Pain and Sedation in the NICU Dennis E. Mayock and Christine A. Gleason. DOI: /neo.14-1-e22

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1 Article from NeoReviews, American Academy of Pediatrics, Volume 14, (2013), pages e22-e31 License No Pain and Sedation in the Dennis E. Mayock and Christine A. Gleason Neoreviews 2013;14;e22 DOI: /neo.14-1-e22 The online version of this article, along with updated information and services, is located on the World Wide Web at: Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since. Neoreviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, Copyright 2013 by the American Academy of Pediatrics. All rights reserved. Print ISSN:. Downloaded from by Betty Burns on October 26, 2013

2 Pain and Sedation in the Dennis E. Mayock and Christine A. Gleason Neoreviews 2013;14;e22 DOI: /neo.14-1-e22 Updated Information & Services References Subspecialty Collections Permissions & Licensing Reprints including high resolution figures, can be found at: This article cites 6 articles, 2 of which you can access for free at: This article, along with others on similar topics, appears in the following collection(s): Anesthesiology/Pain Medicine ain_medicine_sub Fetus/Newborn Infant nfant_sub Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Information about ordering reprints can be found online: Downloaded from by Betty Burns on October 26, 2013

3 Article pharmacology Pain and Sedation in the Dennis E. Mayock, MD, Christine A. Gleason, MD Author Disclosure Drs Mayock and Gleason have disclosed no financial relationships relevant to this article. This commentary does contain a discussion of an unapproved/ investigative use of a commercial product/ device. Practice Gaps 1. Many neonates do not receive adequate sedation for procedures in the. 2. There is no evidence to guide appropriate sedation during extracorporeal life support. 3. The risks of some sedatives may outweigh their potential benefits. 4. Nonpharmacologic methods of sedation need further evaluation. Abstract Recognition and treatment of procedural pain and discomfort in the neonate remain a challenge. Procedural sedation and control of pain and discomfort are frequently managed together, often by using the same intervention. Therefore, although this article focuses on sedation, separating sedation from pain control is not always possible or wise. Despite significant progress in the understanding of human neurodevelopment, pharmacology, and more careful attention to how we care for sick infants, we still have much to learn. Protecting and comforting our fragile patients requires us to use poorly validated tools to assess and intervene to minimize distress, often applying data derived from adult patients to infants. Our first priority should be to minimize pain and distress. Further exploration of nonpharmacologic methods of procedural pain and distress control are needed. When pharmacologic intervention is necessary for procedural pain control and sedation, we need to use the least amount of drug that controls the pain and distress for the shortest period of time. As newer techniques and medications are introduced to clinical practice, we must demonstrate that such additions achieve their goal of sedation or pain control, and are safe over the lifetimes of our patients. Clinicians should identify appropriately the need for and use of sedatives and analgesics in the neonate. Objectives After completing this article, readers should be able to: 1. Understand the challenges of using pain scores to assess the need for, and response to, neonatal sedation. 2. Describe the uses of sedation for facilitation of neonatal procedures. 3. Discuss pharmacologic approaches to neonatal sedation. 4. Discuss nonpharmacologic approaches to neonatal comfort care. Introduction Advances in neonatology have significantly improved morbidity and mortality, but pain, discomfort, and stress remain sad realities for infants in the. Assessing, managing, and trying to limit these clinical realities while providing optimal care for critically ill neonates is challenging and increasingly controversial. Fortunately, there has been considerable research and much clinical dialogue aimed at developing best clinical practices in this problematic area. Sedation can be defined as the reduction of irritability or Abbreviations: agitation, usually by administration of sedative drugs. In the EMCO: extracorporeal membrane oxygenation, sedation is used both to facilitate care (by limiting EMLA: eutectic mixture of local anesthetics movement/agitation) and to minimize pain, discomfort, and M3G: morphine-3-glucuronide stress during procedures and intensive care. Appropriate identification of the need for and use of sedatives and analgesics, based M6G: morphine-6-glucuronide on the best available evidence, should be clinicians objective. Division of Neonatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA. e22 NeoReviews Vol.14 No.1 January 2013

4 Assessment of Neonatal Sedation: Pain Scores More than 40 infant pain scales have been developed, most often for use in clinical trials to assess treatment efficacy; few have been validated for general clinical use for acute pain assessment. These pain scores are also frequently used to assess adequacy of sedation, even though they were not developed for this purpose nor were they designed or validated for assessment of chronic pain or discomfort associated with mechanical ventilatory support, or for use in paralyzed or neurologically compromised infants. The American Academy of Pediatrics (AAP) and the American Academy of Pediatric Dentistry have recently published an update on pediatric sedation, which recommends using a carefully staged process to plan for and carry out sedation for diagnostic and therapeutic procedures (Coté et al, 2006). Sedation can be categorized according to the level of consciousness, effect on protective airway reflexes, patency of the airway, and response to stimulation. The level of sedation can progress from conscious sedation to deep sedation to general anesthesia (Table 1). The optimal approach to sedation management should include reducing the frequency of painful procedures and environmental stressors, facilitating developmentally appropriate care, determining the best technique to minimize the pain and stress associated with procedures, delegating responsibility for pain/sedation assessment and treatment to the bedside nursing staff, and using a balanced multimodal approach to procedural sedation (Allegaert et al, 2009). Sedation for Mechanical Ventilation Use of mechanical ventilation in neonates who have respiratory failure is a common practice. In the past, sedation (most often with opiates) was frequently used in pediatric and adult ICU patients who required mechanical ventilation. Extrapolation of evidence from early studies in nonneonatal patients led to frequent use of opiate sedation in neonates during mechanical ventilation, with limited information as to safety and efficacy. However, in the past decade, use of pharmacologic sedation in the adult ICU has been significantly reduced because of concerns regarding adverse cognitive outcomes and longer duration of ventilator support. These concerns have led to a rethinking of this practice in both pediatric and neonatal ICUs. The following discussion is a historical review of this issue. Mechanical ventilation in neonates is associated with an increase in hormonal stress responses, including increased cortisol and catecholamine levels. In the past, infants who appeared uncomfortable while on ventilatory support demonstrated asynchronous respiratory effort ( fighting the ventilator ), compromised gas exchange, and altered stress responses. Clinical studies from the 1990s demonstrated that opiate treatment prevented these adverse effects and reversed the previously described hormonal stress changes. Opiate sedation decreased stress scores in ventilated newborns. In ventilated term infants, the severity of respiratory failure as assessed by using the oxygenation index directly correlated with the need for analgesia and sedation. More recently, with the introduction of surfactant replacement therapy and synchronized ventilatory Table 1. Levels of Sedation According to the American Academy of Pediatrics Category Level of consciousness Protective airway reflexes Airway patency Response to stimulation Minimal Sedation (Anxiolysis) Minimally depressed consciousness Protective airway reflexes maintained Maintained independently and continuously Responds to physical stimulation or verbal command Moderate (Conscious) Sedation Deep Sedation General Anesthesia State of depressed consciousness Protective airway reflexes maintained Maintained independently and continuously Responds to physical stimulation or verbal command purposefully State of depressed consciousness or unconsciousness Partial or complete loss of protective airway reflexes Inability to maintain airway independently Cannot be easily aroused but responds purposefully to repeated verbal or painful stimulation State of unconsciousness Complete loss of protective airway reflexes Inability to maintain airway independently Unable to respond purposefully to painful physical or repeated verbal stimulation Source: American Academy of Pediatrics; American Academy of Pediatric Dentistry; Coté CJ; Wilson S; Work Group on Sedation. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update. Pediatrics. 2006; 118(6): NeoReviews Vol.14 No.1 January 2013 e23

5 technology, many of these previous problems with infants fighting the ventilator have been eliminated. Furthermore, clinical trials have shown that preemptive narcotic use in ventilated infants may actually have detrimental effects. A small randomized trial of routine morphine infusion in ventilated preterm infants concluded that morphine lacked a measurable analgesic effect and there was absence of a beneficial effect on poor neurological outcome. The larger clinical trial which followed (NEOPAIN, published in 2004) reported no beneficial effect of preemptive morphine infusions in ventilated preterm infants and an increased incidence of severe intraventricular hemorrhage in 27- to 29-week gestational age preterm infants. Indeed, additional bolus doses of morphine resulted in worse respiratory outcomes and longer requirement for ventilatory support. These controlled clinical trials provide no evidence that routine narcotic sedation during mechanical ventilatory support in neonates is beneficial. One approach to this dilemma has been to minimize the use of ventilatory support as much as possible. A recent Cochrane Reviews article evaluated the effects of preemptive opioid sedation on pain scales, duration of mechanical ventilation, mortality, growth, and development in neonates requiring mechanical ventilation (Bellù et al, 2008). The authors found no differences in mortality, duration of mechanical ventilation, or short- and longterm neurodevelopmental outcomes. However, very preterm infants given morphine took longer to achieve full enteral feeding. If morphine sedation prolongs time to full enteral feeds, we should expect an increase in the risk of complications related to the use of venous lines (bloodstream infections) and parenteral nutrition (cholestasis). Indeed, the duration of morphine use was a strong predictor for development of severe necrotizing enterocolitis. The overall conclusion of the Cochrane Reviews article regarding use of sedation during mechanical ventilation was that there is insufficient evidence to recommend routine use of opioids in mechanically ventilated newborns. Sedation for Procedures Infants undergoing intensive care endure many painful procedures, often several times each day. Although new pharmacologic and nonpharmacologic treatment strategies have been developed to decrease or eliminate some of this pain and stress, we have a long way to go in developing evidence-based best practices. Blood Sampling and Monitoring Heel sticks are routinely performed to obtain blood samples in neonates. The most appropriate method for relieving pain from a heel stick has yet to be determined. EMLA (eutectic mixture of local anesthetics; 2.5% lidocaine and 2.5% prilocaine) does not relieve the pain of a heel lance. Neonates experiencing venipuncture had lower pain scores than those who underwent heel stick. In neonates, venipuncture should be used preferentially over heel stick. The pain of arterial puncture can be decreased by infiltrating the site with 0.1 to 0.2 ml of 0.5% or 1% lidocaine using the smallest-gauge needle possible. Buffering the lidocaine with sodium bicarbonate is recommended to decrease the burning caused by lidocaine. EMLA may reduce the pain of arterial puncture. Endotracheal Intubation The use of premedication to minimize the pain and stress of endotracheal intubation benefits the neonate. However, concerns about rapid medication availability, ability to maintain the airway, and the ability to provide ongoing ventilatory support have caused controversy. Premedications typically include atropine, narcotics for sedation, and muscle relaxants. Atropine abolishes vagal bradycardia. Narcotics attenuate the increases in arterial blood pressure. Muscle relaxants attenuate the increases in intracranial pressure. Combination treatment decreases time and number of attempts needed to intubate the infant. When one is considering the use of medications for intubation, several questions need to be asked: Does the infant have adequate vascular access? What is the urgency of intubation need? Is the infant known to have a difficult airway? When was the last feeding? Can the infant be preoxygenated while avoiding gastric distension? If the decision is made to use medications for intubation, typical dosages include: Atropine 0.02 mg/kg fast intravenous (IV) push Fentanyl 2 mg/kg slow IV push (over at least 5 minutes) Vecuronium 0.1 mg/kg IV push Alternativemusclerelaxantsmay include succinylcholine 1 to 2 mg/kg IV push or rocuronium 1 mg/kg IV push. Propofol has been used as a premedication for intubation. As a single agent, it is easier and faster to prepare compared with a preparation of three separate drugs. Propofol is a hypnotic agent without anesthetic properties. However, propofol is painful when injected into small veins, and extremely painful if it extravasates. A major advantage is continued spontaneous breathing during e24 NeoReviews Vol.14 No.1 January 2013

6 the intubation procedure. The dose is 2.5 mg/kg intravenously; this dose might need to be repeated. Concerns with the use of propofol for intubation in neonates include minimal published experience in neonates, uncertain pharmacokinetics and duration of action, restricted availability in some institutions, and incompatibility with peripherally inserted central catheter lines. Circumcision The 2012 AAP Technical Report on Male Circumcision recommends that analgesia be provided to infants undergoing circumcision. EMLA cream, dorsal penile nerve block, and subcutaneous ring block are all possible options. The AAP reports that subcutaneous ring block may provide the best analgesia and has published a videotape demonstrating the use of local anesthesia for this procedure. Subcutaneous ring block is more effective than EMLA or dorsal penile nerve block. Dorsal penile nerve block is more effective than EMLA. EMLA is superior to placebo for pain relief during circumcision. An effective method for applying EMLA in preparation for circumcision is to apply one third of the dose to the lower abdomen, extend the penis upward gently, pressing it against the abdomen, and then apply the remainder of the dose to an occlusive dressing placed over the penis. The dressing is taped to the abdomen so the cream surrounds the penis and is left on for 60 to 90 minutes. Another method is to apply the cream and then place plastic wrap around the penis in a tube-like fashion to help direct the urine stream out and away from the cream. Acetaminophen is ineffective for the management of acute pain associated with the circumcision procedure but may provide some analgesia in the postoperative period. Other Invasive Procedures Placement of a central venous catheter requires topical anesthesia with EMLA or infiltration of the skin with lidocaine. In addition, a parenteral opioid such as morphine or fentanyl is typically used. Consideration should also be given to regional blocks for central line placement if anesthesia expertise is available for this method. The pain of a lumbar puncture is compounded by both the needle puncture and the distress caused by the body position required for the procedure. EMLA has been shown to decrease the pain of lumbar puncture in children. Sedatives are generally not recommended. Chest tube insertion is painful and requires an intravenous opioid, adequate local analgesia (lidocaine), or both. Sedation for Imaging Procedures Imaging of neonates in the typically includes routine diagnostic radiographs and ultrasound examinations, including echocardiograms. Sedation is rarely required for these procedures. More detailed imaging requires specialized scanning such as computed tomography or magnetic resonance imaging. Although they provide more specific diagnostic and predictive information, such imaging usually requires transportation of the infant from the to distant facilities. For high-quality computed tomography and magnetic resonance imaging, sedation is often considered to minimize artifacts from patient movement. Sedation in these circumstances can add substantial risk and cost to the procedure. Various approaches to avoid the use of sedation have been employed. Sleep promotion is often used, with scanning scheduled soon after a feeding (30 minutes), use of immobilization (swaddling) and restraint devices, and administration of sucrose drops before and during the scanning. Use of pacifiers during magnetic resonance imaging scanning, while often calming to the infant, can add motion artifact. Sedation During Therapeutic Hypothermia Therapeutic hypothermia is used increasingly for neuroprotection in newborns who have neonatal encephalopathy. Shivering is an uncommon finding in neonates, but it has been described frequently in infants undergoing therapeutic hypothermia and is an adverse effect that counteracts the physiologic intent of this intervention. Morphine sedation is usually adequate to minimize shivering. Dexmedetomidine, clonidine, meperidine, and propofol have been used for this purpose in adults. Benzodiazepines should be avoided because they can mask seizure activity. Pharmacologic neuromuscular blocking agents are not used unless the patient has uncontrollable shivering or generalized clonus that cannot be controlled with other sedatives or anticonvulsants. Sedation During Extracorporeal Life Support Sedation and analgesia are frequently needed during extracorporeal life support (also known as extracorporeal membrane oxygenation [ECMO]) to prevent cannula displacement with body movement. Muscle relaxants are also often used. No controlled trials have been published to provide guidance. It is important to understand that multiple factors influence drug pharmacokinetics during ECMO and that prediction of appropriate dosing is not possible. Factors leading to need for increased drug doses: NeoReviews Vol.14 No.1 January 2013 e25

7 Increased volume of distribution from ECMO circuit priming volume Binding/sequestration of drugs in oxygenator/other circuit components Hemofiltration of small molecules Factors leading to need for decreased drug doses: Renal and hepatic injury decreasing drug clearance Immature organ function in neonates Active drug metabolites Sedatives such as midazolam and opiates such as fentanyl are commonly used. However, achieving the desired effect of these medications frequently results in substantial dose escalation, requiring prolonged periods of slow drug weaning to avoid abstinence symptoms. Dexmedetomidine may be useful as a short-term adjunct for ECMO sedation. Pharmacologic Sedative Interventions The expected severity of the discomfort, its etiology, available administration routes, and potential adverse effects should all be considered when selecting a sedative for a planned procedure. Once medication administration has begun, careful monitoring for these effects can decrease potential adverse events. A key component of effective sedation management is ongoing assessment during and after an intervention or procedure. It is important to be prepared to rescue the infant if needed from a deeper level of sedation than originally planned. Nonopioid Analgesics NONSTEROIDAL ANTI-INFLAMMATORY DRUGS. Nonsteroidal anti-inflammatory drugs (eg, indomethacin, ibuprofen) inhibit prostaglandin synthesis by inhibiting the action of cyclooxygenase enzymes. These agents have many physiologic effects, including sleep cycle disruption, increased risk of pulmonary hypertension, cerebral blood flow alterations, decreased glomerular filtration rate, alteration in thermoregulatory control, and changes in platelet function. Moreover, development of the central nervous, cardiovascular, and renal systems are all dependent on prostaglandins. These drugs have been used frequently in the for pharmacologic closure of a patent ductus arteriosus, and aside from effects on renal and perhaps mesenteric circulation (which are difficult to separate from the patent ductus arteriosus), no clear-cut adverse effects have been reported. However, there is no robust evidence that they have analgesic efficacy in infants aged less than 3 months, thus limiting their use in neonates. ACETAMINOPHEN. Acetaminophen is the most widely administered analgesic in patients of all ages despite little evidence of efficacy in infants less than 3 months of age. Acetaminophen inhibits the activity of cyclooxygenase in the central nervous system, decreasing the production of prostaglandins and peripherally blocking pain impulse generation. Neonates are able to form the metabolite that results in hepatocellular damage; however, it is inappropriate to withhold acetaminophen in newborns because of concerns of liver toxicity. The immaturity of the newborn s cytochrome P-450 system may actually decrease the potential for toxicity by reducing production of toxic metabolites. Current recommendations call for less frequent oral dosing (every 8 to 12 hours in preterm and term neonates) because of slower clearance times and for higher rectal dosing due to decreased absorption. Oral dosages for acetaminophen are 10 mg/kg per dose every 6 to 8 hours for preterm neonates and 12.5 mg/kg per dose every 4 to 6 hours for term infants. The maximum recommended daily dose is 75 mg/kg for infants, 60 mg/kg for term and preterm neonates greater than 32 to 34 weeks postconceptual age, and 40 mg/kg per day for preterm neonates 28 to 32 weeks postconceptual age. Rectally administered acetaminophen has a longer half-life, but absorption is highly variable because it is dependent on the individual infant and placement of the suppository. It should also be noted that the drug may not be uniformly distributed throughout the suppository and therefore should be divided lengthwise if a partial dose is desired. The analgesic effect of acetaminophen may be additive when the agent is administered with opioids; coadministration may enable a decrease in the opioid dose and in corresponding opioid adverse effects. However, demonstration of this potential benefit awaits further study. OPIOID ANALGESICS. Opioids are believed to be the most effective sedative and analgesic for control of moderate to severe pain in patients of all ages. There is a wide range of interpatient pharmacokinetic variability. Opioid dosing depends on the severity of the anticipated procedural pain as well as the age and clinical condition of the infant. Opioids should be used in infants younger than age 2 months in a monitored setting only. Some clinicians propose a more conservative recommendation, restricting use of opioids to monitored settings for any infant younger than age 6 months. MORPHINE. Morphine remains the gold standard for procedural pain management in neonates despite lack e26 NeoReviews Vol.14 No.1 January 2013

8 of proven efficacy in many circumstances. Morphine is metabolized in the liver by uridine diphosphate glucuronyltransferase into two active metabolites: morphine-6- glucuronide (M6G), a potent opiate receptor agonist, and a second metabolite, morphine-3-glucuronide (M3G), a potent opiate receptor antagonist. Both metabolites and some unchanged morphine are excreted in the urine. The predominant metabolite in preterm and term neonates is M3G. Because of slow renal excretion, the metabolites can accumulate substantially over time. There is a potential for late respiratory depression due to a delayed release of morphine from less well-perfused tissues and the sedating properties of the M6G metabolite. Because the predominant metabolite of morphine in infants is M3G, a potent opiate receptor antagonist, one should consider using the lowest dose possible to achieve the needed sedation. As we escalate the morphine doses, we are also increasing the levels of M3G and potentially interfering with our goal of adequate sedation. Doses as low as 1 to 5 mg/kg per hour can provide adequate sedation/analgesia, minimizing the risk of accumulation of high M3G levels with that metabolite s prolonged half-life. Clearance or elimination of morphine and other opioids is prolonged in infants because of the immaturity of the cytochrome P-450 system. The rate of elimination and clearance of morphine in infants aged 6 months and older approaches that of adults. Chronologic age seems to be a better indicator of opioid metabolism in infants than gestational age. Infants are at greater risk for opioid-associated respiratory depression because of their immature respiratory center responses to hypoxia and hypercarbia. Furthermore, there is an increase in unbound or free morphine and M6G available to reach the brain as a result of the reduced concentration of albumin and a 1 -acid glycoproteins. Dosing recommendations currently reflect the wide range of interpatient pharmacokinetic variability. Previously, a 0.03 mg/kg bolus of IV morphine was suggested as a starting dose in nonventilated infants (Acute Pain Management Guideline Panel, 1992) whereas 0.05 to 0.1 mg/kg of IV morphine was recommended as an appropriate starting dose in ventilated infants. Recently, much lower doses have been recommended ( mg/kg as a bolus dose or 1 5 mg/kg per hour as a continuous infusion). Titration to the desired clinical effect is required in adjusting both the dose and the frequency of administration. Furthermore, it is important to continually assess need and responses. As we further explore the use of morphine for analgesia and sedation in neonates, it is becoming concerning that some of the risks may outweigh any potential benefits. FENTANYL. Fentanyl is 80 to 100 times more potent than morphine and causes less histamine release, making it a more appropriate analgesic/anesthetic choice for infants who have hypovolemia, hemodynamic instability, or congenital heart disease. Another potential clinical advantage of fentanyl is its ability to reduce pulmonary vascular resistance, which can be of benefit for infants who have undergone cardiac surgery, have persistent pulmonary hypertension, or need ECMO. Bolus doses of fentanyl must be administered slowly over a minimum of 5 minutes to avoid chest wall rigidity, a serious adverse effect observed after rapid infusion. Chest wall rigidity, which can result in difficulty or inability to ventilate, can be treated with naloxone or a muscle relaxant such as pancuronium or vecuronium. Recommended bolus doses are 1 to 2 mg/kg by slow IV infusion. Continuous infusion dosing should start at low levels (1 2 mg/kg per hour) and titrate to effect. Fentanyl is highly lipophilic. It has a quick onset and relative short duration of action. Because of this short duration of action, fentanyl is typically used as a continuous infusion for sedation and postoperative pain control. In infants age 3 to 12 months, total body clearance of fentanyl is greater than that of older children, and the elimination half-life is longer owing to its increased volume of distribution. Fentanyl has a prolonged elimination halflife in infants who have increased abdominal pressure. Due to tachyphylaxis, continuous infusions of fentanyl are frequently increased to maintain constant levels of sedation and pain management. Infusion dosing can reach substantial levels requiring prolonged withdrawal. A rebound transient increase in plasma fentanyl levels is a phenomenon known to occur after discontinuation of therapy in neonates. It is a result of fentanyl s accumulation in fatty tissues, which may prolong its effects after continued use. Therefore, caution must be exercised in the use of repeated doses or a continuous infusion. ORAL OPIOIDS. Oral methadone can be used to wean infants from long-term opioid use, although there are limited data on its efficacy and pharmacokinetics in this population. The respiratory depressant effect of methadone is longer than its analgesic effect. Methadone is metabolized very slowly via hepatic N-methylation resulting in accumulation in the body, and its half-life is very long (16 to 25 hours) in neonates. Codeine has been prescribed at 0.5 to 1 mg/kg orally every 4 hours as needed. Scarce data are available to recommend use of codeine in neonates. Most pharmacies NeoReviews Vol.14 No.1 January 2013 e27

9 supply acetaminophen and codeine in a set formula consisting of acetaminophen 120 mg and codeine phosphate 12 mg per 5 ml with 7% ethanol. The dose prescribed is limited by both the appropriate dose of codeine and the safe dose of acetaminophen. This combination is not recommended in neonates. Oxycodone is not recommended in neonates because no data are available for dosing guidelines. The liquid form is not universally available. BENZODIAZEPINES. Benzodiazepines such as lorezapam and midzaolam are sedatives that activate g-aminobutyric acid receptors and should not be used in place of an appropriate pain medication because this class of medication has no analgesic effect. Benzodiazepines can be administered to decrease irritability and agitation in infants and to provide sedation for procedures. In ventilated infants, benzodiazepines can help avoid hypoxia and hypercarbia from breathing out of sync with the ventilator, although, as noted previously, this is not as much of a problem today as it was in the past. When given as continuous infusions, dosing often escalates rapidly to maintain apparent sedation, resulting in the need for prolonged weaning. These medications have been associated with abnormal neurologic movements in both preterm and term infants. In rats, prenatal exposure to diazepam results in long-term functional deficits and atypical behaviors, and exposure of 7-day-old mice to diazepam induces widespread cortical and subcortical apoptosis. Midazolam potentiates pain behavior, sensitizes cutaneous reflexes, and has no sedative effect in newborn rats. Whether these data can be extrapolated to human infants is unknown, but clinicians have reason to be concerned and should use these drugs with caution in the. DEXMEDETOMIDINE. Dexmedetomidine is a potent relatively selective a 2 -adrenergic receptor agonist indicated for the short-term sedation of patients in ICU settings, especially those receiving mechanical ventilatory support. It is administered by either bolus doses for short procedural sedation (1 3 mg/kg) or by continuous IV infusion ( mg/kg per hour). Because dexmedetomidine does not produce significant respiratory depression, it has been used for procedural interventions in spontaneously breathing infants. As neonatologists become more familiar with dexmedetomidine, its use may increase. However, short- and long-term safety and effectiveness need to be assessed in human infants because preliminary work in a neonatal rodent model suggests that it may alter brain development. TOPICAL ANESTHETICS. EMLA cream reduces the pain of circumcision. It must be applied 60 to 90 minutes before the procedure; longer application times provide deeper local anesthetic penetration but may lead to toxicity. There is a slight risk of methemoglobinemia with the use of EMLA cream in infants and patients who are G6PD-deficient. This rare occurrence (methemoglobinemia) occurs when hemoglobin is oxidized by exposure to prilocaine. EMLA should not be used in patients who have methemoglobinemia or infants younger than age 12 months who are also receiving methemoglobinemia-inducing drugs, such as acetaminophen, sulfonamides, nitrates, phenytoin, and class I antiarrhythmic agents. A study of 30 preterm infants found that a single 0.5-g dose of EMLA applied for 1 hour did not lead to a measurable change in methemoglobin levels. A systematic review concluded that EMLA diminishes the pain during circumcision. Limited efficacy was noted with pain from venipuncture, arterial puncture, and percutaneous venous line placement. EMLA did not diminish pain from heel lancing. Oral sucrose or glucose may be as effective as EMLA for venipuncture. Nonpharmacologic Analgesic Interventions There are numerous nonpharmacologic interventions available for prevention and/or relief of neonatal procedural pain and stress, either as the sole method of pain control or in combination with pharmacologic interventions. Because pharmacologic analgesia and sedation have not been proven effective and may be harmful, these alternative methods of pain and stress relief need to be assessed for their efficacy and safety. As clearly stated by Golianu et al (2007), These therapies may optimize the homeostatic mechanisms of the infant, thereby mitigating some of the adverse consequences of untreated pain, as well as facilitating healthy physiologic adaptions to stress. However, widespread adoption of specific interventions is not consistent. Following are summaries of currently available information on selected interventions: Breastfeeding reduces the physiologic and behavioral responses to acute procedural pain and stress in neonates and has been recommended as the first line of treatment. Nonnutritive sucking using pacifiers reduces pain responses to heel prick, injections, venipuncture, and circumcision procedures. Infant massage decreases plasma cortisol and catecholamine levels in preterm infants during painful procedures. e28 NeoReviews Vol.14 No.1 January 2013

10 Maternal skin-to-skin contact (kangaroo care) is associated with greater physiologic stability and reduced responses to acute procedural pain. Kangaroo care can decrease pain scores after vitamin K injections. Maternal rocking has been shown to diminish neonatal distress. Multisensory stimulation (simultaneous gentle massage, soothing vocalizations, eye contact, smelling a perfume, and sucking on a pacifier) has been associated with analgesia and calming of the infants in several reports from one unit. Music therapy may reduce the behavioral and physiological responses to acute procedural pain. Oral sucrose reduces pain behavior in preterm and term infants. The mechanism of oral sucrose analgesia is not known but may be related to stimulation of endogenous opioid release. Of all these methods and techniques, oral sucrose has been the most widely studied and used. As more data regarding the limitations of pharmacologic treatment are published, consideration of nonpharmacologic interventions will likely become more important and commonplace. Long-term Consequences of Neonatal Opioid Exposure Experimental Animal Studies Perinatal and neonatal opioid exposure in experimental animals is associated with both short- and long-term adverse neurologic effects. These effects should make clinicians wonder whether the use of such medications, with questionable benefits, should continue. Perinatal narcotic exposure restricts brain growth, induces neuronal apoptosis, and alters behavioral pain responses later in life. One area of particular concern to clinicians is the developing cerebral circulation, which is extremely vulnerable to physiologic perturbations and drug effects. Cerebrovascular effects of drug exposure early in development may have lifelong consequences, including increased risk for stroke. The acute effects of exogenous narcotics, including morphine, on the developing cerebral circulation have been described in piglets and include modulation of prostaglandin-induced pial artery dilation during hypoxia, alteration in endothelin production, and increases in endothelin A receptor messenger RNA expression. Endogenous opioids are important regulators of cerebrovascular tone and angiogenesis. Exposure to morphine in fetal sheep and neonatal rats permanently alters cerebrovascular control mechanisms. Permanent neurobehavioral and neuropathologic changes have reportedly been found in a rodent model of neonatal stress and morphine exposure. These animal studies demonstrated short- and long-term effects of neonatal morphine exposure, which is not surprising because opioid receptor mediated signaling likely plays a role in several aspects of early brain development. However, the clinical relevance of these animal studies regarding the long-term effects of neonatal opioids is difficult due to species differences in timing of brain development, the development of opiate receptors and major neurotransmitter systems, and the pharmacokinetics of administered opioids. Clinical Studies Clinical studies addressing the short- and long-term effects of prolonged opiate use in human neonates are limited. The few that exist are contradictory and confounded by illness severity. Reversible encephalopathic changes in neonates receiving long-term sedative and narcotic infusions have been described. One study demonstrated no adverse neurodevelopmental outcomes in a small group of newborns who received morphine for a median of 5 days. A second study presented 5-year neurodevelopmental outcomes in very low birthweight infants exposed to prolonged sedation and/or analgesia (defined as >7 days of sedative and/or opioid drugs). Exposed very low birthweight infants had more severe or moderate disability at 5 years (42%) compared with those not exposed (26%). Preterm infants (23 32 weeks gestation at birth) evaluated at 36 weeks postconceptual age in the NEOPAIN study demonstrated neurobehavioral abnormalities if exposed to morphine during ventilatory support. Summary Recognition and treatment of procedural pain and discomfort in the neonate remain a challenge. There is still much to learn about human neurodevelopment, pharmacology, and how to best care for sick infants. Because we try to protect and comfort our fragile patients, and because external regulatory forces have required us to document discomfort by using poorly validated tools and to intervene to minimize distress, we often apply what is known from data in adult patients to infants. Our care should minimize the risks of adverse effects of both drugs and pain/stress on neurodevelopment. Further exploration of nonpharmacologic methods of procedural pain and distress control is needed. As newer techniques and medications are introduced to clinical practice, we must demonstrate that such additions achieve their goal of sedation or pain control, and also establish their safety over the lifetime of our patients. Escalation of drug doses NeoReviews Vol.14 No.1 January 2013 e29

11 may, in fact, be adding to our problem. Better tools are needed to help us optimize the outcomes of infants. American Board of Pediatrics Neonatal Perinatal Content Specifications For therapeutic drugs commonly used in the neonate (eg, opiates, methylxanthines, barbiturates), know indications for their use, clinical effects, pharmacokinetics, adverse effects, and toxicity. Suggested Reading Allegaert K, Veyckemans F, Tibboel D. Clinical practice: analgesia in neonates. Eur J Pediatr. 2009;168(7): Anand KJ, Hall RW, Desai N, et al; NEOPAIN Trial Investigators Group. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet. 2004;363(9422): Anand KJS, Anderson BJ, Holford NHG, et al; NEOPAIN Trial Investigators Group. Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial. Br J Anaesth. 2008;101(5): Bellù R, de Waal KA, Zanini R. Opioids for neonates receiving mechanical ventilation. Cochrane Database Syst Rev. 2008;(1): CD American Academy of Pediatrics; American Academy of Pediatric Dentistry; Coté CJ, Wilson S; Work Group on Sedation. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update. Pediatrics. 2006;118(6): Golianu B, Krane E, Seybold J, Almgren C, Anand KJ. Nonpharmacological techniques for pain management in neonates. Semin Perinatol. 2007;31(5): Mayock DE, Gleason CA. Neonatal pain and stress: assessment and management. In: Gleason CA, Devaskar SU, eds. Avery s Diseases of the Newborn. 9th ed. Philadelphia, PA: Elsevier; 2012: Walden M, Carrier CT. Sleeping beauties: the impact of sedation on neonatal development. J Obstet Gynecol Neonatal Nurs. 2003; 32(3): NeoReviews Quiz New minimum performance level requirements Per the 2010 revision of the American Medical Association (AMA) Physician s Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 Credit TM. In order to successfully complete 2013 NeoReviews articles for AMA PRA Category 1 Credit TM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. In NeoReviews, AMA PRA Category 1 Credit TM can be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved. 1. Which of the following is true concerning sedation during mechanical ventilation? A. There are more than 40 infant scales that have been validated in mechanically ventilated infants. B. Mechanical ventilation in neonates is associated with an increase in cortisol and catecholamine levels. C. Preemptive narcotic use in ventilated infants in modern s is likely to have a beneficial effect on both short-term outcomes and long-term neurodevelopment. D. The use of narcotics will decrease the length of respiratory support needed for both preterm and term infants on mechanical ventilation. E. Although the benefits of routine narcotic use for ventilated infants are not clear, the lack of any potential harm tips the balance toward using morphine routinely for ventilated infants. 2. A 10-day-old, 34 weeks gestational age male is about to receive a heel stick for laboratory evaluation. The parent asks you, Will he feel any pain with this procedure? An appropriate response may be: A. He is too young to feel any pain. He may cry, but all babies cry, sometimes for no reason. e30 NeoReviews Vol.14 No.1 January 2013

12 B. He may feel a little prick, but this should hurt less than getting blood from his vein. C. No, the heel is absent of nerve fibers. That is why we get blood from there. D. He may feel some pain; we may not be able to completely eliminate that pain, but we will try our best to minimize that pain as much as possible before, during, and after the procedure. E. Yes, but we will apply a local anesthetic cream, which has been proven to eliminate pain completely for this procedure. 3. A 41 weeks gestational age female is being placed on extracorporeal membrane oxygenation (ECMO) for refractory persistent pulmonary hypertension. Which one of the following considerations is correct? A. All drug doses should be increased by approximately double because the volume of distribution is doubled with the addition of the ECMO circuit. B. Sedation of ECMO patients should be avoided at all costs because it may cause respiratory depression. C. There is a clear consensus of sedation and analgesia practice based on clinical trials that should be standard of care for all patients receiving ECMO. D. Due to the complex factors that affect pharmacokinetics in a patient receiving ECMO, dosing of analgesic and sedative drugs in this patient may be difficult to predict. E. Once the patient is off ECMO, all sedation and pain medications should be discontinued within 1 to 2 days to speed recovery. 4. A 30 weeks gestational age male requires a peripherally inserted central catheter line for total parenteral nutrition and antibiotics. If you plan to give one medication for the procedure, which of the following medications and rationale are most appropriate? A. Lorazepam would be the best choice because it will help the infant to keep still. B. A low dose of morphine can be given for the procedure with adjustment of dosing as needed, but the patient should be monitored closely for respiratory depression. C. A eutectic mixture of local anesthetics cream placed at the site for 1 hour will be sufficient to eliminate pain and not cause any adverse effects. D. Fentanyl can be given as a quick push over 5 seconds and repeated twice as necessary. E. A peripherally inserted central catheter placement is a relatively minor procedure that should not require any sedation or analgesia. 5. A 1-day-old, 32 weeks gestational age female has been receiving continuous positive airway pressure since birth for respiratory distress syndrome. She has increased work of breathing and oxygen requirement, and the decision is made to intubate for mechanical ventilation. She has umbilical arterial and venous catheters in place and is NPO (nothing by mouth). What is an appropriate choice for medications before intubation? A. At this age, it will be most efficient and safest to intubate without any premedication. B. A combination of atropine, fentanyl, and vecuronium can be administered. C. To avoid excessive medication use, only one medication should be used (preferably atropine). D. If the first two or three attempts are unsuccessful, a dose of morphine can be given to facilitate the procedure. E. Because the patient has been on continuous positive airway pressure, an oral dextrose solution provided on a pacifier just before intubation should be sufficient. NeoReviews Vol.14 No.1 January 2013 e31