Pain and agitation are common in critically ill patients. As our understanding of these processes in critically ill children has evolved, we now recognize the vital importance of appropriate analgesia and sedation in such patients.⁴⁸ In 1986, the World Health Organization first published its Analgesic Ladder for the management of cancer pain (Fig. 5-1). This paradigm and others like it are now widely accepted as guidelines for analgesia and sedation in all patients. Despite such advances, considerable progress remains to be made. Caregiver education should enhance awareness of the crucial need for appropriate analgesia and sedation in critically ill children. Practice patterns must continue to change to include appropriate analgesia and sedation as essential components of pediatric critical care. Ongoing research must continue to explore the nature of these complex processes and their optimal management.

Fig. 5-1 The World Health Organization Analgesic Ladder. First described in 1986 for management of cancer pain, the World Health Organization Analgesic Ladder has since become a widely accepted paradigm for analgesia and sedation in patients of all ages and in all clinical settings. Interventions are provided concordant to severity of pain and agitation, with openness to adjuvant measures including nonpharmacologic interventions throughout.

(With permission from: Cancer pain relief and palliative care in children. Companion volume to: Cancer pain relief, with a guide to opioid availability. Geneva 1998, World Health Organization. Available from: http://whqlibdoc.who.int/publications/9241545127.pdf. Accessed October 23, 2010.)

In the past, many caregivers mistakenly assumed the immature pediatric nervous system rendered children incapable of experiencing pain or agitation, or caregivers mistakenly believed that children could not safely tolerate analgesics or sedatives. Particularly in pediatric patients, caregivers often interpreted lack of request for analgesia or sedation as indicating lack of pain or agitation, so pediatric patients often received inadequate analgesia. We now know that children of all ages can feel pain and experience pain without expressing the need for analgesia and they can safely receive a wide variety of analgesic interventions. We also know that agitation is common in pediatric patients, and children often receive inadequate sedation.

Assessment of pain and agitation is especially challenging when patients are unable to articulate their experiences and feelings, and analgesia and sedation may be particularly inadequate in these patients. Critically ill children are at risk for significant pain and agitation, and pediatric critical care providers must be vigilant in providing appropriate analgesia and sedation.

Appropriate analgesia and sedation have been shown to attenuate the stress response associated with critical illness, hastening recovery while lessening incidence and severity of complications. Nurses should assess each patient individually, and interventions including pharmacologic agents should be tailored to the patient and the setting. Nurses should regularly assess patient status, including response to interventions, and modify interventions as appropriate.

All pharmacologic agents used to provide analgesia, sedation, and neuromuscular blockade have potential side effects and complications, particularly a risk of respiratory depression and cardiovascular compromise. Risk may be higher in pediatric patients, especially when they are developmentally immature or medically fragile.⁵⁴ Ongoing patient monitoring is essential.

Anatomy, physiology, and embryology of pain

Pain is a complex phenomenon, representing the interaction of many anatomic pathways, physiologic processes, and psychosocial factors. Pain has thus proven remarkably difficult to define, particularly in children. A widely accepted definition of pain is that suggested by the International Association for the Study of Pain: an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. This definition underscores the degree to which pain is a highly personal and subjective experience.

Clinical care of patients in pain is complicated by lack of objective indicators: no vital sign, radiologic study, or laboratory value can reliably quantify or even indicate pain. Except perhaps in the setting of malingering or drug-seeking, rare in pediatric practice, the best clinical approach is usually to accept the patient’s description or indication of pain as truthful and accurate, and to provide analgesia as appropriate.

Nociception

Nociception is the normal process through which pain is experienced (Fig. 5-2). Nerve pathways underlying pain sensation in humans are fully developed at term (see Anatomy, Physiology and Embryology of Pain in the Chapter 5 Supplement on the Evolve Website). Most pain in critically ill children is nociceptive in nature and tends to respond to conventional antinociceptive analgesics.

Fig. 5-2 Simplified diagram of the neuroanatomy of nociception. 1, Transduction of painful stimuli occurs with activation of peripheral nociceptors. 2, Transmission along first-order primarily A-delta (δ) and c-fibers carries nociceptive input to the dorsal horn of the spinal cord, and from there via second- and third-order neurons, chiefly to the contralateral thalamus and cerebral cortex. 3, Perception occurs when pain becomes a conscious subjective experience. 4, Modulation can affect nociception at any point in this process, for example via descending inhibitory pathways.

(From Lewis SM. Medical-surgical nursing: assessment and management of clinical problems, ed. 8, St. Louis, 2011, Mosby.)

Nociception appears to involve four steps: transduction, transmission, perception, and modulation. Transduction refers to the initiation of pain sensation through activation of sensory nerve endings, or nociceptors. Stimulation above the nociceptor activation threshold causes depolarization of the nerve cell membrane, with subsequent propagation of a nerve impulse, or action potential, along the sensory nerve fiber. Nerve cell depolarization, propagation of the action potential, and subsequent repolarization all result from transmembrane flow of ions through channels in the nerve cell membrane.

Transmission refers to the propagation of a nerve impulse, or action potential, along sensory nerve fibers of the peripheral nervous system to the dorsal horn of the spinal cord, and from there to other locations in the central nervous system. Peripheral transmission relies primarily on two types of sensory nerve fibers, A-delta (δ) and c-fibers. A-delta fibers are larger, high-threshold, myelinated fast fibers that transmit fairly localized, acute, sharp pain. The c-fibers are smaller generalized-stimulus unmyelinated slow fibers that transmit less well-localized dull or aching pain. The c-fibers can remain stimulated, even after cessation of painful stimuli, and can play an important role in chronic pain.

Nociceptive sensory nerve fibers terminate in the dorsal horn of the spinal cord, where they synapse with dorsal horn nerve cells. The pain impulse is then carried toward the brain primarily via the spinothalamic tracts. These tracts receive input from sensory nerve fibers in laminae of the dorsal horn of the spinal cord, cross to contralateral spinal cord laminae, and ascend to the thalamus and other higher centers. Further transmission then occurs from the thalamus to the cerebral cortex with extensive cross-connections throughout the central nervous system.

Perception refers to the complex and poorly understood process by which pain becomes a conscious experience. Perception includes the physical sensation of noxious stimuli and the entire conscious experience of such stimuli with attendant emotional and behavioral components.²² Perception is a unique process in each patient and is affected by age, developmental maturity, and underlying medical condition. Perception is also a highly dynamic process, varying among patients and in the same patient at different times.

Modulation refers to modification of pain by other nervous system input. Modulation can ameliorate or exacerbate pain and may explain some of the tremendous variability in subjective pain experience, especially in children. Modulation is a highly complex process and can take place at any point in transduction, transmission, and perception. A particularly important modulatory pathway is the descending pain system, with nerve axons projecting from the brainstem and other supraspinal centers to various laminae of the spinal cord. These descending fibers inhibit transmission of painful sensory stimuli, enhancing analgesia. Anxiety can also modulate pain, causing increased sensitivity to pain and resultant pain-related disability, particularly in chronic pain.⁴⁰

Hypersensitization and Preemptive Analgesia

Acute pain warns of actual or potential tissue injury. Persistent or severe pain, however, can contribute to adverse processes. Inadequately treated surgical pain may impair breathing and compromise pulmonary toilet, promoting inadequate ventilation, atelectasis, and pneumonia. Pain also induces a neuroendocrine stress response, increasing sympathetic activity and releasing stress hormones and inflammatory mediators. The resultant hypermetabolic, catabolic state may be complicated by impaired immune function that can increase morbidity and mortality.

Tissue injury and inflammation potentiate nociceptor activity, leading to hypersensitivity to painful stimuli. Dorsal horn neurons respond to sustained afferent stimulation with neurophysiologic and morphologic changes consistent with increased excitability. Hypersensitization can alter normal sensory perception, accentuate pain caused by stimuli, and even produce pain in response to normally innocuous stimuli, suggesting that hypersensitization at the cellular level correlates with clinical hypersensitivity to pain.

Administration of preemptive analgesia before tissue injury can inhibit nociception, blunting neuroendocrine stress response and preventing development of peripheral and central hypersensitization. General anesthesia alone is not sufficient for such purposes; nonsteroidal antiinflammatory drugs (NSAIDs), opioids, and a variety of regional anesthetic techniques have been used with variable results. Although animal models suggest that preemptive analgesia decreases overall pain severity and duration, clinical human studies have yielded conflicting and frequently negative results, particularly in children. As a result, preemptive analgesia as a strategy for blunting hypersensitization and reducing pain remains a subject of ongoing investigation. Timing of analgesia appears less important than its administration.

Classification of Pain

Pain is often classified temporally as acute or chronic, anatomically as somatic or visceral, and pathophysiologically as nociceptive or neuropathic (Table 5-1). Such classifications are not mutually exclusive; clinical presentations may suggest considerable overlap, and clear distinctions are not always possible.

Table 5-1 Classifications of Pain

Temporal Classification*
*Acute Pain*	*Chronic Pain*
Expected duration, often hours to days	Prolonged duration, often weeks to months
Somatic or visceral	Somatic or visceral
More commonly nociceptive	Nociceptive or neuropathic
Anatomic Classification
*Somatic Pain*	*Visceral Pain*
Originates in somatic innervation of periphery	Originates in autonomic innervation of viscera
Acute or chronic	Acute or chronic
Nociceptive or neuropathic	Nociceptive or neuropathic
Pathophysiologic Classification
*Nociceptive Pain*	*Neuropathic Pain*
Result of normal nervous system function	Associated with nervous system dysfunction
Acute or chronic	More commonly chronic
Somatic or visceral	More commonly somatic
Typically responds to conventional analgesics	Responds poorly to conventional analgesics

* Classifications are not mutually exclusive: clinical presentations frequently suggest considerable overlap, and clear distinctions are not always possible.

Neuropathic Pain

Neuropathic pain is thought to arise from nervous system dysfunction, although underlying pathophysiologic mechanisms are incompletely understood. Hypersensitivity of sensory nerve fibers causing repetitive depolarization has been proposed, as has wind-up hyperexcitability of dorsal horn neurons secondary to prolonged noxious stimuli. Subjective reporting of neuropathic pain is frequently disproportionate to observed physical findings and to objective assessment of patient comfort. Neuropathic pain can be described as a more intermittent shock-like, shooting, radiating, or stabbing pain, or a more constant burning, prickling, tingling, or aching pain. These descriptors often overlap.

Neuropathic pain often responds poorly to conventional antinociceptive analgesics, but may respond favorably to other medications, particularly some anticonvulsants and some antidepressants. Aggressive physical rehabilitation services and ongoing mental healthcare are often helpful, particularly for chronic neuropathic pain.

Phantom or deafferentation pain is a variant of neuropathic pain associated with central nervous system dysfunction following disruption of peripheral sensory input. Phantom pain can occur long after denervation of affected areas and may persist chronically or even permanently. Phantom pain may be seen following traumatic or surgical amputation and has even been described after dental extraction.⁴⁶ The pathophysiology of phantom pain is complex and incompletely understood.

Complex regional pain syndrome (CRPS) is a variant of neuropathic pain associated with autonomic dysfunction. Signs can include changes in skin color or appearance, alterations in hair distribution or texture, and eventually musculocutaneous atrophy. CRPS pain may be associated with prior nerve injury (CRPS type 2, formerly referred to as causalgia) or may be idiopathic (CRPS type 1, formerly referred to as reflex sympathetic dystrophy). The pathophysiology of CRPS is complex and poorly understood, and a significant psychosocial component is often present.

Patient assessment

Recognition and treatment of pain and agitation can be particularly challenging in the absence of reliable objective quantitative assessments on which to base clinical decisions. Patient descriptions can guide analgesic and sedative interventions. However, even verbal children may find it difficult to express this information, particularly in the setting of critical illness. Children may be nonverbal or otherwise incommunicative secondary to age, developmental immaturity, medical illness, surgical procedures, or interventions such as intubation. Caregivers must recognize patient behaviors or behavioral patterns that provide clues to the presence, location, severity, and even cause of pain and agitation, and must monitor changes to guide therapy. No single objective assessment strategy will be sufficient or appropriate for every patient in every setting.³¹

Pain, particularly when acute, may produce evidence of increased sympathetic tone, the so-called fight-or-flight response. This response includes pupil dilation, tachycardia, hypertension, alteration in respiratory pattern, hyperglycemia, and change in emotional state. These indicators, however, are not sensitive in discriminating pain from other sources of distress, and do not reliably quantify or even indicate pain. Limited evidence supports the use of vital signs as indicators of pain, but only in the context of acute onset or acute increase in pain. Significant pain may be present without physiologic evidence of distress.

A common cause of inadequate analgesia and sedation is failure of the caregiver to accept and act on the patient report of pain and agitation. Although the patient report must always be taken in context, it is the most reliable assessment of patient experience and should be considered the standard for patient assessment. Caregivers must respect any patient report of pain and agitation, performing timely assessment and providing appropriate treatment.

In the absence of a patient report, caregivers must perform regular and appropriate objective assessments. Caregiver reliance on subjective impression, gut feeling, or personal belief introduces significant potential for variation and bias among caregivers, often leading to inconsistent or inadequate analgesia and sedation.

Patient or family fears and beliefs can hinder adequate analgesia and sedation. Patients or families may not wish to bother busy nursing staff. Children may deny distress, fearing painful injections or unpalatable oral preparations. Patients or families may hope to facilitate early discharge by minimizing reports of pain or agitation, or by limiting requests for analgesia and sedation. Distress may be regarded as a sign of weakness or failure. Fear of side effects, in particular addiction, leads many patients and families to avoid even appropriate analgesia and sedation. Nurses should address these concerns directly and provide education as necessary.

Caregiver fears and beliefs may also hinder adequate analgesia and sedation. Caregivers may fear providing unnecessary analgesia or sedation, particularly controlled substances. They may misinterpret regulations and legal requirements associated with these medications, or may fear promoting patient addiction. In terminal or palliative care settings, caregivers may fear hastening or even causing death. These issues must be addressed within the healthcare team (see Chapter 3).

Nurses should seek accurate and thorough information from the patient, family, and other caregivers to clarify onset, nature, severity, and time course of pain and agitation, as well as response to interventions. This history is particularly important when patients receive significant pharmacologic analgesia or sedation that can produce tolerance. What has helped? What has been ineffective or made things worse? Do interventions provide complete or only partial relief? How long does relief persist? Incomplete relief can suggest a need for additional interventions or increased medication dose, whereas complete but transient relief may suggest a need for more frequent or longer-acting interventions. The psychosocial component of pain and agitation can be significant, and nurses should assess available social and emotional support systems.

Regulatory guidelines and legal mandates require that patient care regimens be reviewed and reconciled at admission, at transfer of location or level of care, and at discharge. This helps ensure accuracy and efficacy of interventions, and it is particularly important when critically ill children transition to care settings where previous interventions may be unavailable. Continuation of medications at equipotent doses without inadvertent omission or unnecessary addition helps maintain analgesia and sedation while minimizing the risk of inadequate or excessive dosing.

Pediatric Pain Behavior

Patient behaviors or behavioral patterns can provide powerful clues to the presence, location, severity, and even cause of pain and agitation. Changes in patient behaviors or behavioral patterns may help guide analgesic and sedative interventions. Pain and agitation can be difficult to recognize even in healthy children who are young or developmentally immature; recognition in critically ill children may be complicated by the child’s illness or interventions.

Agitation itself can indicate pain. Children in pain are often restless and cannot be easily distracted. They may cry or fuss, have a short attention span, or fail to respond to previously effective interventions. Facial expression can indicate pain; infants in particular may fail to make or hold eye contact. Children often hold or guard painful body parts rigidly. Pain can produce sleep disturbance, anxiety, nausea, anorexia, and lethargy. Pain—particularly when chronic—may precipitate profound changes in affect and emotional state. Formal psychiatric diagnoses such as anxiety disorder, acute or posttraumatic stress disorder, and major depression are frequently associated with chronic pain. Critical illness itself can produce many of these same behaviors.

Pediatric pain behaviors may be affected by psychosocial stressors and other factors, varying considerably among children or in the same child over time. Children in pain may be frightened or may exhibit developmental regression. Some children may seek attention through dramatic or disruptive behavior; others may be conditioned by gender or parental admonishment to be stoic. Children may fear upsetting or disappointing family and caregivers by admitting distress, or may feel they are being punished. Parents and other caregivers can be valuable interpreters of pediatric behavior.

Sedation or sleep can be mistaken for comfort. Patients of all ages may sleep despite severe pain, particularly if the pain is chronic. Pain itself can induce a state of decreased interaction that inaccurately suggests adequate analgesia. Critical illness and its treatment often exact a tremendous physiologic and emotional toll on patients. The resultant fatigue can produce decreased responsiveness to stimuli including pain. The nurse must consider overall patient status, combining data from assessment tools and other behavioral evaluation as appropriate.

Assessment Tools

Assessment tools typically are scales that can help to quantify pain and agitation in many clinical settings. However, the numeric scores generated must not be taken in isolation; they represent one component of comprehensive patient evaluation, just as vital signs represent one component of physical assessment. Any score must be considered in overall clinical context.

Assessment tools generally rely on subjective patient report, or on objective caregiver evaluation of patients who are unable to provide subjective report. Many assessment tools of both types have been developed for and validated in children. Scores generated using one tool will not necessarily correlate directly with those obtained using another. Caregivers should select an assessment tool appropriate for the patient and use it consistently over time.

Subjective Patient Report

Assessment tools relying on a subjective patient report ask the patient to indicate status on a continuum. Pain scales commonly range from 0 (no pain) to 10 (maximum possible pain); sedation scales vary more widely. Verbal children who are able to count may simply be asked to indicate their pain score on a 0-10 scale. Interactive but nonverbal children, or children unable to count, may be asked to indicate their pain score on a continuum scale using colors, pictures of children, or drawings of faces that represent degrees of distress. Three such pain assessment tools commonly used in pediatric practice are the Oucher! (see Evolve Fig. 5-1 in the Chapter 5 Supplement on the Evolve Website), the McGrath Faces Pain Scale, and the Hicks Faces Pain Scale-Revised (Fig. 5-3). See Patient Assessment in the Chapter 5 Supplement on the Evolve Website.

Fig. 5-3 A recently revised version of a faces scale for use in pediatric patients. Children are asked to point to the face best representing their pain, or for young children, how much they hurt. The six faces can be given scores (from left to right) of 0-2-4-6-8-10 or 0-1-2-3-4-5. Faces represented as more anatomically accurate oval cartoons have improved consistency in scores across diverse ethnic groups when compared to previous versions. The no-pain face is affect-neutral, reducing discrepancies between pain and agitation.

(With permission from Hicks CL, et al: The Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement. Pain 93:173−83, 2001. With permission from the International Association for the Study of Pain (IASP).)

Tools are also available to help children quantify their pain experience through activities such as counting poker chips (the Hester Poker Chip Scale) or coloring an outline drawing of a child (the Eland Color Tool). Use of such activity tools requires patient interaction and caregiver time that may be impractical in the critical care setting.

Objective Caregiver Evaluation

When patients are unable to provide subjective reports, objective caregiver evaluation may be necessary. Although intrinsically less reliable than subjective patient report, objective caregiver evaluation may be the only means available to assess pain and agitation in many critically ill children. Objective caregiver evaluation may also be used judiciously to complement confusing or inconsistent patient reports.

Many assessment tools for objective caregiver evaluation of pain and agitation have been developed for and validated in the pediatric setting. Examples include the FLACC scale (characterizing the patient’s Face, Legs, Activity, Cry, Consolability using specific options) for assessment of pain in nonverbal children (Table 5-2), the COMFORT scale (assessing overall comfort by evaluating specific physical characteristics) for assessment of agitation in critically ill children, and the State Behavioral Scale for assessment of agitation in infants and children during mechanical ventilation.¹⁹ Examples of these tools may be found in Evolve Fig. 5-2 in the Chapter 5 Supplement on the Evolve Website. Additional tools have been reported for use in specific patient populations or particular clinical settings.⁵⁰

Table 5-2 FLACC Scale: Used for Assessment of Pain in Nonverbal Children

Management Planning

With appropriate intervention, most critically ill children should experience little pain and minimal distress. Following comprehensive patient assessment, an appropriate management plan is developed to address patient pain and agitation.⁴⁸ The goals of any management plan should be to maximize analgesia and sedation, minimize side effects and complications, and if possible aid in diagnosis and treatment of underlying critical illness. Ideally, all caregivers should be involved in development of this plan and should be aware of planned interventions. During and after interventions, caregivers must perform regular and periodic patient reassessment to evaluate patient response and guide further interventions. Management must be individualized for each patient, combining nonpharmacologic and pharmacologic interventions as appropriate.

Nonpharmacologic interventions

Nonpharmacologic interventions are important adjuncts in pediatric analgesia and sedation. Because pain and agitation include significant cognitive and affective components, the child often responds to cognitive interventions that invoke the child’s imagination, suggestibility, and sense of play. Behavioral interventions help the child focus on relaxation and deep breathing rather than on the pain or painful stimulus. Biophysical modalities may affect nociceptive transmission and have a significant psychological component. Noninvasive and generally inexpensive, nonpharmacologic interventions can provide patients and families a sense of personal involvement in their care.

Family involvement in nonpharmacologic interventions often increases their effectiveness. Although the child may appear more distressed when family members are present, this may indicate that the child is more willing to express pain, fear and agitation in their presence. Children should receive positive reinforcement for engagement in nonpharmacologic interventions, but should never be punished or ridiculed for being frightened or uncooperative. Child Life specialists and other trained professionals, if available, provide valuable support.

Analgesia and sedation are generally optimized when appropriate treatment modalities are combined. For mild to moderate pain and agitation, nonpharmacologic interventions alone may suffice. For moderate to severe pain, nonpharmacologic interventions should complement, but not necessarily replace, pharmacologic therapy. Comprehensive care of critically ill children uses suitable nonpharmacologic techniques in combination with appropriate medications to optimize analgesia and sedation, minimize side effects, and facilitate recovery.

Cognitive and Behavioral Modalities

Cognitive and behavioral modalities are likely to enhance analgesia and sedation by influencing perception and modulation of pain at the supraspinal level. They also address cognitive and affective causes of anxiety. Cognitive modalities include distraction, relaxation and guided imagery, music therapy and hypnosis. Behavioral modalities include deep breathing and relaxation techniques. Cognitive and behavioral interventions are used most successfully in combination with other nonpharmacologic techniques and in conjunction with appropriate medications.

Preparation for Procedures

Preparation for and explanation of procedures will increase patient and family understanding, can help reduce fear of the unknown, and can enhance analgesia and sedation. Use may be limited by time and clinical conditions.

Honest and straightforward information should be provided in a manner and at a level appropriate for the child’s age and psychosocial development. Anticipatory activities such as tours, coloring books, dolls, puppets, and play therapy may be used as time and clinical context allow. Suggestions for coping strategies should be provided, allowing children to practice such strategies and families to rehearse supportive roles. Children should be encouraged to express fears and concerns, and parents and other family members should be involved as appropriate.

Distraction

Simple distraction may significantly enhance analgesia and sedation. Distraction engages children in other activities, refocusing attention on something more pleasant. Distraction does not reduce intensity of noxious stimuli, but can modulate pain and lessen agitation, enhancing analgesia and sedation during the distracting activity. Pain and agitation will likely increase again when distraction ceases.

Distraction can take many forms, such as listening to music, talking about pets or school, blowing bubbles, squeezing hands, and singing or counting. The activity should be appropriate to patient age, developmental level, and interests. Children can be distracted by parents and other family members, in person or on recordings, or by favorite toys, books, and activities. Interactive computer and video games can provide distraction for children able to use them.

Relaxation and Guided Imagery

Relaxation and guided imagery can augment analgesia and sedation, and need not be complex to be effective. Bright lights, loud noises, and other potentially noxious stimuli should be minimized, although this can be challenging in the critical care setting. Soothing music and talking in a soft, calm voice can promote relaxation. Muscle tension intensifies distress and can be alleviated in older children by deep breathing and progressive relaxation exercises. Controlled breathing can be used alone or in combination with other techniques. Such techniques can enhance the child’s feelings of control and involvement in care.

As a relaxation strategy, imagery encourages children capable of abstract thinking to focus on something unrelated to their pain and agitation. Imagery is a form of guided self-distraction, and is considered to be a variant of self-hypnosis. Children may also imagine medication traveling through the body to help them, super heroes attacking the source of distress, or other therapeutic scenarios. Imagery can be more effective if it enlists several senses. Guided imagery of playing at the beach might include imagining the touch of sand, the sound of waves, the warmth of sunshine, the smell of the ocean, and the taste of favorite foods as combined sensations.

Music Therapy

Music therapy can provide both distraction and relaxation in children. It has been used effectively in the operating room, postanesthesia care unit, neonatal critical care unit,⁴ ^,32 and oncology ward. Music choice should be based on patient age, culture, and preference, guided as necessary by parents, other family members, and friends. Listening to music through headphones offers the added benefit of masking chaotic auditory stimuli.

Hypnosis

Hypnosis capitalizes on a child’s prolific imagination and high degree of suggestibility to induce a hypnotic state in which pain and agitation are lessened. Hypnosis has been successful with pediatric oncology patients, in pediatric emergency departments, and for treatment of children with burns or sickle cell disease. When combined with guided imagery, hypnosis has been shown to decrease pain scores, reduce patient anxiety, and shorten duration of hospitalization in pediatric surgical patients. Hypnosis requires specific training and expertise. Sufficient time and an appropriate setting can be elusive in the critical care setting.

Biophysical Modalities

Biophysical modalities are thought to affect nociceptive transmission at or below the level of the spinal cord, although precise mechanisms of action are incompletely understood. These modalities may also have a significant psychological component. Many modalities may be more effective when combined. Use of biophysical modalities is limited by time and logistical constraints, and some require specific training or equipment.

Cutaneous and Oral Stimulation

Many children respond positively to touch, particularly from parents or other loved ones. Positioning family members as close to the bedside as feasible will facilitate ongoing physical contact. Some parents may need to be encouraged to hold or touch their critically ill child. Pleasant cutaneous stimulation, such as stroking, patting, or massaging produces muscle relaxation and may reduce pain and agitation. Massage therapy has been shown to reduce pain associated with dressing changes in pediatric burn patients. Infants can be soothed with pleasant cutaneous stimulation such as gentle rubbing of the head, and they respond particularly well to pacifiers and other oral stimulation. Sugar water provides analgesia for infants undergoing painful procedures such as heel stick blood collection, and is synergistic with pacifier use. When family members perform these techniques, they provide emotional benefits and promote family-centered care.

Cold and Heat Therapy

Cold and heat therapy are cutaneous stimulation techniques. Cooling enhances analgesia by reducing inflammation and slowing nociceptive transmission. Examples include rubbing ice above and below an injury and applying ice or ethyl chloride spray before injection or venipuncture. Monitor the treated area and the child’s response, and avoid excessive cooling that can cause skin irritation, cellular injury, and frostbite.

Heat promotes circulation, relaxes muscles, and reduces stiffness. Heat application before venipuncture promotes vasodilation and can reduce pain. Hydrotherapy, often used by physical therapists, combines the benefits of heat with those of water immersion, but can be difficult to provide in the critical care setting. Monitor the treated area, and avoid excessive heating that can cause skin irritation, cellular injury, and burns.

Transcutaneous Electrical Nerve Stimulation (TENS)

TENS delivers weak electrical current to the skin through superficial electrodes. TENS may modulate nociceptive transmission at the spinal cord level, and may also induce release of endorphins and other endogenous neurotransmitters, similar to acupuncture. TENS has been used effectively for children undergoing venipuncture or dressing changes, and it has been used as an adjunctive modality in pediatric chronic pain management. TENS may be particularly useful for treatment of musculoskeletal and myofascial pain. Physical therapists typically oversee TENS therapy and provide instruction for patients and families. TENS is usually well tolerated by patients old enough to understand its use, although some children may find the tingling sensation unpleasant.

Acupuncture

Acupuncture is gaining acceptance and is practiced by both physicians and licensed acupuncturists in the United States. The precise mechanisms of action are incompletely understood. Acupuncture may precipitate release of endorphins, encephalins, serotonin, and other endogenous neurotransmitters, inhibiting nociceptive pathways and enhancing analgesia. Pediatric acupuncture has been used primarily as adjunctive therapy to treat chronic pain. The practice of acupuncture requires specific training.

Systemic analgesics

Numerous systemic analgesics are available for use in children (Table 5-3). Systemic analgesics can have a wide range of physiologic effects, particularly in critically ill children. Knowledge of the agents being administered is essential for optimal efficacy and patient safety. Nurses must be aware of expected clinical effect, usual time of onset, likely duration, and potential side effects of each agent administered. Medications ordered on an as-needed basis are effective only when given appropriately with ongoing and recurring patient assessment. Frequent requirement for a drug ordered only on an as needed basis should prompt consideration of scheduled administration and additional interventions. Intramuscular injection is painful and absorption variable; it should be avoided except perhaps in the setting of difficult intravenous access. Although many systemic analgesics can produce sedation, they should not be used primarily for this purpose.

Table 5-3 Systemic Analgesics

Drug	Dose	Comments
Acetaminophen
Acetaminophen and NSAIDs are generally synergistic and may be given together without need to alternate or stagger doses.
Acetaminophen	Load: 20 mg/kg PO (maximum 1000 mg), then	Good antipyretic; hepatic toxicity with overdose
	Main: 15 mg/kg PO (maximum 1000 mg) q4-6 h	Loading dose especially useful for procedural or perioperative analgesia
	Load: 40 mg/kg PR (maximum 1300 mg), then	FDA now advises maximum single adult dose of 650 mg for over-the-counter use
	Main: 20 mg/kg PR (maximum 1300 mg) q4-6 h
	Maximum 4 g/24 h PO/PR
Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Acetaminophen and NSAIDs are generally synergistic, and may be given together without the need to alternate or stagger doses.
Choline magnesium trisalicylate	10 mg/kg PO/PR (maximum 1500 mg) q6-8 h	Only NSAID without platelet dysfunction
	Maximum 4 g/24 h PO/PR	No association with Reye syndrome
Ibuprofen	10 mg/kg PO/PR (maximum 800 mg) q6-8 h	Good antipyretic (IV dose: 5 mg/kg may be used for antipyretic)
	IV: 10 mg/kg (for pain)
	Maximum 3200 mg/24 h PO/PR	IV formula recently approved analgesic in adults
Ketorolac	0.5 mg/kg IM/IV (maximum 30 mg) q6 h	Potentially significant platelet dysfunction
	Total therapy must be <5 days
Lower Potency Oral Opioids
Recommended doses are for initial administration in opioid-naïve patients: titration to clinical effect is required; recommended initial opioid doses should typically be reduced 35% to 50% in neonates and young infants.
Codeine	1 mg/kg PO q4 h (adult dose, 30-60 mg)	Tablet and liquid preparations typically in combination with acetaminophen
		High incidence of gastrointestinal side effects
Hydrocodone	0.2 mg/kg PO q4 h (adult dose, 10-15 mg)	Tablet and liquid preparations typically in combination with acetaminophen or NSAID
		Moderate incidence of gastrointestinal side effects
		Sustained-release product available as antitussive, under study as analgesic
Oxycodone	0.1 mg/kg PO q4 h (adult dose, 5-10 mg)	Tablet preparations with or without acetaminophen or NSAID
		Liquid preparations contain only oxycodone
		Low incidence of gastrointestinal side effects
		Sustained-release product available for chronic therapy
Higher Potency Opioids
Recommended doses are for initial administration in opioid-naive patients: titration to clinical effect is required; recommended initial opioid doses should typically be reduced 25% to 50% in neonates and young infants; PCA demand dose typically q 8-10 min for patient-controlled analgesia, q 15-60 min for nurse or parent-controlled analgesia.
Fentanyl	5-15 mcg/kg PO (adult dose 400 mcg)	Dosing interval for oral preparation not well defined
	0.5-2 mcg/kg IV (adult dose 100 mcg) q 1 h
	Infusion 0.5-2 mcg/kg per hour (adult dose 100 mcg/h)	Rapid IV infusion may cause chest wall rigidity in infants
	Patch 25 mcg = 1 mg/h IV morphine
	PCA demand dose 0.5-1 mcg/kg IV (adult dose 50-100 mcg)	Tachyphylaxis common
	PCA basal 0.5-1 mcg/kg per hour IV (adult dose 50-100 mcg/h)	Transdermal patch not for acute management
Hydromorphone	20-40 mcg/kg PO (adult dose 2-4 mg) q 3 h	Sustained-release oral product under study as analgesic
	10-20 mcg/kg IM/IV/SC (adult dose 1-2 mg) q 3 h
	Infusion 4 mcg/kg per h (adult dose 0.2-0.3 mg/h)	Less histamine release than morphine
	PCA demand dose 4 mcg/kg IV (adult dose 0.2-0.3 mg)
	PCA basal 4 mcg/kg per hour IV (adult dose 0.2-0.3 mg/h)
Meperidine	0.25-0.5 mg/kg IM/IV/SC (adult dose 12.5-25 mg)	Doses for treatment of shivering
	Infusion/PCA not recommended	Neurotoxic metabolite may induce seizures
		No hepatobiliary advantage over any other opioid
		No longer recommended as primary analgesic
Methadone	0.1 mg/kg PO (adult dose 5-10 mg) q6-12 h	Useful for chronic therapy Treatment of addiction must be in federally licensed facility
	0.05 mg/kg IV (adult dose 2.5-5 mg) q6-12 h
	Infusion/PCA not generally used
Morphine	0.3 mg/kg PO (adult dose 15-30 mg) q3 h	Sustained-release oral product available for chronic therapy
	0.05-0.1 mg/kg IM/IV/SC (adult dose: 5-10 mg) q3 h
	Infusion 0.02 mg/kg per h (adult dose 1-1.5 mg/h)	Potentially significant histamine release
	PCA demand dose, 0.02 mg/kg IV (adult dose 1-1.5 mg)
	PCA basal 0.02 mg/kg per hour IV (adult dose 1-1.5 mg/h)

FDA, U.S. Food and Drug Administration; h, hour; IM, intramuscular; IV, intravenous; Load, loading dose; Main, maintenance dose; mcg, microgram; PCA, patient-controlled analgesia; PO, by mouth; PR, by rectum; q, every; SC, subcutaneous.

Nonopioid Analgesics

Often overlooked, nonopioid analgesics are important pharmacologic options. Nonopioid analgesics alone may be adequate for mild to moderate pain and generally reduce opioid requirement in moderate to severe pain. Nonopioid analgesics generally demonstrate a ceiling effect: exceeding recommended doses does not significantly improve analgesia, but will increase risk of side effects and toxicity. As with nonpharmacologic interventions, nonopioid analgesics are most effective in the context of a comprehensive management plan. Commonly used nonopioid analgesics include acetaminophen and NSAIDs; ketamine is discussed with other systemic sedatives.

Acetaminophen

Acetaminophen is widely used as an analgesic and an antipyretic. It can provide complete analgesia for mild to moderate pain and may reduce opioid requirement in moderate to severe pain, particularly when given on a scheduled basis. Acetaminophen is not an NSAID. Although it is a cyclooxygenase inhibitor, it has virtually no antiinflammatory activity, and therefore has few gastrointestinal, renal, or hematologic side effects. The primary toxicity of acetaminophen is hepatic, seen with both acute and chronic overdose, although renal toxicity has been described.⁴²

Acetaminophen is at least as effective an analgesic as codeine,¹² and it is synergistic with NSAIDs.⁵² Acetaminophen and NSAIDs can be given simultaneously without need to alternate or stagger doses. As with most nonopioid analgesics, acetaminophen demonstrates a ceiling effect: exceeding recommended doses does not significantly improve analgesia and increases risk of side effects and toxicity. Recently, an FDA advisory committee recommended the maximum single adult dose for over-the-counter products be reduced to 650 mg because of risk of hepatic injury.²⁴

Rectal acetaminophen is useful for a patient who is unwilling or unable to tolerate an oral dose. Because rectal absorption is slower and bioavailability is more variable than with oral administration, higher rectal doses are needed for adequate analgesia. Rectal acetaminophen with a loading dose of at least 40 mg/kg has been shown to reduce pain scores and reduce opioid requirement following surgery in children.

Nonsteroidal Antiinflammatory Drugs

Like acetaminophen, NSAIDs can provide complete analgesia for mild to moderate pain and can reduce opioid requirement in moderate to severe pain, particularly when given on a scheduled basis. NSAIDs are often particularly effective for musculoskeletal pain. Because NSAIDs have significant antiinflammatory activity, they can produce gastrointestinal, renal, and hematologic side effects. Risk of side effects is greater with higher dose or prolonged administration, and with certain agents. NSAIDs reduce splanchnic and renal perfusion, potentially predisposing to gastrointestinal ulcers and renal insufficiency. Most NSAIDs impair platelet function and may increase risk of bleeding. Acetaminophen and NSAIDs are generally synergistic and can be given simultaneously without need to stagger doses. As with most nonopioid analgesics, NSAIDs demonstrate a ceiling effect: exceeding recommended doses does not significantly improve analgesia and does increase the risk of side effects and toxicity.

Aspirin is no longer considered a routine primary analgesic in children. Aspirin induces potent inhibition of platelet function through irreversible acetylation of platelet cyclooxygenase. Anticoagulation persists for several days in patients with normal hepatic and hematopoietic function, until synthesis of new functional platelet cyclooxygenase. Pediatric aspirin use has declined dramatically in recent decades because of a described association with Reye syndrome in children with primary varicella and influenza. Although varicella vaccination has probably lessened such risk, aspirin use in infants and children is largely reserved for long-term anticoagulation, and in some cases for management of rheumatic disease.

The most widely used oral NSAID in children in the United States is ibuprofen, available in a variety of liquid, tablet, and capsule preparations. Intravenous ibuprofen, like intravenous indomethacin, is approved only for medical closure of patent ductus arteriosus in infants. Ibuprofen is a moderate potency analgesic and excellent antipyretic with an impressive pediatric safety record; it is underused for procedural and perioperative pain management in children. Ibuprofen is at least as effective an analgesic as acetaminophen, and it is superior to codeine.¹² Ibuprofen and acetaminophen are synergistic.⁵² The liquid preparation can be given rectally at similar doses to patients unwilling or unable to tolerate oral doses.

Ketorolac is the only intravenous NSAID approved in the United States for use as an analgesic. Ketorolac is the most potent and most effective NSAID analgesic, with efficacy approaching that of many opioids. It provides superior postoperative analgesia compared with acetaminophen and other NSAIDs. However, it also has the highest incidence of side effects. Ketorolac is most commonly administered intravenously; oral ketorolac has not been approved for use in children. Total duration of ketorolac therapy must not exceed 5 days to avoid potentially serious gastrointestinal ulceration and renal insufficiency.

Significant platelet dysfunction can develop after a single dose of ketorolac, and its use in patients with risk for bleeding is controversial. Although initial experience suggested greater blood loss during tonsillectomy in children receiving perioperative ketorolac, prospective randomized trials showed only nonsignificant trends toward increased bleeding without clinical complications.^51a It may be prudent to avoid ketorolac in patients at risk for bleeding until more definitive information is available.

Choline magnesium trisalicylate is unique among NSAIDs in not causing significant platelet dysfunction, and it can be useful in patients at risk for bleeding. Although it is an aspirin derivative, choline magnesium trisalicylate has no known association with Reye syndrome. Despite this apparent safety, it may be prudent to limit use of choline magnesium trisalicylate to children who have had documented varicella or received appropriate immunization. Choline magnesium trisalicylate is available in liquid and tablet preparations. The liquid preparation can be given rectally at similar dose to patients unwilling or unable to tolerate oral doses.

Opioid Analgesics

Opioids remain the mainstay of pharmacologic analgesia in patients of all ages. Acting on opioid receptors in the central nervous system and elsewhere, opioids cause dose-dependent analgesia and respiratory depression. Other side effects include somnolence, pupil constriction, decreased gastrointestinal motility, nausea, and urinary retention. Many opioids induce histamine release, causing urticaria, pruritus, nausea, bronchospasm, and occasionally hypotension. Pruritus is more common and typically more intense with neuraxial administration, likely caused by central nervous system opioid effect rather than histamine release. Opioid side effects can be managed with a variety of agents (Table 5-4).

Table 5-4 Agents for Management of Opioid Side Effects

The opioid antagonist naloxone rapidly reverses opioid effects. Naloxone may precipitate withdrawal in opioid-dependent patients, and pulmonary edema has been reported with higher doses. Low-dose naloxone infusion has been described for prevention and treatment of side effects secondary to ongoing opioid administration.⁴¹ For treatment of opioid overdose, support of effective ventilation before naloxone administration may prevent excessive adrenergic response.

Several agents with mixed opioid agonist-antagonist activity are available; their ceiling effect theoretically limits side effects and improves safety, but also limits analgesia. Opioid agonists and antagonists, particularly nalbuphine, are often used for management of opioid-induced side effects, but are of limited utility as primary analgesics.

Opioid analgesics do not generally have maximum effective doses. Recommended doses are for initial administration in opioid-naive patients and must be titrated to clinical effect. Increasing dose requirement, also known as tolerance or tachyphylaxis, is often observed with ongoing administration. Opioid therapy longer than 7 to 10 days can result in physical dependence, requiring weaning to avoid withdrawal. Tolerance and dependence are separate phenomena. Addiction, a formal psychopathologic diagnosis of volitional drug-seeking behavior, rarely develops in children receiving appropriate opioid analgesia and is not a valid reason to withhold therapy.

Opioid analgesics are commonly administered in conjunction with systemic sedatives; this increases the risk of side effects, especially respiratory depression. Nurses should carefully titrate doses, provide appropriate monitoring, and keep resources to manage complications (including appropriate reversal agents) readily available.

Opioid use in neonates and young infants has generated much controversy. Historical studies in rats and humans suggested increased permeability of the neonatal blood-brain barrier to opioids, particularly morphine, producing greater respiratory depression (see additional references in the Chapter 5 Supplement on the Evolve Website). It is now clear that pharmacologic properties and clinical effects of opioids in human neonates are highly variable. In general, opioid clearance is decreased and elimination is prolonged in neonates, particularly premature infants, with values approaching adult levels by several months of life. Opioid-naive neonates and young infants receiving opioids should be monitored closely and initial doses generally reduced by 25% to 50%. There is no reason to withhold opioid therapy from any child on the basis of age, provided that doses are individualized and regimens titrated to clinical effect.

Meperidine (Demerol) is no longer recommended as a primary analgesic, although low-dose meperidine is useful for treatment of shivering. Meperidine otherwise offers no advantages over other opioids and causes similar hepatobiliary spasm at equipotent doses. Use of the lytic cocktail of meperidine, promethazine (Phenergan), and chlorpromazine (Thorazine), historically given by intramuscular injection to provide analgesia and sedation for minor procedures, is no longer recommended.

Oral Opioids

When analgesic requirements allow and gastrointestinal function permits, oral opioids offer freedom from parenteral therapy. Onset of action is generally slower than with IV administration, rendering oral opioid therapy generally unsuitable for acute management of severe pain. Several lower potency oral opioids are used commonly for management of mild to moderate pain in children. Higher potency opioids may also be given orally, particularly in patients with oncologic or other life-limiting disease.

Codeine is available in liquid and pill forms that commonly include acetaminophen. Codeine requires hepatic conversion to morphine for its analgesic effect and frequently causes considerable gastrointestinal upset. Most patients reporting allergy to codeine actually have gastrointestinal intolerance.

Immediate-release hydrocodone is available in liquid and pill forms, commonly in combination with acetaminophen or an NSAID. Sustained-release hydrocodone is available in liquid form as an antitussive cough suppressant, and a pill form is being evaluated as an analgesic. Hydrocodone tends to cause less gastrointestinal upset than codeine.

Immediate-release oxycodone is available in liquid form alone, and in pills with or without acetaminophen or an NSAID. Sustained-release oxycodone is available in pill form for chronic therapy. Oxycodone is generally well tolerated and causes little gastrointestinal upset, but has been associated with high rates of inappropriate use and diversion.

Immediate-release morphine is available in liquid and pill forms. Sustained-release morphine is available in pill forms for chronic therapy. Morphine induces histamine release and may cause nausea, urticaria, pruritus, bronchospasm, and even hypotension at higher doses, although these are more common with IV administration.

Immediate-release hydromorphone is available in liquid or pill form. Sustained-release hydromorphone in pill form is being evaluated as an analgesic. Hydromorphone causes less histamine release than morphine, and it is generally associated with fewer and less severe histamine-mediated side effects.

Methadone has prolonged onset and duration of action, making it poorly suited for management of acute or dynamic pain, but well suited for chronic therapy in patients with stable analgesic requirements. Use of methadone as an analgesic, or for weaning in the setting of tolerance or dependence, is appropriate and legal. Use of methadone for treatment of psychopathologic addiction is restricted to federally licensed facilities. Although methadone may cause Q-T prolongation and ventricular arrhythmias, particularly at higher doses, recent suggestions to consider screening electrocardiogram before and at intervals during methadone therapy ³⁵ ^,36 remain controversial.²⁷

Fentanyl is available for oral administration as a lozenge attached to a stick, the so-called fentanyl lollipop. Oral fentanyl has been used for pre-anesthetic sedation in children, although it is no longer marketed for this indication. Oral fentanyl has more recently been used to provide analgesia and sedation for painful procedures, and for patients with breakthrough acute and chronic pain.⁵ Nausea and emesis are fairly common. Intranasal fentanyl is increasingly used for management of acute pain in the emergency department⁹ and for treatment of breakthrough pain in opioid-dependent oncology patients.³⁷ Onset of action is rapid with either route: analgesia and respiratory depression may develop quickly.

Intravenous Opioids

Intravenous opioids remain the mainstay of pharmacologic analgesia for moderate to severe pain in patients of all ages. Because subcutaneous and intramuscular administration can cause additional pain and distress, particularly in children, these routes are typically avoided unless there is difficulty in obtaining IV access. Side effects are more common and potentially more serious with intravenous opioids. Nurses must provide appropriate monitoring and promptly manage complications. Equipotent opioid doses entail similar risk of side effects; no single opioid is intrinsically superior or safer than another.

Morphine is the traditional intravenous opioid analgesic. Morphine induces histamine release and may cause nausea, urticaria, pruritus, bronchospasm, and even hypotension at higher doses, particularly with rapid administration. Hydromorphone tends to induce less histamine release than morphine. Methadone is generally more appropriate for chronic therapy in patients with stable analgesic requirements than for management of acute or dynamic pain, although intravenous methadone has been used successfully in pediatric surgical patients.

Fentanyl tends to cause little histamine release and has few hemodynamic effects, and it is widely used in the critical care setting. Fentanyl may induce mild bradycardia, and may cause potentially significant chest wall and abdominal rigidity, particularly with high dose or rapid administration and in infants. Opioid reversal or neuromuscular blockade may be required if chest wall rigidity prevents adequate ventilation. Fentanyl is highly lipophilic; high dose, repeated, or sustained administration results in significant tissue accumulation which may markedly prolong clinical effect.

Fentanyl is available as a transdermal patch providing continuous absorption that mimics intravenous infusion. Use in smaller patients is limited by dose, because the patches cannot be cut. Onset is slow (approximately 18 hours), and absorption may be variable. Like methadone, transdermal fentanyl is not indicated for acute analgesia, but is well suited for chronic therapy in patients with stable analgesic requirements.

Opioid infusion is an effective means of providing analgesia to patients requiring more than occasional doses of intravenous opioid. Respiratory depression is uncommon in healthy patients at suggested doses; opioid infusion should not prevent spontaneous ventilation or delay weaning from mechanical ventilatory support.

Nurses should frequently and regularly assess patients receiving opioid infusion. Nurses should evaluate adequacy of analgesia, level of sedation, and presence of respiratory depression or other side effects and titrate the infusion appropriately. Continuous pulse oximetry is recommended for patients receiving opioid infusion, at least when initiating the infusion and with any significant increase in regimen. Consider continuous cardiorespiratory monitoring for opioid-naive neonates and young infants.

Patient-Controlled Analgesia (PCA)

If an opioid is administered only after a patient reports pain, this can create a vicious cycle of suffering, a delay in drug administration, and resultant persistent pain or excessive sedation. Optimal opioid administration provides pain relief, but avoids respiratory depression or excessive sedation, preserving a balance between desired efficacy and undesired side effects (Fig. 5-4). Intermittent dosing is time-consuming for providers and frequently upsets this analgesic balance. Continuous infusion eventually establishes a drug level steady state, but is independent of patient request. A safe, effective, and readily titratable modality for ongoing opioid administration in children is PCA. PCA modalities maximize analgesia, minimize side effects, and reduce overall opioid consumption in patients of all ages.

Fig. 5-4 Opioid analgesic window. A, Idealized illustration of continuum of opioid effect from pain to analgesia to coma. B, Optimal therapy, as in patient-controlled analgesia, maintains plasma opioid levels within the middle (Analgesia) third of the graph representing the analgesic window between inadequate analgesia (Pain) and excessive sedation (Coma).

(With permission from Berde CB: Pediatric postoperative pain management. Pediatr Clin North Am 36:921−940, 1989. Copyright Elsevier 1989.)

Drug delivery in PCA is controlled by a microprocessor providing dose administration in response to patient or proxy request, usually with the press of a button. Appropriate lockout intervals and maximum doses are programmed to prevent overdose. Analgesia is generally excellent. With adequate instruction, most developmentally appropriate school-aged children can safely and effectively manage their own PCA. Nurse- or parent-controlled PCA, so-called PCA by proxy, can be used for children who are unable or unwilling to control their own pump, although the risk of respiratory depression increases if dosing intervals are not adjusted, particularly in combination with basal infusions. Prevalence of complications during PCA by proxy is similar to that during conventional PCA, although serious complications may be more common.⁶⁰

Morphine is the most common opioid for PCA, but hydromorphone and fentanyl are also used. Meperidine PCA is not recommended. Methadone PCA has been described in pediatric cancer patients with significant opioid requirement and tolerance to other agents. PCA regimens typically allow demand dose administration every 8 to 10 minutes for patient-controlled administration, or every 15 to 60 minutes for PCA by proxy. Longer dosing intervals may be safer in younger or medically fragile patients. Simultaneous basal infusion can be provided to ensure ongoing analgesia, but does not reliably improve analgesia in most patients. PCA basal infusions in adults increase the risk of respiratory complications, but this has not been observed in children. Basal infusion, if used, should be concordant with demand dose.

Nurses should assess patients receiving opioid via PCA frequently and regularly. The nurse should evaluate adequacy of analgesia, level of sedation, and presence of respiratory depression and other side effects and titrate the regimen appropriately. Consider pulse oximetry for all patients and continuous cardiorespiratory monitoring for opioid-naive neonates and young infants. Instruct patients, families, and caregivers regarding appropriate PCA use.

Local anesthetics

Local anesthetics impair nerve conduction through the blockade of nerve cell sodium channels. Local anesthetics are potentially neurotoxic, altering level of consciousness or inducing seizures if therapeutic levels are exceeded. Local anesthetics are also potentially cardiotoxic and may induce arrhythmias including ventricular tachycardia, ventricular fibrillation, and cardiac arrest. Prolonged resuscitation after local anesthetic overdose may be required, particularly with long-acting agents. Recent reports suggest that administration of intravenous lipid emulsion increases the likelihood of successful resuscitation after local anesthetic toxicity, perhaps by serving as a binding reservoir.²⁵

Lidocaine and bupivacaine are the most commonly used local anesthetics in pediatric practice. Lidocaine provides dense analgesia, but has a relatively short duration of action and often induces motor block. In topical preparations, lidocaine is commonly combined with prilocaine, which can cause methemoglobinemia, particularly in large doses or small patients. Bupivacaine is widely used because of its long duration of action and relative selectivity for sensory over motor block. Bupivacaine is highly cardiotoxic, with similar thresholds for cardiac and neurologic toxicity: arrhythmias can occur before obtundation or seizures are noted.

Two newer agents, levobupivacaine and ropivacaine, are potentially less toxic alternatives to bupivacaine. Levobupivacaine, the L-isomer of bupivacaine, induces conduction block similar to bupivacaine, with a somewhat higher threshold for cardiotoxicity. Ropivacaine has somewhat greater selectivity for sensory over motor block than does bupivacaine, also with a somewhat higher threshold for cardiotoxicity. The use of these newer agents is limited primarily by cost.

Local anesthetics provide analgesia by blocking conduction in sensory nerve fibers; they are given through direct infiltration, topical application, or regional anesthetic techniques. Local anesthetics can reduce or even eliminate the need for systemic analgesics, and may be particularly useful in patients with increased sensitivity to opioids, including neonates and children with underlying neurologic or respiratory disease. In pediatric practice, this theoretical advantage is somewhat offset by the frequent requirement for sedation or general anesthesia to tolerate local anesthetic administration. Some children will require supplementary systemic analgesia despite apparently successful local anesthesia. This may result from apprehension and variability in developmental and emotional maturity.

Infiltration

Direct infiltration of local anesthetic is technically straightforward and provides rapid onset of analgesia. Use in children is limited largely by their fear of needles and pain associated with injection. Nonpharmacologic interventions and systemic sedatives may be used as appropriate. Initial cutaneous analgesia may be obtained by topical application if time and clinical context permit. The acidic pH of many local anesthetic solutions enhances solubility and prolongs shelf life, but is largely responsible for injection pain. Simple pH buffering with small volumes of sodium bicarbonate added to local anesthetic solutions immediately before use helps reduce such pain and may increase efficacy.

Topical Application

Many local anesthetics are formulated to provide cutaneous analgesia without the need for potentially painful injections (Table 5-5). Such preparations enhance usefulness of topical anesthetics for minor procedures, and in many instances they reduce or eliminate the need for supplementary systemic analgesia and sedation. The use of topical formulas is limited primarily by cost and time of onset. Specific agents are discussed in Local Anesthetics, Topical Application in the Chapter 5 Supplement on the Evolve Website.

Table 5-5 Topical Local Anesthetics

Product/Compound	Ingredients	Comments
Lidocaine cream or gel	Liposomal lidocaine 3%, 4% or 5%	Apply for 30 min
		No dressing required
		Nonprescription
EMLA (generic): Eutectic mixture of local anesthetics	Lidocaine 2.5% + prilocaine 2.5%	Apply for 1-4 h
		Requires occlusive dressing
		Prilocaine may cause methemoglobinemia
TAC: tetracaine, adrenaline, cocaine	Tetracaine 0.5-1% + adrenaline (epinephrine 1:2000-4000) + Cocaine 4-11.8%	Apply for 15-20 min
		Avoid mucous membranes
		Avoid terminally perfused areas
		Potential cocaine toxicity
LET: lidocaine, epinephrine, tetracaine	Lidocaine 4% + epinephrine 1:2000 + tetracaine 0.5%	Contains lidocaine rather than cocaine
		Apply for 15-20 min
		Avoid mucous membranes
		Avoid terminally perfused areas
Synera	70 mg lidocaine/70 mg tetracaine in a topical patch	FDA-approved for children 3 years of age and older
		Apply for 20-30 min
		Erythema common; monitor for allergic reaction

Regional Anesthetic Techniques

The use of regional anesthetic techniques is expanding in the operating room and beyond. These techniques enhance surgical anesthesia and can provide excellent procedural and perioperative pain management for children, potentially reducing the requirement for systemic analgesia and sedation. Regional anesthesia may have a lower risk of adverse effects (e.g., nausea, sedation, respiratory depression) than systemic opioids; in some settings they have been shown to improve outcomes. Analgesia may persist for hours to days or more depending on the medications and technique. Regional anesthetic techniques commonly used in children include a variety of peripheral nerve, plexus, and neuraxial blocks.

Peripheral Nerve Blocks

Virtually any peripheral nerve can be blocked with appropriate equipment and sufficient provider interest. Typically, a small volume of local anesthetic is injected adjacent to the appropriate nerve or nerves to provide anesthesia in the desired distribution. For additional information about these blocks, please see Regional Anesthetic Techniques in the Chapter 5 Supplement on the Evolve Website.

Plexus Blocks

Pediatric providers are gaining experience with plexus blocks, including brachial plexus,²¹ lumbosacral, and paravertebral blocks. Intravenous regional anesthesia of the extremities, or Bier block, has been described in children, but widespread use has been limited by the theoretical risk of local anesthetic toxicity. Although rare in clinical practice, systemic local anesthetic toxicity may warrant observation in the critical care setting given risk for neurologic and cardiac compromise. Plexus blocks are discussed in greater detail in Regional Anesthetic Techniques in the Chapter 5 Supplement on the Evolve Website.

Neuraxial Blocks

Neuraxial blocks include spinal and epidural techniques. Anesthetic is administered by single injection, repeated injections, or continuous infusion through an indwelling catheter. Spinal (i.e., subarachnoid) block entails injection of anesthetic directly into cerebrospinal fluid, and is performed in pediatric practice primarily in infants at high risk of apnea following general anesthesia. Epidural (i.e., peridural) block entails injection of anesthetic into the potential epidural space between the ligamentum flavum and dura mater surrounding the spinal cord, and is considerably more common in pediatric practice.

Epidural block in children is most commonly performed as a caudal block, a variant of epidural block in which the epidural space is accessed through the sacral hiatus over the posterior aspect of the lower sacrum. Caudal block is most commonly performed as a single injection, providing reliable analgesia below the umbilicus in patients weighing 30 kg or less. The technique is straightforward, success rate is high, and complication rate is low. Specific agents for caudal block are discussed in greater detail in the Chapter 5 Supplement on the Evolve Website.

Excellent analgesia may be provided by repeated injection or continuous infusion of anesthetic through indwelling epidural catheters. Epidural catheters can be inserted caudally and threaded to the desired vertebral level, particularly in infants and young children. Epidural catheters can also be placed directly at the desired vertebral level. As with other invasive access, skin preparation with chlorhexidine rather than iodine confers a lower risk of subsequent epidural catheter colonization. Many combinations of local anesthetic, opioid, and adjuvant agents are commonly used for epidural administration in the United States (Table 5-6). Placement of epidural catheters and selection of agents for epidural injection or infusion are discussed in greater detail in the Chapter 5 Supplement on the Evolve Website.

Table 5-6 Agents for Epidural Infusion

Local Anesthetic*	Opioid/Adjuvant	Infusion Rates
Bupivacaine 0.0625-0.1% (maximum dose 0.4 mg/kg per h)	Fentanyl 0.5-1 mcg/kg per h (adult dose 50-100 mcg/h)	Thoracic typically 0.2-0.3 mL/kg per h (maximum 5-10 mL/h)
-OR-	-OR-
Levobupivacaine 0.0625-0.1% (maximum dose 0.4 mg/kg per h)	Hydromorphone 2-4 mcg/kg per h (adult dose 150-300 mcg/h)	Lumbar typically 0.3-0.4 mL/kg per h (maximum 10-15 mL/h)
-OR-	-OR-
Lidocaine 0.1-0.5% (maximum dose 3 mg/kg per h)	Morphine 3-6 mcg/kg per h (adult dose 250-500 mcg/h)	Caudal typically 0.4-0.5 mL/kg per h (maximum 15-20 mL/h)
-OR-	-AND/OR-
Ropivacaine 0.1-0.2% (maximum dose 0.5 mg/kg per h)	Clonidine 0.1-0.5 mcg/kg per h (adult dose 25-50 mcg/h)

Nurses should assess patients receiving epidural infusion frequently and regularly, monitoring adequacy of analgesia, degree of motor and sensory block, level of sedation, and presence of respiratory depression and other side effects. Patients receiving epidural opioid should be placed on continuous pulse oximetry, at least on initiation of epidural infusion and with any significant increase in regimen. Continuous cardiorespiratory monitoring may be considered for opioid-naive neonates and young infants. Patients receiving a more hydrophilic opioid, such as hydromorphone or morphine, may need more intensive monitoring. Instruction of patients, families, and caregivers regarding epidural infusion is essential.

Systemic sedatives

Sedation comprises a continuum ranging from mild anxiolysis to general anesthesia. Definitions of stages of sedation along this continuum are imprecise, particularly in children. Light sedation, or anxiolysis, is less helpful in children, given their often vigorous response to interventions. Moderate (formerly conscious) sedation is commonly preferred for increased depth of sedation with preservation of airway reflexes and spontaneous ventilation. Even moderate sedation, however, may be inadequate for many pediatric patients, and its usefulness in children has been questioned. Deep sedation produces greater depression of consciousness and diminished response to stimuli, and it may be required for invasive procedures. Deep sedation can also obtund airway reflexes, compromise ventilation, and impair cardiovascular function, so it requires continuous and close monitoring of cardiorespiratory status.

Because of the variability of individual responses, particularly in children, administration of systemic sedatives with intent to provide light or moderate sedation can rapidly and unexpectedly induce deep sedation or general anesthesia. All sedation depresses level of consciousness and increases risk of airway obstruction, respiratory depression, aspiration, and cardiovascular depression; any of these complications can produce significant morbidity and potential mortality. Because children are particularly prone to such complications, nurses caring for children receiving systemic sedatives must be extremely vigilant.¹^–³ ^,16 ^,17

Sedative-Hypnotic Agents

Systemic sedatives produce a wide range of physiologic effects. Knowledge of the agents being administered is essential for optimal efficacy and greatest patient safety. Nurses must be aware of expected clinical effect, usual time of onset, likely duration, and potential side effects of each agent. Medications ordered on an “as needed” basis are effective only when given appropriately in response to ongoing and recurring patient assessment. If a drug ordered on an “as needed” (PRN) basis is required frequently, the healthcare team should consider a change to scheduled administration and other interventions to improve patient comfort. Intramuscular injection is painful and should be avoided if possible, except perhaps in the setting of difficult intravenous access. Most systemic sedatives lack analgesic efficacy and should not be used primarily for analgesia. Many sedative-hypnotic agents are used in children; selection is determined by anticipated depth and duration of sedation desired, risk of potential side effects, and available routes of administration (Table 5-7).

Table 5-7 Sedative-Hypnotic Agents

Drug	Indication	Dose
Chloral hydrate	Procedural sedation	25-100 mg/kg PO/PR (maximum 2 g)
Pentobarbital	Procedural sedation	1-2 mg/kg IV (adult dose 50-100 mg) initial dose;
	Procedural sedation	0.25-0.5 mg/kg IV (adult dose 25-50 mg) q5-10 min
	Ongoing sedation	1-2 mg/kg IV (adult dose 50-100 mg) q1-2 h
	Infusion	1-2 mg/kg per h IV (adult dose 50-100 mg/h)
Midazolam	Premedication	0.25-0.5 mg/kg PO/PR (maximum 20 mg)
	Premedication	0.2-0.4 mg/kg SL/nasally (maximum 10 mg)
	Procedural sedation	0.05-0.1 mg/kg IV (adult dose 5 mg) initial dose;
	Procedural sedation	0.025-0.05 mg/kg IV (adult dose 2 mg) q5-10 min
	Ongoing sedation	0.05-0.1 mg/kg IV (adult dose 2-5 mg) q1-2 h
	Infusion	0.05-0.1 mg/kg per h IV (adult dose 2-5 mg/h)
Ketamine	Procedural sedation	4-10 mg/kg PO (adult dose 300-500 mg)
		3-4 mg/kg IM (150-300 mg)
		0.5-1 mg/kg IV (adult dose 50-100 mg)
	Ongoing sedation	0.5-1 mg/kg IV (adult dose 50-100 mg) q1-2 h
Propofol	Procedural sedation	0.5-2 mg/kg IV (adult dose 50-100 mg) initial dose;
	Procedural sedation	0.5 mg/kg IV (adult dose 25-50 mg) q5-10 min
	Infusion	50-150 mcg/kg per min IV
Dexmedetomidine	Premedication	1-2 mcg/kg nasally
	Procedural sedation	1-2 mcg/kg IV over 10 min
	Infusion	0.2-1 mcg/kg per h IV

Recommended doses are for initial administration: titration to clinical effect is required. Appropriate analgesia should be provided in settings entailing significant pain.

IM, Intramuscular; IV, intravenous; PO, by mouth; PR, by rectum; q, every; SL, sublingual.

Many systemic sedatives do not have maximum effective doses. Recommended doses are for initial administration in agent-naive patients. Titration to clinical effect is required, and higher doses may be necessary. Increasing dose requirement, also known as tolerance or tachyphylaxis, is often observed with ongoing administration. Systemic sedative therapy longer than 7 to 10 days can result in physical dependence, requiring weaning before discontinuation to avoid withdrawal. Tolerance and dependence are separate phenomena. Addiction, a formal psychopathologic diagnosis of volitional drug-seeking behavior, rarely develops in children receiving appropriately dosed systemic sedatives, and it is not a valid reason to withhold therapy.

Chloral Hydrate

Chloral hydrate is a sedative-hypnotic agent without specific analgesic efficacy. Rapidly metabolized in the liver to trichloroethanol, chloral hydrate induces a state of intoxication likely through a combination of gamma-aminobutyric acid (GABA) agonism and N-methyl-d-aspartate (NMDA) antagonism. Available in liquid and suppository forms, chloral hydrate has been widely used for sedation in infants and children, primarily because of its low risk of serious complications.

Chloral hydrate has hepatotoxic metabolites and a structural similarity to several known carcinogens, which has prompted concern. Continued administration has been associated with increased risk of malignancy in rodents. No similar observation has been made in humans despite decades of widespread use. Disadvantages of chloral hydrate include pungent preparations, slow onset of action, prolonged recovery, lack of a reversal agent, and significant rates of inadequate sedation and paradoxical agitation. Risk of respiratory and hemodynamic depression with higher doses warrants continuous cardiorespiratory monitoring.

Chloral hydrate remains a popular systemic sedative for nonpainful pediatric procedures such as computed tomography scanning and magnetic resonance imaging. It is not indicated for repeated or continued administration. Because chloral hydrate lacks specific analgesic efficacy, appropriate analgesia should be provided in settings entailing significant pain.

Barbiturates

Barbiturates are sedative-hypnotic agents without specific analgesic efficacy. Barbiturate mechanism of action likely derives from stimulation of GABA-ergic inhibitory pathways in the central nervous system. All barbiturates produce dose-dependent respiratory and cardiovascular depression in addition to sedation. Because barbiturates lack analgesic properties, appropriate analgesia should be provided in settings entailing significant pain.

The intermediate-acting barbiturate pentobarbital is a useful agent for pediatric sedation, particularly for pain-free radiologic studies, or for rescue sedation when other agents prove inadequate. Pentobarbital lends itself well to titrated intravenous administration and can be given orally, rectally, or intramuscularly at similar doses. Larger doses may be required in patients with significant barbiturate tolerance. Continuous infusion may be useful if repeated dosing becomes necessary or if ongoing sedation is anticipated. Side effects of pentobarbital infusion, including respiratory and cardiovascular depression are common, requiring meticulous hemodynamic monitoring in critical care settings. Children may demonstrate agitation during recovery from pentobarbital.

Benzodiazepines

Benzodiazepines, among the most widely used systemic sedatives in critical care, are sedative-hypnotic agents without specific analgesic efficacy. Unlike other systemic sedatives, benzodiazepines also have specific anxiolytic and amnestic effects. Acting on the benzodiazepine receptor of the GABA receptor complex, benzodiazepines induce sedation, reduce anxiety, and prevent recall. The principal significant adverse effect of benzodiazepines is respiratory depression; risk increases with higher or repetitive doses, or with concomitant administration of other agents. Because benzodiazepines lack analgesic efficacy, appropriate analgesia should be provided in settings entailing significant pain.

Flumazenil, a specific benzodiazepine receptor antagonist, can provide rapid reversal of benzodiazepine effects. Flumazenil is a proconvulsant and should be used cautiously in patients at risk of seizure.

Given its rapid onset and short duration of action, midazolam is widely used in pediatric practice. Oral, rectal, and nasal administration are commonly used for perioperative and procedural sedation. Currently available preparations often have a bitter taste and sting the nasal mucosa, and children may find oral or nasal administration unpleasant. Intravenous midazolam produces rapid onset of sedation, anxiolysis, and amnesia, and is well suited to incremental titration or continuous infusion. Larger doses may be required in patients with significant benzodiazepine tolerance.

Many other benzodiazepines are available, although relatively few are commonly used in children. Lorazepam has a longer time of onset than midazolam, and it is less likely to induce acute respiratory depression. Lorazepam also has a longer duration of action than midazolam and may be useful when longer-term sedation is desired. Lorazepam is also widely used as an acute anticonvulsant. Diazepam has even slower time of onset and longer duration of action, and it can be useful for maintenance therapy in patients with significant benzodiazepine tolerance or when ongoing prolonged sedation is desired.³⁴ Commercial preparations of lorazepam and diazepam contain propylene glycol as a solvent and benzyl alcohol as a preservative. Higher or repetitive doses or continuous infusion should be administered with caution to neonates and other patients susceptible to benzyl alcohol toxicity. Although significant propylene glycol accumulation has been documented in critically ill children receiving lorazepam infusion, other laboratory abnormalities were not noted. Peripheral intravenous administration of diazepam can cause significant discomfort and chemical phlebitis; intramuscular administration is not recommended.

Ketamine

Ketamine is a sedative-hypnotic agent similar to the now illicit drug phencyclidine. Unlike other systemic sedatives, ketamine is a potent dissociative analgesic, producing in lower doses a state in which pain is felt but not perceived as unpleasant. Ketamine is an NMDA receptor antagonist with weak agonist activity at opioid receptors and many other sites. Ketamine produces dose-dependent analgesia and sedation, inducing general anesthesia at higher doses; amnesia is variable. As with other phencyclidine derivatives, hallucinations and delirium may occur, but may be less frequent and less severe in younger patients. Ketamine induces bronchodilation, but also potentially significant salivation. Ketamine promotes release of endogenous catecholamines; tachycardia and hypertension may be significant. Although ketamine increases pulmonary arterial pressure, a concomitant increase in inotropy (strength of myocardial contraction) generally preserves cardiovascular function. Ketamine increases intracranial pressure and is a proconvulsant, so it should be used cautiously in patients with intracranial pathology or seizures.

Ketamine is most commonly administered intravenously to induce general anesthesia in medically fragile infants and children, and intramuscularly in patients who are unable to cooperate or who have no reliable intravenous access. Ketamine is used as an analgesic for children with burns ⁴⁴ or receiving palliative care¹³ and when other analgesics prove inadequate. PCA with ketamine has been described.⁶² Ketamine is widely used for procedural sedation in children and has become particularly popular in pediatric emergency departments given its favorable safety profile. Continuous infusion may be useful if repeated dosing becomes necessary or if a need for ongoing sedation is anticipated. Emergence may be prolonged after oral administration, particularly with a higher dose, and emergence delirium is common. Although an anticholinergic agent such as atropine or glycopyrrolate can be given to prevent excessive salivation, the effectiveness of this practice has been questioned, as has concomitant administration of benzodiazepines to decrease the likelihood of hallucinations and delirium.²⁸

Propofol

Propofol is a sedative-hypnotic agent without specific analgesic effect; it is commonly used for induction and maintenance of sedation and anesthesia. Chemically unrelated to other systemic sedatives, its mechanisms of action are unknown, although propofol likely has significant GABA agonism. Propofol is available only for intravenous administration. It is supplied in a lipid emulsion with an alkaline pH and may cause significant pain on injection. Propofol has considerable antiemetic efficacy,²³ and like ketamine it promotes bronchodilation. Propofol has an extremely rapid onset of action, and with relatively prompt hepatic conjugation and renal excretion it allows for rapid recovery after intermittent dosing or brief infusion. Propofol is also highly lipophilic, leading to significant tissue accumulation and potentially prolonged emergence after repeated administration or prolonged infusion. Because propofol lacks analgesic efficacy, appropriate analgesia should be provided for significant pain.

Prolonged propofol infusion is associated with a rare but often fatal syndrome of metabolic acidosis and cardiovascular failure. Current recommendations suggest propofol infusion in children not exceed 48 hours, although death from apparent propofol infusion syndrome has been reported with shorter duration or with reexposure to the drug. The etiology of this life-threatening reaction to propofol infusion in some patients is unknown, although impairment of mitochondrial oxidative phosphorylation and altered lipid metabolism have been suggested.²⁶

Propofol induces dose-dependent sedation, loss of airway reflexes, hypoventilation, apnea, and cardiovascular depression. Higher doses of propofol induce general anesthesia. Although there has been considerable concern over the safety of propofol administration by nonanesthesiologists,³⁹ current evidence suggests that such use is safe under controlled circumstances.¹⁸ Propofol has been safely and successfully used for pediatric procedural sedation in numerous settings, including the pediatric critical care unit, burn unit, radiology suite, emergency department, ambulatory procedure center, and dental clinic. Although such success is impressive, patient safety was protected by the restriction of propofol use to appropriately trained personnel working in the context of a dedicated sedation team, following carefully designed protocols and adhering to appropriate standards for patient monitoring and management. Propofol infusion may be used in the critical care setting during weaning from mechanical ventilation or for rescue sedation when other agents prove inadequate.⁵⁹

Dexmedetomidine

Dexmedetomidine is a newer sedative-hypnotic agent that is becoming popular in pediatric practice,¹⁸ although the drug is formally approved only for use in adults. As an alpha (α)-2 adrenergic agonist similar to clonidine, dexmedetomidine induces potentially profound sedation with little associated respiratory depression. Dexmedetomidine can cause significant bradycardia and hypotension, particularly at high dose or with rapid administration. Heart rate and blood pressure during anesthesia with dexmedetomidine infusion tend to be lower and recovery more prolonged than during anesthesia with propofol infusion.³⁰

Dexmedetomidine is marketed for intravenous use, although the commercially available form can be given nasally, and subcutaneous administration in children has been described.⁵⁷ Nasal dexmedetomidine lacks unpleasant taste or odor, it provides preoperative sedation comparable to⁵⁶ or greater than⁶⁴ oral midazolam, and it may enhance postoperative analgesia.⁵³

Dexmedetomidine is often used for pediatric procedural and perioperative sedation ⁴⁵ and for weaning mechanical ventilation.¹¹ ^,20 Dexmedetomidine is also used to treat postoperative shivering in children⁸ and to facilitate weaning from opioids⁵⁸ and benzodiazepines. Although officially approved for use up to 24 hours, prolonged dexmedetomidine infusion for days or even weeks for sedation of critically ill infants and children,⁵¹ including pediatric cardiothoracic surgical patients,⁷ has been described. Dexmedetomidine provides little direct analgesia and is useful as a sole agent only when significant analgesia is not required.⁶ Appropriate analgesia should be provided when significant pain is present.⁴⁵

Procedural Sedation

Diagnostic and therapeutic procedures requiring sedation in children have increased dramatically in recent years. Although anesthesiologists provide care for many such interventions, procedural sedation for children is also administered by other healthcare providers, including those in the pediatric critical care setting.¹⁸ ^,38

The American Academy of Pediatrics has established guidelines for the monitoring and management of children undergoing procedural sedation,¹^–³ and different guidelines have been published by other organizations.¹⁶ This has created considerable debate, occasional confusion, and some inconsistency, but all guidelines share the common goal of fostering safe and efficient practice.

Supervision of pediatric procedural sedation by knowledgeable and competent personnel is mandatory. Many practice guidelines recommend that the provider performing the procedure (often referred to as the “operator”) not also supervise sedation. Guidelines by the American Academy of Pediatrics and American Society of Anesthesiologists stipulate that an appropriate provider be assigned specifically to supervise sedation of pediatric patients, with only intermittent additional duties during administration of light or moderate sedation and no additional duties while conducting deep sedation. Adherence to these guidelines has been shown to reduce complications.

Because of the small but real risk of serious adverse events associated with pediatric procedural sedation, equipment and medications for emergency resuscitation should be readily and rapidly available. Equipment and medications should be appropriate for the ages and sizes of children receiving care, and providers should be skilled in their use. Providers supervising pediatric procedural sedation should, at a minimum, be trained in basic pediatric life support, and training in pediatric advanced life support is recommended. Serious complications associated with pediatric procedural sedation may be avoided by adequate evaluation and preparation of patients prior to sedation, and by close monitoring and early detection of changes in patient status during and after administration of systemic sedatives. Evaluation and monitoring of pediatric patients undergoing procedural sedation is discussed in Procedural Sedation in the Chapter 5 Supplement on the Evolve Website.

To minimize the risk of aspiration of gastric contents, oral intake should be suspended before any elective procedure for which sedation is planned, as for any elective procedure entailing anesthesia (Table 5-8). If sedation must be provided despite recent oral intake, urgency of the intervention should be documented and systemic sedatives administered cautiously to minimize depression of airway reflexes and risk of aspiration. Agents such as metoclopramide, ranitidine, and sodium bicitrate may be considered to augment gastric motility, decrease gastric volume, and increase gastric pH. When appropriate fasting intervals cannot be observed and deep sedation is anticipated, airway protection with induction of anesthesia and rapid sequence intubation may be advisable.

Table 5-8 Recommended Fasting Intervals Before Elective Sedation or Anesthesia

Type of Intake*	Recommended Fasting Interval (h)
Clear liquids, including water, juice without pulp, carbonated beverages, clear tea, black coffee	2
Human breast milk	4
Nonhuman milk, infant formula, light meal without significant protein or fat content	6
Heavy meal with significant protein or fat content, including particularly fried foods or meat	8

* These recommendations apply regardless of patient age.

Adapted from American Society of Anesthesiologists Task Force on Preoperative Fasting: Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures: a report by the American Society of Anesthesiologists Task Force on Preoperative Fasting. Anesthesiology 90:896–905, 1999.

Neuromuscular blockade

Neuromuscular blockade, or muscle relaxation, entails pharmacologic inhibition of voluntary muscle movement. Description as paralysis should be avoided because of negative connotations for patients and families. Neuromuscular blockade has no effect on level of consciousness and provides neither analgesia nor sedation. Neuromuscular blockade should be used only when clinically essential,¹⁴ ^,29 and never in isolation. Neuromuscular blockade should never be used simply to keep patients from moving. Appropriate airway and ventilatory support are mandatory. Neuromuscular blockade may be used to facilitate endotracheal intubation, provide surgical relaxation, and allow mechanical ventilation. Prolonged neuromuscular blockade may be necessary in some settings, as after surgical airway reconstruction.²⁹

Normal neuromuscular function relies on the release of acetylcholine from motor nerve terminals at the neuromuscular junction (Fig. 5-5). Acetylcholine crosses the synaptic cleft between motor nerve and skeletal muscle fiber, transiently binding to and briefly opening nicotinic acetylcholine receptors on the myocyte motor end plate. The resultant transmembrane flow of ions, primarily sodium, potassium, and calcium depolarizes the surrounding muscle cell membrane, eventually causing myocyte contraction if an appropriate action potential is achieved. Acetylcholine is subsequently metabolized by acetylcholinesterase within the junctional folds.

Fig. 5-5 The neuromuscular junction. Diagram of the neuromuscular junction between motor nerve and skeletal muscle fiber. Neuromuscular blocking agents act on acetylcholine receptors at the motor end plate. Ach, acetylcholine; AChE, acetylcholinesterase; JF, junction fold; M, mitochondrion; V, vesicle.

Throughout infancy and early childhood, the neuromuscular junction matures physically and biochemically, the contractile properties of skeletal muscle change, and the amount of muscle in proportion to body weight increases. Age-related changes in volume of distribution, drug redistribution and clearance, and rate of metabolism also profoundly influence pharmacologic profiles of neuromuscular blocking agents. Pediatric patients exhibit wide variability in sensitivity to neuromuscular blockade, so the degree and duration of blockade in children may be unpredictable.

Neuromuscular Blocking Agents

Neuromuscular blockade is achieved through blockade of nicotinic acetylcholine receptors at the neuromuscular junction. Neuromuscular blocking agents are classified according to their mechanism of action as depolarizing or nondepolarizing agents (Table 5-9). Depolarizing agents activate nicotinic acetylcholine receptors, inducing myocyte depolarization. As long as they persist at the neuromuscular junction, they prevent any further myocyte depolarization, thereby maintaining muscle relaxation. Nondepolarizing agents compete directly with acetylcholine for binding sites on nicotinic acetylcholine receptors, preventing binding of acetylcholine without activating the receptor. Neuromuscular blockade persists as long as sufficient nondepolarizing agent remains to prevent acetylcholine receptor activation. Nondepolarizing agents are eliminated by a wide range of mechanisms. Younger patients, particularly infants, are generally relatively resistant to depolarizing agents but relatively sensitive to nondepolarizing agents.

Table 5-9 Neuromuscular Blocking Agents

Depolarizing Agent: Succinylcholine

The only depolarizing neuromuscular blocking agent available in the United States is succinylcholine. Succinylcholine mimics the action of acetylcholine at the neuromuscular junction and at cholinergic sites diffusely, inducing rapid muscle relaxation but also increasing vagal tone and potentially inducing transient bradycardia, particularly in infants and young children. Antimuscarinic agents such as atropine or glycopyrrolate are typically given before administration of succinylcholine to prevent bradycardia in susceptible patients.

Succinylcholine is the most rapid-acting of all currently available muscle relaxants, used when rapid onset of neuromuscular blockade is desired. Administration of succinylcholine may induce transient muscle fasciculations secondary to myocyte depolarization, less so in infants and young children, and in older patients may predispose to significant subsequent myalgias. Succinylcholine causes modest increases in intraocular and intracranial pressure, and it is often avoided in the setting of open globe injury or critical intracranial pathology. Increases in intraocular and intracranial pressure can be attenuated by pretreatment with a low-dose nondepolarizing agent. Succinylcholine is rapidly metabolized by plasma pseudocholinesterase; patients with pseudocholinesterase deficiency may demonstrate prolonged neuromuscular blockade up to several hours after even a single dose of succinylcholine.

Succinylcholine-induced myocyte depolarization causes efflux of intracellular potassium, increasing serum potassium in healthy patients by approximately 0.5 mEq/L. Such an increase may be poorly tolerated in patients with preexisting hyperkalemia. In some settings, the release of intracellular potassium following succinylcholine administration is excessive and can rapidly induce life-threatening hyperkalemia, even in patients with a previously normal serum potassium concentration. Risk is increased in several central nervous system and neuromuscular diseases, in addition to injuries associated with significant tissue destruction. Settings associated with increased risk of succinylcholine-induced hyperkalemia are discussed in Depolarizing Agents: Succinylcholine in the Chapter 5 Supplement on the Evolve Website.

Nondepolarizing Agents

Common nondepolarizing neuromuscular blocking agents are classified as either benzylisoquinolinium or aminosteroid compounds. Benzylisoquinolinium compounds, of which curare can be considered the historical prototype, generally include -urium in their generic nomenclature. Benzylisoquinolinium compounds tend to promote histamine release, potentially inducing urticaria, bronchospasm, and even hypotension, particularly with high dose or rapid administration. Aminosteroid compounds are structurally similar to glucocorticoids, and generally include -onium in their generic nomenclature. Some aminosteroid compounds have vagolytic effects potentially inducing tachycardia.

Mivacurium is a short-acting benzylisoquinolinium compound rapidly metabolized by plasma cholinesterase. Metabolism may be impaired in the setting of severe hepatic disease, but is independent of renal function. As with succinylcholine, patients with atypical pseudocholinesterase variants demonstrate impaired metabolism of mivacurium and will generally experience prolonged neuromuscular blockade following its administration. Histamine release may be significant, particularly with large dose or rapid administration.

Atracurium and its isomer cisatracurium are intermediate-acting benzylisoquinolinium compounds notable for elimination through Hofmann degradation; under physiologic conditions they degrade spontaneously, independent of hepatic or renal function. Atracurium and cisatracurium are frequently chosen for use in patients with significant hepatic or renal disease. Laudanosine, a hepatically excreted breakdown product of both compounds, is neurotoxic and can cause seizures, although clinical laudanosine toxicity has not been reported. Histamine release may be significant, particularly with large dose or rapid administration.

Doxacurium is a long-acting benzylisoquinolinium compound causing relatively little histamine release; it is a useful alternative to aminosteroid compounds for ongoing neuromuscular blockade.

Rocuronium is a short-acting aminosteroid compound with particularly rapid onset, and it is generally regarded as the most reasonable alternative to succinylcholine when the latter should be avoided. Elimination of rocuronium is primarily through hepatobiliary excretion of the parent compound; duration of action may be prolonged in patients with significant hepatic disease.

Vecuronium is an intermediate-acting aminosteroid compound similar in potency to pancuronium but with a shorter duration of action. Vecuronium has virtually no vagolytic effects and causes little change in hemodynamic parameters. Elimination of vecuronium is largely through hepatobiliary excretion of the parent compound, although renal excretion also occurs. Duration of action may be markedly prolonged in patients with significant hepatic disease, and modestly prolonged in patients with significant renal disease.

Pancuronium is a long-acting aminosteroid compound with significant vagolytic effects. Pancuronium is a popular choice in pediatric practice because it can induce tachycardia, helping to preserve cardiac output. Elimination of pancuronium is largely through renal excretion of the parent compound. Duration of action may be prolonged in patients with significant renal disease.

Neuromuscular blockade can be maintained with repeated dosing or continuous infusion of any agent.¹⁰ Repeated dosing typically requires 25% to 50% of the usual initial dose, whereas continuous infusion typically requires 25% to 50% of the usual initial dose per hour, depending on drug pharmacology and underlying patient disease. Whenever neuromuscular blockade is maintained through repeated dosing or continuous infusion, nurses should monitor the degree of neuromuscular blockade (see section, Neuromuscular Monitoring) to prevent unnecessary and excessive dosing.¹⁵ ^,49 Neuromuscular monitoring is discussed in greater detail in the Chapter 5 Supplement on the Evolve Website.

Reversal of Neuromuscular Blockade

Neuromuscular blockade induced by succinylcholine cannot be pharmacologically reversed. The return of neuromuscular function relies on metabolism of succinylcholine by pseudocholinesterase, and it may be prolonged in patients with atypical pseudocholinesterase variants. In contrast, neuromuscular blockade induced by nondepolarizing agents may be pharmacologically reversible.

Pharmacologic reversal of nondepolarizing neuromuscular blockade has traditionally been accomplished through administration of cholinesterase inhibitors, which are discussed in greater detail in the Chapter 5 Supplement on the Evolve Website. These agents inhibit metabolism of acetylcholine, increasing its concentration in the synaptic cleft and out-competing any remaining nondepolarizing agent. Currently available cholinesterase inhibitors are nonspecific, potentiating acetylcholine at the neuromuscular junction and at cholinergic sites throughout the body. An antimuscarinic agent such as atropine or glycopyrrolate is typically given before the cholinesterase inhibitor to prevent cholinergic side effects, particularly bradycardia.

Sugammadex is a recently developed gamma (γ)-cyclodextrin capable of binding an aminosteroid nondepolarizing agent. The sugammadex molecule encapsulates or traps the aminosteroid compound within a central pore, and the resultant complex is renally excreted.⁵⁵ Initial experience with sugammadex has been encouraging,⁴³ although pediatric experience is limited⁴⁷ and the drug is not yet approved for use in the United States. Preliminary data suggest that this agent may increase the safety of longer acting, nondepolarizing neuromuscular blockers.

Critical Illness Polyneuropathy and Myopathy

Prolonged muscle weakness after pharmacologic neuromuscular blockade in critically ill patients is common, affecting many adults requiring mechanical ventilation.⁶³ Although a similar syndrome of prolonged muscle weakness following critical illness in children is increasingly recognized, particularly after pharmacologic neuromuscular blockade,³³ the condition is thought to be much less common in the pediatric setting, reportedly affecting approximately 1% of critically ill children. The condition has recently been termed critical illness polyneuropathy and myopathy, and it is increasingly recognized in pediatric patients.⁶³

Critical illness, particularly sepsis, is associated with prolonged subsequent muscle weakness, as well as with immobility and muscle atrophy. Many drugs, particularly aminoglycoside antibiotics and high-dose steroids, are known to cause a predisposition to prolonged muscle weakness. Many other agents, including diuretics such as furosemide and sedatives such as benzodiazepines, may also contribute. Pharmacologic neuromuscular blockade is highly associated with subsequent prolonged muscle weakness, particularly after prolonged blockade, and the risk appears greater with aminosteroid compounds.¹⁰ Concomitant administration of multiple agents predisposing to prolonged muscle weakness likely heightens risk. The etiology of critical illness polyneuropathy and myopathy is likely multifactorial.

Critical illness polyneuropathy and myopathy can vary in clinical presentation from mild diffuse muscle weakness to profound flaccid quadriplegia with respiratory failure. The condition appears to be associated with neuromuscular pathology, including muscle atrophy with denervation and axonal neuropathy, even in the absence of significant inflammation. Clinical weakness may persist for months or years, with neurodiagnostic abnormalities lasting even longer.⁶¹ Pediatric patients generally seem to have a somewhat more favorable prognosis than do adults, although recovery is less likely in very young patients, particularly neonates and premature infants in whom neuromuscular development is still incomplete.

Critical illness polyneuropathy and myopathy is best treated through prevention, although the condition can develop despite all such efforts. All drugs, in particular agents predisposing the patient to prolonged muscle weakness, should be administered at appropriate doses and intervals, with monitoring of drug levels as necessary. Providers should avoid concomitant administration of multiple agents predisposing the patient to prolonged muscle weakness, in particular combinations of steroids, aminoglycoside antibiotics, and neuromuscular blocking agents. Risk appears to be greater with aminosteroid compounds, which are perhaps best avoided for prolonged administration or for concomitant administration with steroid or aminoglycoside.

Neuromuscular Monitoring

During repeated dosing or continuous infusion of any neuromuscular blocking agent, providers should consider neuromuscular monitoring to prevent unnecessary and excessive dosing.⁴⁹ Neuromuscular monitoring can be challenging in many patients,¹⁵ particularly small infants, and findings can be influenced by factors such as peripheral edema, level of hydration, electrolyte and acid-base balance, and hemodynamic status. Ideally, providers should evaluate response to “train-of-four” stimulation (i.e., response to provision of 4 pulses in sequence from a nerve stimulator)⁴⁹ at least once every 24 hours. If monitoring proves unreliable and patient safety permits, providers may consider daily discontinuation of neuromuscular blockade to assess for respiratory effort and spontaneous movement. Neuromuscular monitoring is reviewed in more detail in the Chapter 5 Supplement on the Evolve Website. Ongoing physical rehabilitation services should be provided to all patients with ongoing critical illness, particularly those receiving pharmacologic neuromuscular blockade.