing environmental stressors
Facilitating neurologic development
Determining the best technique to minimize the pain and stress associated with procedures
Empowering nurses to manage pain assessment and treatment
Using a balanced multimodal approach to pain control

Parents remain an underutilized resource in managing neonatal pain, in part because of medical paternalism. Parent awareness of their own role, as well as how NICU staff engage with and educate them, impacts how they advocate for pharmacologic and nonpharmacologic analgesia for their children. When providers perceive maternal information regarding premature infant pain as sufficient and necessary, maternal involvement during painful procedures increases. Parents randomized to receive a pain information booklet were better prepared to understand infant pain cues and comforting techniques and took more active roles in their hospitalized infant’s pain care.

Ontogeny and Development of Pain and Stress Responses

Pain is a progressive, adaptive process that develops gradually throughout fetal life. The human fetus must develop both neurons to sense pain and the cortex to process painful sensations to experience pain. Direct thalamocortical fibers not specific to pain emerge between 23 and 30 weeks’ gestational age. These thalamic afferent neurons reach the cortical plate as early as 24 weeks’ gestation. Neuronal connections within the cortex appear to form at approximately 22 weeks’ gestation. Cortical activity can be captured by electroencephalogram (EEG) as early as 24 weeks as well. However, thalamocortical pathways may not begin functioning until 29 to 30 weeks’ gestational age, suggesting that higher cortical level pain processing may be limited despite the presence of a behavioral response. Facial movements consistent with pain response are noted as early as 28 weeks. The possibility of interpreting these facial movements with 4-dimensional ultrasound to assess fetal pain responses is an area of intrigue for those performing fetal surgery.

When infants are born preterm, the sensory system is immature ( Fig. 22.1 ). Afferent input from both noxious and nonnoxious stimuli terminate in the dorsal horn of the spinal cord in a diffuse manner on multiple cells, resulting in the infants’ inability to distinguish between noxious and nonnoxious stimuli and limits the care provider’s ability to correctly interpret the infants’ behavioral response. In the neonatal rat, separation of sensory input is not complete until 3 to 4 weeks after birth (approximately 1 to 2 years in humans); this prevents the newborn from consistently differentiating touch from painful sensory input. The responses of the infant are therefore nonspecific. Local tissue injury resulting from repeated heel sticks and invasive procedures trigger increased proliferation of nerve endings in surrounding tissues, particularly when this damage occurs early in gestation. As a result, scars (e.g., from heel sticks, old intravenous sites) and surrounding tissues can remain hypersensitive well beyond the neonatal period.

Fig. 22.1, 1 , In early postnatal life, descending fibers are present, but inhibitory and excitatory influences are weak or absent. The connections gradually strengthen, becoming fully functional at the end of the third postnatal week. 2 , A-fibers are the first primary afferents to enter the dorsal horn gray matter and are present during the last few embryonic days. Their distribution is diffuse with exuberant, more superficial projections gradually retracting over the first 3 postnatal weeks. C-fibers are present in the dorsal horn during late embryonic stages but only enter the gray matter 2 to 3 days before birth. Unlike A-fibers, they project to topographically appropriate regions in lamina II of the spinal cord as soon as they enter. C-fiber synaptic connectivity is present, although weak at the time of birth, with connections strengthening over the first 2 postnatal weeks. 3 , At birth, the majority (approximately 80%) of dorsal root ganglion (DRG) neurons express the nerve growth factor (NGF) receptor trkA. Over the first postnatal week, this population reduces, with approximately half of these neurons losing their trkA expression and beginning to express receptors for glial cell line-derived neurotrophic factor (GDNF) (identifiable as the IB4-binding population). 4 , The balance of excitation and inhibition in the superficial dorsal horn develops postnatally through changes in both local interneuron circuitry and descending fibers. A-fiber input is stronger in the neonate and weakens as the influence of C-fiber input increases. 5 , Primary afferent innervations of the skin occur earlier than central projections. By late embryonic stages, primary afferents of all classes have reached the skin and innervate through the dermis into the epidermis. These projections die back during the immediate perinatal period to leave the full adult situation of dermal innervations present soon after birth.

Infants may lose any discriminatory ability with repeated painful exposures and develop hypersensitive states for long periods. This hypersensitivity persists even if nonnoxious stimuli are introduced. The responses are less synchronized in the immature central nervous system because of underdeveloped myelination and slower synaptic transmission as manifested in longer and more variable latencies. In addition, the neonate lacks sufficient descending modulatory control, thereby limiting their ability to benefit from endogenous control over noxious stimuli compared with adults.

Neurophysiologic investigations have dramatically changed our understanding of nociception in newborns. Using research methods such as near-infrared spectroscopy and EEG techniques such as amplitude-integrated EEG, it is clear that cerebral cortical activation occurs with noxious stimulation, such as needle pokes, as early as 24 weeks’ gestation. Moreover, cortical activation has been noted even in infants who manifest no behavioral response to a stimulus. The converse has also been found in studies reporting that oral sucrose administration decreases clinical observational scores with no changes noted in cortical activation from noxious stimulation. Such findings raise the question that our patients may be perceiving pain at a cortical level despite our pain-relieving interventions (pharmacologic and nonpharmacologic) and that pain scoring tools may only provide limited information, possibly underestimating pain in neonates.

Noxious stimuli in adults result in the release of inflammatory and trophic factors that activate and sensitize nociceptors in the injured tissue. Such noxious stimuli lead to nociceptive afferent input to the central nervous system, exciting nociceptive circuits in the spinal cord, brainstem, thalamus, somatosensory cortex, cingulate cortex, and amygdala. However, noxious stimuli in infants do not evoke similar patterns of central nervous system activity. The response to noxious stimuli is more diffuse and less spatially focused in infants. Studies in rats demonstrate significant alterations in neuronal circuitry with maturation. These animal data may parallel developmental changes that have been noted in humans.

Behavioral responses to noxious stimuli in infants are not always predictable because of the immaturity of the central nervous system. Typical changes in facial expression related to noxious stimulation are inconsistent before 34 weeks’ gestational age. This makes an assessment of pain and response to therapeutic intervention unreliable. Significant structural and functional changes occur in pain pathways during development, and these continue after birth.

In summary, the immature infant’s nervous system

Lacks the ability to discriminate consistently between noxious and nonnoxious stimuli, often reacting with similar behavior to a variety of stimuli
Lacks the ability to modulate pain responses
Does not consistently manifest signs or symptoms that allow care providers to accurately assess the infant’s level of pain and discomfort

Recognizing and Treating Pain

Neonatal care providers and parents all play front-line roles in recognizing and ameliorating neonatal pain. The factors at play in assessing the depth and breadth of pain and determining its treatment include nationality, level of education of bedside providers, use of clinical pain scales, time of day, and unit acuity. Surveys of neonatal providers from around the world note deficits in recognizing and treating pain. Despite efforts to garner awareness and provide systematic approaches toward ameliorating pain, the provision of analgesia is not consistent.

A prospective cohort of 6680 neonates enrolled in 243 NICUs in 18 European countries, dubbed the EUROPAIN (EUROpean-Pain-Audit-In-Neonates) cohort, cataloged demographics, methods of respiration, use of continuous or intermittent sedation, analgesia, or neuromuscular blockers, pain assessments, and drug withdrawal symptoms over the first 28 days of admission. Wide variations in practice were documented regarding the recording of pain scores, genres of respiratory support and their association with analgesia, and use of analgesia for any neonates receiving any modality of respiratory support. Despite the results of trials such as NEOPAIN, the median use of sedation or analgesia for intubated neonates was 89%, with 74% of these neonates receiving opioids, 25% receiving midazolam, and 25% receiving neuromuscular blockers. The large, prospective nature of this study provides a compelling snapshot of how pain is assessed and how pharmacologic analgesia is prescribed for many neonates in the NICU. Continuous pain assessments occurred in fewer than one third of NICU admissions and daily in only 10% of neonates.

Infant Pain Scores

Multiple neonatal pain scoring tools integrate physiologic, behavioral, and biobehavioral indicators into a total score; these tools assess the response to noxious stimuli by categorizing the infant’s behavioral or physiologic reactions or a combination of both. The behavioral responses include limb movements, muscle tone, crying, and characteristic facial expressions; crying is the least reliable indicator of neonatal pain. The physiologic measures include heart rate, oxygen saturation, and respiratory rate. Specific facial expression changes are believed to be the most reliable indicators of pain (brow bulge, eye squeeze, nasolabial furrow, taut lips, and open mouth). See Fig. 22.2 for examples of these characteristic facial changes. The use of facial expression changes can be challenging when the infant’s face is partially covered with adhesives used to secure tubes and lines, respiratory equipment, or with a phototherapy mask in place.

Fig. 22.2, Facial expressions of physical distress and pain in the infant.

Many discrete scoring tools exist to assess pain in neonates, but the majority have been validated only for research purposes. Scoring tools that provide a multidimensional assessment of pain are preferred; however, they are still subjective. Some tools lack sensitivity and specificity by relying, for example, only on changes in vital signs. Recent publications list currently available neonatal pain assessment tools. Only five of these neonatal pain scales have undergone rigorous psychometric testing with patients serving as their own controls:

Neonatal Facial Coding System
Premature Infant Pain Profile (PIPP)
Neonatal Pain and Sedation Scale (NPASS)
Behavioral Infant Pain Profile (BIPP)
Douleur Aiguë du Nouveau-né (DAN).

The PIPP scale is one of the most commonly used and well-validated scales. A review of 62 studies of the PIPP scores over 13 years reinforced this scoring measure as valid, reliable, clinically feasible, and useful at measuring acute, procedural, or postoperative pain with strength lying in a composite (measuring behavioral and physiological indicators) approach. In 2014, researchers refined the scoring tool further, termed the PIPP-Revised score, to better encompass markers of pain and distress across the spectrum of gestational age.

Ideally, a neonatal pain-scoring tool would be matched with the anticipated types of pain that an infant may suffer (such as acute, procedural, postoperative, or chronic pain). A common conundrum is that providers find themselves treating chronic pain related to complications of intensive care using tools designed and validated for acute, procedural, and postoperative pain. Several studies have tried to match specific pain scales to specific clinical populations. For example, a prospective comparison of multiple pain scores in neonates after cardiac surgery demonstrated that the COMFORT score was most closely correlated with the infants’ pain and analgesic response. COMFORT and N-PASS scales are most effective for pain assessment in mechanically ventilated infants while PIPP and CRIES are recommended for assessment of acute and postoperative pain. Another example is a validated scoring tool called the Echelle Douleur Inconfort Nouveau-Né (EDIN), which was developed specifically to assess prolonged pain in preterm infants.

Practically speaking, it is difficult to train and maintain provider skills in the use of multiple scoring tools in a single NICU. Determining which scoring tool best matches local patient composition allows care providers to become experts in using a single tool or two. The current reliance on routine assessment and documentation of pain scores as a proxy for routine pain assessment for preterm and term neonates throughout their hospital stay may not adequately capture what patients experience, both because of the manner with which they are assigned and the lens through which any given tool was developed.

Bedside Noninvasive Neurophysiologic Measures to Evaluate Pain and Stress

Changes in infant electrophysiological and hemodynamic brain activity occur in response to noxious stimuli. Brain-derived approaches such as near-infrared spectroscopy and amplitude-integrated electroencephalography to capture neonatal and infant pain are promising, as they can assess cortical activation in neonates in response to tactile and painful stimuli. A proposed template of nociceptive brain activity can guide researchers in measuring and interpreting neonatal and infant pain with more precision. The evoked brain activity described by this template is meant to aid researchers but is not yet validated or generalized for direct pain measurement in individual patients.

Clinical pain scores, based on pain-related behavioral changes, do not consistently overlap with noxious-evoked brain activity. Simultaneously measuring physiology, behavior, and cortical response to painful stimuli will help elucidate how best to assess, and then treat, neonatal pain. The Procedural Pain in Premature Infants (Poppi) study was one such trial. Because NIRS and EEG do not consistently reflect noxious-evoked brain activity when pain scores and biomarkers such as cortisol suggest a painful response, these tools raise questions about how to define a pain response and what composite measures should be used in research and clinical settings.

Long-Term Consequences of Neonatal Pain and Stress

Untreated pain and stress experienced during the neonatal period are linked to adverse long-term outcomes. The acute physiologic responses to pain—elevations of cortisol, catecholamines, and lactate; hypertension, tachycardia, respiratory instability, glucose instability, and changes in cerebral blood flow—affect developing organs, especially the brain. Exposure to pain and painful procedures is related to the acuity of the hospitalization; studies evaluating a direct relationship between pain and outcomes must account for multiple clinical confounders.

Data suggest that structural changes on MRI at both terms corrected and 7 years of age may be related to increased exposure to pain. Untreated pain in the NICU is also associated with altered pain perception to subsequent immunizations after circumcision without anesthesia, abnormal cortisol responses to stress in later infancy and at school age, and altered pain responses in childhood. Cortisol levels and overall hypothalamic pituitary adrenal axis function at school age for children born preterm are influenced by pain and stress in the neonatal period. Higher cortisol levels at 4 years of age are associated with sensory processing and cortisol reactivity to stress.

Greater neonatal pain exposure is associated with lower body weight percentiles at 32 weeks’ corrected gestation. A prospective daily assessment of acute pain and chronic pain/stress concluded that increased pain and stress exposures in the first 4 weeks of life result in altered habituation and stress responses for former preterm infants at 36 weeks’ corrected gestational age. There is concern that such hormonal changes might lead to the development of cardiovascular disease and type 2 diabetes in adulthood.

Higher numbers of skin-breaking procedures from birth to term-corrected gestation predict lower cognitive and motor development indices of Bayley Scales of Infant Development at 8 and 18 months, after controlling for early illness severity, overall morphine exposure, and days of postnatal dexamethasone. Prolonged placement of indwelling arterial lines to decrease the frequency of skin-breaking painful procedures in the preterm neonates improved thalamic growth and school-age neurodevelopment.

Chronic pain can affect growth, immune function, recovery, and length of hospitalization. In addition, a growing body of evidence has drawn attention to the potentially deleterious effects of repeated handling, stress, and pain on long-term memory, social and cognitive development, and neural plasticity. Greater neonatal invasive procedures are associated with lower thalamic and amygdala volumes, leading to poorer cognitive, visual-motor, and behavioral outcomes.

Clinical Pain and Stress Management Strategies

Fetal Interventions

The fetus has increasingly become a candidate for interventions to repair fetal anomalies and to treat fetal disorders such as severe anemia secondary to hemolytic diseases. The type of anesthesia prescribed to pregnant mothers during fetal surgery falls into one of three categories: anesthesia for minimally invasive fetal surgery, anesthesia for open fetal surgery, and anesthesia for an Ex Utero Intrapartum Treatment (EXIT) procedure. Prescription of maternal anesthesia requires an understanding of placental pharmacology to ensure the fetus is appropriately anesthetized for each procedure. Fetal pain management should aim to attenuate fetal physiologic and hormonal stress responses.

Fetal anesthesia is not without risk. Fetal exposure to opioids may result in smaller brain volumes in neonates after birth. There are no human studies examining the effect of anesthesia on the developing fetal brain. Despite this, the US Food and Drug Administration issued a warning in 2016 regarding impaired brain development in children, including fetuses during the third trimester of pregnancy, following exposure to the inhalational anesthetics isoflurane, sevoflurane, and desflurane, and the intravenous agents propofol and midazolam. The impact of these recommendations places the burden of weighing the risks and benefits of anesthesia for fetal surgery on the parents and providers for each fetal and neonatal surgical procedure.

Postoperative Pain Management Strategies

Pain management after surgical intervention, like acute pain management, requires knowledge of the developmental status and function of the end-organ system and the potential adverse and toxic effects of specific analgesic agents. Unfortunately, the current body of neonatal pain literature focuses heavily on procedural pain management and lacks systematic data on acute perioperative pain management in neonates. In the developing world, if infants survive the challenges of diagnosis and surgery for their congenital anomalies, postoperative pain is often not considered or under-managed.

Postoperative pain trajectory in neonates is variable. Ilhan et al. described typical and atypical pain trajectories in infants under 6 months undergoing major thoracic or abdominal surgery, with those in the atypical group having more days and instances of pain. These infants had higher rates of iatrogenic neonatal abstinence syndrome. Taylor et al., surveyed 10 NICUs regarding their postoperative pain assessment and management practices; they found that pain assessment documentation was inconsistent. Nursing documentation was done for most infants, whereas few physicians documented any assessment. Most infants were treated with opioids, benzodiazepines, or both, and some infants (7%) received no analgesia despite recent major surgery. Van der Marel et al. evaluated the use of rectal acetaminophens as an adjuvant treatment to continuous morphine infusion in postoperative neonates and could not demonstrate any additional analgesia effect. However, a quality improvement initiative by Grabski et al. demonstrated that postoperative IV acetaminophen for 48 hours and provider education reduced opioid use, postoperative ventilation time, and use of parenteral nutrition without worsening pain scores. Neonates likely require less morphine to control pain and discomfort than older infants do, based on monitoring of pain scale data. Bouwmeester et al. determined that neonates required less morphine for postoperative pain control and that the dose requirement increased with age. Both studies found that morphine was equally effective whether given by bolus or continuous infusion.

Epidurals are effective in treating postoperative pain and alleviating unwanted side effects of systemic opioids in adults and older children. While the literature does support benefits of epidurals for perioperative pain control for term and preterm neonates, there is concern that the risk of placing thoracic epidurals by physicians without sufficient experience exposes neonates to the possibility of catastrophic neurologic outcomes. In a study of infants <6 months of age who required thoracotomy for congenital pulmonary malformations, those randomized to epidural anesthesia had faster time to full feedings and reduced intensity of postoperative care when compared to those randomized to systemic analgesia. Regional anesthesia, when used alone, may also reduce the incidence of postoperative apnea in preterm infants. Studies of parent- and nurse-controlled analgesia (PNCA) as an alternative to continuous opioid infusion for pain management in postsurgical infants in the NICU provides promising data that PNCA may provide more individualized care and potentially reduce opioid consumption.

Mechanical Ventilation

Despite an ongoing shift in neonatology toward noninvasive respiratory support for neonates with immature lungs or infants with lung injury, invasive mechanical ventilation is still frequently utilized to save lives. Adults who require mechanical ventilation are routinely sedated. This finding prompted research surrounding opiate sedation in ventilated neonates, despite limited information regarding safety and efficacy in neonates. Preemptive use of pharmacologic sedation during mechanical ventilation in newborns, especially preterm infants, remains controversial.

Mechanical ventilation in neonates is associated with an increase in hormonal stress responses, including increased cortisol and catecholamine levels. In the past, infants who appeared uncomfortable while ventilated demonstrated asynchronous respiratory effort (i.e., “fighting” the ventilator), compromised gas exchange, and altered stress responses. Pain and stress in newborns receiving mechanical ventilation was associated with decreased pulmonary compliance, atelectasis, and intrapulmonary shunting. However, with the introduction and use of surfactant replacement therapy, noninvasive ventilatory support, and synchronized ventilation, many of these problems have been minimized or eliminated.

A randomized, double-blind, placebo-controlled clinical trial of nearly 900 neonates (NEOPAIN) reported no beneficial effect of preemptive morphine infusions in ventilated preterm infants and an increased incidence of severe intraventricular hemorrhage in preterm infants born at 27 to 29 weeks’ gestation receiving pre-emptive morphine. A parallel study conducted by Simmons in 2003 randomized 150 ventilated neonates to lower dose preemptive analgesia with morphine. This study failed to find any benefit of empiric morphine analgesia and did not recommend this practice. Secondary analysis of the NEOPAIN trial found that morphine infusions were independently associated with increased risk for air leak, a longer requirement for ventilatory support , and a longer time to reach full-volume enteral feedings. Neither this trial nor the smaller pilot trials that preceded it provided evidence that routine narcotic sedation during mechanical ventilatory support in neonates is beneficial.

A subsequent trial conducted in 2013 randomized premature neonates to continuous infusion of fentanyl or placebo. Similar to prior trials of morphine results demonstrated increased duration of mechanical ventilation and no decrease in prolonged pain in the treatment group. Continuous fentanyl infusion reduced acute pain scores and had fewer side effects than open-label fentanyl boluses. The authors concluded that, just like morphine, “there is no place for the routine use of continuous fentanyl infusion in ventilated preterm newborns because of a lack of continued pain score reduction and increased side effects of continuous infusion compared with the bolus administration of fentanyl.”

A Cochrane Review combining outcomes of these and other, smaller trials evaluated the effects of opioid analgesics on pain, duration of mechanical ventilation, mortality, growth, and development in neonates requiring mechanical ventilation. The authors found no differences in mortality, duration of mechanical ventilation, and short- and long-term neurodevelopmental outcomes. As morphine sedation prolongs ventilatory support and time to full enteral feedings, an increase in complications related to the use of intravenous lines (bloodstream infections) and parenteral nutrition (cholestasis) can occur. Two independent reviews concluded “there is insufficient evidence to recommend routine use of opioids in mechanically ventilated newborns.”

One comprehensive review of analgesia and sedation for ventilated neonates produced five standard-of-care recommendations :

Reduce neonatal stress and use nonpharmacological analgesia during invasive ventilation.
Favor intermittent boluses of opioids, administered after pain scores and before invasive procedures, during short, expected periods of mechanical ventilation.
Do not use morphine infusion in preterm infants under 27 gestational weeks.
Always use algometric (pain sensitivity) scores to titrate analgesic drug doses.
Use premedication before endotracheal intubation.

Additionally, studies of midazolam infusions as an alternative to either morphine or fentanyl infusions for intubated and ventilated infants have raised safety concerns. Midazolam infusions are thus not recommended for neonates.

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