POLICY STATEMENT |
| ABSTRACT |
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Key Words: pain neonates
Abbreviations: IVH—intraventricular hemorrhage PVL—periventricular leukomalacia ROP—retinopathy of prematurity
| INTRODUCTION |
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Background
The prevention of pain in neonates is an expectation of parents.1 However, there are major gaps in our knowledge regarding the most effective way to accomplish this. Although it may not be possible to completely eliminate pain in neonates, much can be done to reduce the amount and intensity of pain. The prevention of pain is important not only because it is an ethical expectation but also because repeated painful exposures can have deleterious consequences.2–21 These consequences include altered pain sensitivity5, 7–9 (which may last into adolescence15) and permanent neuroanatomic and behavioral abnormalities, as found in animal studies.5, 14 It seems that altered pain sensitivity can be ameliorated if effective pain relief is provided.7, 17 There is growing concern that the long-term consequences of repeated pain in vulnerable neonates may also include emotional, behavioral, and learning disabilities3, 4, 6, 10, 13, 16; however, there are no definitive data in humans. During the last few years, there has been considerable interest in the diagnosis and treatment of acute pain in the neonate, but there has been little published on the related subjects of stress and chronic pain in this population. In the original statement, stress and chronic pain were briefly discussed in addition to acute pain.2 However, neither chronic pain nor stress has been specifically defined for the neonate, and only an intuitive understanding of these concepts is possible. Therefore, this updated statement deals primarily with acute pain prevention.
Neonates at greatest risk of neurodevelopmental impairment as a result of preterm birth (ie, the smallest and sickest neonates) are also those most likely to be exposed to the greatest number of painful stimuli in the NICU,18 creating a "double-hit" phenomenon. Although effective pain relief is now usually provided for neonates during and after a major surgical procedure,21 pain-reducing therapies are often underused for the numerous minor procedures that are a part of routine medical and nursing care for neonates.20, 21 Because the most effective and safest ways to prevent pain in the neonate are unknown, striking a proper balance between effective pain relief and avoidance of serious adverse effects from pain medications is a major challenge for caregivers. The subject of pain in the neonate was recently the focus of the Newborn Drug Development Workshop sponsored by the National Institute of Child Health and Human Development and the US Food and Drug Administration. The reader is referred to their publications for a detailed review and their discussions.22–24
| ASSESSMENT OF PAIN AND STRESS IN THE NEONATE |
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When pain is prolonged, striking changes occur in the infant's physiologic and behavioral indicators. During episodes of prolonged pain, neonates enter a state of passivity with few, if any, body movements; an expressionless face; decreased heart rate and respiratory variability; and decreased oxygen consumption, all suggestive of a marked conservation of energy. Prolonged or repeated pain also increases the response elicited by future painful stimuli (hyperalgesia) and even by usually nonpainful stimuli (allodynia). Therefore, pain scales that are used in postoperative neonates should be sensitive to the changes in response that can occur when pain is prolonged.27
The most commonly used assessment tools are listed in Table 1. 30–45 For each tool, the physiologic and behavioral indicators of pain are described, the population for which they have been validated are delineated, and unique aspects are listed. Whatever assessment tools are used, continual multidisciplinary training of staff in the recognition of neonatal pain and in the use of the chosen pain-assessment tools should be provided.26 Although in recent years, increased interest and research in the assessment of pain and stress in the neonate has occurred, there remains a need to develop a tool to measure pain in pharmacologically paralyzed and severely neurologically impaired infants.40
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| REDUCING PAIN FROM BEDSIDE CARE PROCEDURES |
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Reduction of Painful Events
Clearly, the most effective way of reducing minor procedural pain in the neonate is to reduce the number of procedures performed.58 There currently is a paucity of research regarding effective ways to accomplish this, but strategies for reducing the number of procedures that neonates experience should be developed and their effectiveness should be tested.55 Such an approach might include reducing the number of bedside disruptions in care.55, 60, 61 Other strategies might include bundling interventions, eliminating unnecessary laboratory or radiographic procedures, using transcutaneous measurements when possible, and minimizing the number of repeat procedures performed after failed attempts.58
Nonpharmacologic Pain Prevention for Minor Procedures
A variety of nonpharmacologic pain-prevention and -relief techniques have been shown to effectively reduce pain from minor procedures in neonates. These include use of oral sucrose/glucose,62–76 breastfeeding,77 nonnutritive sucking,49, 78 "kangaroo care" (skin-to-skin contact),55, 58 facilitated tuck (holding the arms and legs in a flexed position),79 swaddling,80 and developmental care, which includes limiting environmental stimuli, lateral positioning, the use of supportive bedding, and attention to behavioral clues.61 These measures have been shown to be useful in preterm and term neonates in reducing pain from a heel stick,68, 70–73, 79, 80 venipuncture,62, 64, 65, 67, 74, 77, 81 and subcutaneous injections81 and are generally more effective when used in combination than when used alone.63, 65, 68, 69, 80, 82 Concentrated oral sucrose has been widely studied. Oral sucrose eliminates the electroencephalographic changes associated with a painful procedure83 in a neonate, but the mechanism of pain relief by sucking oral sucrose is not known for certain. In one study, endogenous endorphin concentrations did not increase with administration of oral sucrose as originally proposed.84 Although the intraoral administration of sucrose to preterm infants without suckling is effective, intragastric administration is not.72 Concentrated oral glucose has also been used and diminishes the pain response of venipuncture, but it does not decrease oxygen consumption or energy expenditure, suggesting there may still be a stress response.85
A wide range of oral sucrose doses have been used in neonates for pain relief, but an optimal dose has not been established.75, 86 The dosage range of sucrose for reducing pain in neonates is 0.012 to 0.12 g (0.05–0.5 mL of 24% solution).75, 86 Some authors have suggested that multiple doses for a procedure (2 minutes before and 1–2 minutes after) are more effective than a single dose.73, 75 The long-term safety of multiple doses of oral sucrose for painful procedures in neonates has not been established.87 Additional research is needed to fully understand the mechanism of action, optimal dose, and safety of repeated doses of oral sucrose in neonates; nevertheless, available data suggest that this is an effective means of alleviating pain for many minor neonatal procedures. Because oral sucrose reduces but does not eliminate pain in neonates, it should be used with other nonpharmacologic measures to enhance its effectiveness.
Topical Anesthetic Pain Prevention for Minor Procedures
Topical anesthetics can effectively reduce pain from some procedures such as a venipuncture,62, 88–90 lumbar puncture,91 and intravenous catheter insertion91 in term and preterm neonates. These agents must be applied for a sufficient length of time before the procedure (usually 30 minutes for neonates), and they are not effective for a heel-stick blood draw,92, 93 because the pain from heel sticks is primarily from squeezing the heel and not from the lancet.48 Other nonpharmacologic means of alleviating pain mentioned previously should be used for heel sticks. Topical anesthetics were not effective for peripheral intravenous central catheter placement in one trial.94 There is a risk of methemoglobinemia after use of topical lidocaine-prilocaine cream in certain situations.95, 96 The risks can be minimized if used no more than once daily, on intact skin only, and not with other drugs known to cause methemoglobinemia.97, 98
Prolonged Mechanical Ventilation
Many preterm neonates receiving intensive care undergo prolonged mechanical ventilation, and its use defines a population of patients experiencing numerous minor painful procedures as described previously. The routine use of continuous pain medication and sedatives for ventilated preterm neonates has been evaluated.24 Two large randomized, controlled trials of the continuous use of intravenous morphine primarily as a potential means of decreasing poor neurologic outcome in preterm neonates receiving mechanical ventilation were published recently.56, 57 In both studies, additional open-label morphine was allowed if infants were considered to be in pain. In the first study,56 continuous morphine infusion was used for 7 days or less as clinically needed. In this study, morphine had no apparent analgesic effect and did not alter the risk of a poor neurologic outcome (severe intraventricular hemorrhage [IVH], periventricular leukomalacia [PVL], or death). In the second study,57 a continuous morphine infusion was used for up to 14 days. In this study, morphine use reduced pain scores slightly but did not alter the risk of severe IVH, cystic PVL, or a composite outcome (severe IVH, cystic PVL, or death within 28 days). In a subsequent analysis, the authors concluded that the use of morphine prolonged the duration of mechanical ventilation.99 No large studies on the continuous infusion of fentanyl in ventilated preterm infants have been published, but the literature includes many smaller studies that have recently been reviewed.24 In these studies, fentanyl seemed to result in increased ventilator settings.24 Concern about adverse respiratory effects of continuous opioid infusions in chronically ventilated preterm infants and lack of a demonstrated long-term benefit suggest that their routine use cannot be recommended at this time.
Midazolam has been evaluated as a sedative in mechanically ventilated preterm infants. A Cochrane Database Systematic Review100 recently concluded that there were insufficient data to promote use of midazolam because of a lack of demonstrated benefit and concern for an increased risk of poor neurologic outcome. This conclusion was supported by another recent review.24 Ketamine hydrochloride was evaluated in a randomized, controlled trial for relief of procedural pain associated with endotracheal suctioning in ventilated preterm neonates.101 However, these authors concluded that ketamine was only modestly effective at reducing pain scores and did not alter physiologic responses in heart rate and systemic blood pressure.
| REDUCING PAIN FROM SURGERY |
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Because of the physiologic and metabolic immaturity of the neonate, doses of medications that are effective for the reduction of pain may be close to the doses that cause toxicity. Therefore, the concept of a "balanced analgesia" has arisen, whereby several approaches to pain reduction can be used simultaneously to decrease the dosage required of each medication and, thereby, reduce toxicity. Early and effective pain treatment is associated with a lower total dose of medications, although therapy should be guided by ongoing pain assessment. The developmental pharmacology of the agents used must also be kept in mind. For example, fentanyl, a drug that is metabolized rapidly in older infants, has a half-life averaging approximately 10 hours in the neonate,107 and clearance is even lower in preterm infants.108 The residual effects of intraoperative medications also need to be considered. Muscle relaxants completely prevent behavioral pain responses and may last for several hours postoperatively.
As far as possible, stress and preoperative pain should be relieved before surgical interventions. An infant who is stressed and disturbed, unclothed, hypothermic, overstimulated by noise and light, and already experiencing pain will have elevated basal concentrations of adrenal cortical and medullary hormones and will be susceptible to further stress and complications postoperatively. However, there has been little direct investigation of the effects of preoperative analgesia in neonates. A full discussion of intraoperative strategies to reduce pain in neonates is beyond the scope of this statement. However, anesthesia of sufficient depth to prevent intraoperative pain and stress responses must be provided to decrease postoperative analgesic requirements. For some procedures, regional anesthesia is an effective way of controlling intraoperative pain in neonates, but a detailed discussion about regional anesthesia is also beyond the scope of this statement.
Postoperatively, opioids can be given by continuous infusion or by regular bolus. Randomized trials do not show any substantial benefit of continuous infusion of opioids over intermittent dosing, probably because of the long half-life of many of these agents in the neonate.109 More recently developed rapidly metabolized agents given by infusion hold promise for nurse-controlled anesthesia using a pump (the nurse providing additional boluses of medication as needed). This technique has not been widely investigated but holds promise for reducing the total dose of and complications from opioids.
Intravenous nonsteroidal antiinflammatory agents such as ketorolac and ketoprofen are well established as a means of reducing postoperative opioid requirements in adults. A small number of randomized, controlled trials in children have also shown effective analgesia, with a reduction in morphine requirements leading to reduced postoperative vomiting compared with an opioid-based analgesic.110 However, bleeding time may be increased,111 and some reports112 show an increase in postoperative clinical bleeding, although there are no randomized, controlled trials that have included neonates. A case series of infants younger than 6 months after abdominal surgery suggested a reduction in morphine requirements when ketorolac was used.113 Lacking any substantial evidence in the neonatal period, nonsteroidal antiinflammatory agents cannot be recommended for use as an adjunct to postoperative anesthesia outside a prospective clinical trial.
Acetaminophen administered orally postoperatively has been shown to reduce morphine requirements after tonsillectomy.114 It is associated with less postoperative vomiting than with an opioid-based analgesic115 and does not affect coagulation. Studies in neonates seem to be limited to use for circumcision, in which it is ineffective for operative and immediate postoperative pain but decreases later postoperative pain scores at 6 hours.116 Acetaminophen should not be used alone for severe pain but can be considered for use during the later postoperative period, after minor procedures, or as an adjunct to other measures. Dosing guidelines based on extensive literature review have been developed,117 and a population kinetic study with a large sample size produced similar guidelines.118 However, rectal acetaminophen should be used cautiously because of erratic absorption.
Although there are few data specific to the neonate, regional analgesia can provide effective postoperative pain relief in some situations.119, 120 There has been little systematic study of ancillary comfort measures in the postoperative neonate. Despite the importance of good pharmacologic treatment, the nonpharmacologic means of reducing pain in neonates discussed previously can also be used postoperatively and should be part of a coordinated effort to reduce the pain and stress experienced by infants during the postoperative period.
| REDUCING PAIN FROM OTHER MAJOR PROCEDURES |
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Chest-Drain Removal
Removal of the chest drain is also known to be very painful.122 A prospective study of methohexital for chest-tube removal in the neonate has demonstrated good pain control without significant respiratory compromise.123 In older children, low-dose morphine and topical lidocaine-prilocaine cream were equally effective.122
Intubation
The experience of being intubated is unpleasant124, 125 and painful.21 Morphine seems not to reduce the occurrence of severe hypoxia with bradycardia during intubation, probably because of the delayed onset of action.126 Opioids with a more rapid onset of action, such as fentanyl, are probably preferable.127 In a randomized trial, thiopentone was shown to reduce apparent pain in neonates undergoing intubation.128 Methohexital in an uncontrolled study was associated with smooth intubating conditions and no apparent distress during intubation.129 Studies on medications for use during endotracheal intubation are needed to address the requirements for analgesia, prevention of adverse physiologic responses (particularly bradycardia), and pharmacologic paralysis. This complex issue will be discussed further in a forthcoming statement from the American Academy of Pediatrics and Canadian Paediatric Society on the use of medications for elective intubation of neonates.
Retinal Examination and Surgery for Retinopathy of Prematurity
Retinal examinations for retinopathy of prematurity (ROP) are painful,130, 131 and the pain is not completely relieved by use of oral sucrose.132, 133 Topical anesthetics are used often, but their effectiveness is limited.134 Retinal surgery is also painful and leads to substantial physiologic disturbance that is not adequately treated with topical anesthesia.130 There are limited data on the effective prevention of pain from ROP surgery. One small uncontrolled study suggested that continuous intravenous infusion of remifentanil effectively reduced pain from laser therapy for ROP.135
Circumcision
Pain relief for circumcision should always be provided. The American Academy of Pediatrics has published a separate statement on this subject.136
| RECOMMENDATIONS |
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Reducing Pain From Bedside Care Procedures
Reducing Pain From Surgery
Reducing Pain From Other Major Procedures
| COMMITTEE ON FETUS AND NEWBORN, 2005–2006 |
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David H. Adamkin, MD
* Daniel G. Batton, MD
Edward F. Bell, MD
Susan E. Denson, MD
William A. Engle, MD
Gilbert I. Martin, MD
| LIAISONS |
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Canadian Paediatric Society
Tonse N.K. Raju, MD
National Institutes of Health
Laura Riley, MD
American College of Obstetricians and Gynecologists
Kay M. Tomashek, MD
Centers for Disease Control and Prevention
*Carol Wallman, MSN, RNC, NNP
National Association of Neonatal Nurses
| STAFF |
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| Section on Surgery, 2005–2006 |
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Michael D. Klein, MD
Richard R. Ricketts, MD
Brad W. Warner, MD
Keith P. Lally, MD
Kurt D. Newman, MD
Thomas R. Weber, MD
Richard G. Azizkhan, MD
Mary L. Brandt, MD
A. Alfred Chahine, MD
Frederick J. Rescorla, MD
Michael A. Skinner, MD
George W. Holcomb, III, MD
Frederick C. Ryckman, MD
| Staff |
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| SECTION ON ANESTHESIOLOGY AND PAIN MEDICINE, 2005–2006 |
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Joseph P. Cravero, MD, Chairperson-Elect
Constance S. Houck, MD
Lynne G. Maxwell, MD
Jeffrey L. Koh, MD
David M. Polaner, MD
Zeev Kain, MD
Patricia J. Davidson, MD, Past Chairperson
| LIAISON |
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American Society of Anestheiologists
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| STAFF |
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| FOOTNOTES |
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| REFERENCES |
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