Sedation and Analgesia in Critically Ill Children

Transcription

1 AACN Advanced Critical Care Volume 23, Number 4, pp , AACN Sedation and Analgesia in Critically Ill Children Peter N. Johnson, PharmD, BCPS Jamie L. Miller, PharmD, BCPS Tracy M. Hagemann, PharmD, FCCP, FPPAG ABSTRACT The interplay of pain, discomfort, and fear can cause agitation in critically ill children. Therefore, sedation and analgesia are essential components in the intensive care unit setting and are best managed with a multidisciplinary team approach. No one standard approach exists to assess and manage pain and anxiety. Many tools are available for the assessment of pain and sedation, but each tool has its advantages and disadvantages. Clinicians should consider adopting a validated tool for routine continuous assessment. Multiple pharmacological therapies are available to manage pain, anxiety, fear, and agitation. Dosing of these agents can be influenced by age-related pharmacokinetic and pharmacodynamic changes. Agents should be selected on the basis of the child s disease state, desired level of sedation, and cardiac and respiratory status. Keywords: analgesia, children, dexmedetomidine, opioids, pediatric intensive care, sedation Management of pain and sedation in children is challenging, as pain, fear, and anxiety are intertwined. The pediatric population is heterogeneous; therefore, a onesize-fits-all approach for assessment and treatment is not practical. The cause of acute pain can be a result of diagnostic and therapeutic procedures, suctioning, burns, or surgery. 1 Separation from caregivers, fear of machines and procedures, disruptions in the sleep cycle, and noises are common reasons for anxiety in children that may require sedation. 2 Appropriate assessment and treatment of pain and sedation are important because inadequate management can be associated with adverse physiological changes (eg, delayed wound healing, hyperglycemia), especially in neonates. Clinicians should take care when selecting appropriate agents and dosing. Analgesic and sedative agents have a narrow therapeutic window and are among the primary classes implicated in medication errors in children. Complications Associated With Pain and Agitation Pain transmission involves several mediators, including bradykinin, prostaglandin, histamine, substance P, and serotonin. 3 The pathways for pain perception do not differ between children and adults; however, neonatal pain management differs on the basis of several neurophysiological Peter N. Johnson is Associate Professor, Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, 1110 N Stonewall Ave, CPB 206, Oklahoma City, OK (peter-johnson@ouhsc.edu). Jamie L. Miller is Assistant Professor, Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City. Tracy M. Hagemann is Associate Professor, Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City. Conflict of interest: Dr Hagemann is a consultant for Lexicomp, Inc, and serves on the Pediatric Advisory Board for Ofirmev (Cadence Pharmaceuticals); Drs Johnson and Miller have no disclosures. DOI: /NCI.0b013e31826b4dea 415

2 JOHNSON ET AL AACN factors, which is specifically true for premature neonates at less than 32 weeks gestation. The descending pain pathway is not fully developed until 30 to 32 weeks gestation, with complete maturation occurring at 37 weeks gestation. 1 As a result, premature neonates may have a lower threshold for painful stimuli. Early experience of pain and the initiation of pain responses can negatively affect long-term changes in pain perception. 4 Pain, discomfort, and fear contribute to the development of agitation, which may be related to the underlying illness or invasive procedures. Sedative agents can be used in conjunction with analgesic agents to minimize these complications. Children being treated with mechanical ventilation may require sedation to prevent asynchronous ventilation, improve oxygenation, and prevent inadvertent extubation. Agitation may also lead to selfinjury, including removal of catheters or sutures, and/or increased physical activity, leading to further harm. In addition to physical harm, inadequate anxiolysis and analgesia may lead to mental and emotional complications. Playfor and colleagues 5 surveyed 38 children following pediatric intensive care unit (PICU) admission and found that 29% remembered being in pain, 21% remembered being scared, and 16% had sleeping difficulties. In this study, most of the children were treated with sedative and analgesic agents, at doses deemed appropriate by their clinicians. Agitation and pain are interrelated such that inadequate sedation or analgesia could cause psychological complications beyond the intensive care unit (ICU) stay. A causal link between inadequate analgesia in the PICU and the development of posttraumatic stress disorder has been proposed. 6 Assessment of Pain and Sedation Pain is recognized as the fifth vital sign. 7, 8 The Joint Commission mandates that institutions execute uniform pain assessment using validated tools ( Table 1 ) In the PICU Table 1: Summary of Pain Measurement Tools in Children a Name Behavioral/ physiological scales (eg, FLACC) Graphic scale (eg, color analog scale) FACES Scale (eg, Wong-Baker) Recommended Age Range or Groups General Description 2 mo to 7 y Evaluates age-appropriate behavioral and physiological factors; useful for nonverbal children but nonspecific 4 y and older Used for preschool children; limited utility in subpopulations (eg, cognitive impairment, color-blind children) 3 y and older Simple scoring tool used for pain discrimination; used for very young preschool children; children may confuse their current emotional state with corresponding pain rating Visual analog scale 8 y and older Straightforward, 1-dimensional scoring tool for older children; limited utility in subpopulations (eg, cognitive impairment) Numerical Rating Scale NCCPC-PV 7 y and older Simple scoring tool that can be given verbally or as a written instrument; application of scores to specific treatment decisions is inappropriate Cognitively impaired children Validated tool for pain assessment in children with cognitive impairment; assessment is time consuming (eg, 10 min) MAPS revised 0 mo to 3 y Validated tool for critically ill, nonverbal infants and children; incorporates vital sign changes into assessment Abbreviations: FLACC, Face Legs Arms Cry Consolability Scale; MAPS, Multidimensional Assessment of Pain Scale; NCCPC-PV, Noncommunicating Children s Pain Checklist Postoperative Version. a Data from references 9 to 16. Useful for Nonverbal Patients Yes No No No No Yes Yes 416

3 VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 PAIN AND SEDATION IN CHILDREN setting, children may not be able to communicate their pain as a result of cognitive impairment or invasive and noninvasive ventilation strategies. As a result, some pain assessment tools that are used for verbal patients would not be appropriate in this population (eg, FACES Scale, visual analog scale, and Numerical Rating Scale) ( Table 1 ). Other assessment scales (eg, Multidimensional Assessment of Pain Scale and Faces Legs Arms Cry Consolability Scale) may be better suited for these children because they use physiological and/or behavioral measurements, including vital signs, body posture and movements, and facial expressions to indicate the level of pain that a patient may experience. Sedation-scoring tools should be used concomitantly with routine pain assessments. Twite et al 17 surveyed 39 critical care fellowship directors; most respondents used a scoring tool to evaluate sedation, with the most common being the COMFORT Scale. However, some reported using a scoring tool that is not validated in children (eg, Ramsay score, sedation analgesia score) or not specifically designed to evaluate sedation (eg, Faces Legs Arms Cry Consolability Scale score, visual analog scale score). A few tools (eg, COMFORT and COMFORT-Behavioral Scale) were developed to assess both pain and sedation, whereas most were developed to assess only sedation. A pain scale (eg, Multidimensional Assessment of Pain Scale) should be used in this situation to ensure proper assessment. Table 2 provides an overview of sedation tools for children; some have been validated, but others have not, even though they have been used successfully at individual institutions. No single scoring tool is more effective than another, although some may be limited in their utility in paralyzed children. These tools should be used routinely on initiation of therapy, continuously with maintenance therapy (eg, each shift), and following dose adjustments. Several tools have been developed to assess withdrawal symptoms following iatrogenic exposure to sedative agents and opioids. Examples of scoring tools include the Withdrawal Assessment Tool (WAT-1) and the Lipsitz Tool. 25, 26 These scoring tools should not be used to assess pain or sedation but should be used in all children who are at risk of withdrawal from iatrogenic opioid and sedative exposure. No one withdrawal assessment tool is agreed on by all clinicians. A complete description of the assessment of withdrawal is beyond the scope of this article. Pharmacokinetic and Pharmacodynamic Considerations Clinicians should consider age-related pharmacodynamic and pharmacokinetic changes when selecting an analgesic or sedative agent and determining its dose. Significant changes occur in the absorption, distribution, metabolism, and excretion (ADME) within the first years of life. For example, topical absorption of medications is enhanced in neonates and infants because of their thinner, more hydrated stratum corneum and increased skin surface area to body weight ratio, 27, 28 which may result in excessive exposure of topical medications. 29 As a result of unpredictable absorption, transdermal fentanyl should be avoided in children younger than 2 years. 30 Neonates and infants have a diminished capacity to metabolize medications through the liver, including the cytochrome P450 (CYP) and glucuronidation enzymatic reactions. For example, several studies have noted diminished efficacy with morphine in preterm infants as a result of underdeveloped liver function. Morphine is metabolized to an active metabolite (ie, morphine-6-glucuronide) by glucuronidation. Carbajal and colleagues 31 suggest that concentrations of morphine-6-glucuronide are decreased in this population, with greater production of morphine-3-glucuronide. Elevated concentrations of morphine-3-glucuronide may antagonize the effects of morphine and morphine-6-glucuronide. These metabolic pathways usually mature by about 6 months of age. 34 Glomerular filtration rate and tubular secretion are diminished in neonates. 34 Medications or active metabolites that are renally eliminated may require adjusted dosing intervals or dose reductions to prevent excessive accumulation. This principle also applies for patients with renal insufficiency or failure. For example, both morphine-3-glucuronide and morphine-6- glucuronide are renally excreted, and neurotoxic effects (eg, myoclonus) could occur in neonates or patients with renal insufficiency. 35 Obese children may have additional ADME alterations. Approximately 16.9% of children aged 2 to 19 years in were classified as obese. 36 A paucity of pharmacokinetic data in obese children poses a unique challenge for this population. Alterations, including a 417

4 JOHNSON ET AL AACN Table 2: Summary of Validated Sedation-Scoring Tools in Children a Name Seattle Children s Hospital PICU Comfort Score State Behavioral Scale Penn State Children s Sedation Algorithm COMFORT- Behavioral Scale Hartwig Sedation Scale University of Michigan Sedation Scale Children s Hospital of Wisconsin Sedation Scale a Data from references 18 to 24. Recommended Age Range or Groups General Description Validated Patients younger than 21 y 6 wk to 6 y of age Children younger than 18 y Children younger than 18 y 1 mo to 5 y of age 4 mo to 5 y of age Children younger than 18 y Seven-item scoring tool (ie, 0-6) derived from the adult Ramsay sedation tool Six-dimension scoring tool (ie, 3 to 2) derived from state/ behavioral dimensions and numeric rating scale Six-item scoring tool (ie, level 1-6) that defines target goals of sedation related to the amount of ventilator support required Seven-domain scoring tool that assesses consciousness, agitation, respiratory response, crying, physical movement, muscular tone, facial tone; useful in patients treated with mechanical ventilation and not treated with mechanical ventilation Five-domain scoring tool that assesses motor response, mimic ability, eye-opening, ventilation toleration, reaction to painful measures Five-point scale (ie, 0 wide awake to 4 unarousable ) Seven-domain scoring tool (ie, inadequate sedation to anesthesia ) derived from the adult Ramsay sedation tool Used to Assess Pain Used in Ventilated Patients Used in Paralyzed Patients No No Yes Yes Yes No Yes No No Yes Yes Yes Yes Yes Yes No No Yes Yes No No No No No No No No No higher volume of distribution for lipophilic medications and increased glomerular filtration rate, have been noted in obese adults. 37 The higher volume of distribution suggests that larger initial loading doses of lipophilic agents (eg, fentanyl) may be needed to achieve a desired level of analgesia. 38 Because adipose tissue serves as a depot for lipophilic medications, obese patients may exhibit a longer elimination half-life with these medications (eg, fentanyl, sufentanil). 38 Clinicians may use lower maintenance doses and titrate to desired effect to avoid oversedation. Because of the limited studies in obese children, implementing 418

5 VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 PAIN AND SEDATION IN CHILDREN a specific dosing strategy for children weighing more than 40 kg may be practical. For example, for single-dose medications, use pediatric dosing (eg, mcg/kg) unless the patient s dose exceeds the recommended adult dose for the indication. In contrast, weight-based dosing (eg, mcg/kg per hour) should be avoided in these children when prescribing continuous infusions (CIs). Instead, we recommend that clinicians use adult dosing strategies (eg, mcg per hour) for CIs to avoid the possibility of oversedation in this population. 37 Underweight patients may also have ADME alterations. Heiskanen and colleagues 39 evaluated the transdermal absorption of fentanyl in cachectic adult patients with cancer. Significantly lower concentrations of fentanyl were noted at 48 and 72 hours in cachectic patients. The authors attributed this impaired absorption of fentanyl to alterations in skin permeability associated with cachexia and not to differences in amount of adipose tissue. The clinical implication is that transdermal delivery may not be the best route of administration in underweight patients, but this implication has not been investigated in children. In addition, the effects of underweight status on other routes of administration in both adults and children are unclear. Acute Pain Management Misconceptions about pain recognition and management in children have resulted in suboptimal treatment outcomes. 40 Suboptimal or avoidance of treatment can result in behavioral and biochemical consequences, manifesting as delayed healing and added stress for patients and caregivers The World Health Organization s analgesic ladder classifies pain in 3 categories, mild, moderate, and severe, 44 which can be extrapolated to acute pain or chronic pain. Nonopioid analgesic agents are the mainstay of mild pain treatment. Opioids can be combined with nonopioids for mild to moderate pain. Severe pain requires initiation of scheduled opioids. Intermittent doses can be useful for breakthrough pain, although this strategy may result in fluctuations of plasma concentrations. As a result, patients with severe postoperative pain or those who are being treated with mechanical ventilation should receive patient-controlled analgesia (PCA) or opioid CI, respectively. Nonopioid Analgesic Agents Nonopioid analgesic agents include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and sucrose. Table 3 provides an overview of these agents. Acetaminophen agents and NSAIDs have demonstrated opioidsparing effects. 35, 45 These agents may have limited benefit in moderate to severe pain because of a ceiling effect with dosing, in which risk for toxicity exceeds benefits of efficacy. Adverse effects limiting dosing are specific for the individual agents; however, unlike opioid analgesic agents, these agents are not associated with respiratory depression, constipation, urinary retention, or drug withdrawal. Acetaminophen Acetaminophen is a centrally acting cyclooxygenase-3 inhibitor that, unlike NSAIDs, does not possess any anti-inflammatory activity. 46 It is the most widely used nonopioid analgesic agent and is available in various formulations, including oral tablets and liquid dosage forms, an intravenous (IV) solution, and suppositories. When prescribing oral acetaminophen and/or acetaminophen-containing products (eg hydrocodone/acetaminophen), clinicians should ensure that patients younger than 12 years receive no more than 75 mg/kg per day or 2.6 g per day of acetaminophen. For children older than 12 years, acetaminophen should be limited to less than 3 g per day, per recent changes in labeling by McNeil, the makers of Extra Strength Tylenol. 35 Particular attention should be paid to maximum doses in obese children, as their calculated dose could easily exceed these established limits. Rectal acetaminophen is as an alternative for children who may be unable to tolerate enteral administration. Absorption is slower and erratic. Peak serum concentrations occur at 2 to 4 hours. 47 Most references recommend rectal dosing equivalent to oral dosing. 35 However, a loading dose of 20 to 30 mg/kg per dose is recommended to achieve a quicker response. Higher doses for postoperative pain have been evaluated, but the optimal dose and frequency remain to be determined. 47 Providing an accurate acetaminophen dose is difficult with suppositories because they come in fixed dosage forms (eg, 80, 120, 325, and 650 mg). 35 Kim et al 48 evaluated the accuracy of alteration of rectal suppositories by 10 anesthesiologists, using the same technique they would use in practice. The authors demonstrated a wide range of variability, with the mean dose ranging from 17% less than expected to 30% more than expected. Limiting use to unaltered dosages 419

6 JOHNSON ET AL AACN Table 3: Nonopioid Analgesic Agents a Medication Route Pharmacokinetics Dose Acetaminophen PO Onset: 30 min 12 years old: mg/kg per dose every 4-6 h (max dose do not exceed 5 doses per day, 75 mg/kg/d, or 2.6 g/d) t½: 3-7 h (children to neonates) 12 years old: mg every 4-6 h or 1 g every 8 h (max dose 3 g/d) Acetaminophen RC Onset: Unknown 12 years old: mg/kg per dose every 4-6 h t½: Unknown 12 years old: mg every 4-6 h or 1 g every 6-8 h (max dose 4 g/d) Acetaminophen IV Onset: 15 min after a 15-min infusion t½: 3-7 h (children to neonates) 2-12 years old or weight 50 kg: 15 mg/kg per dose every 6 h or 12.5 mg/kg per dose every 4 h (max single dose 750 mg; max dose per day 75 mg/kg/d or 3.75 g) Weight 50 kg: 1 g every 6 h or 650 mg every 4 h (max single dose 1 g; max dose per day 4 g) Ibuprofen PO Onset: 1-2 h 12 years old: 4-10 mg/kg per dose every 6-8 h (max dose 40 mg/kg/d) t½: 1-2 h (children) 12 years old: mg every 4-6 h (max dose 2.4 g/d) Ketorolac IV/IM Onset: 30 min FDA indication for 2-16 years old or weight 50 kg: t½: 3-6 h (children) IM: 1 mg/kg per dose (max dose 30 mg) IV: 0.5 mg/kg per dose (max dose 15 mg); 0.5 mg/kg per dose IV every 6 h for no more than 5 d 16 years old or weight 50 kg: 30 mg IV every 6 h (120 mg/d) for no more than 5 d Choline magnesium PO Onset: NA Based on total salicylate content: trisalicylate t½: 2-3 h (adults) Children: mg/kg/d divided 3 or 4 times per day Sucrose PO Onset: 2 min 2 ml of 24% solution 2 min prior to procedure with pacifier t½: Unknown Abbreviations: IM, intramuscular; IV, intravenous; max, maximum; NA, not available; PO, oral; RC, rectal; t½, half-life;. a Data from Lexi-Comp Online, Pediatric Lexi-Drugs Online 35 and Ofirmev. 45 is prudent to ensure accuracy in achieving the targeted dose, as some patients would receive subtherapeutic or supratherapeutic dosing with this practice. Some institutions have adopted a rectal acetaminophen dosing protocol in which doses are rounded to the nearest half or whole suppository dose based on the patient s weight (eg, 60-mg dose for patients weighing between 4 and 5.9 kg). Intravenous administration of acetaminophen provides an alternative for children unable to tolerate rectal and enteral administration. It has a US Food and Drug Administration (FDA) labeled indication for moderate pain in children 2 years and older. 45 Studies are under way to determine appropriate dosing in children younger than 2 years. The package insert suggests a 33% reduction in dose for children younger than 2 years and a 50% reduction in dose for neonates. 45 The IV formulation has a quicker onset and higher peak concentration; however, the total area under the curve is similar to enteral administration. 49 Interpretation of these findings indicates that IV acetaminophen 420

7 VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 PAIN AND SEDATION IN CHILDREN is no more effective than enteral acetaminophen. Therefore, IV administration is most appropriately used in patients with acute pain and an inability to tolerate enteral administration (eg, postoperative pain). Intravenous acetaminophen is available only as a 1000 mg vial, which costs about 10 times as much as oral acetaminophen. 49 Once opened, the product is stable for only 6 hours. 45 In pediatric institutions, the large vial size, in conjunction with the short stability, could result in significant wastage of product and resources. Nonsteroidal Anti-inflammatory Drugs The most common NSAIDs used in the PICU and the neonatal ICU include ibuprofen, choline magnesium trisalicylate, and ketorolac. They exhibit analgesic and anti-inflammatory activity via inhibition of prostaglandin synthesis through the cyclooxygenase pathway. Intravenous ibuprofen and ketorolac are parenteral NSAIDs with an FDA-labeled indication for pain. Intravenous ibuprofen is approved for patients older than 17 years, although ongoing studies are evaluating its use in children. 50 Another IV form, ibuprofen lysine, is available. However, it is indicated for closure of patent ductus arteriosus in neonates, and no studies have evaluated its use for pain. Ketorolac has an FDA-labeled indication for children older than 2 years as a single IV/ intramuscular (IM) dose for moderately severe pain, but no FDA-labeled recommendations are available for scheduled dosing in children. Two studies have evaluated multiple scheduled doses of IV ketorolac in children hospitalized for medical and surgical diagnoses. 51, 52 Moffett and colleagues 52 report on the use of ketorolac in 53 neonates and infants receiving a multiple dosage regimen following cardiac surgery. These patients received a median loading dose of mg/kg followed by a maintenance regimen of mg/kg per dose every 6 to 8 hours. Because of the retrospective nature of the study, the authors were unable to evaluate efficacy, but they proposed that the agent provided beneficial analgesic effects in these children after cardiac surgery. The use of NSAIDs for treatment of pain may be limited because of the increased incidence of bleeding as a result of their effects on platelet aggregation. Choline magnesium trisalicylate should be considered the NSAID of choice in patients with thrombocytopenia or increased risk of bleeding, because it is the only NSAID with no appreciable effects on platelet aggregation. However, this agent is available only in a liquid preparation, which may limit its use in patients who are taking nothing by mouth. 35 Other adverse effects of NSAIDs include nephropathy and gastrointestinal bleeding caused by the inhibition of protective prostaglandins in the kidney and stomach, respectively. Ketorolac has been associated with a significant increase in gastrointestinal bleeding, ulceration, and perforation that appears to be related to duration of therapy and dosing; this agent has a black-box warning related to this complication, and its use is limited to 5 days. 35 Nonsteroidal anti-inflammatory drugs have been associated with fluid retention and edema, especially in patients with congestive heart failure and cardiac decompensation. However, the recent report by Moffett and colleagues 52 suggests that this is a safe option in children after cardiac surgery. Nonsteroidal anti-inflammatory drugs should be used with caution in patients with orthopedic injuries and are the drugs of choice for bone pain. However, animal research suggests that NSAIDs impair bone healing, although reports are conflicting. 53 Some sources recommend a benefit versus risk evaluation. Kokki 53 recommends the limited use of NSAIDs in populations in whom bone healing may be a significant issue (eg, patients recovering from posterior or anterior spinal fusions). Sucrose Oral sucrose solutions may be considered for use in infants for prevention of pain associated with minor procedures (eg, venipunctures, nasogastric tube insertion). 35 These solutions are thought to stimulate the release of endorphins that act at opioid receptors. 35 Sucrose has a duration of action of 5 minutes and should not be used for longer procedures. Carbajal and colleagues 54 demonstrated that additive benefit is observed when sucrose is combined with the use of a pacifier in neonates undergoing painful procedures. The American Academy of Pediatrics recommends that sucrose solutions, in combination with a pacifier, be administered to infants younger than 6 months. 8 In comparison with newborns, older infants may experience decreased analgesia from sucrose (ie, shorter duration of effect) and require higher concentrations. 55 Three brands of 24% sucrose solutions are available 421

8 JOHNSON ET AL AACN on the market. One of these, Sweet-Ease Natural, does not contain preservatives. Some institutions have adopted compounded formulations of sucrose. Opioid Analgesic Agents Opioid analgesic agents inhibit the transmission of nerve impulses through the ascending pain pathway in the spinal cord and higher levels in the central nervous system by binding to opiate receptors. However, they do not affect pain transmission through the peripheral nervous system. Opioids vary in potency. Table 4 lists the equianalgesic doses for the opioid agents together with suggested equianalgesic potencies. 10,34,35,56,57 Equianalgesic conversions may differ between resources, on the basis of potency and the pharmacokinetic parameters of acute versus chronic administration. Clinicians should choose one set of equianalgesic conversions and use it consistently in their practice. When changing from one opioid agent to another in opioid-tolerant patients, cross tolerance is often incomplete. Clinicians should consider starting the newer agent at 50% to 75% of the calculated equivalent dose and titrate to effect. Intermittent IV doses may be effective for patients needing immediate relief of pain, but they have been associated with inadequate pain control when plasma concentrations decrease between doses. 58, 59 Continuous infusions and PCA are useful in patients requiring consistent steady-state opioid concentrations and are effective in the postoperative setting. 59, 60 Studies have shown that PCA is effective in children as young as 6 years. 61 Patient-controlled analgesia involves the use of 5 components administered through an IV delivery pump: initial dose, basal rate, PCA bolus dose, lockout time between doses (eg, 5-20 minutes), and maximum opioid dose per hour or per every 4 hours (ie, depending on the institution s policy). 62 The 3 most commonly used agents for PCA and CI are morphine, hydromorphone, and fentanyl ( Table 5 ). Morphine Morphine is one of the most frequently prescribed agents for IV intermittent doses and is renally eliminated with a half-life of 1 to 3 hours in older infants and children and 10 to 20 hours in preterm neonates. 35 Some experts recommend against using morphine in neonates. Emerging evidence has shown that CI of morphine is less efficacious in neonates because of a reduced ability to produce the morphine-6-glucuronide metabolite, so fentanyl is more commonly used in the neonatal population. Morphine produces a significant degree of hypotension that may limit its use. Proposed mechanisms for this hypotension include histamine-mediated vasodilation, negative chronotropic and inotropic effects, and a decrease in baroreceptor reflex response. 61 This adverse event has been associated most often with morphine use in hemodynamically unstable patients, but it can also occur with other opioids. The morphine-mediated histamine release may exacerbate episodes of bronchospasm in patients in status asthmaticus. 63 In these cases, an alternative opioid such as hydromorphone or fentanyl is recommended. Hydromorphone Hydromorphone is generally 5 times more potent than morphine and may be preferred over morphine for intermittent dosing for patients in renal failure because of fewer metabolites. 61 It is less associated with histamine release than morphine. 2 Hydromorphone may be used as a PCA and CI. Only 1 study has evaluated CI of hydromorphone in children. Reiter and colleagues 56 retrospectively evaluated 92 critically ill children being treated with mechanical ventilation who had received CI of hydromorphone, and they found it to be effective in managing pain in this setting. Fentanyl Fentanyl is a synthetic opioid that is structurally similar to meperidine. It is 70 to 100 times more potent than IV morphine but is more lipophilic. 2, 35 Compared with morphine, fentanyl is not associated with significant histamine release and may be preferred in hemodynamically unstable children. 2 Fentanyl has an onset of action of 30 seconds versus 10 minutes for IV morphine, as well as a short half-life of about 2 hours in children. 35 With its quick onset and short half-life with intermittent IV dosing, it is useful for short procedures (eg, intubation, dressing changes, and lumbar puncture). However, with CI, fentanyl has a context-sensitive half-life of 21 hours as a result of its accumulation in peripheral tissue. 64 These patients should receive a bolus dose of fentanyl before increasing the rate of the CI because of this increased half-life. 422

9 VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 PAIN AND SEDATION IN CHILDREN Table 4: Opioid Analgesic Agents a Equianalgesic Dose Initial IV Dosages Initial PO Dosages Medication IV (mg) PO (mg) Weight 40 kg Weight 40 kg Weight 40 kg Weight 40 kg Morphine Bolus: mg/kg per dose every 2-4 h (max 15 mg per dose) CI: mg/kg/h Bolus: mg every 2-4 h CI: mg/h mg/kg per dose every 4-6 h IR mg every 4 h IR Hydromorphone Bolus: mg/kg per dose every 3-6 h CI: mg/kg/h Bolus: mg every 2-4 h CI: mg/h mg/kg per dose every 3-4 h (max 5 mg per dose) 2-4 mg every 3-4 h Fentanyl 0.1 NA Bolus: 1-2 mcg/kg per dose every 1-2 h CI: 1-2 mcg/kg/h Bolus: mcg every 1-2 h CI: mcg/h NA NA Methadone Bolus: NR CI: NR Bolus: NR CI: NR 0.1 mg/kg per dose every 6 h 3 doses; then 0.1 mg/kg per dose every 8-12 h (max 10 mg per dose) 5-10 mg every 4-12 h Meperidine Bolus: mg/kg per dose every 3-4 h CI: NR Bolus: mg every 3-4 h CI: NR mg/kg per dose every 3-4 h mg every 3-4 h Oxycodone and NA acetaminophen b (oxycodone) NA NA mg/kg per dose every 4-6 h (max 5 mg per dose of oxycodone) 1 or 2 tablets (5 mg of oxycodone) every 4-6 h Codeine and NA 200 (codeine) NA NA mg/kg per dose acetaminophen b every 4-6 h (max 60 mg per dose) 1 or 2 tablets (30 mg of codeine) every 4-6 h Hydrocodone and NA acetaminophen b (hydrocodone) NA NA 0.2 mg/kg per dose every 4-6 h 1 or 2 tablets (5 mg of hydrocodone) every 4-6 h Abbreviations: CI, continuous intravenous infusion; IR, immediate release; IV, intravenous; max, maximum; NA, not applicable; NR, not recommended; PO, oral. a Data from references 10, 34, 35, 56, and 57. b These opioids are available as an oral combination product with acetaminophen. Do not exceed the maximum acetaminophen dose per day. 423

10 JOHNSON ET AL AACN Table 5: PCA Initiation Doses for Opioid-Naive Patients a Opioid PCA Dose Lockout Time (Between PCA Doses), min Basal Rate Morphine 0.02 mg/kg mg/kg/h Hydromorphone 2-5 mcg/kg mcg/kg/h Fentanyl mcg/kg mcg/kg/h Abbreviation: PCA, patient-controlled analgesia. a Data from Lexi-Comp Online, Pediatric Lexi-Drugs Online 35 and Plate and Goldstein. 62 Chest wall rigidity can occur with fentanyl, which has been noted during anesthetic induction with doses of 25 to 50 mcg/kg, but it has also occurred with rapid administration of doses of 3 to 5 mcg/kg. 65 Dewhirst et al 66 described 2 cases of chest wall rigidity in infants receiving nurse-controlled analgesia, with doses ranging from 1.5 to 2.7 mcg/kg. Chest wall rigidity can be managed with 10 to 40 mcg/kg of IV naloxone, a dose of an IV neuromuscular blocker before the fentanyl bolus, and/or adjustment of the ventilator for 65, 66 intubated patients. Studies describe increased dosage requirements for morphine, hydromorphone, and fentanyl in patients requiring extracorporeal membrane oxygenation (ECMO). 56, Several proposed theories include development of opioid tolerance and drug binding to the ECMO membrane oxygenator. 68, 69 Fentanyl is particularly prone to the latter effect because 70% of IV dosing is lost in the circuit. 70 Leuschen et al 68 found increased fentanyl dosing requirements in patients early in their course but their dosing stabilized after they were treated with ECMO for 5 days, which could suggest fentanyl binding to the circuit with extended duration. Continuous infusions of all 3 opioids are associated with increased dosing requirements. Standard dosing should be initiated and titrated on the basis of the sedation score and comfort. Withdrawal can occur with ECMO discontinuation as a result of restoration of hepatic blood flow, leading to increased hepatic metabolism, so infusions should be tapered slowly during ECMO decannulation. 69, 70 Methadone Methadone is a long-acting opioid used commonly in the PICU for treatment of iatrogenic opioid withdrawal. It has an extended half-life of hours (range, 4-62 hours) in children. 35 Methadone has the same potency as morphine, but IV methadone has a peak onset of action of 1 to 2 hours versus 10 minutes for IV morphine. 35 It is structurally similar to verapamil and may exert calcium channel blockade. 71 All methadone formulations have been associated with bradycardia, hypotension, and cardiac arrhythmias. 35 Karir 71 highlighted significant bradycardia with a widened QRS complex in 1 patient after CI of methadone. The rapid IV administration of a methadone bolus dose in hemodynamically unstable patients could increase the likelihood of cardiovascular toxicities. Therefore, clinicians should avoid the use of IV methadone in children who can tolerate enteral administration of medications. Various studies have evaluated oral methadone doses for a weight-based approach versus a formula-based approach derived from pharmacokinetic and equianalgesic conversions. 57 A recent review noted no differences in incidence of withdrawal symptoms between these methods, but some patients receiving a formulabased approach had excessive sedation. 57 Most patients can be successfully treated with methadone 0.1 mg/kg per dose every 6 hours, followed by a taper schedule ( Table 4 ). 57 Meperidine Meperidine is a synthetic opioid that is less potent, with a shorter duration of action than IV morphine. It has limited use in the acute setting because of accumulation of its metabolite, normeperidine; this metabolite is associated with seizures, agitation, and hyperreflexia. 35 Higher doses of meperidine and use in patients with renal failure increase the risk for adverse events. 72 Meperidine should be reserved for treatment of rigors associated with blood products or amphotericin administration and for postanesthetic shivering. Opioid-Acetaminophen Combination Medications Three oral opioids are available in combination with acetaminophen (ie, codeine, hydrocodone, 424

11 VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 PAIN AND SEDATION IN CHILDREN and oxycodone). Codeine is used for mild to moderate pain, whereas hydrocodone and oxycodone are used for moderate to severe pain. Weight-based dosing is calculated according to the opioid analgesic component. Clinicians should ensure that patients receiving these agents do not exceed the maximum acetaminophen dose per day. Clinicians should note the recent concerns with the use of codeine that suggest that differences in metabolism may lead to complications. Codeine is metabolized to morphine by CYP 2D6 and demethylation. 35 One third of children in one study were found to be poor metabolizers because of decreased activity of CYP 2D6, resulting in decreased analgesic effects. 73 Conversely, some patients may be ultra-fast metabolizers because of additional activity of the CYP 2D6, resulting in respiratory depression and death. 74, 75 No widespread, clinically useful laboratory test is available to identify these variations with CYP 2D6; thus, codeine should not be used routinely. Opioid Adverse Effects Several adverse events occur with the use of opioids; see Table 6 for intervention 61, strategies. Respiratory depression and apnea are specific concerns in infants younger than 6 months because of decreased renal elimination and 34, 76 hepatic immaturity. Clinicians are recommended to treat oversedation and respiratory depression with low doses of naloxone ( mg/kg) administered every 2 to 3 minutes as needed on the basis of response to avoid complete reversal of analgesia. 35 Constipation, sedation, nausea/vomiting, and pruritus are the most commonly observed adverse effects. All patients receiving opioids should have a scheduled bowel regimen to prevent constipation. Pruritis can be managed by administering oral or IV antihistamines. In refractory cases, CI of low-dose naloxone can be used at a dose of 0.25 to 1 mcg/kg per hour. 77 Naloxone doses greater than 2 mcg/kg per hour should be avoided, as loss of analgesia has been demonstrated. 77 Nausea and vomiting can be attenuated through the use of antiemetics (eg, promethazine, ondansetron). Promethazine should be avoided in children younger than 2 years because of the FDA black-box warning for respiratory depression. 35 Prolonged use of opioids can be associated with tolerance. Tolerance is a decrease in Table 6: Pharmacological Management of Opioid Adverse Events a Adverse Event First-Line Intervention Alternative Interventions Respiratory depression Decrease dose if possible Add low-dose opioid antagonist (eg, naloxone). Nausea/vomiting Decrease dose if possible Add motility agent (eg, metoclopramide) Add antiemetic agent b Consider use of low-dose opioid antagonist (eg, naloxone). Constipation Stool softener (eg, docusate) Add osmotic laxative (eg, polyethylene glycol) Pruritus Add stimulant laxative (eg, bisacodyl). Switch to a different opioid agent (eg, fentanyl) Add antihistamine Consider enema Consider the use of low-dose opioid antagonist (eg, naloxone). Consider the use of low-dose opioid antagonist (eg, naloxone, nalbuphine) Tolerance Increase opioid dose Add a nonopioid analgesic agent or an agent Change to a longer acting that prevents or delays tolerance (eg, opioid 2 -agonist, low-dose naloxone) Withdrawal a Data from references 61, 76 to 79. Taper opioid dose slowly or add long-acting opioid agonist (eg, methadone, extended-release morphine) b Promethazine has a black-box warning for children younger than 2 years for respiratory depression. Add a 2 -agonist (eg, dexmedetomidine, clonidine) or gabapentin 425

12 JOHNSON ET AL AACN analgesic effect despite a consistent serum plasma opioid concentration. 78 It can be managed by increasing the opioid dose, switching to another opioid, or adding another agent (eg, 78, 79 ketamine, low-dose naloxone). Patients receiving synthetic opioids (eg, fentanyl) for extended durations are at greater risk. 79 Extended use of opioids can also result in physiological dependence, which occurs in up to 52% of critically ill children receiving opioids for prolonged periods in the ICU. 80 Abrupt discontinuation of opioids results in iatrogenic opioid abstinence syndrome (IOAS). Symptoms of IOAS include central nervous system irritability (eg, anxiety, agitation, sleep disturbance), gastrointestinal dysfunction (eg, vomiting, diarrhea), and autonomic dysfunction (eg, tachypnea, diaphoresis, hypertension). 80 The WAT-1 and Lipsitz scales should be used consistently across the continuum of care in patients at risk for IOAS. Several treatment options have been suggested for IOAS. Gradual tapering of the opioid CI is the most recommended treatment, but it can prolong ICU length of stay and theoretically increase the risk of other complications (eg, catheter infections). 78, 79 Other options, including longacting oral morphine and methadone tapers, transdermal fentanyl, and concomitant 2 -agonists, have been suggested. 80 A thorough review of tapering methods and procedures for management of IOAS is beyond the scope of this article; however, a general rule is that the length of the taper should not exceed the duration of the total opioid exposure. Sedative Agents Several sedative agents are available ( Table 7 ). 2, 35, The sedative agents can be differentiated by the mechanism of action, pharmacokinetic profile, and advantages and disadvantages of use. Etomidate and chloral hydrate are options for short-term sedation. Etomidate has a good cardiovascular profile but should be used only for procedural sedation. However, etomidate can cause adrenal suppression following even 1 IV dose. 35 Rectal and oral chloral hydrate are no longer available from the manufacturer, although some institutions may still have a limited supply remaining. 83 Benzodiazepines Benzodiazepines act as -aminobutyric acid (GABA) receptor agonists to provide sedation and anxiolysis. They do not possess analgesic activity but have demonstrated opioid-sparing effects by modifying the anticipation of pain. 84 These agents differ in onset time, half-life, and requirement for adjustment of dose in renal and/or hepatic failure ( Table 7 ). Midazolam is the most common benzodiazepine used in the PICU. 17 It is metabolized by CYP. Dose decreases may be needed in children with renal impairment, as up to 80% of the active metabolite is renally eliminated. 35 Diazepam is used less frequently in the PICU. 17 Its half-life is variable, ranging from 15 to 95 hours, depending on the age of the child. 35 Diazepam should be adjusted in hepatic and/or renal failure because it undergoes extensive hepatic metabolism to 2 active metabolites that are renally eliminated. In patients with hepatic failure, lorazepam is the benzodiazepine of choice because it is metabolized by glucuronidation to inactive metabolites and does not require dose adjustment in hepatic failure. 35 Lorazepam has a long half-life and may be preferred over midazolam for intermittent IV dosing. Although sedative agents are highly effective in the ICU setting, they can be associated with substantial toxicity. All sedative agents cause respiratory depression that appears to be dose dependent and increases with coadministration with other sedative agents and/or opioids. 85 Flumazenil, a GABA receptor antagonist, can be used to reverse this effect. Flumazenil should be used cautiously because it may cause seizures by antagonism of the GABA receptor. 2 In addition, benzodiazepines can cause hemodynamic effects by decreasing central sympathetic outflow and systemic vascular resistance, especially in children with cyanotic heart defects or hypovolemia. 2 In these patients, start with the lowest dose possible and slowly administer IV intermittent doses to avoid rapid changes in cardiac output. Diazepam is associated with extravasation and tissue necrosis, so caution must be used with IV administration ( Table 7 ). Both lorazepam and diazepam contain propylene glycol (PG) in the IV formulations. 35 Propylene glycol toxicity can lead to lactic acidosis. Chicella et al 86 performed a prospective study evaluating PG accumulation in 11 children receiving lorazepam via CI and found that PG concentrations increased from to mcg/ml, but this increase was not associated with significant changes in serum lactate level from baseline. The investigators excluded patients with renal failure. Propylene glycol is 426

13 VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 PAIN AND SEDATION IN CHILDREN Table 7: Overview of Sedative Agents a Agent Pharmacokinetics Initial Dosing Recommendations Advantages Disadvantages Benzodiazepines Lorazepam Onset: min after IV injection t½: h (children to neonates) Active metabolite(s): None Midazolam Onset: 1-5 min after IV injection t½: h (children to neonates) Active metabolite(s): Yes Diazepam Onset: 1-3 min after IV injection Central 2 -agonists t½: h (children to neonates) Active metabolite(s): Yes Clonidine Onset: min after oral administration t½: 8-72 h (children to neonates) Active metabolite(s): None Dexmedetomidine Onset: 30 min after IV injection Miscellaneous t½: h Active metabolite(s): None Propofol Onset: 30 seconds after IV injection t½: h (adults) Active metabolite(s): None Intermittent dose: mg/kg per dose (max 2 mg per dose) IV every 4-8 h CI dose: mg/kg/h (max 2 mg/h) Need for dosage adjustment: Yes (renal failure) Intermittent dose: mg/kg per dose (max 5 mg per dose) IV every 2-4 h CI dose: mg/kg/h (max 7 mg/h) Need for dosage adjustment: Yes (renal and hepatic failure) Intermittent dose: mg/kg per dose (max 10 mg per dose) IV every 2-4 h CI dose: NR Need for dosage adjustment: Yes (hepatic failure) Oral intermittent dose: 3-6 mcg/kg/d ( mg/kg/d) divided every 4-6 h Transdermal dose: mg/d Need for dosage adjustment: No Bolus dose: mcg/kg over 10 min CI dose: mcg/kg/h Need for dosage adjustment: Yes (hepatic failure) Bolus dose: mg/kg IV CI dose: mcg/kg/min Need for dosage adjustment: No Long half-life for intermittent sedation; not metabolized by CYP system Short half-life; faster onset and offset than lorazepam Longest half-life for intermittent sedation Available as oral and transdermal formulation More potent than clonidine; limited effects on respiratory mechanics Short half-life; fast onset and offset Contains propylene glycol; toxicity associated with metabolic acidosis, seizures, renal failure Renally eliminated; hepatically metabolized; increased accumulation in liver/renal failure (active metabolites) IV administration concerns (eg, pain, thrombophlebitis, tissue necrosis); increased accumulation in liver/renal failure Not available as IV formulation; associated with rebound hypertension IV bolus associated with hypertension/hypotension; associated with rebound hypertension; increased accumulation in liver failure Contains 1.1 kcal/ml of intralipids; associated with PRIS (continues) 427

14 JOHNSON ET AL AACN Table 7: Overview of Sedative Agents a ( Continued ) Agent Pharmacokinetics Initial Dosing Recommendations Advantages Disadvantages Ketamine Onset: 30 s-30 min after IV injection b t½: 2.5 h Active metabolite(s): Yes Intermittent dose (procedures and induction): IV: mg/kg; IM: 3-7 mg/kg CI dose: 5-20 mcg/kg/min Need for dosage adjustment: Yes (hepatic failure) Possesses sedative and analgesic properties; may decrease opioid tolerance; limited effects on respiratory mechanics Hypertension; increased intracranial pressure; increased oral secretions; associated with emergence phenomenon; increased accumulation in liver failure Pentobarbital Onset: 3-5 min after IV injection t½: 26 ± 16 h (children) Active metabolite(s): None Intermittent dose: 1-2 mg/kg IV CI dose: 1-6 mg/kg/h Need for dosage adjustment: No Decreased cerebral metabolic rate and intracranial pressure; useful for patients with concomitant seizures Negative inotrope; associated with IV incompatibility and infiltration and extravasation due to alkaline ph Etomidate Onset: 30 s 1 min after IV injection t½: h (adults) Active metabolite(s): None Intermittent dose: mg/kg IV for procedures; may repeat CI dose: NA Need for dosage adjustment: No Ultra-short acting; useful for procedural sedation Associated with adrenal suppression Chloral hydrate c Onset: min after oral administration t½: 1 h (parent drug); h (trichloroethanol) d Active metabolite(s): Yes Oral intermittent dose: mg/kg per dose PO/RC CI dose: NA Need for dosage adjustment: Yes (renal failure) Does not interfere with EEG results; used without IV access Active metabolite with long half-life; rectal and PO forms discontinued Abbreviations: CI, continuous intravenous infusion; CYP, cytochrome P450 enzyme system; EEG, electroencephalogram; IM, intramuscular; IV, intravenous; max, maximum; NA, not applicable; NR, not recommended; PO, oral; PRIS, propofol-related infusion syndrome; RC, rectal; t½, half-life. a Data from references 2, 35, 80 to 82. b Onset time for analgesia for ketamine is 30 minutes, whereas onset time for anesthesia is 30 seconds. c Chloral hydrate 500 mg/5 ml syrup is currently not available on the market. d Trichloroethanol metabolite is the agent primarily responsible for sedative effects. 428

15 VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 PAIN AND SEDATION IN CHILDREN 50% renally excreted, so patients with renal failure may be at increased risk for metabolic acidosis. 86 Periodic monitoring of lactic acid levels and osmolar gap should be performed, and these agents should be discontinued if PG toxicities occur. Drug withdrawal can occur with benzodiazepines following abrupt cessation. 87 Benzodiazepine withdrawal is not well studied. Most children in the PICU receive concomitant opioids, so it is difficult to determine the true frequency and characteristics of benzodiazepine withdrawal. Unlike opioids, benzodiazepines are not associated with gastrointestinal symptoms. 88 Monitoring for withdrawal can be conducted using assessment tools; however, only a few (eg, WAT-1) have been validated to assess for benzodiazepine withdrawal in children. 25 Treatment can be accomplished by gradual tapering of the CI or by switching to an enteral lorazepam or diazepam taper Antagonists Clonidine and dexmedetomidine are centrally acting 2 -agonists. In the locus coeruleus, they activate the 2A receptor and inhibit the release of excitatory catecholamines. 35 Clonidine is available as immediate release tablets, a transdermal patch, and an injection for epidural use. It is also available as an extemporaneous 0.1 mg/ml suspension. 35 Intravenous clonidine is not currently available in the United States. An extended release oral tablet and suspension are available, but no studies have evaluated these formulations for sedation. 35 The transdermal patch may not be suitable for many children because the lowest dosage form is 0.1 mg/ 24 hours, and this dose may exceed the recommended initial dose per kilogram. Some researchers have suggested cutting patches to deliver smaller doses; however, this practice is discouraged because of difficulty in obtaining consistent pharmacokinetic concentrations. 80 A recent systematic review summarized the use of IV, enteral, and transdermal clonidine in the PICU. 89 The authors concluded that clonidine may be beneficial for analgesia and sedation, and even for preventing or treating withdrawal symptoms, but that additional evidence must be available to support routine use. Note that clonidine is dosed in microgram per kilogram, which increases the chance for dosing errors because of confusion between mcg and mg when compounding an extemporaneous suspension or prescribing. Dexmedetomidine is 6 to 8 times as potent as clonidine and is available only as an IV formulation, although other routes of administration have been attempted. It has an 80, 90 FDA-labeled indication in nonintubated adults for procedural sedation and for sedation of intubated adults. 35 The FDA-labeled dosing for intubated patients is 1 mcg/kg as a bolus dose followed by a maintenance infusion of 0.2 to 0.7 mcg/kg per hour for less than 24 hours. Diaz and colleagues 91 have shown that dexmedetomidine pharmacokinetics in children aged 4 months and older are similar to those in adults. Doses up to 2.5 mcg/kg per hour have been used in children. 82 Additional evidence suggests that children younger than 1 year require higher doses. 92 The manufacturer recommends that the maximum duration of CI should be less than 24 hours, but published reports indicate duration of use up to 451 hours in children. 82 The major adverse events of 2 -agonists include hypotension (during maintenance IV infusion) and bradycardia. Dexmedetomidine causes hypertension with rapid IV administration of the loading dose. 35 Abrupt discontinuation of either agent can result in rebound hypertension and neurological manifestations 93, 94 (eg, agitation, asymmetric pupils, seizures). Tapering of the dose may be warranted. Alternatively, clinicians may consider adding enteral clonidine in children receiving dexmedetomidine via CI to allow discontinuation of IV access. Propofol Propofol is an anesthetic used for its sedative and amnesic effects, but it lacks analgesic activity. It is available as a 10% lipid emulsion consisting of soybean oil, glycerol, and egg lecithin. 35 Clinicians should consider the volume of propofol per day that a patient receives because it can significantly contribute to their total fat intake. Table 7 provides dosing information. Because of the lipophilicity of this agent, special consideration should be taken when dosing obese children. A recent study evaluated the initial dose of propofol in children undergoing a surgical procedure; the investigators 95 found that obese children required a lower weight-based dose than normal-weight children. In addition, the investigators recommended that a 2 mg/kg IV induction dose be administered to obese patients on the basis of actual body weight but that normalweight children should receive a 3.2 mg/kg IV 429

16 JOHNSON ET AL AACN induction dose. Further studies should be conducted in obese children to evaluate the effect of propofol dosing. Several adverse events occur with propofol. Hypersensitivity reactions may occur in patients with egg or soy allergies. 35 Serious adverse events include hypotension, bradycardia, seizures, metabolic acidosis, and hyperlipidemia. Propofol-related infusion syndrome (PRIS) has been reported and includes severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, and cardiac and renal failure. Propofol-related infusion syndrome has also been associated with mortality. 35 Risk factors for PRIS include CI doses greater than 4 mg/kg per hour and duration greater than 48 hours. 96 However, PRIS could occur with shorter duration if a high dose is used. Many clinicians now reserve propofol for procedural sedation and limited duration of use (eg, facilitation of extubation). Ketamine Ketamine is an anesthetic with sedative and analgesic activity. It acts at the cortex and limbic system to induce a dissociative state and blocks the N -methyl- D -aspartate receptor, inhibiting the activity of the excitatory neurotransmitter, glutamate. 35 The N -methyl- D - aspartate receptor has been associated with increased opioid tolerance and withdrawal, and some reports have described a potential role for ketamine as an opioid-sparing sedative. 79, 97, 98 It also stimulates the release of endogenous catecholamines, which has been associated with the reversal of refractory bronchospasm in patients with asthma or pulmonary infections. 99 Unlike benzodiazepines and barbiturates, it is not associated with respiratory depression and hypotension; thus, it may be useful in patients requiring procedural sedation and analgesia not receiving ventilator support and in patients who are hemodynamically unstable and unable to tolerate benzodiazepines and barbituates. Ketamine is commercially available as a solution for injection (IV or IM); the dose for IM administration is higher than that for IV use. Ketamine is typically given as a bolus dose for procedures and as a CI for maintenance sedation. However, some sources provide dosing information for oral administration for procedures. 35 Several unique adverse effects are linked to ketamine. Ketamine is associated with dose-related tachycardia and hypertension associated with endogenous catecholamine release. Increased oral secretions occur as a result of activation of central cholinergic receptors, which can be managed using an anticholinergic agent (eg, glycopyrrolate). Activity at the central cholinergic receptors leads to increased intracranial pressure (ICP) due to cerebral vasodilation. Therefore, ketamine should be avoided in patients with increased ICP. Emergence phenomena have been reported in 12% of patients receiving ketamine; symptoms include vivid dreams, hallucinations, or delirium following discontinuation of ketamine. 35 The incidence is lower in children. Youssef-Ahmed and colleagues 99 retrospectively evaluated 17 children being treated with mechanical ventilation who were receiving ketamine via CI and noted only 1 patient (5.9%) with emergence phenomena. This effect can be minimized by administration of a benzodiazepine 5 minutes before the administration of ketamine or by concomitant use of a benzodiazepine infusion. 2 Pentobarbital Pentobarbital is a short-acting barbiturate with anticonvulsant and sedative and hypnotic properties but no analgesic activity. It is useful in patients with status epilepticus or elevated ICP. Pentobarbital is dosed as a CI and titrated on the basis of continuous electroencephalographic monitoring targeting burst suppression, ICP and cerebral perfusion pressure, and/ or pharmacokinetic monitoring (eg, mcg/ml for medically induced coma). It is a direct, negative inotrope and is associated with bradycardia and hypotension in up to 25% of patients. 100 Symptoms are exaggerated with concomitant benzodiazepine and/or opioid use and with rapid IV administrations (ie, 50 mg/min). 2, 35 It also contains 40% PG, and one case report describes an adult who developed metabolic acidosis following a CI of pentobarbital. 101 Pentobarbital has a ph of 9 to 11, which leads to a risk for IV extravasation and compatibility problems. 2, 35 Thus, it is recommended to administer via a large bore vein or central catheter. 35 Drug Selection and Practical Applications Several options and approaches are available for analgesia and sedation. Nonopioids and/or opioids should be used to treat pain before the addition of sedative agents. Intermittent IV 430

17 VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 PAIN AND SEDATION IN CHILDREN opioids (eg, morphine or hydromorphone) and benzodiazepines (eg, lorazepam) could be used for procedural sedation or in children being treated with mechanical ventilation. This approach, however, may not be optimal for long-term use (eg, 24 hours) due to the need for frequent administration. Continuous infusions of sedative and analgesic agents may be more practical for rapid titration. Children receiving CIs but still experiencing breakthrough pain or agitation can be treated with 2 approaches. They could receive intermittent IV doses as needed. In this case, children requiring multiple intermittent IV doses should have their CI increased. The second approach is to increase the CI without administration of intermittent IV doses. With this approach, children may not respond initially to this change because of the delay in achieving a steady-state concentration for the new dosage regimen. An intermittent IV dose equivalent to the new hourly infusion rate should be initiated prior to any increase in the CI maintenance dose to avoid the delay in onset. Sedative and analgesic agents may be associated with numerous complications. Pain and sedation scales should be used routinely to provide objective assessment to minimize these complications. Some sedation scales (eg, COMFORT-Behavioral Scale) have been validated to assess both pain and sedation, whereas other scales (eg, State Behavioral Scale) have been validated to assess only sedation. With the latter scales, a separate scoring tool should be used to assess pain. Clinicians should be familiar with advantages and limitations of the scales at their institutions. These scales should be used on initiation and after subsequent dosage changes to determine appropriate management. Several studies support the use of the scales as part of a strategy to minimize morbidity 18, 102 associated with sedation and analgesia. Daily interruption of the sedative agent is one successful approach that has been associated with reduction in ICU length of stay and the number of days of treatment with mechanical 103, 104 ventilation in adults. One recent report evaluating a daily interruption strategy in children supports these findings and suggests a decrease in drug costs. 102 Another approach is nursing-driven sedation protocols. Deeter and colleagues 18 reported the results of a retrospective study, evaluating patients managed via a protocol versus historical controls. The investigators found a clinically but not statistically significant difference in number of days of treatment with mechanical ventilation and ICU lengths of stay between groups. The implementation of a protocol may also decrease morbidity associated with sedative and analgesic agents. No studies have compared these 2 approaches. Theoretically, a nursing-driven protocol may be more feasible in critically ill children because of the higher risk of inadvertent extubations or self-injury compared with adults. Whatever approach is selected, a multidisciplinary team consisting of physicians, nurse practitioners, physician assistants, nurses, pharmacists, and respiratory, physical, and occupational therapists should be involved in its development, implementation, and continuous quality improvement. A one-size-fits-all approach cannot be adopted for selection of sedative and analgesic agents. The patient s hemodynamic/respiratory status, disease state, and desired level of sedation should be considered before selection. Nonopioids should be considered for children with mild to moderate pain or as an adjuvant agent for moderate to severe pain to reduce the need for opioids. Fentanyl and hydromorphone are the preferred agents for CI because they have fewer hemodynamic effects compared with morphine. Opioid tolerance may be problematic, especially with fentanyl. Thus, the addition of a sedative agent may be necessary to keep a child comfortable and avoid excessive opioid exposure. Continuous infusions of benzodiazepine (ie, lorazepam and midazolam) are often used first. Children with hemodynamic instability or those at risk for respiratory depression who are being treated with mechanical ventilation may benefit from dexmedetomidine or ketamine. Continuous infusion of pentobarbital should be reserved as a last-line therapy because of its multiple adverse events. Propofol should be reserved for procedural sedation and short-term use (eg, facilitation of extubation) because of the risk for PRIS. Conclusion Sedation and analgesia are essential to the care of critically ill children. No one standard approach exists to assess and manage pain and anxiety. Critically ill children should be routinely assessed for pain and anxiety using validated tools. Multiple pharmacological therapies are available to manage pain, anxiety, fear, and agitation. Agents should be selected on the basis of the child s disease state, desired level of 431

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19 VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 PAIN AND SEDATION IN CHILDREN 40. Schechter NL, Allen A, Hanson K. Status of pediatric pain control: a comparison of hospital analgesic usage in children and adults. Pediatrics ; 77 : Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet ; 349 : Taddio A, Shah V, Gilbert-MacLeod C, Katz J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA ; 288 : Walker SM, Franck LS, Fitzgerald M, Myles J, Stocks J, Marlow N. Long-term impact of neonatal intensive care and surgery on somatosensory perception in children born extremely preterm. Pain ; 141 : WHO s Pain Ladder. painladder/en. Accessed May 30, Ofirmev [package insert]. San Diego, CA : Cadence Pharmaceuticals ; Sciulli MG, Seta F, Tacconelli S, et al. Effects of acetaminophen on constitutive and inducible prostanoid biosynthesis in human blood cells. Br J Pharmacol ; 138 : Buck ML. 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