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BEYOND THE BASICS: ADVANCED PHYSIOLOGYAND CARE CONCEPTS KSENIAZUKOWSKY,RN, MSN, CRNP, AN>JAY S. GREENSPAN,MD, SFRIESEDITORS CEU

OFFERING

THE REALITY OF NEONATAL PAIN MARY PUCHALSKI, RNC, MS, CNS, APN, AN> PAT HUMMFL, RNC, MA, NNP, PNP, APN

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ain has been unrecognized and undertreated throughout the history of neonatal care. Health care providers have long believed that newborn infants have a blunted or absent ability to feel pain because of the immaturity of their nervous system. Coupled with exaggerated fears of side effects from analgesic medication administration, this misconception has led many neonatal health care providers to perform surgical and other invasive procedures without providing analgesia or anesthesia to infants (eg, patent ductus arteriosis ligation, chest tube insertion, and circumcision). 1,z Pain is defined by the International Association of Pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage...pain is always subjective".3,4 The emphasis on self-report made this definition difficult to apply to nonverbal populations such as infants. In 2001, the definition was further clarified by the following statement: "the inability to communicate in no way negates the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment," highlighting the importance of pain assessment and intervention in all populations. 5 Emerging evidence suggests that infants not only experience pain, they experience it more acutely than adults. 6-s Neural pathways for afferent/ ascending pain transmission are present in even the smallest preterm infant.9"14However, the immaturity of the central nervous system (CNS) as a whole makes them unable to modulate and ill equipped to cope with their pain experience through internal or external mechanisms. 15,16 The number of invasive procedures infants undergo while in the neonatal intensive care unit (NICU) is staggering. One infant born at 23 weeks gestation underwent 488 painful procedures during the initial hospitalization.17 It is a moral imperative that consideration of the shortand long-term implications of the ongoing pain and stress these infants are experiencing be addressed. Research supports the potential of pain management strategies to improve neonatal outcomes. 18"21 Although significant strides have been made to correct misconceptions about infants and their anatomic and physiologic capability to feel, remember, and express pain, research disproving these misconceptions has not consistently penetrated practice. 22 A thorough understanding of the capabilities of the neonatal sensory system and the long-term effects of undertreated pain serves to motivate routine pain assessment and interventior, Advances in Neonatal Care,

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Definitions Term

Definition

AIIodynia -

"Pain due t o a stimulus which does not normally provoke pain" (eg, touch, light pressure, or moderate cold o r warmth)4

protocols. This article reviews the embryonic development of pain sensation, lends supportive evidence to refute some of the misconceptions, and describes the long-term outcomes of consistently undertreated or untreated pain in neonates. See Table 1 for definitions of terms used to describe the physiology of pain. DEVELOPMENT OF NOClCEPTIVE SENSORY PATHWAYS ortical awareness of pain involves the development of 3 primary connections within the sensory nervous system. First, pain information is sensed pe-

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ripherally by nociceptors--pain-signaling nerve endings. Mechanical tissue damage causes cells to release sensitizing substances (prostaglandins, bradykinin, serotonin, substance P, histamine) that change the pain information into an impulse (transduction). Pain is then transmitted when neurons line up, form a pathway, and propagate an impulse from cell to cell along that pathway. 23 Nociceptive information is transmitted from the sensory nerve endings to the dorsal horn of the spinal column. From the dorsal horn of the spinal column, the pain information is sent in 2 directions: back to the periphAdvances in Neonatal Care, Vol 2, No 5 (October), 2002: pp 233-247

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F I G U R E I. Timeline for nociception. CRL, crown-rump length. Reprinted from Moore and Persaud. Before We Are Born. 5th Ed. Philadelphia, PA: Saunders; 1998:102, with permission. ery, initiating an immediate, reflexive withdrawal reaction (autonomic awareness), and simultaneously to the thalamic region of the cortex (cortical awareness). 12,24 The thalamic region facilitates discrimination and localization of the pain stimulus, relaying and disseminating the pain information throughout the brain. Cortical awareness of pain enables the individual to understand where the pain is coming from, how to get away from it, and how to avoid it in the future. In the embryo, sensory nerve endings first develop in the perioral area during the seventh week of gestation (Fig 1). 9 The development of sensory nerve endings extends to the entire face, palms of the hands, and soles of the feet of the fetus by 11 weeks gestation, the trunk and proximal extremities by 15 weeks gestation, and mucous membranes and remaining cutaneous areas by 20 weeks gestation. At 20 weeks the fetus has an even greater density of nociceptive (pain signaling) nerve endings peripherally than an adult. 1°,1~ At approximately 12 weeks gestation, the neural pathway connecting the peripheral nociceptive nerve endings and the spinal dorsal horn cells begins to develop. From 12 to 20 weeks, the pathway from the spinal dorsal horn cells to the cerebral cortex is incomplete; therefore, the fetus does not possess a cognitive awareness of the pain sensation or its source. The fetus is able to reflexively withdraw in response to painful stimuli, lz The pathway connecting the spinal dorsal horn cells to the brain (the thalamic track) is complete by 24 to 26 weeks gestation. ~,z3 Cortical pain perception is now Advances in Neonatal Care, Vol 2, No 5 (October), 2002: pp 233-247

possible. The fetus, or neonate, is now equipped to perceive where the pain is coming from and even attempt to purposely move away from it, a defensive reaction to noxious stimuli. ~4 Another factor in pain perception is the ability of the neuron to transmit pain information along a pathway, propagating an impulse from neuron to neuron. Myelin is the lipid sheath that surrounds the axon of many neurons (Fig 2). This sheath functions to insulate the axon and increase the conduction velocity of the impulse. 25 For many years, it was believed unmyelinated nerve tracts were either unable to conduct an impulse or conducted

Dendrites

F I G U R E 2, The neuron. Myelin is the lipid sheath surrounding the permission. 2s

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response). Although the reaction may be delayed or less robust, this response is observed in even the most immature infants, a more generalized reaction accompanies or immediately follows, which can include facial grimacing, audible cry, and other body movements. EXTRAUTERINE BRAIN DEVELOPMENT AND PLASTICITY he development of the premature infant's CNS occurs in a very abnormal environment, at a time when cell growth and development is critical. Neonates are producing tens of thousands of brain cells per minute. The number of cortical neurons increases by a factor of 10 from 17 to 28 weeks, peaks at 28 to 32 weeks, and then stabilizes by 40 weeks, zs These cells are programmed to migrate to specific locations in the brain. Pruning of unnecessary cells (apoptosis) occurs and pathways between neurons (synapses) develop. In the developing brain, overstimulation of one neural pathway (eg, the nociceptive pathway) can lead to understimulation and underdevelopment of another pathway (eg, the "good" touch or nonpain pathway). The concept that every experience of the premature infant has the potential to alter brain development is known as plasticity,z9 Plasticity is "the capability of being formed or molded." Differences in both brain structure and function are seen after experiences in the NICU. 3°,31 Similar changes are not seen after parallel experiences in adults, likely because of the limited ability to reroute pathways in the fully developed adult brain. The neonatal rat is the primary animal model used to investigate the developing human nervous system. A series of anatomic, neurochemical, and electrophysiologic experiments in neonatal rats have revealed that repetitive painful experiences or prolonged tissue or nerve damage can lead to long-lasting neurobehavioral sequelae. Changes in peripheral and central sensory pathways have been observed after nerve injury; these differences persist into adulthood and may explain alterations in behavior. 3z Perinatal brain plasticity increases the vulnerability to early adverse experiences, potentially leading to abnormal development and behavior. 33 The plasticity of the perinatal brain is both a benefit and a detriment. On the positive side, it enables the fetus and infant to remodel his or her brain, regenerate neurons, and to recover from brain insults. 34 On the negative side, it increases the vulnerability to early adverse experiences, potentially leading to abnormal development and behavior.

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F I G U R E 3. Primary nervous system connections for pain perception. Pain stimuli are picked up by nociceptors. The pain message is relayed to the spinal cord, then immediately back to the extremity to ( I ) the flexor muscles, which then pull away from the stimulus, and (2) to inhibit extensor muscles. Simultaneously, the pain message is relayed to the brain, which interprets the pain experience. Adapted from Fitzgerald with permission. 37

the impulse poorly. It is now known that impulses travel quite well along unmyelinated nerve tracks. Even some mature nerve fibers remain unmyelinated (C-polymodal fibers transmitting dull, slow pain) or only thinly myelinated (A delta fibers transmitting sharp fast pain) into adulthood, z6 Myelinization of the brain stem and thalamic tract is complete by 30 weeks gestation. The entire nociceptive tract is completely myelinated by 37 weeks gestation. 27 Although the pain impulse may travel more slowly in the preterm infant with unmyelinated pathways, the impulse has a notably shorter interneuron and total distance to travel when compared with an older infant or mature adult. This may offset the significance of the speed factor. In summary, developmental physiology provides strong scientific evidence that newborn infants, even the extremely premature, are anatomically and physiologically equipped to perceive, react to, and have some understanding of pain. The ability to perceive and react to pain is illustrated by the infant's response to a heelstick blood draw (Fig 3). When the lancet pierces the skin, there is an immediate withdrawal reaction of the extremity (if there is sufficient energy reserve to mount a motor

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THE PHYSIOLOGIC BASIS FOR HYPERALGESIA eyond the simple ability to sense pain, the preterm infant may experience hyperalgesia--hypersensitivity to painful stimuli. Although the ascending nociceptive neural pathways are intact after 24 weeks gestation, the descending inhibitory pathways are underdeveloped ie and ultimately mature postnatally.6,24 These descending inhibitory pathways activate neuromodulators (serotonin, norepinephrine, y-aminobutyric acid [GABA], and neurotensin) that block continued transmission of pain stimuli.26 This paucity of inhibitory neuromodulators results in prolonged and exaggerated responses to stimuli, especially in the preterm infant. Tissue injury contributes to neonatal hyperalgesia. Local tissue injury (eg, heelstick or insertion of intravenous devices) triggers the release of a number of chemicals (calcium and potassium ions) and cellular mediators (bradykinin, histamine, prostaglandins, serotonin, and substance P). These chemicals activate the process of the inflammatory cascade, including transmission of the pain impulse by the nociceptive cells, local inflammation, and resulting hypersensitivity. 23 Even touch can be transmitted as pain. This sensitivity or tenderness persists long after the stimulus is removed and extends into adjacent noninjured tissue. 7 Although this inflammatory reaction is similar to an adult's, the hypersensitivity in preterm infants is less transient because of a proliferation of new nerve endings in the injured area known as hyperinnervation. Hyperinnervation is most pronounced in the extremely premature infant. It causes increased pain and hypersensitivity of the injured area that persists long after the wound has healed, possibly into adulthood.S,15,24.31,35 Under normal circumstances, impulses travel along the intended pathway. In the infant, there exists the theoretic possibility for an impulse to jump tract and be conducted along an unintended pathway (Fig 4). Nerve fibers that carry pain messages are located in the dorsal horn of the spinal cord. In the newborn, these nerve fibers are in close proximity to those that carry touch messages, significantly closer than in adults. The potential exists for touch-stim,ulated impulses to jump over to the pain pathway, resulting in touch being transmitted and perceived as pain. 36,37 In the neonatal rat model, the incidence of this phenomenon was observed more frequently when the pain pathway was frequently or continuously activated. 38

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Gro~5-~e~uon

F I G U R E 4. Anatomical differences in the dorsal horn of the spinal column of the adult and infant. There is a greater proximity between the touch and pain fibers in the dorsal horn of the spinal column of the infant than in the adult. This enables the possibility that a touch impulse will jump over to the pain pathway and be transmitted and perceived as pain. Adapted from Fitzgerald with permission. 37

Touch transmitted as pain may be responsible for the clinical observation in infants who sometimes exhibit the same withdrawal reaction to light touch and painful stimuli.14,36 An altered response to nonpainful stimuli (ie, perceiving and reacting to it as pain) is different from hyperalgesia and is termed allodynia. Pain has a strong arousal effect on the entire sensory system.26 The body becomes hypersensitive to any stimuli. This is even more pronounced in the preterm infant because of a prolonged and heightened level of excitability of their nerve cells. 12a5 Information continues to be transmitted long after the stimulus is removed. The preterm infant has a limited ability to cope with the volume of visual, auditory, tactile, and other stimuli experienced simply by virtue of the immaturity of their entire CNS. Caregivers may observe a number of signs and symptoms of hyperalgesia and allodynia. Immature infants may have an exaggerated response to caregiving, even when handling is gentle and the intervention is not considered painful. It takes less of a stimulus to induce a reaction in preterm infants (lower tactile thresholds) than term infants. Repeated exposures to painful stimuli further decrease thresholds (windup phenomenon)J 4 This altered excitability spreads to multiple levels of the spinal cord and may cause non-noxious stimuli such as handling, physical examination, and other nursing procedures to be perceived as noxious stimuli, evoking a systemic physiologic stress responses.39 Symptoms may be immediate or appear delayed and might include, but are not limited to desaturation, apnea, bradycardia, reflux or vomiting, mottling or changes in skin perfusion, hypertonicity, or a flaccid withdrawal response.

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INNATE COPING MECHANISMS he infant, especially if preterm, also has a very limited ability to naturally block or cope with pain. Infants cannot rub a painful area and stimulate non-nociceptive touch fibers that would block the pain sensation, nor can they distract themselves through visualization. 4° The primary coping method available to the infant is sucking. Sucking stimulates sensory fibers that block the transmission of pain. 16,41 Infants are largely dependent on caregivers to provide something for them to suck on, especially if their hands are restrained or covered or if they lack the muscle strength and/or coordination to get their hands to their mouth. See Sidebar 1, which highlights a recent study suggesting that breastfeeding may have an analgesic effect in a small sample of full-term infants. The preterm infant's hypersensitivity is compounded by their multisystem immaturity. Inadequate subcutaneous fat stores exist to insulate against thermal insult. 4z The iris does not constrict until 32 weeks gestation, limiting the ability to reduce the amount of light entering the eye.43 The eyelid skin is very thin, resulting in elevated light levels entering the eye even if the lids are closed. 44 Noise within the plastic incubator environment is amplified. 45,46 These vulnerabilities place the preterm infant at risk for an overwhelming volume of sensory input resulting in stress. This stress may be amplified further by painJ 1 Limiting sensory stimulation through implementation of developmental care may provide infants with greater ability to cope with and decrease the stress of the hospital environment.47,4s Proponents of developmental care have increased awareness of the stressors encountered by the premature infant. 29 They have suggested a host of strategies to promote physical and neurologic stability through environmental control, behavioral accommodations, and individualization of care. In spite of the possibility

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that developmental interventions may assist the infant in modulating a painful experience, they were never intended as a substitute for analgesia in painful situations.

ALTERED PAIN RESPONSES he long-standing myth that infants do not anticipate or remember pain is being systematically debunked by recent studies. 49"54 Inflicting pain on an adult after administering medication to induce sedation/amnesia without also providing an analgesic is morally and ethically wrong. A corollary is that it is also morally and ethically wrong to justify inflicting pain on infants with the assumption or excuse that they will not remember it anyway. The most convincing evidence of pain memory was provided in trials evaluating response to immunization at 4 to 6 months of age. A blinded, randomized, controlled trial evaluating the efficacy of pain relief from the application of topical lidocaine-prilocaine 5% cream (eutectic mixture of local anesthetics [EMLA] cream) for routine immunization (diphtheria-pertussistetanus [DPT], hemophilus influenza type B conjugate [HIB], or both) anecdotally found that male infants had a greater pain response than female infants. 55 A post-hoc analysis of the data was subsequently published, evaluating only the male infant's (n = 60) pain reactions. Circumcised males were found to have higher pain scores (P = 0.02 DPT; P = 0.01 HIB) and longer crying (P = 0 . 0 2 ) . 49 This study was repeated with a prospective cohort design (n = 87 infants). 5° Three groups were evaluated: (1) circumcised with minor anesthetic (EMLA cream); (2) circumcised without analgesia (placebo); and (3) uncircumcised. Again, males who had been circumcised had a significantly stronger pain response to immunization than those who had not (P < 0.05). Furthermore, those circumcised without any analgesia

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(placebo) had a significantly stronger pain response that those circumcised with a minor anesthetic (P <

0.05). The premature infant's response to painful stimuli changes over time. An increased response to a heelstick has been documented in infants who had experienced this intervention on the previous day. 51 Another research team used a cross-sectional design to compare the responses of infants of 32 weeks gestation, less than 1 week old (n = 53), with a group of infants born at 28 weeks (n = 36) who were 4 weeks old (32 weeks corrected gestation). 51 Infants with 4 weeks of NICU experience showed increased cardiovascular (P < 0.0001) and decreased behavioral responses compared with the infants without extended NICU experience (P < 0.0001). Differences in these response patterns were correlated with the total number of invasive procedures experienced since birth. The more procedures the infant had endured, the less behavioral responses were observed (P < 0.0007). The impact of previous exposure to pain was further examined in a prospective cohort design of infants (n = 136 infants less than or equal to 1,500 g) who underwent heelstick phlebotomy at 32 weeks postconceptual age. 39 They evaluated the relationship of early neonatal factors and previous medication exposure to subsequent reactivity to the acute pain of a heelstick. Their results supported the findings of previous work; a decreased behavioral reaction to pain was found in infants with higher previous exposure to pain (P < 0.001). Contrary to other findings, the cardiovascular response in these infants was decreased. Diminished pain responses were also found to be related to lower gestational age at birth (P < 0.01) and a higher number of days of exogenous steroid administration (P < 0.001). The infants who had received the most morphine early in their hospitalization showed a decreased behavioral response, but a normal cardiovascular response to later pain. Little is known about the premature infant's maturational response to pain over time. k quasiexperimental, repeated-measure study evaluated the pain responses in infants of 24 to 26 weeks gestational age (n = 11) weekly for a total of 6 weeks (until 27 to 32 weeks corrected gestational age). 56 An increasing robustness in facial pain expression was observed with advancing gestational age. Thus, both experience and neurophysical maturity play a role in how the preterm infant responds to noxious stimuli. Parents of premature infants also report an altered response to pain in childhood. Former low-birthweight (LBW) infants studied at 18 months of age were described by parents as less reactive to everyday pain Advances in Neonatal Care, Vol 2, No 5 (October), 2002: pp 233-247

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than full birth-weight toddlers. 57 Increased somatization has been shown in 4- to 5-year-old children who were formerly LBW infants. 53 The same researchers compared the pain ratings with painful situations of LBW and full-term groups of 8- to 10-year-old children. 54 The 2 groups of children did not differ overall in their perceptions of pain intensity or effect. Unlike the full-term group, the LBW group rated medical pain significantly higher than psychosocial pain (P < 0.004). A longer duration Of NICU stay was directly related to increased pain ratings when shown pictures of pain experienced in recreational and daily living settings. Parent reports of somatization did not differ in this study. Despite the burgeoning scientific understanding of the developing brain, many questions remain unanswered. It is clear that full-term infants exposed to short-term pain early in life have an increased response to later painful procedures, whereas preterm infants exposed to multiple painful experiences early in life have a decreased behavioral response to procedures later in their hospitalization. In addition, preterm infants show altered responses to pain later in childhood. SHORT- AND LONG-TERM EFFECTS OF NEONATAL PAIN

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ain is a major cause of stress for the infant in a NICU, with adverse multisystem physiologic consequences. It triggers the fight-or-flight response, a biochemical reaction wherein the sympathetic nervous system is activated leading to the release of glucocorticoids. These glucocorticoids (cortisol, epinephrine, and norepinephrine) are catabolic in nature, inhibiting cell division and growth, protein synthesis, and neuronal myelinization.5s Heart rate, blood pressure, and heart rate variability are all increased with pain. Venous and intracranial pressure may rise, and arterial oxygen saturation and skin blood flow fall. Acute pain changes intrathoracic pressure and respiratory movements, which alters intracranial blood volume and cerebral blood flow. z3,59 Multiple invasive procedures in premature infants cause marked fluctuations in intracranial pressure, possibly leading to intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL). 6° One study revealed a direct correlation between the number of episodes of hypoxia and hypotension in the first 4 days of life and intraventricular hemorrhage, ventriculomegaly, or brain parenchymal lesions in premature infants. 61 Animal studies suggest a consistent association be-

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tween early pain and stress and altered clinical outcomes, brain development, and subsequent behavior. These studies are significant for humans because of similarities in pain pathways and the comparable neurologic maturity of the rat at birth and the human infant at 23 to 24 weeks gestation. 6z Peripheral tissue injury in neonatal rats results in structural changes in the nerve pathways. A classic experiment showed this principle by injuring the rat's extremity with the application of an irritant. The nerves and brain were later examined. An increased number and responsiveness of nerve cells in the spinal cord were noted on the side of the injury, with decreased withdrawal response to subsequent painful stimuli in the injured extremity. 63 Another investigator exposed neonatal rats to needle pricks 4 times per day from birth to 7 days old. The rats had significantly lower pain thresholds at 16 and 22 days of age. In adulthood, these rats had an increased preference for alcohol, increased anxiety, and defensive withdrawal behaviors. 3° Based on this and other animal evidence, some investigators have suggested that later criminal behavior and psychiatric disorders may be sequelae of prematurity. 33,64 Abnormal conditions around birth have been associated with behavioral and emotional problems during childhood, major psychoses (such as schizophrenia, anxiety, or depression), and suicides in adolescence and adulthood. 65"67 However, a recent longitudinal study followed very low-birth-weight (VLBW) survivors (n = 242 VLBW infants) who were born between 1977 and 1979. 68 Outcomes at 20 years of age were assessed and compared with 233 controls. The VLBW group had a lower m e a n IQ and lower academic achievement scores, and fewer graduated from high school. The VLBW group also had higher rates of neurosensory impairments and subnormal height. This study revealed less alcohol and drug use

and lower rates of pregnancy than normal-birth-weight controls. Although untreated pain has been associated with differences in long-term outcome, causality is still under investigation. Follow-up studies of premature infants show many differences from their full-term counterparts, suggesting alternate brain development. School-age former LBW infants have increased rates of the following: • • • • • • • • •

Cognitive deficits Learning disorders Motor deficits Behavior problems Attention deficits Impulsivity Diminished social control Inability to cope with novel situations Poor adaptive behavior

Poor neurologic outcomes are correlated significantly with severity of illness and medical events. Although it is not possible to predict the long-term developmental outcome for an individual infant based on these factors, the sickest and smallest infants are at the highest risk for neurodevelopmental compromise.68-70 It is also important to note that the long-term neurodevelopmental impact of analgesic medications has not been well studied in this population. Analgesic administration for known or anticipated pain has been shown to be effective in modulating the physiologic and behavioral signs of pain in preterm and full-term infants. It may also improve both short- and long-term outcomes. In a randomized clinical trial, infants of 24 to 32 weeks gestation (n = 67) showed a decrease in the incidence of poor neurologic outcomes with the use of continuous infusions of low-dose morphine, is Other studies have shown a reduction in mortality rates,

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stabilization of blood pressure, and decreased frequency of hypoxic episodes with the administration of opioid analgesics. 19-n

CLINICAL CONTROVERSIES AND CHALLENGES

he survival of extremely premature infants has risen steadily over the past decade. Follow-up studies of these infants provide the opportunity to evaluate the long-term effects of common NICU treatments and interventions on the developing brain as these children are now approaching adulthood. Current studies may not accurately reflect outcomes related to modern care practices and to the survival of extremely low-birth-weight (ELBW) infants. As survival rates increase, so does the length of stay and the potential for increased exposure to acute and prolonged pain. During their NICU stay, infants experience a multitude of stressors: separation from parents, exposure to excessive levels of light and sound, variable thermal environments, and numerous randomly occurring invasive procedures. They may also experience suboptimal nutrition and inappropriate physical handling. These negative experiences are occurring at the same time as major developmental changes in the CNS. All too often, pain is denied, ignored, or simply overlooked. 64 Developmental care has sensitized health care providers to the potential impact of the environment and caregiving on brain development and organization. More research is needed to evaluate individual developmental interventions for specific benefit. 4s Clearly, more than simple modifications of the environment and awareness of individual signals are needed for genuinely painful events. The need to revise our approach to neonatal pain management has come to the forefront of attention with the revision of the Joint Commission on Accreditation of Healthcare Organization's (JCAHO) pain standards in the year 2000. 71 Pain management guidelines have recently been published by the National Association of Neonatal Nurses and the American Academy of Pediatrics, emphasizing a proactive approach to pain managment. 72"74 The International Evidence-Based Group for Neonatal Pain published a consensus statement recommending specific interventions for neonatal pain. 75 Pain management for their hospitalized infant is a primary concern to parents. 47,76

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Although research has established the role of painful NICU experiences in altering the infant's brain and outcome, well-designed, prospective, randomized controlled clinical trials are needed to evaluate the effect of specific interventions and pain control strategies on the developing infant brain. Neonatology has an illustrious history of importing therapies originating in adults or older children, but are never studied in premaicure infants. 77 Sidebar 2 highlights the current use of midazolam in the NICU. Caution is imperative when implementing untested medications or treatments that may in themselves damage the developing brain5 s

Peer-Reviewed

Resources on Pain

Evidence-Based Medicine Resources Cochrane Reviews: http:llwww, cochrane.orgl

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PERMEATING PRACTICE W I T H RESEARCH he definition of pain provided by the International Association of Pain emphasizes that pain is a subjective experience; each individual learns a response to pain through experiences related to injury in early life. The painful experiences in the N I C U contribute to pain responses later in life. Painful experiences for infants and adults are more than a simple transmission of the pain signal and brain interpretation or reflexive action to that signal. Painful experiences are complex neural phenomena that affect all levels of the developing brain. The pain system has a remarkable adaptive neuronal and neurochemical process. This process is dependent on the character of the noxious stimuli, the context in which it was applied, behavioral states at the time of the stimulus, previous experience, and the gestational age of the infant. 79 Infants, even extremely premature infants, do feel pain. They often feel it more intensely than an older child or adult because of the immaturity of their metabolic processes. Infants in the N I C U have the ability to remember pain, with changes in pain responses over time. Furthermore, early painful experiences alter brain structure. Pain is detrimental to the infant's short- and long-term growth and development. Regardless of the setting (eg, emergency room, newborn nursery, N I C U , or office setting) every health care provider that cares for infants must understand their unique responses to

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pain. Pain should be anticipated, assessed, and appropriately treated. Pain assessment and treatment is a primary nursing focus. To assure a consistent, state-of-the-art approach to pain management, initiate a comprehensive unitwide educational program for every bedside nurse. See Table 2 for a list of peer-reviewed resources on pain. Adopt a valid and reliable pain assessment tool, and use these assessments to guide clinical care. Routinely evaluate infants for signs of pain, and proactively implement interventions based on a scoring system. O n a unit level, develop interdisciplinary, evidencebased, unit-specific protocols to standardize interventions for procedures that are known to be painful (heelstick, intravenous access, arterial sampling, suctioning, chest tube insertion, intubation, chest tube placement, lumbar punctures, etc). Teach parents to recognize their infant's pain signals and empower them to advocate for their infant. Actively participate in research to evaluate developmental, pharmacologic, and procedure-specific interventions. These strategies should explore the most effective methods to maximize brain development, cull out those practices that do not make a difference, and evaluate all aspects of care for potefitial harm. Our 2 highest priorities as clinicians caring for this vulnerable population are (1) to do no harm and (2) prevent developmental sequelae. A n increased awareness of the impact of pain on developing infants is an important step toward achieving these priorities.

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efficacy of developmentally sensitive interventions and sucrose for relieving procedural pain in very low birth weight neonates. Nursing Res. 1999;48:35-43. Barker DP, Rutter N. Exposure to invasive procedures in neonatal intensive care unit admissions. Arch Dis Child Fetal Neonatal Ed. 1995;72:F47-48. Anand KJ, Barton BA, McIntosh N, Lagercrantz H, Pelausa A, et al. Analgesia and sedation in preterm neonates who require ventilatory support: Results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates. Arch Pediatr Adolesc Med. 1999;153:331-338. Barker DP, Rutter N. Stress, severity of illness, and outcome in ventilated preterm infants. Arch Dis Child Fetal Neonat Ed. 1996;75:F187-190. Goldstein RF, Brazy JE. Narcotic sedation stabilizes arterial blood pressure fluctuations in sick premature infants. J Perinatol. 1991;11:365-371. Pokela ML. Pain relief can reduce hypoxemia in distressed neonates during routine treatment procedures. Pediatrics. 1994; 93:379-383. Stevens B, Anand K. An overview of neonatal pain. In: Anand K, Stevens B, McGrath P (eds). Pain in Neonates. 2nd Revised and Enlarged Ed. Amsterdam, The Netherlands: Elsevier Science; 2000:1-7. Pasero C, Paice JA, McCaffery M. Basic mechanisms underlying the causes and effects of pain. In: McCaffery M, Pasero C (eds). Pain: Clinical Manual. 2nd Ed. St. Louis, MO: Mosby; 1999:1534. Coskun V, Anand KJS. Development of supraspinal pain processing. In: Anand KJS, Stevens BJ, McGrath PJ (eds). Pain in Neonates. 2nd Revised and Enlarged Ed. Amsterdam, The Netherlands: Elsevier Science; 2000:23-54. Sugerman R. Structure and function of the neurologic system. In: McCance KL, Huether SE (eds). Pathophysiology: The Biological Basis for Disease in Adults and Children. 3rd Ed. St. Louis, MO: Mosby; 1998:380-421. Leo J, Huether SE. Pain, temperature regulation, sleep, and sensory function. In: Huether SE (ed). Pathophysiolo~: The Biologic Basis for Disease in Adults and Children. St. Louis, MO: Mosby; 1998. Dooling EC. Myelinated tracts: Growth patterns. In: Gilles FH, Leviton A, Dooling EC (eds). The Developing Human Brain: Growth and Epidemiologic Neuropathology. Boston, MA: John Wright; 1983. Rabinowicz T, de Courten-Myers GM, Petetot JM, Xi G, de los Reyes E. Human cortex development: Estimates of neuronal numbers indicate major loss late during gestation. J Neuropathol Exp Neurol. 1996;55:320-328. Als H, Lawhon G, Duffy FH, McNulty GB, Gibes-Grossman R, et al. Individualized developmental care for the very low-birthweight preterm infant. Medical and neurofunctional effects. JAMA. 1994;272:853-858. Anand KJ, Coskun V, Thrivikraman KV, Nemeroff CB, Plotsky PM. Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol Behav. 1999;66:627-637. De Lima J, Alvares D, Hatch DJ, Fitzgerald M. Sensory hyperinnervation after neonatal skin wounding: Effect of bupivacaine sciatic nerve block. Br J Anaesth. 1999;83:662-664. Alvares D, Torsney C, Beland B, Reynolds M, Fitzgerald M. Modeling the prolonged effects of neonatal pain. ProgBrain Res. 2000;129:365-373. Anand KJ, Scalzo FM. Can adverse neonatal experiences alter

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lidocaine-prilocaine cream for vaccination pain in infants. J Pediatr. 1994;124:643-648. Walden M, Penticuff JH, Stevens B, Lotas MJ, Kozinetz CA, et al. Maturational changes in physiologic and behavioral responses of preterm neonates to pain. Newborn Infant Nurs Rev. 2001;1: 94-106. Grunau RV, Whitfield MF, Petrie JH. Pain sensitivity and temperament in extremely low-birth-weight premature toddlers and preteim and full-term controls. Pain. 1994;58:341-346. Piano MR, Huether SE. Mechanisms of Hormonal Regulation. In: McCance KL, Huether SE (eds). Pathophysiology: The Physiological Basis for Disease in Adults and Children. 3rd Ed. St. Louis, MO: Mosby; 1998:625-655. Stevens B, Johnston C, Gibbins S. Pain assessment in neonates. In: Anand KJS, Stevens BJ, McGrath PJ (eds). Pain in Neonates. Vol 10. 2nd Revised and Enlarged Ed. Amsterdam, The Netherlands: Elsevier Science; 2000:101-134. Anand KJ. Clinical importance of pain and stress in preterm neonates. Biol Neonate. 1998;1:1-9. Low JA, Froese AB, Smith JT, Galbraith RS, Sauerbrei EE, et al. Hypotension and hypoxemia in the preterm newborn during the four days following delivery identify infants at risk of echosonographically demonstrable cerebral lesions. Clin Invest Med. 1992; 15:60-65. Fitzgerald M, Anand KJS. The developmental neuroanatomy and neurophysiology of pain. In: Yaster M (ed). Pain Management in Infants, Children, and Adolescents. Baltimore, MD: Williams and Wilkins; 1993:11-32. Ruda MA, Ling QD, Hohmann AG, Peng YB, Tachibana T. Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science. 2000;289:628-631. Anand KS, Gmnau RVE, Oberiander TF. Developmental character and long-term consequences of pain in infants and children. [Review]. CMd Adolesc Psychiat Clin North Am. 1997;614: 703-724. Jacobson B, Eklund G, Hamberger L, Linarsson D, Sedville G, et al. Perinatal origin of adult self-destructive behavior. Acta Psychiatr Scand. 1987;76:364-371. Cannon M, Murray RM. Neonatal origins of schizophrenia. Arch Dis Child. 1998;78:1-3. Zomberg GL, Buka SL, Tsuang MT. Hypoxic-ischemia-related fetal/neonatal complications and risk of schizophrenia and other nonaffective psychoses: A 19-year longitudinal study. Am J Psychiatry. 2000;157:196-202.

68. Hack M, Flannery DJ, Schluchter M, Carter L. Borowski E, et al. Outcomes in young adulthood for very-low-birth-weight infants. N Engl J Med. 2002;346:149-157. 69. Bregman J. Developmental outcome in very low birthweight infants. Current status and future trends. Pediatr Clin North Am. 1998;45:673-690. 70. Bennett FC, Scott DT. Long-term perspective on premature infant outcome and contemporary intervention issues. Semin Perinatol. 1997;21:190-201. 71. JCAHO. Implementing the new pain management standards. Oak Brook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations; 2000. 72. Walden M. Pain Assessment and Management: Guidelines for Practice. Glenview, IL: National Association of Neonatal Nurses; 2001. Document 1222. 73. Anonymous. Prevention and management of pain and stress in the neonate. American Academy of Pediatrics. Committee on Fetus and Newborn. Committee on Drugs. Section on Anesthesiology. Section on Surgery. Canadian Paediatric Society. Fetus and Newborn Committee. Pediatrics. 2000;105:454-461. 74. Anonymous. Circumcision policy statement. American Academy of Pediatrics. Task Force on Circumcision. Pediatrics. 1999; 103:686-693. 75. Anand KJ. Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med. 2001;155:173-180. 76. Franck LS, Scurr K, Couture S. Parent views of infant pain and pain management in the neonatal intensive care unit. Newborn Infant Nurs Rev. 2001;1:106-113. 77. Silverman WA. The future of clinical experimentation in neonatal medicine. Pediatrics. 1994;94:932-938. 78. Whitfield MF, Grunau RE. Behavior, pain perception, and the extremely low-birth weight survivor. Clin Perinatol. 2000;27: 363-379. 79. Anand KJS. Long-term effects of pain in neonates and infants. In: Wiesenfeld-Hallin Z (ed). Progress in Pain Research and Management. Vol 8. Seattle, WA: IASP Press; 1997:881-892. 80. Stedman's Medical Dictionary. 27th Ed. Philadelphia, PA: Lippincott; 2000. 81. Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit [systematic review]. Cochrane Database Syst Rev. 2002:2.

Mark Your Calendar Now! The 5th International Neonatal Nursing Conference Diversity in Care May 12 -15, 2004 For more information contact: Shahirose S. Premji, RN, PhD, Assistant Professor and NNP, University of Calgary, Faculty of Nursing. Phone: 403220-8053; E-maih [email protected]

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Official Journal of the

The Reality of Neonatal Pain Self-Study Continuing Education Course 1.0 CEU

National Association of Neonatal Nurses

Learning Objectives: Upon the completion of this self-directed learning activity, the learner will be able to do the following: 1. 2. 3. 4.

Describe the embryonic development of pain sensation and identify some common misconceptions. Outline the capabilities of the neonatal sensory system. Describe the short-term and long-term outcomes of undertreated or untreated neonatal pain. Recognize the importance of routine pain assessment and treatment in infants.

CONTINUING EDUCATION QUESTIONS 1. Historically, health care providers believed that newbom infants have a blunted or absent ability to feel pain due to the immaturity of their nervous system. A. True B. False 2. Emerging evidence suggests that not only do infants experience pain, they may experience it more acutely than adults. A. True B. False 3. Which region of the brain functions as a relay station for pain stimuli, facilitating discrimination and localization of pain? A. Hypothalmus B. Pituitary C. Thalmic region of the cortex D, Anterior ventricles 4. After mechanical tissue damage, which substances are released by ceils and change the pain information frora nociceptors into an impulse? A. Hemoglobin and bilirubin B. Prostaglandins, bradykinin, serotonin, substance P, and histamine C. All of the above D. None of the above 5. Cortical pain perception is possible at _ _ ? A. 7 Weeks B. 11 Weeks C. 20 Weeks D. 24 to 26 Weeks 6. In the embryo, sensory nerve endings first develop in which area? A. Trunk B. Mucous membranes C. Perioral area D. Peripheral cutaneous areas 7. The ability of the neuron to transmit pain information along a pathway, propagating an impulse from neuron to neuron, occurs on which of the following? A. Myelinated nerve tracks B. Unmyelinated nerve tracks C. Neurons D. A and B Advances in Neonatal Care, Vol 2, No 5 (October), 2002: pp 233-247

8. At which gestational age is mylenization of the entire nociceptive tract complete? A. 20 Weeks B. 26 Weeks C. 30 Weeks D. 37 Weeks 9. The ability to detect noxious stimuli is called: A. Apoptosis B. Synaptogenesis C. Plasticity D. Nociception 10. Perinatal brain plasticity implies A. Alterations in behavior B. Recovery from brain insults C. Abnormal brain development D. All of the above 11. Some studies suggest that pain is more pronounced in the preterm infant because of which of the following reasons? A. Increased activity of inhibitory neuromodulators in the preterm infant B. Equal levels of inhibitory neuromodulators in both the preterm and the term infants C. Immaturity of the descending inhibitory pathways and lack of neuromodulators D. A decreased level of neuromodulators in the term infant 12. Which of the following terms describes responding to nonpainful stimuli as if it were painful? A. Allodynia B. Hyperalgesia C. Hyperinnervation D. Pain insensitivity 13. The primary coping method available to the newborn during painful experiences is which of the following? A. Effleurage B. Visualization C. Withdrawal D. Sucking 14. Factors that contribute to the premature infant's hypersensitivity to pain include all of the following except: A. Multisystem immaturity B. Inadequate subcutaneous fat stores C. Increased energy level D. Thin eyelid skin

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15. Effective nonpharmacologic nursing interventions that may assist the infant in modulating a painful experience include which of the following? A. Environmental control B. Individualized care C. Behavioral accommodations D. All of the above

19. Physiologic markers of "stress" include _ _ A. Triglycerides and lipids B. Glucocorticoids C. Insulin D. CBC with differential 20. According to a recent study, former VBLW infants have increased rates of all except which of the following? A. Cognitive and learning deficits B. Neurosensory impairments C. Alcohol and drug use D. Subnormal height

16. Studies suggest that over time preterm infants in the NICU show what ? A. A n increased behavioral response to pain B. A decreased behavioral response to pain C. No difference in their response to pain D. No studies on this exist

2I. Routine use of which of the following drugs is not recommended in premature infants? A. Morphine B. Midazolam C. Acetaminophen D. Fentanyl

17. Which of the following play a role in how the preterm infant responds to noxious stimuli? A. Experience B. Neurophysical maturity C. Energy level D. All of the above

22. Which of the following stressors do infants experience during their NICU stay? A. Separation from parents B. Exposure of excessive levels of light and sound C. Variable thermal environments D. Numerous randomly occurring invasive procedures E. All of the above

18. Full-term male infants who were circumcised without analgesia exhibited which kind of response to immunizations? A. A n increase in behavioral response B. A decrease in behavioral response C. No change in behavioral response D. No studies have been done

Directions: Mail or fax your completed test, demographic form, and payment to: O~cial Journal of the National Associationof Neonatal Nurses

• • • •

The National Association of Neonatal Nurses Attention: Director of Education 4700 W. Lake Avenue Glenview, IL 60025-1485 fax: 888-477-6266

CEU fees are nonrefundable. The cost is $15.00. All test materials must be complete in order to process the CEU. Participants must achieve a test score of 70% or better to qualify for CEU credit. Test must be postmarked by October 31, 2004. All answer sheets must be postmarked by that day.

Certification: This program has been approved for 1.0 contact hour through the National Association of Neonatal Nurses, a continuing education provider approved by the California BRN provider number CEP 8659 and Florida Board of Nursing FBN 2695.

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Essential Demographic Information Name:

Address:

City:

State:

Postal Code:

Province:

Country:

Telephone Number: NANN Membership Number: Nursing License Number: Form of Payment:

State License Issued In: Credit Card Number:

Expiration Date:

Authorized Signature:

Program Evaluation: A.

B.

C. D. E.

Program objectives were met: • Objective #1 • Objective ~2 • Objective #3 • Objective #4

Agree ~ [] 23 ~

The content was apppropriate? [] The level of difficulty of this activity was: ~3 Easy C3 Moderately Challenging f3 Very Difficult My usual practice setting is: [] Newborn C1 Level II NICU [] Level Ill NICU [] Level IV NICU Other comments or suggestions:

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Neutral ~ [] [] ~

Disagree 21 [] []

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