Consensus Statement for the Prevention and Management of Pain in the Newborn

ARTICLE Consensus Statement for the Prevention and Management of Pain in the Newborn

K. J. S. Anand, MBBS, DPhil; and the International Evidence-Based Group for Neonatal Pain

Objective: To develop evidence-based guidelines for pre- Results: Recognition of the sources of pain and routine as- venting or treating neonatal pain and its adverse conse- sessments of neonatal pain should dictate the avoidance of quences. Compared with older children and adults, neo- recurrent painful stimuli and the use of specific environ- nates are more sensitive to pain and vulnerable to its long- mental, behavioral, and pharmacological interventions. term effects. Despite the clinical importance of neonatal Individualized care plans and analgesic protocols for spe- pain, current medical practices continue to expose in- cific clinical situations, patients, and health care settings can fants to repetitive, acute, or prolonged pain. be developed from these guidelines. By clearly outlining areas where evidence is not available, these guidelines may also Design: Experts representing several different coun- stimulate further research. To use the recommended thera- tries, professional disciplines, and practice settings peutic approaches, clinicians must be familiar with their ad- used systematic reviews, data synthesis, and open dis- verse effects and the potential for drug interactions. cussion to develop a consensus on clinical practices that were supported by published evidence or were Conclusion: Management of pain must be considered commonly used, the latter based on extrapolation of an important component of the health care provided to evidence from older age groups. A practical format all neonates, regardless of their gestational age or sever- was used to describe the analgesic management for ity of illness. specific invasive procedures and for ongoing pain in neonates. Arch Pediatr Adolesc Med. 2001;155:173-180

EWBORNS routinely ex- sponses to the pain caused by mild, mod- perience pain associ- erate, or highly invasive procedures, and the ated with invasive pro- magnitude of their responses increase with cedures such as blood postnatal age.6,7,13 Compared with older sampling, immuniza- children, neonates exhibit greater hor- tion,N vitamin K injection, or circumci- monal, metabolic, and cardiovascular re- sion. The sick or preterm infant may ex- sponses to surgical operations, and may re- perience repetitive or prolonged pain quire relatively higher doses of anesthetics resulting from many diagnostic, surgical, and analgesics for adequate pain con- or therapeutic procedures.1-4 trol.5,14-17 The metabolism and clearance Multiple lines of evidence suggest an rates of most analgesic agents in preterm increased sensitivity to pain in neonates neonates are slower than in term neo- compared with older age groups.5,6 This nates, but increase rapidly with age.18,19 pain sensitivity is further accentuated in pre- Management of pain in the newborn term neonates, and may not be clinically is hampered by the lack of awareness evident.5-8 Critically ill and preterm neo- among health care professionals that the nates do not mount vigorous behavioral re- neonate is capable of experiencing pain, sponses to pain, and therefore require par- and by fears about the adverse effects as- ticularly detailed assessment.6-8 The pain sociated with analgesic use. Current evi- modulation systems that operate in older dence supports the general principles listed From the International children and adults do not appear to be fully in Table 1 for the routine management Evidence-Based Group 9-11 for Neonatal Pain, whose functional in newborns or may func- of neonates using safe and effective envi- members are listed in the tion only during maternal contact in healthy ronmental, behavioral, and pharmacologi- acknowledgments at the end newborns.12 Even the most immature pre- cal interventions for relieving pain and for of this article. term neonates mount increasing re- preventing its adverse consequences.20

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. General Principles for the Prevention METHODS and Management of Pain in Newborns

1. Pain in newborns is often unrecognized and undertreated. Neonates These guidelines were developed from 2 consensus de- do feel pain, and analgesia should be prescribed when indicated velopment meetings (in April 1998 and August 1999). during their medical care. A detailed search of the published literature on neona- 2. If a procedure is painful in adults, it should be considered painful in tal pain was conducted to identify the experts who were newborns, even if they are preterm. invited to these meetings. Databases searched were 3. Compared with older age groups, newborns may experience a MEDLINE, Embase, and PubMed using the following greater sensitivity to pain and are more susceptible to the long-term effects of painful stimulation. terms:pain,nociception,stress,infant-newborn,andinfant- 4. Adequate treatment of pain may be associated with decreased premature. Faculty members were selected by the chair- clinical complications and decreased mortality. man (K.J.S.A.) based on their expertise in specific top- 5. The appropriate use of environmental, behavioral, and ics related to neonatal pain, coupled with a concerted pharmacological interventions can prevent, reduce, or eliminate effort to include professionals trained in different dis- neonatal pain in many clinical situations. ciplines and representing different countries and dis- 6. Sedation does not provide pain relief and may mask the neonate’s tinct practice settings (eg, children’s hospitals, general response to pain. hospitals, office practices). The disciplines represented 7. Health care professionals have the responsibility for assessment, were pediatrics, neonatology, child psychology, anes- prevention, and management of pain in neonates. thesiology,neuroscience,endocrinology,neonatalnurs- 8. Clinical units providing health care to newborns should develop ing, pharmacy/pharmacology, rehabilitation medicine, written guidelines and protocols for the management of neonatal pain. critical care medicine, rheumatology/immunology, and others. At the time of these meetings, faculty members were affiliated to academic institutions in Australia, Bra- zil, Canada, Denmark, France, Germany, Israel, Italy, Poland, Sweden, Switzerland, the Netherlands, United Table 2. Painful Procedures Commonly Performed Kingdom, and the United States. in the Neonatal Intensive Care Unit Faculty members performed a systematic review of the published literature on their specific topic, criti- Diagnostic cally evaluated the quality of published data, and syn- Arterial puncture thesized these findings. Data from all relevant studies Bronchoscopy were presented at these meetings and were discussed Endoscopy by the experts present. Other faculty members were en- Heel lancing couraged to present additional data and ample time was Lumbar puncture allowed for detailed discussion. Guidelines were de- Retinopathy of prematurity examination Suprapubic bladder tap veloped after reaching a consensus on the clinical prac- Venipuncture tices that were prevalent in most countries. As such, Therapeutic these guidelines were based on a combination of pub- Bladder catheterization lished evidence (from randomized controlled trials, sys- Central line insertion/removal tematic reviews, or meta-analyses of trials) and its criti- Chest tube insertion/removal cal evaluation by the faculty members. Between Chest physiotherapy September 1999 and April 2000, 3 separate draft ver- Dressing change sions of this statement were circulated and modified Gavage tube insertion by all members of the participating faculty. Approval Intramuscular injection of all faculty members was obtained for the final ver- Peripheral venous catheterization sion of the consensus statement, which is organized Mechanical ventilation around broad general principles (Table 1) and evidence- Postural drainage based guidelines for neonatal pain management. The Removal of adhesive tape pharmacological interventions recommended in these Suture removal guidelines are not the exclusive products of the phar- Tracheal intubation/extubation maceutical company that funded these meetings, and Tracheal suctioning the representatives of this company have had no in- Ventricular tap put in the format or content of these guidelines. Surgical Circumcision Other surgical procedures

RESULTS

EVIDENCE-BASED GUIDELINES FOR THE eter insertion, chest tube placement, tracheal intuba- MANAGEMENT OF NEONATAL PAIN tion or suctioning, lumbar puncture, and subcutaneous or intramuscular injections (see Table 2 for additional Recognition of the Sources of Pain procedures).1-4 Other sources of pain may include areas of inflammation and hyperalgesia around previous tis- Some of the painful procedures commonly performed on sue injury, postoperative pain, localized infection or in- neonates in the neonatal intensive care unit (NICU) inflammation, and skin burns or abrasions caused by trans- clude heel lancing, venipuncture, venous or arterial cath- cutaneous probes, monitoring leads, or topical agents.

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Premature Infant Pain Neonatal Facial Coding Neonatal Infant Pain Profile (PIPP)27,31 Scale (NFCS)28,32 Scale (NIPS)29 CRIES Score25 Variables assessed Gestational age Brow bulge Facial expression Crying Behavioral state Eye squeeze Cry Requires increased Heart rate Nasolabial furrow Breathing patterns oxygen administration Oxygen saturation Open lips Arms Increased vital signs Brow bulge Stretch mouth Legs Expression Eye squeeze Lip purse State of arousal Sleeplessness Nasolabial furrow Taut tongue Chin quiver Tongue protrusion Reliability data Interrater and intrarater Interrater and intrarater Interrater reliability Ͼ0.92 Interrater reliability Ͼ0.72 reliability Ͼ0.93 reliability Ͼ0.85 Forms of validity Face, content, construct Face, content, construct, Face, construct, and Face, content, established (in preterm and term and convergent concurrent discriminant, and neonates) (r = 0.89) (r = 0.53-0.84) concurrent (r = 0.49-0.73) Clinical utility Feasibility and utility Feasibility established at Not established Nurses preferred CRIES established at bedside bedside over another scale

Table 4. Recommended Analgesic Doses for Neonates*

Agent Intermittent Dose Infusion Dose Local/Topical Opioid analgesics Morphine sulfate 0.05-0.1 mg/kg intravenously (IV) 0.01-0.03 mg/kg per hour . . . Fentanyl citrate 0.5-3 µg/kg IV 0.5-2 µg/kg per hour . . . Anesthetic agents Lidocaine (local/topical) ...... 2-5 mg/kg subcutaneously; 0.5-1 mg/kg endotracheally EMLA† (local/topical) ...... 0.5-2 g under occlusive dressing 1 h before the procedure Ketamine hydrochloride (systemic) 0.5-2 mg/kg IV 0.5-1 mg/kg per hour . . . Thiopental sodium (systemic) 2-5 mg/kg IV ...... Other agents Acetaminophen 10-15 mg/kg orally; 20-30 mg/kg rectally‡ Sucrose 12%-24% solution given orally 2 min before the procedure, 2 mL for term neonates and 0.1-0.4 mL for preterm neonates

*It is advised that neonatal intensive care units use only 1 opioid analgesic agent to ensure familiarity with its use. The opioid doses noted are only applicable for opioid-naive patients. All patients receiving analgesic or anesthetic agents should be monitored and carefully observed, particularly if they are breathing spontaneously. †EMLA indicates eutectic mixture of local anesthetics (lidocaine and prilocaine hydrochloride in an emulsion base). ‡Maximum daily dose: preterm infants (28-32 wk) = 40 mg/kg; preterm infants (32-36 wk) and term infants (Ͻ10 d) = 60 mg/kg; term infants (Ն10 d) = 90 mg/kg.

Assessment of Pain • Pain assessment must be performed after each poten- tially painful clinical intervention and to evaluate the • Concomitantly with the vital signs, assessment of neo- efficacy of behavioral, environmental, and pharmaco- natal pain must be undertaken and documented ev- logical agents.21,23,33,34 ery 4 to 6 hours or as indicated by the pain scores or clinical condition of the neonate.21-24 Management of Pain in the Newborn • Standardized pain assessment methods with evidence of validity, reliability, and clinical utility should • Strategies for prevention, particularly by avoiding re- be used25-32 (Table 3). current painful stimuli.20,33 • Pain assessment instruments should be sensitive and • Use of environmental interventions to reduce stress in specific for infants of different gestational ages and/or the NICU.33,35,36 with acute, recurrent, or continuous pain.13,32,33 Ex- • Behavioral methods, including sucrose and nonnutri- amples of ongoing, continuous pain may include post- tive sucking.12,20,37-56 operative pain or inflammatory conditions.1,3,33 • Pharmacological agents for preemptive analge- • Pain assessment should be comprehensive and mul- sia20,57-76 (Table 4). tidimensional, including contextual, behavioral, and • Pharmacological therapy for ongoing pain17,19,34,58,71-80 physiological indicators.8,13,21-23 (Table 4).

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 SUGGESTED MANAGEMENT APPROACHES • Apply EMLA to the proposed site, if nonurgent.60,90 FOR NEONATAL PAIN • Consider subcutaneous infiltration of lidocaine.58,70 • Consider slow intravenous opioid infusion (mor- In the following sections, an asterisk indicates that evidence phine sulfate* or fentanyl citrate*).73,76 from studies in neonates is available to support the proposed • Consider using general anesthesia for the proce- intervention. The combined use of multiple interventions dure.15,70,76,91 may have additive or synergistic clinical effects. Umbilical Catheter Insertion Heel Lance (Umbilical Arterial/Umbilical Venous)

• Consider use of venipuncture instead of heel lance in • Consider the use of a pacifier with sucrose.39,41 full-term neonates and more mature preterm neo- • Use swaddling, containment, or facilitated tuck- nates* (because it is less painful, more efficient and 37,38 62,81-87 ing. requires less resampling). This approach may not • Avoid the placement of sutures or hemostat clamps on apply to the care of extremely preterm infants. the skin around the umbilicus. • Use a pacifier* with sucrose* (concentration 12%- 24%) given 2 minutes before the procedure.39-48,51-55 Peripherally Inserted • Use swaddling, containment,* or facilitated tuck- Central Catheter Placement ing.37,38 • Consider skin-to-skin contact with the mother.*12 • Use a pacifier with sucrose.39,41 • Use a mechanical spring-loaded lance, eg, Au- • Use swaddling, containment, or facilitated tuck- tolance.*62,85,86 ing.37,38 EMLA (a eutectic mixture of local anesthetics: li- • Apply EMLA* to the proposed site (when non- 58,60,90 docaine and prilocaine hydrochloride in an emulsion urgent). base), acetaminophen, and warming the heel are inef- • Consider opioid dose(s), if intravenous access is avail- 58,76,91 fective for heel lancing*; squeezing for blood collection able. 70,81-85,87 is the most painful part of the procedure. Lumbar Puncture Percutaneous Venous Catheter Insertion • Use a pacifier* with sucrose.39,41 60 39,41,70,81-84 • Apply EMLA to the proposed site. • Use a pacifier* with sucrose.* 58,70 • Use swaddling, containment, or facilitated tuck- • Consider subcutaneous infiltration of lidocaine. ing.37,38 • Because containment is not possible, careful physical • Apply EMLA* to the proposed site (when non- handling is advised. urgent).60,82,88,89 • Consider opioid dose(s),* if intravenous access is avail- Subcutaneous or Intramuscular Injection able.58,73 • Consider a similar approach for venipuncture.88,89 • Avoid subcutaneous and intramuscular injections; give drugs intravenously whenever possible. Percutaneous Arterial Catheter Insertion If necessary: 39,41 • Use a pacifier* with sucrose.39,41 • Use a pacifier with sucrose. • Use swaddling, containment, or facilitated tuck- • Use swaddling, containment, or facilitated tuck- 37,38 ing.37,38 ing. • Apply EMLA to the proposed site.60,70 • Apply EMLA to the proposed site (evidence for this 58,70 approach is available from studies in children, but not • Consider subcutaneous infiltration of lidocaine. 92-94 • Consider a similar approach for arterial puncture. from studies in neonates).

Peripheral Arterial or Venous Cutdown Endotracheal Intubation • Use a pacifier with sucrose.39,41 Many variations in clinical approach have been noted; • Use swaddling, containment, or facilitated tuck- the superior efficacy of any one technique is not sup- 33,58,70,95-97 ing.37,38 ported by current evidence : 58,60,70 • Apply EMLA to the proposed site. • Use combination of atropine sulfate and ketamine hy- • Consider subcutaneous infiltration of lidocaine; avoid *95 58,70 drochloride intravascular injection. • Use combination of atropine, thiopental sodium,* and • Consider opioid dose(s), if intravenous access is avail- 97 15,58,76 succinylcholine chloride. able. • Use combination of atropine, morphine, or fentanyl, Central Venous Line Placement and nondepolarizing muscle relaxant (pancuronium, vercuronium, rorcuronium).15,58 • Use a pacifier* with sucrose.39,41 • Consider using a topical lidocaine spray, if avail- • Use swaddling, containment, or facilitated tuck- able.98,99 ing.37,38 • Other drug combinations are frequently used.58,70

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Tracheal intubation without the use of analgesia or sedation should be performed only for resuscitation in the Table 5. Adverse Effects of Analgesic Agents in Neonates delivery room or for other life-threatening situations associated with the unavailability of intravenous access.95-97 Analgesic Agents Adverse Effects Reference(s) Morphine sulfate Respiratory depression 129-134 Endotracheal Suction Decreased gastrointestinal 135 motility This is considered a stressful procedure and may be as- Hypotension† 136-138 sociated with the same physiological responses that ac- Urinary retention 139 71,100-104 company other painful procedures : Fentanyl citrate Respiratory depression 75, 140 39,41 Hypotension 141 • Use a pacifier; may consider giving sucrose. Muscle rigidity 142-146 • Use swaddling, containment, or facilitated tuck- Hypothermia 147, 148 37,38 ing. Lidocaine Hematoma at injection site 64, 111 • Consider continuous intravenous infusion of opioids Recurrent seizures 149 (morphine*)71 or slow injection of intermittent opi- Heart block 150 oid doses (fentanyl,* meperidine,* or alfentanil*).100-104 EMLA* Redness, blistering, 111, 151 petechial rash Nasogastric or Orogastric Tube Insertion Methemoglobinemia† 61, 90, 152, 153 Ketamine Respiratory depression 154-156 39,41 • Use a pacifier with sucrose. hydrochloride or apnea • Use swaddling, containment, or facilitated tuck- Increased secretions† 157 37,38 ing. Thiopental sodium Hypotension 158 • Use a gentle technique and appropriate lubrica- Acetominophen None reported‡ . . . tion.105 Sucrose Hyperglycemia† 39-41, 54 Chest Tube Insertion • Anticipate the need for intubation and ventilation in *EMLA indicates eutectic mixture of local anesthetics (lidocaine and neonates breathing spontaneously.58 prilocaine hydrochloride in an emulsion base). 39,41 †These adverse effects have not been reported or reported rarely or • Use a pacifier with sucrose. uncommonly in neonates. • Consider subcutaneous infiltration of lidocaine.58,70 ‡No side effects are reported with therapeutic doses of acetaminophen, • Consider slow intravenous opioid infusion (mor- and neonates are relatively less susceptible to the hepatotoxicity resulting from acetaminophen overdose. phine or fentanyl; see Table 4 for dosages).15,58 • Other approaches may include the use of short- acting anesthetic agents.15,58,76 • Consider acetaminophen therapy. The use of intravenous midazolam is not recom- The efficacy and safety of repeated acetaminophen mended.106,107 doses is unknown, rectal absorption is variable, and in- Circumcision travenous propacetamol is not available in the United States.77-80,87 If deemed necessary108,109: • Reduce acoustic, thermal, and other environmental • Use an appropriate clamp (Mogen clamp preferred over stresses.33,35,36 Gomco*).110,111 • Apply EMLA* to the proposed site.57,60,111 COMMENT • Place a dorsal penile nerve block,*64,111,112 ring block,*65,66 or caudal block,67,68,113-116 using plain or buff- Recognition of the clinical importance of neonatal pain ered lidocaine.*117-119 and stress has been delayed5,20 by outdated professional • Use a pacifier* with sucrose.*39,41,56,111,118 attitudes (that newborns are less sensitive to pain),120-126 • Consider acetaminophen for postoperative pain.*69 lack of education,127,128 need for accurate assessment methods, and lack of evidence for the safety and efficacy of Analgesics can be combined for maximum effi- management approaches that can be applied to the rou- cacy,67,110,111,118 although the addition of sodium bicar- tine care of neonates. This is a preliminary attempt to pre- bonate to lidocaine does not alter the neonatal re- sent the available evidence so that it may be useful to the sponses to lidocaine injection.117-119 clinicians at the bedside. We hope to stimulate further Ongoing Analgesia for Routine research by clearly outlining the areas where current evi- NICU Care and Procedures dence is not available for defining the efficacy of specific therapeutic approaches. Although these manage- • Use swaddling, containment, or facilitated tuck- ment approaches are mainly applicable for established ing.37,38 39,41 NICUs that provide advanced medical and nursing care • Use a pacifier; may consider giving sucrose. for critically ill neonates, they can be adapted for man- • Low-dose continuous infusion of morphine* or fen- 71-75 agement of neonatal pain in other clinical settings or geo- tanyl* if patient is ventilated. graphical locations. There is no evidence to show that neonates can be Adverse effects that may result from these thera- safely sedated for several weeks or months20,71,72,74,75 and pies are listed in Table 5,129-158 and all clinicians using the use of midazolam is not recommended.71,106,107 these guidelines must be familiar with the safe use of an-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 algesic agents in healthy or critically ill, term and pre- 3. Johnston CC, Collinge JM, Henderson SJ, Anand KJS. A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive care term neonates. Professionals working with neonates are units. Clin J Pain. 1997;13:308-312. expected to be knowledgeable about the current assess- 4. Porter FL, Anand KJS. Epidemiology of pain in neonates. Res Clin Forums. 1998; ment and management approaches through participa- 20:9-18. 5. Anand KJS. Clinical importance of pain and stress in preterm newborn infants. tion in ongoing pain education, interaction with pain ex- Biol Neonate. 1998;73:1-9. perts, attention to the most recent research evidence, and 6. Johnston CC, Stevens BJ, Yang F, Horton L. Differential response to pain by very premature neonates. 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