Acta Anaesthesiologica Taiwanica xxx (2014) 1e8
Contents lists available at ScienceDirect
Acta Anaesthesiologica Taiwanica journal homepage: www.e-aat.com
Review Article
Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management Souvik Maitra 1, Dalim Kumar Baidya 1 *, Puneet Khanna 2, Bikash Ranjan Ray 2, Shasanka Shekhar Panda 3, Minu Bajpai 3 1 2 3
Department of Anaesthesia and Intensive Care, All India Institute of Medical Sciences, New Delhi, India Department of Anesthesiology, Post-Graduate Institute of Medical Education and Research, Chandigarh, India Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 July 2013 Accepted 10 February 2014
Current literature lacks systematic data on acute perioperative pain management in neonates and mainly focuses only on procedural pain management. In the current review, the neurophysiological basis of neonatal pain perception and the role of different analgesic drugs and techniques in perioperative pain management in neonates are systematically reviewed. Intravenous opioids such as morphine or fentanyl as either intermittent bolus or continuous infusion remain the most common modality for the treatment of perioperative pain. Paracetamol has a promising role in decreasing opioid requirement. However, routine use of ketorolac or other nonsteroidal anti-inflammatory drugs is not usually recommended. Epidural analgesia is safe in experienced hands and provides several benefits over systemic opioids such as early extubation and early return of bowel function. Copyright Ó 2014, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved.
Key words: acute perioperative pain; epidural; neonates; opioids
1. Introduction
2. Methods
Pain is the most common complaint when a patient presents to a physician. Pain management in neonates warrants special consideration because the present knowledge of developmental neurophysiology is improved every day. The neonates are a special group of population where a fine balance between optimal pain relief and adverse effects of drugs is of utmost importance. With the advancement of various surgical techniques and improved perioperative care, an increasing number of sick neonates undergo surgery, and optimal perioperative pain management may improve clinical outcomes in these neonates. In this evidence-based review, we have reviewed the neurophysiology of neonatal pain perception, long-term effects of suboptimal pain relief, and role of various drugs and techniques used in acute perioperative pain management in neonates.
Electronic searches were performed in MEDLINE, PubMed Central, Embase, and Scopus using the keywords “neonate,” “postoperative,” “pain,” and “acute pain.” The following professional society/organization’s web-based guidelines were also searched “Association of Pediatric Anesthesiologists,” “American Association of Pediatrics,” and “British Pain Society.” The level of evidences (LOEs) was decided according to the following guidelines1:
Conflicts of interest: None of the authors received any financial support for the preparation of the manuscript. * Corresponding author. Department of Anaesthesia and Intensive Care, Room Number 507, 5th Floor, Academic Wing, CDER, All India Institute of Medical Sciences, New Delhi 110029, India. E-mail address: [email protected] (D.K. Baidya).
Level I: Evidence obtained from at least one properly designed randomized controlled trial (RCT). Level II-1: Evidence obtained from well-designed controlled trials without randomization. Level II-2: Evidence obtained from well-designed cohort or casecontrol analytic studies, preferably from more than one center or research group. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
http://dx.doi.org/10.1016/j.aat.2014.02.004 1875-4597/Copyright Ó 2014, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
2
S. Maitra et al.
3. Developmental neurobiology of pain The immature nervous system develops from early gestation and continues to change in the postnatal period. Nociception involves peripheral sensory receptors, afferent sensory nerve fibers, the spinal dorsal horn, spinothalamic and thalamocortical tracts, and the sensory cortex. During maturation, C-fiber projections are the last group of primary afferents to enter the dorsal gray matter, after proprioceptive and low-threshold A fibers. By Week 30, nerve tracts are myelinated up to the thalamic level. Afferent neurons in the thalamus project axons migrating into the neocortex. Synaptic connections of these thalamocortical tracts might occur at 24 weeks’ gestation. After reviewing the literature, Lee et al2 concluded that direct thalamocortical fibers that are not specific for pain begin to emerge between 21 and 28 weeks’ developmental age (23 and 30 weeks’ gestational age). Fitzgerald stated that most pain responses in preterm infants, 36 wk
7.5e10 7.5e10 15
6e8 6 6
40 50 60
PCA ¼ postconceptional age.
The reserves of glutathione needed for detoxification of the toxic metabolic intermediate from paracetamol (N-acetyl-p-benzoquinone) may be depleted after repeated therapeutic doses. The metabolic activation of paracetamol is a prerequisite for hepatotoxicity. Neonates can produce these potentially hepatotoxic metabolites, but there are suggestions of a lower activity of cytochrome P450 in neonates.44 This may explain the resistance to paracetamol-induced hepatotoxicity seen in neonates. However, at present, the use of intravenous paracetamol in preterm neonates with a PCA of less than 32 weeks may not be justified before further pharmacokinetic/pharmacodynamic studies are conducted.45 9.2. Nonsteroidal anti-inflammatory drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of drugs having antipyretic, analgesic, and antiinflammatory effects. They act by reducing PG biosynthesis through inhibition of cyclooxygenase (COX), which exists as two major isoforms (COX-1 and COX-2). The PGs produced by the COX-1 isoenzyme protect the gastric mucosa, regulate renal blood flow, and induce platelet aggregation. The anti-inflammatory effects of NSAIDs are thought to occur primarily through inhibition of the inducible isoform, COX-2. The NSAIDs are well established as a part of multimodal analgesia in older children. A recent meta-analysis46 of 27 RCTs concluded that use of perioperative NSAIDs is associated with less opioid consumption and postoperative nausea and vomiting. However, similar robust data in neonates are lacking until today. In 2004, a small observational study47 assessed the effect of ketorolac in neonates. They found ketorolac to be an effective analgesic at a dose of 1 mg/kg without any clinical and biochemical adverse effects on the renal, hepatic, or hematological system. Later, a retrospective review48 also reported similar results. In 2009, a study on the safety and efficacy of ketorolac in infants younger than 6 months of age concluded that intravenous ketorolac appears to be safe when used in infants less than 6 months of age with biventricular circulations following cardiothoracic surgery, but it does not decrease the use of standard analgesic therapy.49 However, in 2011, another retrospective analysis50 found that infants younger than 21 days and less than 37 weeks’ completed gestational age are at significantly increased risk for bleeding events and should not be candidates for ketorolac therapy. In the absence of prospective RCTs, routine use of NSAIDs in neonates cannot be recommended at this time. 9.3. Opioids Opioids are the mainstay of pain management following a major surgery even in neonates. Morphine is the most commonly used opioid in the postoperative period; however, fentanyl is also being increasingly used. Opioids exhibit narrow therapeutic window between analgesic doses and the dose that may cause respiratory depression. Analgesia from opioid is mediated by spinal or supraspinal activation of opioid receptors, leading to decreased release of
neurotransmitters from nociceptive neurons inhibiting the ascending neuronal pain pathways and altering the perception and response to pain.51 Opioid receptors also exist outside the central nervous system in the dorsal root ganglia and on the peripheral terminals of primary afferent neurons.52 Neonates receiving opioids should have continuous pulse oximetry monitoring and should be managed in a setting in which rapid intervention for airway management is possible, because respiratory-rate monitoring alone may be an inadequate predictor of impending apnea.53 9.4. Fentanyl Fentanyl is almost 100 times more potent than morphine and is considered as a selective m-receptor agonist. Fentanyl has a rapid, predictable onset of action with a short duration of action mostly due to its high lipid solubility. It is associated with greater hemodynamic stability.54 Fentanyl may be the preferred analgesic agent for critically ill patients with hemodynamic instability and patients with symptoms related to histamine release during morphine infusion.55 However, fentanyl may be associated with rapid development of tolerance56,57 and chest wall rigidity.58 All metabolites of fentanyl are inactive and a small amount of fentanyl is eliminated by the renal route without metabolism. Fentanyl clearance can be impaired by decreased hepatic blood flow (e.g., from increased intra-abdominal pressure) in neonates after major abdominal surgery.59 The clearance of fentanyl is immature at birth but increases dramatically thereafter. Fentanyl clearance is 70e80% of adult values in term neonates and, standardized to a 70-kg person, appears to reach adult levels within the first 2 weeks of life.60 Fentanyl has been shown to effectively prevent preterm neonates from surgical stress responses and to improve postoperative outcomes.7 A large double-blind RCT concluded that fentanyl may be superior to morphine for short-term postnatal analgesia in newborn infants.61 Fentanyl may be used as bolus and/or as an intermittent dosing of 0.5e2.0 mg/kg or as a continuous infusion of 0.5e2.0 mg/kg/hour.62 9.5. Morphine Morphine is the gold standard opioid with which all other opioids are compared and it is the most thoroughly investigated opioid in neonates. Morphine is water soluble and its solubility in lipids is poor compared with other opioids. Although morphine can also act on k-opioid receptor subtypes,63 its analgesic effect is caused mainly by an activation of m receptors. Morphine alleviates postoperative pain,64 reduces behavioral and hormonal responses,65 improves ventilator synchrony,66 and may also reduce acute procedural pain.67 Morphine is metabolized in the liver by the enzyme uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).68 M3G has been shown to have higher analgesic potency than morphine and also has respiratory-depressive effects. M3G has been suggested to antagonize the antinociceptive and respiratory-depressive effects of morphine and M6G, and contributes to the development of tolerance. Although UGT2B7 is mainly found in the liver, it is also present in the intestines and kidneys. Clinical trials studying morphine for postoperative analgesia have shown large interindividual variability in morphine plasma levels and a wide range of morphine requirements.69 However, neonates, particularly those younger than 7 days,65 require significantly less morphine as they have significantly higher plasma concentrations of morphine, M3G, and M6G, and significantly
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
Acute postoperative pain management in neonates
lower M6G-to-morphine ratio than the older children.70 Moreover, morphine metabolism may be delayed during mechanical ventilation.65 In the postoperative period, morphine can be used as either continuous infusion or intermittent bolus. However, the relative safety and efficacy of either method is controversial. One large RCT in thoracic and abdominal surgical population showed that the efficacy of continuous intravenous infusion of 10 mg/kg/hour morphine is similar to that of infusion of 30 mg/kg morphine every 3 hours after surgery.64,71 Ventilatory effects of the aforementioned two morphine regimen are also similar and routine monitoring is mandatory69 during either of the protocol. The recommended dosage of continuous morphine infusion is 10e30 mg/kg/hour and that of the intermittent dose is 50e100 mg/kg.62 A meta-analysis concluded that an initial morphine dose of 7 mg/kg/hour in term neonates is optimum for postoperative analgesia.72 The use of morphine in the NICU for either postoperative pain or mechanical ventilation is not free from adverse outcomes. In a spontaneously breathing neonate, obviously the most important adverse effect is respiratory depression,73 but most neonates after major surgical procedures are mechanically ventilated. Respiratory depression may occur at plasma morphine concentrations of 15 ng/ mL, and when measured by carbon dioxide response curves or by arterial oxygen tension, similar results are obtained in children from 2 to 570 days of age at the same serum morphine concentration.74 In mechanically ventilated neonates, the important adverse effects are hypotension,75 prolonged requirement of ventilation, urinary retention, decreased gastrointestinal (GI) motility, risk of necrotizing enterocolitis,76 and may be long-term neurobehavioral abnormalities as some animal data indicate. At times, morphine may not provide adequate analgesia for short painful procedures.77 However, the Neurological Outcome and Pre-emptive Analgesia in Neonates trial concluded that continuous infusions of morphine do not increase the vulnerability of ventilated preterm neonates to early adverse neurological events, except in neonates who are hypotensive before morphine therapy or those receiving doses higher than 10 mg/kg/hour.78 They also suggested that intravenous morphine boluses should be used with caution in preterm neonates. An RCT79 published in 2003 did not support the routine use of morphine infusions as a standard of care in preterm newborns who have received ventilatory support as this was not associated with better neurologic outcomes. A Cochrane review also did not recommend routine morphine infusion in the ventilated newborns.80 However, the review did not find any difference in mortality, duration of mechanical ventilation, short-term and longterm neurobehavioral abnormalities but reported a delayed oral feeding. The main argument against the treatment of neonatal pain with opioids is the uncertainty about their side effects.81 Animal studies on long-term effects of neonatal opioid use do not provide enough insight, and data from the human studies are even sparser. A study82 in 2009 evaluated the effects of cumulative procedural pain and morphine exposure with subsequent growth and development, and found that greater overall exposure to intravenous morphine was associated with poorer motor development at 8 months, but not at 18 months’ corrected chronological age. A recent pilot study83 also concluded that morphine analgesia for procedural pain in preterm neonates may be associated with delayed growth and development. By contrast, in 2005, Grunau et al13 found that repeated neonatal procedural pain exposure among preterm infants was associated with downregulation of the hypothalamicepituitaryeadrenal axis, which was not counteracted with morphine. In another recent prospective observational study,84 it
5
was found that repetitive procedural pain in preterm infants during a period of physiological immaturity appears to impact postnatal growth and development. 10. Regional anesthesia/analgesia Although single-injection subarachnoid block (SAB) is the commonly performed regional technique in adults and usually provides immediate postoperative analgesia, SAB is of little use in neonates for postoperative analgesia due to its limited duration of action in this age group. 11. Epidural anesthesia in neonates: risk versus benefits Epidural analgesia has been investigated as a modality of pain relief after major surgeries. There is only one RCT85 that has directly compared the safety and efficacy of epidural analgesia with systemic opioid administration after a major surgery in neonates. The authors reported a faster return of intestinal function and less incidence of pneumonia in neonates who received epidural analgesia. In 2011, a small RCT86 compared the benefits of combined spinaleepidural anesthesia with general anesthesia in neonates undergoing GI surgery. The authors found a significantly less pulmonary complication and more cardiovascular stability in the regional anesthesia group in the postoperative period. Somri et al87 reported that combined spinaleepidural anesthesia could be considered as an effective alternative to general anesthesia in highrisk neonates and infants undergoing upper GI surgery when cautiously used by a pediatric anesthesiologist. Bösenberg88 in 1998 reported that use of lumbar/thoracic epidural analgesia in major abdominal surgeries in neonates was associated with a low risk of complication and advantages of reduced need for intraoperative muscle relaxants and opioid analgesics and postoperative ventilatory support.89 In 2009, Shenkman et al90 reported safe use of continuous epidural analgesia in small infants (1400e4300 g) undergoing major surgery. Neuraxial blockade was not found to be associated with hypotension or hemodynamic instability even in neonates with congenital heart disease.91 Regional analgesia may also have respiratory stimulant action,92 and has been associated with reduced need for mechanical ventilation. Surgical stress response is more effectively mitigated by regional anesthesia in comparison with systemic opioid and it is also free of immunosuppressive effects of opioids.93,94 The most important consideration in central neuraxial block in neonates is the safety and possibility of inadvertent injury to the developing spinal cord. Serious complications including neurologic injury have been reported in neonates,95 and many authors87,88 have mentioned that only an experienced pediatric anesthesiologist should perform central neuraxial block in neonates. 12. Epidural catheter insertion: thoracic catheter position through caudal route Although thoracic epidural catheters have been described in neonates96 in some reports, its routine use at this moment cannot be advocated. However, relative fluidity of the epidural fat in neonates and young infants allows advancement of thoracic catheter inserted through the caudal or lumbar route. In 1988, Bösenberg et al97 described the successful insertion of an 18G epidural catheter up to the thoracic level. A thicker gauge catheter is easier to advance but has a higher possibility of neural damage.98,99 There are numerous ways of confirming epidural catheter position, including X-ray,100 electrocardiography,101 ultrasonography,102 and even transesophageal echocardiography.103
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
6
S. Maitra et al.
The lumbar epidural route is less preferred in neonates,104 and there are reports of paraplegia due to intraspinal hematoma during attempted lumbar epidural block.105 The advent of ultrasound may be especially useful in neonates as the ossification of the vertebral column is reduced and the cord structures may be better visualized.106 13. Local anesthetic dosing The most important prerequisite of an epidural block is that the tip of the epidural catheter should be situated at an intraspinal level that corresponds to the dermatome center of the surgical procedure. Caudal bolus injection of 3 mg/kg ropivacaine or a continuous epidural infusion of 0.2e0.4 mg/kg/hour of the same drug was clinically effective and did not result in excessive plasma levels of the drug.107 In an Anesthesia Patient Safety Foundationesponsored study, it was found that all the children who had systemic toxicity had infusion rates in excess of 0.5 mg/ kg/hour of racemic bupivacaine.108 In a recent review, a maximum bolus dosage of 1.5e2.0 mg/kg followed by an infusion of 0.2 mg/kg/hour was recommended; in addition, this should only be continued beyond 48 hours when considerable benefits exist.107 14. Conclusion Despite various opinions regarding the methods of optimum postoperative pain management in neonates, there is little doubt that neonates feel more pain than their older counterparts. Intravenous opioids with the use of morphine or fentanyl remain the most common modality of neonatal pain management. The role of acetaminophen in decreasing opioid requirement seems to be promising. Although ketorolac appears to be safe, further studies are required before its routine use can be recommended. Epidural analgesia/anesthesia when performed by an experienced anesthesiologist is quite safe and has several benefits over systemic opioids. In cases where technical and logistic feasibility is present, it may be a logical option as a part of balanced anesthesia technique. References 1. Ahn Y, Woods J, Connor S. A systematic review of interventions to facilitate ambulatory laparoscopic cholecystectomy. HPB (Oxford) 2011;13:677e86. 2. Lee SJ, Ralston HJ, Drey EA, Partridge JC, Rosen MA. Fetal pain: a systematic multidisciplinary review of the evidence. JAMA 2005;294:947e54. 3. Fitzgerald M. The development of nociceptive circuits. Nat Rev Neurosci 2005;6:507e20. 4. Oberlander TF, Grunau RE, Fitzgerald C, Whitfield MF. Does parenchymal brain injury affect biobehavioral pain responses in very low birth weight infants at 32 weeks’ postconceptional age? Pediatrics 2002;110:570e6. 5. Fisk NM, Gitau R, Teixeira JM, Giannakoulopoulos X, Cameron AD, Glover VA. Effect of direct fetal opioid analgesia on fetal hormonal and hemodynamic stress response to intrauterine needling. Anesthesiology 2001;95:828e35. 6. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987;1:243e8. 7. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326:1e9. 8. Bromage PR, Shibata HR, Willoughby HW. Influence of prolonged epidural blockade on blood sugar and cortisol responses to operations upon the upper part of the abdomen and the thorax. Surg Gynecol Obstet 1971;132:1051e6. 9. Goldman RD, Koren G. Biologic markers of pain in the vulnerable infant. Clin Perinatol 2002;29:415e25. 10. Grunau RE, Oberlander TF, Whitfield MF, Fitzgerald C, Lee SK. Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 weeks’ postconceptional age. Pediatrics 2001;107:105e12. 11. Taddio A, Shah V, Gilbert-MacLeod C, Katz J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA 2002;288:857e61. 12. Buskila D, Neumann L, Zmora E, Feldman M, Bolotin A, Press J. Pain sensitivity in prematurely born adolescents. Arch Pediatr Adolesc Med 2003;157:1079e82.
13. Grunau RE, Holsti L, Haley DW, Oberlander T, Weinberg J, Solimano A, et al. Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain 2005;113:293e300. 14. Anand KJ. International Evidence-Based Group for Neonatal Pain. Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med 2001;155:173e80. 15. Anand KJ. Clinical importance of pain and stress in preterm neonates. Biol Neonate 1998;73:1e9. 16. Gliess J, Stuttgen G. Morphologic and functional development of the skin. In: Stave U, editor. Physiology of the perinatal periodvol. 2. New York: AppletonCentury-Crofts; 1970. pp. 889e906. 17. Bouza H. The impact of pain in the immature brain. J Matern Fetal Neonatal Med 2009;22:722e32. 18. Grunau R. Early pain in preterm infants. A model of long-term effects. Clin Perinatol 2002;29:373e94. 19. Taddio A, Ohlsson A, Einarson TR, Stevens B, Koren G. A systematic review of lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in neonates. Pediatrics 1998;101:E1. 20. Grunau RVE, Craig KD. Facial activity as a measure of neonatal pain expression. In: Tyler DC, Krane EJ, editors. Advances in pain research and therapy. New York: Raven Press; 1990. pp. 147e55. 21. Grunau RV, Johnston CC, Craig KD. Neonatal facial and cry responses to invasive and non-invasive procedures. Pain 1990;42:295e305. 22. Oberlander T, Saul JP. Methodological considerations for the use of heart rate variability as a measure of pain reactivity in vulnerable infants. Clin Perinatol 2002;29:427e43. 23. van Dijk M, de Boer JB, Koot HM, Duivenvoorden HJ, Passchier J, Bouwmeester N, et al. The association between physiological and behavioral pain measures in 0- to 3-year-old infants after major surgery. J Pain Symptom Manage 2001;22:600e9. 24. Hummel P, van Dijk M. Pain assessment: current status and challenges. Semin Fetal Neonatal Med 2006;11:237e45. 25. Herrington CJ, Olomu IN, Geller SM. Salivary cortisol as indicators of pain in preterm infants: a pilot study. Clin Nurs Res 2004;13:53e68. 26. Hullett B, Chambers N, Preuss J, Zamudio I, Lange J, Pascoe E, et al. Monitoring electrical skin conductance: a tool for the assessment of postoperative pain in children? Anesthesiology 2009;111:513e7. 27. Anand KJ, Aranda JV, Berde CB, Buckman S, Capparelli EV, Carlo W, et al. Summary proceedings from the neonatal pain-control group. Pediatrics 2006;117:S9e22. 28. Duhn LJ, Medves JM. A systematic integrative review of infant pain assessment tools. Adv Neonatal Care 2004;4:126e40. 29. Lawrence J, Alcock D, McGrath P, Kay J, MacMurray SB, Dulberg C. The development of a tool to assess neonatal pain. Neonatal Netw 1993;12:59e66. 30. Stevens B, Johnston C, Petryshen P, Taddio A. Premature infant pain profile: development and initial validation. Clin J Pain 1996;12:13e22. 31. Krechel SW, Bildner J. CRIES: a new neonatal postoperative pain measurement score. Initial testing of validity and reliability. Paediatr Anaesth 1995;5:53e61. 32. Suraseranivongse S, Kaosaard R, Intakong P, Pornsiriprasert S, Karnchana Y, Kaopinpruck J, et al. A comparison of postoperative pain scales in neonates. Br J Anaesth 2006;97:540e4. 33. Ambuel B, Hamlett KW, Marx CM, Blumer JL. Assessing distress in pediatric intensive care environments: the COMFORT scale. J Pediatr Psychol 1992;17: 95e109. 34. Franck LS, Ridout D, Howard R, Peters J, Honour JW. A comparison of pain measures in newborn infants after cardiac surgery. Pain 2011;152:1758e65. 35. Hummel P, Puchalski M, Creech SD, Weiss MG. Clinical reliability and validity of the N-PASS: neonatal pain, agitation and sedation scale with prolonged pain. J Perinatol 2008;28:55e60. 36. Arana A, Morton NS, Hansen TG. Treatment with paracetamol in infants. Acta Anaesthesiol Scand 2001;45:20e9. 37. Ceelie I, de Wildt SN, van Dijk M, van den Berg MM, van den Bosch GE, Duivenvoorden HJ, et al. Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial. JAMA 2013;309:149e54. 38. Björkman R, Hallman KM, Hedner J, Hedner T, Henning M. Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. Pain 1994;57: 259e64. 39. Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther 1976;19:284e94. 40. Ryan Cook D, Davis PJ, Lerman J. Pharmacology of pediatric anesthesia. In: Motoyama EK, Davis PJ, editors. Smith’s anaesthesia for infants and children. 6th ed. St. Louis, MO: Mosby; 1996. pp. 160e70. 41. van Lingen RA, Deinum JT, Quak JM, Kuizenga AJ, van Dam JG, Anand KJ, et al. Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonatal Ed 1999;80:F59e63. 42. Allegaert K, de Hoon J, Verbesselt R, Vanhole C, Devlieger H, Tibboel D. Intraand interindividual variability of glucuronidation of paracetamol during repeated administration of propacetamol in neonates. Acta Paediatr 2005;94: 1273e9. 43. De Lima J, Carmo KB. Practical pain management in the neonate. Best Pract Res Clin Anaesthesiol 2010;24:291e307. 44. Roberts I, Robinson MJ, Mughal MZ, Ratcliffe JG, Prescott LF. Paracetamol metabolites in the neonate following maternal overdose. Br J Clin Pharmacol 1984;18:201e6.
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
Acute postoperative pain management in neonates 45. van den Anker JN, Tibboel D. Pain relief in neonates: when to use intravenous paracetamol. Arch Dis Child 2011;96:573e4. 46. Michelet D, Andreu-Gallien J, Bensalah T, Hilly J, Wood C, Nivoche Y, et al. A meta-analysis of the use of nonsteroidal antiinflammatory drugs for pediatric postoperative pain. Anesth Analg 2012;114:393e406. 47. Papacci P, De Francisci G, Iacobucci T, Giannantonio C, De Carolis MP, Zecca E, et al. Use of intravenous ketorolac in the neonate and premature babies. Paediatr Anaesth 2004;14:487e92. 48. Moffett BS, Wann TI, Carberry KE, Mott AR. Safety of ketorolac in neonates and infants after cardiac surgery. Paediatr Anaesth 2006;16:424e8. 49. Dawkins TN, Barclay CA, Gardiner RL, Krawczeski CD. Safety of intravenous use of ketorolac in infants following cardiothoracic surgery. Cardiol Young 2009;19:105e8. 50. Aldrink JH, Ma M, Wang W, Caniano DA, Wispe J, Puthoff T. Safety of ketorolac in surgical neonates and infants 0 to 3 months old. J Pediatr Surg 2011;46: 1081e5. 51. Suresh S, Anand KJ. Opioid tolerance in neonates: mechanisms, diagnosis, assessment, and management. Semin Perinatol 1998;22:425e33. 52. Stein C, Machelska H, Binder W, Schäfer M. Peripheral opioid analgesia. Curr Opin Pharmacol 2001;1:62e5. 53. Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Engl J Med 2002;347:1094e103. 54. Yaster M, Koehler RC, Traystman RJ. Effects of fentanyl on peripheral and cerebral hemodynamics in neonatal lambs. Anesthesiology 1987;66:524e30. 55. Tibboel D, Anand KJ, van den Anker JN. The pharmacological treatment of neonatal pain. Semin Fetal Neonatal Med 2005;10:195e205. 56. Arnold JH, Truog RD, Scavone JM, Fenton T. Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr 1991;119:639e43. 57. Franck LS, Vilardi J, Durand D, Powers R. Opioid withdrawal in neonates after continuous infusions of morphine or fentanyl during extracorporeal membrane oxygenation. Am J Crit Care 1998;7:364e9. 58. Fahnenstich H, Steffan J, Kau N, Bartmann P. Fentanyl-induced chest wall rigidity and laryngospasm in preterm and term infants. Crit Care Med 2000;28: 836e9. 59. Gauntlett IS, Fisher DM, Hertzka RE, Kuhls E, Spellman MJ, Rudolph C. Pharmacokinetics of fentanyl in neonatal humans and lambs: effects of age. Anesthesiology 1988;69:683e7. 60. van Lingen RA, Simons SH, Anderson BJ, Tibboel D. The effects of analgesia in the vulnerable infant during the perinatal period. Clin Perinatol 2002;29:511e34. 61. Saarenmaa E, Huttunen P, Leppäluoto J, Meretoja O, Fellman V. Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: a randomized trial. J Pediatr 1999;134:144e50. 62. Simons SH, Anand KJ. Pain control: opioid dosing, population kinetics and side-effects. Semin Fetal Neonatal Med 2006;11:260e7. 63. Rahman W, Dashwood MR, Fitzgerald M, Aynsley-Green A, Dickenson AH. Postnatal development of multiple opioid receptors in the spinal cord and development of spinal morphine analgesia. Brain Res Dev Brain Res 1998;108: 239e54. 64. van Dijk M, Bouwmeester NJ, Duivenvoorden HJ, Koot HM, Tibboel D, Passchier J, et al. Efficacy of continuous versus intermittent morphine administration after major surgery in 0-3-year-old infants; a double-blind randomized controlled trial. Pain 2002;98:305e13. 65. Bouwmeester NJ, Hop WC, van Dijk M, Anand KJ, van den Anker JN, Tibboel D. Postoperative pain in the neonate: age-related differences in morphine requirements and metabolism. Intensive Care Med 2003;29:2009e15. 66. Dyke MP, Kohan R, Evans S. Morphine increases synchronous ventilation in preterm infants. J Paediatr Child Health 1995;31:176e9. 67. Moustogiannis AN, Raju TN, Roohey T, McCulloch KM. Intravenous morphine attenuates pain induced changes in skin blood flow in newborn infants. Neurol Res 1996;18:440e4. 68. Coffman BL, Rios GR, King CD, Tephly TR. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 1997;25:1e4. 69. Lynn AM, Nespeca MK, Bratton SL, Shen DD. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions. Pain 2000;88:89e95. 70. Bouwmeester NJ, van den Anker JN, Hop WC, Anand KJ, Tibboel D. Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants. Br J Anaesth 2003;90:642e52. 71. Bouwmeester NJ, Anand KJ, van Dijk M, Hop WC, Boomsma F, Tibboel D. Hormonal and metabolic stress responses after major surgery in children aged 0-3 years: a double-blind, randomized trial comparing the effects of continuous versus intermittent morphine. Br J Anaesth 2001;87:390e9. 72. Kart T, Christrup LL, Rasmussen M. Recommended use of morphine in neonates, infants and children based on a literature review: part 2dclinical use. Paediatr Anaesth 1997;7:93e101. 73. Gill AM, Cousins A, Nunn AJ, Choonara IA. Opiate-induced respiratory depression in pediatric patients. Ann Pharmacother 1996;30:125e9. 74. Lynn AM, Nespeca MK, Opheim KE, Slattery JT. Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993;77:695e701. 75. Wood CM, Rushforth JA, Hartley R, Dean H, Wild J, Levene MI. Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates. Arch Dis Child Fetal Neonatal Ed 1998;79:F34e9.
7 76. Hällström M, Koivisto AM, Janas M, Tammela O. Frequency of and risk factors for necrotizing enterocolitis in infants born before 33 weeks of gestation. Acta Paediatr 2003;92:111e3. 77. Carbajal R, Lenclen R, Jugie M, Paupe A, Barton BA, Anand KJ. Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates. Pediatrics 2005;115:1494e500. 78. Anand KJ, Hall RW, Desai N, Shephard B, Bergqvist LL, Young TE, et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet 2004;363:1673e82. 79. Simons SH, van Dijk M, van Lingen RA, Roofthooft D, Duivenvoorden HJ, Jongeneel N, et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA 2003;290: 2419e27. 80. Bellù R, de Waal KA, Zanini R. Opioids for neonates receiving mechanical ventilation. Cochrane Database Syst Rev; 2008. CD004212. 81. Perlman JM. Morphine, hypotension, and intraventricular hemorrhage in the ventilated premature infant. Pediatrics 2005;115:1416e8. 82. Grunau RE, Whitfield MF, Petrie-Thomas J, Synnes AR, Cepeda IL, Keidar A, et al. Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants. Pain 2009;143:138e46. 83. Ferguson SA, Ward WL, Paule MG, Hall RW, Anand KJ. A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood. Neurotoxicol Teratol 2012;34:47e55. 84. Vinall J, Miller SP, Chau V, Brummelte S, Synnes AR, Grunau RE. Neonatal pain in relation to postnatal growth in infants born very preterm. Pain 2012;153: 1374e81. 85. Somri M, Matter I, Parisinos CA, Shaoul R, Mogilner JG, Bader D, et al. The effect of combined spinal-epidural anesthesia versus general anesthesia on the recovery time of intestinal function in young infants undergoing intestinal surgery: a randomized, prospective, controlled trial. J Clin Anesth 2012;24: 439e45. 86. Somri M, Coran AG, Mattar I, Teszler C, Shaoul R, Tomkins O, et al. The postoperative occurrence of cardio-respiratory adverse events in small infants undergoing gastrointestinal surgery: a prospective comparison of general anesthesia and combined spinal-epidural anesthesia. Pediatr Surg Int 2011;27: 1173e8. 87. Somri M, Tome R, Yanovski B, Asfandiarov E, Carmi N, Mogilner J, et al. Combined spinal-epidural anesthesia in major abdominal surgery in high-risk neonates and infants. Paediatr Anaesth 2007;17:1059e65. 88. Bösenberg AT. Epidural analgesia for major neonatal surgery. Paediatr Anaesth 1998;8:479e83. 89. Bösenberg AT, Hadley GP, Wiersma R. Oesophageal atresia: caudo-thoracic epidural anaesthesia reduces the need for post-operative ventilatory support. Pediatr Surg Int 1992;7:289e91. 90. Shenkman Z, Hoppenstein D, Erez I, Dolfin T, Freud E. Continuous lumbar/ thoracic epidural analgesia in low-weight paediatric surgical patients: practical aspects and pitfalls. Pediatr Surg Int 2009;25:623e34. 91. Bösenberg AT, Jöhr M, Wolf AR. Pro con debate: the use of regional vs systemic analgesia for neonatal surgery. Paediatr Anaesth 2011;21:1247e58. 92. von Ungern-Sternberg BS, Regli A, Frei FJ, Hammer J, Schibler A, Erb TO. The effect of caudal block on functional residual capacity and ventilation homogeneity in healthy children. Anaesthesia 2006;61:758e63. 93. Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology 2000;93:858e75. 94. Wolf AR, Doyle E, Thomas E. Modifying infant stress responses to major surgery: spinal vs extradural vs opioid analgesia. Paediatr Anaesth 1998;8: 305e11. 95. Flandin-Bléty C, Barrier G. Accidents following extradural analgesia in children. The results of a retrospective study. Paediatr Anaesth 1995;5:41e6. 96. Ecoffey C, Lacroix F, Giaufré E, Orliaguet G, Courrèges P. Association des Anesthésistes Réanimateurs Pédiatriques d’Expression Française (ADARPEF). Epidemiology and morbidity of regional anesthesia in children: a follow-up one-year prospective survey of the French-Language Society of Paediatric Anaesthesiologists (ADARPEF). Paediatr Anaesth 2010;20:1061e9. 97. Bösenberg AT, Bland BA, Schulte-Steinberg O, Downing JW. Thoracic epidural anesthesia via caudal route in infants. Anesthesiology 1988;69:265e9. 98. Baidya DK, Pawar DK, Dehran M, Gupta AK. Advancement of epidural catheter from lumbar to thoracic space in children: comparison between 18G and 23G catheters. J Anaesthesiol Clin Pharmacol 2012;28:21e7. 99. van Niekerk J, Bax-Vermeire BM, Geurts JW, Kramer PP. Epidurography in premature infants. Anaesthesia 1990;45:722e5. 100. Valairucha S, Seefelder C, Houck CS. Thoracic epidural catheters placed by the caudal route in infants: the importance of radiographic confirmation. Paediatr Anaesth 2002;12:424e8. 101. Tsui BC, Seal R, Koller J. Thoracic epidural catheter placement via the caudal approach in infants by using electrocardiographic guidance. Anesth Analg 2002;95:326e30. 102. Schwartz D, King A. Caudally threaded thoracic epidural catheter as the sole anesthetic in a premature infant and ultrasound confirmation of the catheter tip. Paediatr Anaesth 2009;19:808e10. 103. Ueda K, Shields BE, Brennan TJ. Transesophageal echocardiography: a novel technique for guidance and placement of an epidural catheter in infants. Anesthesiology 2013;118:219e22.
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
8
S. Maitra et al.
104. Vas L, Naregal P, Sanzgiri S, Negi A. Some vagaries of neonatal lumbar epidural anaesthesia. Paediatr Anaesth 1999;9:217e23. 105. Breschan C, Krumpholz R, Jost R, Likar R. Intraspinal haematoma following lumbar epidural anaesthesia in a neonate. Paediatr Anaesth 2001;11:105e8. 106. Willschke H, Bosenberg A, Marhofer P, Willschke J, Schwindt J, Weintraud M, et al. Epidural catheter placement in neonates: sonoanatomy and feasibility of
ultrasonographic guidance in term and preterm neonates. Reg Anesth Pain Med 2007;32:34e40. 107. Lönnqvist PA. Regional anaesthesia and analgesia in the neonate. Best Pract Res Clin Anaesthesiol 2010;24:309e21. 108. Berde CB. Toxicity of local anesthetics in infants and children. J Pediatr 1993;122:S14e20.
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
Contents lists available at ScienceDirect
Acta Anaesthesiologica Taiwanica journal homepage: www.e-aat.com
Review Article
Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management Souvik Maitra 1, Dalim Kumar Baidya 1 *, Puneet Khanna 2, Bikash Ranjan Ray 2, Shasanka Shekhar Panda 3, Minu Bajpai 3 1 2 3
Department of Anaesthesia and Intensive Care, All India Institute of Medical Sciences, New Delhi, India Department of Anesthesiology, Post-Graduate Institute of Medical Education and Research, Chandigarh, India Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 July 2013 Accepted 10 February 2014
Current literature lacks systematic data on acute perioperative pain management in neonates and mainly focuses only on procedural pain management. In the current review, the neurophysiological basis of neonatal pain perception and the role of different analgesic drugs and techniques in perioperative pain management in neonates are systematically reviewed. Intravenous opioids such as morphine or fentanyl as either intermittent bolus or continuous infusion remain the most common modality for the treatment of perioperative pain. Paracetamol has a promising role in decreasing opioid requirement. However, routine use of ketorolac or other nonsteroidal anti-inflammatory drugs is not usually recommended. Epidural analgesia is safe in experienced hands and provides several benefits over systemic opioids such as early extubation and early return of bowel function. Copyright Ó 2014, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved.
Key words: acute perioperative pain; epidural; neonates; opioids
1. Introduction
2. Methods
Pain is the most common complaint when a patient presents to a physician. Pain management in neonates warrants special consideration because the present knowledge of developmental neurophysiology is improved every day. The neonates are a special group of population where a fine balance between optimal pain relief and adverse effects of drugs is of utmost importance. With the advancement of various surgical techniques and improved perioperative care, an increasing number of sick neonates undergo surgery, and optimal perioperative pain management may improve clinical outcomes in these neonates. In this evidence-based review, we have reviewed the neurophysiology of neonatal pain perception, long-term effects of suboptimal pain relief, and role of various drugs and techniques used in acute perioperative pain management in neonates.
Electronic searches were performed in MEDLINE, PubMed Central, Embase, and Scopus using the keywords “neonate,” “postoperative,” “pain,” and “acute pain.” The following professional society/organization’s web-based guidelines were also searched “Association of Pediatric Anesthesiologists,” “American Association of Pediatrics,” and “British Pain Society.” The level of evidences (LOEs) was decided according to the following guidelines1:
Conflicts of interest: None of the authors received any financial support for the preparation of the manuscript. * Corresponding author. Department of Anaesthesia and Intensive Care, Room Number 507, 5th Floor, Academic Wing, CDER, All India Institute of Medical Sciences, New Delhi 110029, India. E-mail address: [email protected] (D.K. Baidya).
Level I: Evidence obtained from at least one properly designed randomized controlled trial (RCT). Level II-1: Evidence obtained from well-designed controlled trials without randomization. Level II-2: Evidence obtained from well-designed cohort or casecontrol analytic studies, preferably from more than one center or research group. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
http://dx.doi.org/10.1016/j.aat.2014.02.004 1875-4597/Copyright Ó 2014, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
2
S. Maitra et al.
3. Developmental neurobiology of pain The immature nervous system develops from early gestation and continues to change in the postnatal period. Nociception involves peripheral sensory receptors, afferent sensory nerve fibers, the spinal dorsal horn, spinothalamic and thalamocortical tracts, and the sensory cortex. During maturation, C-fiber projections are the last group of primary afferents to enter the dorsal gray matter, after proprioceptive and low-threshold A fibers. By Week 30, nerve tracts are myelinated up to the thalamic level. Afferent neurons in the thalamus project axons migrating into the neocortex. Synaptic connections of these thalamocortical tracts might occur at 24 weeks’ gestation. After reviewing the literature, Lee et al2 concluded that direct thalamocortical fibers that are not specific for pain begin to emerge between 21 and 28 weeks’ developmental age (23 and 30 weeks’ gestational age). Fitzgerald stated that most pain responses in preterm infants, 36 wk
7.5e10 7.5e10 15
6e8 6 6
40 50 60
PCA ¼ postconceptional age.
The reserves of glutathione needed for detoxification of the toxic metabolic intermediate from paracetamol (N-acetyl-p-benzoquinone) may be depleted after repeated therapeutic doses. The metabolic activation of paracetamol is a prerequisite for hepatotoxicity. Neonates can produce these potentially hepatotoxic metabolites, but there are suggestions of a lower activity of cytochrome P450 in neonates.44 This may explain the resistance to paracetamol-induced hepatotoxicity seen in neonates. However, at present, the use of intravenous paracetamol in preterm neonates with a PCA of less than 32 weeks may not be justified before further pharmacokinetic/pharmacodynamic studies are conducted.45 9.2. Nonsteroidal anti-inflammatory drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of drugs having antipyretic, analgesic, and antiinflammatory effects. They act by reducing PG biosynthesis through inhibition of cyclooxygenase (COX), which exists as two major isoforms (COX-1 and COX-2). The PGs produced by the COX-1 isoenzyme protect the gastric mucosa, regulate renal blood flow, and induce platelet aggregation. The anti-inflammatory effects of NSAIDs are thought to occur primarily through inhibition of the inducible isoform, COX-2. The NSAIDs are well established as a part of multimodal analgesia in older children. A recent meta-analysis46 of 27 RCTs concluded that use of perioperative NSAIDs is associated with less opioid consumption and postoperative nausea and vomiting. However, similar robust data in neonates are lacking until today. In 2004, a small observational study47 assessed the effect of ketorolac in neonates. They found ketorolac to be an effective analgesic at a dose of 1 mg/kg without any clinical and biochemical adverse effects on the renal, hepatic, or hematological system. Later, a retrospective review48 also reported similar results. In 2009, a study on the safety and efficacy of ketorolac in infants younger than 6 months of age concluded that intravenous ketorolac appears to be safe when used in infants less than 6 months of age with biventricular circulations following cardiothoracic surgery, but it does not decrease the use of standard analgesic therapy.49 However, in 2011, another retrospective analysis50 found that infants younger than 21 days and less than 37 weeks’ completed gestational age are at significantly increased risk for bleeding events and should not be candidates for ketorolac therapy. In the absence of prospective RCTs, routine use of NSAIDs in neonates cannot be recommended at this time. 9.3. Opioids Opioids are the mainstay of pain management following a major surgery even in neonates. Morphine is the most commonly used opioid in the postoperative period; however, fentanyl is also being increasingly used. Opioids exhibit narrow therapeutic window between analgesic doses and the dose that may cause respiratory depression. Analgesia from opioid is mediated by spinal or supraspinal activation of opioid receptors, leading to decreased release of
neurotransmitters from nociceptive neurons inhibiting the ascending neuronal pain pathways and altering the perception and response to pain.51 Opioid receptors also exist outside the central nervous system in the dorsal root ganglia and on the peripheral terminals of primary afferent neurons.52 Neonates receiving opioids should have continuous pulse oximetry monitoring and should be managed in a setting in which rapid intervention for airway management is possible, because respiratory-rate monitoring alone may be an inadequate predictor of impending apnea.53 9.4. Fentanyl Fentanyl is almost 100 times more potent than morphine and is considered as a selective m-receptor agonist. Fentanyl has a rapid, predictable onset of action with a short duration of action mostly due to its high lipid solubility. It is associated with greater hemodynamic stability.54 Fentanyl may be the preferred analgesic agent for critically ill patients with hemodynamic instability and patients with symptoms related to histamine release during morphine infusion.55 However, fentanyl may be associated with rapid development of tolerance56,57 and chest wall rigidity.58 All metabolites of fentanyl are inactive and a small amount of fentanyl is eliminated by the renal route without metabolism. Fentanyl clearance can be impaired by decreased hepatic blood flow (e.g., from increased intra-abdominal pressure) in neonates after major abdominal surgery.59 The clearance of fentanyl is immature at birth but increases dramatically thereafter. Fentanyl clearance is 70e80% of adult values in term neonates and, standardized to a 70-kg person, appears to reach adult levels within the first 2 weeks of life.60 Fentanyl has been shown to effectively prevent preterm neonates from surgical stress responses and to improve postoperative outcomes.7 A large double-blind RCT concluded that fentanyl may be superior to morphine for short-term postnatal analgesia in newborn infants.61 Fentanyl may be used as bolus and/or as an intermittent dosing of 0.5e2.0 mg/kg or as a continuous infusion of 0.5e2.0 mg/kg/hour.62 9.5. Morphine Morphine is the gold standard opioid with which all other opioids are compared and it is the most thoroughly investigated opioid in neonates. Morphine is water soluble and its solubility in lipids is poor compared with other opioids. Although morphine can also act on k-opioid receptor subtypes,63 its analgesic effect is caused mainly by an activation of m receptors. Morphine alleviates postoperative pain,64 reduces behavioral and hormonal responses,65 improves ventilator synchrony,66 and may also reduce acute procedural pain.67 Morphine is metabolized in the liver by the enzyme uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).68 M3G has been shown to have higher analgesic potency than morphine and also has respiratory-depressive effects. M3G has been suggested to antagonize the antinociceptive and respiratory-depressive effects of morphine and M6G, and contributes to the development of tolerance. Although UGT2B7 is mainly found in the liver, it is also present in the intestines and kidneys. Clinical trials studying morphine for postoperative analgesia have shown large interindividual variability in morphine plasma levels and a wide range of morphine requirements.69 However, neonates, particularly those younger than 7 days,65 require significantly less morphine as they have significantly higher plasma concentrations of morphine, M3G, and M6G, and significantly
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
Acute postoperative pain management in neonates
lower M6G-to-morphine ratio than the older children.70 Moreover, morphine metabolism may be delayed during mechanical ventilation.65 In the postoperative period, morphine can be used as either continuous infusion or intermittent bolus. However, the relative safety and efficacy of either method is controversial. One large RCT in thoracic and abdominal surgical population showed that the efficacy of continuous intravenous infusion of 10 mg/kg/hour morphine is similar to that of infusion of 30 mg/kg morphine every 3 hours after surgery.64,71 Ventilatory effects of the aforementioned two morphine regimen are also similar and routine monitoring is mandatory69 during either of the protocol. The recommended dosage of continuous morphine infusion is 10e30 mg/kg/hour and that of the intermittent dose is 50e100 mg/kg.62 A meta-analysis concluded that an initial morphine dose of 7 mg/kg/hour in term neonates is optimum for postoperative analgesia.72 The use of morphine in the NICU for either postoperative pain or mechanical ventilation is not free from adverse outcomes. In a spontaneously breathing neonate, obviously the most important adverse effect is respiratory depression,73 but most neonates after major surgical procedures are mechanically ventilated. Respiratory depression may occur at plasma morphine concentrations of 15 ng/ mL, and when measured by carbon dioxide response curves or by arterial oxygen tension, similar results are obtained in children from 2 to 570 days of age at the same serum morphine concentration.74 In mechanically ventilated neonates, the important adverse effects are hypotension,75 prolonged requirement of ventilation, urinary retention, decreased gastrointestinal (GI) motility, risk of necrotizing enterocolitis,76 and may be long-term neurobehavioral abnormalities as some animal data indicate. At times, morphine may not provide adequate analgesia for short painful procedures.77 However, the Neurological Outcome and Pre-emptive Analgesia in Neonates trial concluded that continuous infusions of morphine do not increase the vulnerability of ventilated preterm neonates to early adverse neurological events, except in neonates who are hypotensive before morphine therapy or those receiving doses higher than 10 mg/kg/hour.78 They also suggested that intravenous morphine boluses should be used with caution in preterm neonates. An RCT79 published in 2003 did not support the routine use of morphine infusions as a standard of care in preterm newborns who have received ventilatory support as this was not associated with better neurologic outcomes. A Cochrane review also did not recommend routine morphine infusion in the ventilated newborns.80 However, the review did not find any difference in mortality, duration of mechanical ventilation, short-term and longterm neurobehavioral abnormalities but reported a delayed oral feeding. The main argument against the treatment of neonatal pain with opioids is the uncertainty about their side effects.81 Animal studies on long-term effects of neonatal opioid use do not provide enough insight, and data from the human studies are even sparser. A study82 in 2009 evaluated the effects of cumulative procedural pain and morphine exposure with subsequent growth and development, and found that greater overall exposure to intravenous morphine was associated with poorer motor development at 8 months, but not at 18 months’ corrected chronological age. A recent pilot study83 also concluded that morphine analgesia for procedural pain in preterm neonates may be associated with delayed growth and development. By contrast, in 2005, Grunau et al13 found that repeated neonatal procedural pain exposure among preterm infants was associated with downregulation of the hypothalamicepituitaryeadrenal axis, which was not counteracted with morphine. In another recent prospective observational study,84 it
5
was found that repetitive procedural pain in preterm infants during a period of physiological immaturity appears to impact postnatal growth and development. 10. Regional anesthesia/analgesia Although single-injection subarachnoid block (SAB) is the commonly performed regional technique in adults and usually provides immediate postoperative analgesia, SAB is of little use in neonates for postoperative analgesia due to its limited duration of action in this age group. 11. Epidural anesthesia in neonates: risk versus benefits Epidural analgesia has been investigated as a modality of pain relief after major surgeries. There is only one RCT85 that has directly compared the safety and efficacy of epidural analgesia with systemic opioid administration after a major surgery in neonates. The authors reported a faster return of intestinal function and less incidence of pneumonia in neonates who received epidural analgesia. In 2011, a small RCT86 compared the benefits of combined spinaleepidural anesthesia with general anesthesia in neonates undergoing GI surgery. The authors found a significantly less pulmonary complication and more cardiovascular stability in the regional anesthesia group in the postoperative period. Somri et al87 reported that combined spinaleepidural anesthesia could be considered as an effective alternative to general anesthesia in highrisk neonates and infants undergoing upper GI surgery when cautiously used by a pediatric anesthesiologist. Bösenberg88 in 1998 reported that use of lumbar/thoracic epidural analgesia in major abdominal surgeries in neonates was associated with a low risk of complication and advantages of reduced need for intraoperative muscle relaxants and opioid analgesics and postoperative ventilatory support.89 In 2009, Shenkman et al90 reported safe use of continuous epidural analgesia in small infants (1400e4300 g) undergoing major surgery. Neuraxial blockade was not found to be associated with hypotension or hemodynamic instability even in neonates with congenital heart disease.91 Regional analgesia may also have respiratory stimulant action,92 and has been associated with reduced need for mechanical ventilation. Surgical stress response is more effectively mitigated by regional anesthesia in comparison with systemic opioid and it is also free of immunosuppressive effects of opioids.93,94 The most important consideration in central neuraxial block in neonates is the safety and possibility of inadvertent injury to the developing spinal cord. Serious complications including neurologic injury have been reported in neonates,95 and many authors87,88 have mentioned that only an experienced pediatric anesthesiologist should perform central neuraxial block in neonates. 12. Epidural catheter insertion: thoracic catheter position through caudal route Although thoracic epidural catheters have been described in neonates96 in some reports, its routine use at this moment cannot be advocated. However, relative fluidity of the epidural fat in neonates and young infants allows advancement of thoracic catheter inserted through the caudal or lumbar route. In 1988, Bösenberg et al97 described the successful insertion of an 18G epidural catheter up to the thoracic level. A thicker gauge catheter is easier to advance but has a higher possibility of neural damage.98,99 There are numerous ways of confirming epidural catheter position, including X-ray,100 electrocardiography,101 ultrasonography,102 and even transesophageal echocardiography.103
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
6
S. Maitra et al.
The lumbar epidural route is less preferred in neonates,104 and there are reports of paraplegia due to intraspinal hematoma during attempted lumbar epidural block.105 The advent of ultrasound may be especially useful in neonates as the ossification of the vertebral column is reduced and the cord structures may be better visualized.106 13. Local anesthetic dosing The most important prerequisite of an epidural block is that the tip of the epidural catheter should be situated at an intraspinal level that corresponds to the dermatome center of the surgical procedure. Caudal bolus injection of 3 mg/kg ropivacaine or a continuous epidural infusion of 0.2e0.4 mg/kg/hour of the same drug was clinically effective and did not result in excessive plasma levels of the drug.107 In an Anesthesia Patient Safety Foundationesponsored study, it was found that all the children who had systemic toxicity had infusion rates in excess of 0.5 mg/ kg/hour of racemic bupivacaine.108 In a recent review, a maximum bolus dosage of 1.5e2.0 mg/kg followed by an infusion of 0.2 mg/kg/hour was recommended; in addition, this should only be continued beyond 48 hours when considerable benefits exist.107 14. Conclusion Despite various opinions regarding the methods of optimum postoperative pain management in neonates, there is little doubt that neonates feel more pain than their older counterparts. Intravenous opioids with the use of morphine or fentanyl remain the most common modality of neonatal pain management. The role of acetaminophen in decreasing opioid requirement seems to be promising. Although ketorolac appears to be safe, further studies are required before its routine use can be recommended. Epidural analgesia/anesthesia when performed by an experienced anesthesiologist is quite safe and has several benefits over systemic opioids. In cases where technical and logistic feasibility is present, it may be a logical option as a part of balanced anesthesia technique. References 1. Ahn Y, Woods J, Connor S. A systematic review of interventions to facilitate ambulatory laparoscopic cholecystectomy. HPB (Oxford) 2011;13:677e86. 2. Lee SJ, Ralston HJ, Drey EA, Partridge JC, Rosen MA. Fetal pain: a systematic multidisciplinary review of the evidence. JAMA 2005;294:947e54. 3. Fitzgerald M. The development of nociceptive circuits. Nat Rev Neurosci 2005;6:507e20. 4. Oberlander TF, Grunau RE, Fitzgerald C, Whitfield MF. Does parenchymal brain injury affect biobehavioral pain responses in very low birth weight infants at 32 weeks’ postconceptional age? Pediatrics 2002;110:570e6. 5. Fisk NM, Gitau R, Teixeira JM, Giannakoulopoulos X, Cameron AD, Glover VA. Effect of direct fetal opioid analgesia on fetal hormonal and hemodynamic stress response to intrauterine needling. Anesthesiology 2001;95:828e35. 6. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987;1:243e8. 7. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326:1e9. 8. Bromage PR, Shibata HR, Willoughby HW. Influence of prolonged epidural blockade on blood sugar and cortisol responses to operations upon the upper part of the abdomen and the thorax. Surg Gynecol Obstet 1971;132:1051e6. 9. Goldman RD, Koren G. Biologic markers of pain in the vulnerable infant. Clin Perinatol 2002;29:415e25. 10. Grunau RE, Oberlander TF, Whitfield MF, Fitzgerald C, Lee SK. Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 weeks’ postconceptional age. Pediatrics 2001;107:105e12. 11. Taddio A, Shah V, Gilbert-MacLeod C, Katz J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA 2002;288:857e61. 12. Buskila D, Neumann L, Zmora E, Feldman M, Bolotin A, Press J. Pain sensitivity in prematurely born adolescents. Arch Pediatr Adolesc Med 2003;157:1079e82.
13. Grunau RE, Holsti L, Haley DW, Oberlander T, Weinberg J, Solimano A, et al. Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain 2005;113:293e300. 14. Anand KJ. International Evidence-Based Group for Neonatal Pain. Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med 2001;155:173e80. 15. Anand KJ. Clinical importance of pain and stress in preterm neonates. Biol Neonate 1998;73:1e9. 16. Gliess J, Stuttgen G. Morphologic and functional development of the skin. In: Stave U, editor. Physiology of the perinatal periodvol. 2. New York: AppletonCentury-Crofts; 1970. pp. 889e906. 17. Bouza H. The impact of pain in the immature brain. J Matern Fetal Neonatal Med 2009;22:722e32. 18. Grunau R. Early pain in preterm infants. A model of long-term effects. Clin Perinatol 2002;29:373e94. 19. Taddio A, Ohlsson A, Einarson TR, Stevens B, Koren G. A systematic review of lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in neonates. Pediatrics 1998;101:E1. 20. Grunau RVE, Craig KD. Facial activity as a measure of neonatal pain expression. In: Tyler DC, Krane EJ, editors. Advances in pain research and therapy. New York: Raven Press; 1990. pp. 147e55. 21. Grunau RV, Johnston CC, Craig KD. Neonatal facial and cry responses to invasive and non-invasive procedures. Pain 1990;42:295e305. 22. Oberlander T, Saul JP. Methodological considerations for the use of heart rate variability as a measure of pain reactivity in vulnerable infants. Clin Perinatol 2002;29:427e43. 23. van Dijk M, de Boer JB, Koot HM, Duivenvoorden HJ, Passchier J, Bouwmeester N, et al. The association between physiological and behavioral pain measures in 0- to 3-year-old infants after major surgery. J Pain Symptom Manage 2001;22:600e9. 24. Hummel P, van Dijk M. Pain assessment: current status and challenges. Semin Fetal Neonatal Med 2006;11:237e45. 25. Herrington CJ, Olomu IN, Geller SM. Salivary cortisol as indicators of pain in preterm infants: a pilot study. Clin Nurs Res 2004;13:53e68. 26. Hullett B, Chambers N, Preuss J, Zamudio I, Lange J, Pascoe E, et al. Monitoring electrical skin conductance: a tool for the assessment of postoperative pain in children? Anesthesiology 2009;111:513e7. 27. Anand KJ, Aranda JV, Berde CB, Buckman S, Capparelli EV, Carlo W, et al. Summary proceedings from the neonatal pain-control group. Pediatrics 2006;117:S9e22. 28. Duhn LJ, Medves JM. A systematic integrative review of infant pain assessment tools. Adv Neonatal Care 2004;4:126e40. 29. Lawrence J, Alcock D, McGrath P, Kay J, MacMurray SB, Dulberg C. The development of a tool to assess neonatal pain. Neonatal Netw 1993;12:59e66. 30. Stevens B, Johnston C, Petryshen P, Taddio A. Premature infant pain profile: development and initial validation. Clin J Pain 1996;12:13e22. 31. Krechel SW, Bildner J. CRIES: a new neonatal postoperative pain measurement score. Initial testing of validity and reliability. Paediatr Anaesth 1995;5:53e61. 32. Suraseranivongse S, Kaosaard R, Intakong P, Pornsiriprasert S, Karnchana Y, Kaopinpruck J, et al. A comparison of postoperative pain scales in neonates. Br J Anaesth 2006;97:540e4. 33. Ambuel B, Hamlett KW, Marx CM, Blumer JL. Assessing distress in pediatric intensive care environments: the COMFORT scale. J Pediatr Psychol 1992;17: 95e109. 34. Franck LS, Ridout D, Howard R, Peters J, Honour JW. A comparison of pain measures in newborn infants after cardiac surgery. Pain 2011;152:1758e65. 35. Hummel P, Puchalski M, Creech SD, Weiss MG. Clinical reliability and validity of the N-PASS: neonatal pain, agitation and sedation scale with prolonged pain. J Perinatol 2008;28:55e60. 36. Arana A, Morton NS, Hansen TG. Treatment with paracetamol in infants. Acta Anaesthesiol Scand 2001;45:20e9. 37. Ceelie I, de Wildt SN, van Dijk M, van den Berg MM, van den Bosch GE, Duivenvoorden HJ, et al. Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial. JAMA 2013;309:149e54. 38. Björkman R, Hallman KM, Hedner J, Hedner T, Henning M. Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. Pain 1994;57: 259e64. 39. Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther 1976;19:284e94. 40. Ryan Cook D, Davis PJ, Lerman J. Pharmacology of pediatric anesthesia. In: Motoyama EK, Davis PJ, editors. Smith’s anaesthesia for infants and children. 6th ed. St. Louis, MO: Mosby; 1996. pp. 160e70. 41. van Lingen RA, Deinum JT, Quak JM, Kuizenga AJ, van Dam JG, Anand KJ, et al. Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonatal Ed 1999;80:F59e63. 42. Allegaert K, de Hoon J, Verbesselt R, Vanhole C, Devlieger H, Tibboel D. Intraand interindividual variability of glucuronidation of paracetamol during repeated administration of propacetamol in neonates. Acta Paediatr 2005;94: 1273e9. 43. De Lima J, Carmo KB. Practical pain management in the neonate. Best Pract Res Clin Anaesthesiol 2010;24:291e307. 44. Roberts I, Robinson MJ, Mughal MZ, Ratcliffe JG, Prescott LF. Paracetamol metabolites in the neonate following maternal overdose. Br J Clin Pharmacol 1984;18:201e6.
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
Acute postoperative pain management in neonates 45. van den Anker JN, Tibboel D. Pain relief in neonates: when to use intravenous paracetamol. Arch Dis Child 2011;96:573e4. 46. Michelet D, Andreu-Gallien J, Bensalah T, Hilly J, Wood C, Nivoche Y, et al. A meta-analysis of the use of nonsteroidal antiinflammatory drugs for pediatric postoperative pain. Anesth Analg 2012;114:393e406. 47. Papacci P, De Francisci G, Iacobucci T, Giannantonio C, De Carolis MP, Zecca E, et al. Use of intravenous ketorolac in the neonate and premature babies. Paediatr Anaesth 2004;14:487e92. 48. Moffett BS, Wann TI, Carberry KE, Mott AR. Safety of ketorolac in neonates and infants after cardiac surgery. Paediatr Anaesth 2006;16:424e8. 49. Dawkins TN, Barclay CA, Gardiner RL, Krawczeski CD. Safety of intravenous use of ketorolac in infants following cardiothoracic surgery. Cardiol Young 2009;19:105e8. 50. Aldrink JH, Ma M, Wang W, Caniano DA, Wispe J, Puthoff T. Safety of ketorolac in surgical neonates and infants 0 to 3 months old. J Pediatr Surg 2011;46: 1081e5. 51. Suresh S, Anand KJ. Opioid tolerance in neonates: mechanisms, diagnosis, assessment, and management. Semin Perinatol 1998;22:425e33. 52. Stein C, Machelska H, Binder W, Schäfer M. Peripheral opioid analgesia. Curr Opin Pharmacol 2001;1:62e5. 53. Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Engl J Med 2002;347:1094e103. 54. Yaster M, Koehler RC, Traystman RJ. Effects of fentanyl on peripheral and cerebral hemodynamics in neonatal lambs. Anesthesiology 1987;66:524e30. 55. Tibboel D, Anand KJ, van den Anker JN. The pharmacological treatment of neonatal pain. Semin Fetal Neonatal Med 2005;10:195e205. 56. Arnold JH, Truog RD, Scavone JM, Fenton T. Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr 1991;119:639e43. 57. Franck LS, Vilardi J, Durand D, Powers R. Opioid withdrawal in neonates after continuous infusions of morphine or fentanyl during extracorporeal membrane oxygenation. Am J Crit Care 1998;7:364e9. 58. Fahnenstich H, Steffan J, Kau N, Bartmann P. Fentanyl-induced chest wall rigidity and laryngospasm in preterm and term infants. Crit Care Med 2000;28: 836e9. 59. Gauntlett IS, Fisher DM, Hertzka RE, Kuhls E, Spellman MJ, Rudolph C. Pharmacokinetics of fentanyl in neonatal humans and lambs: effects of age. Anesthesiology 1988;69:683e7. 60. van Lingen RA, Simons SH, Anderson BJ, Tibboel D. The effects of analgesia in the vulnerable infant during the perinatal period. Clin Perinatol 2002;29:511e34. 61. Saarenmaa E, Huttunen P, Leppäluoto J, Meretoja O, Fellman V. Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: a randomized trial. J Pediatr 1999;134:144e50. 62. Simons SH, Anand KJ. Pain control: opioid dosing, population kinetics and side-effects. Semin Fetal Neonatal Med 2006;11:260e7. 63. Rahman W, Dashwood MR, Fitzgerald M, Aynsley-Green A, Dickenson AH. Postnatal development of multiple opioid receptors in the spinal cord and development of spinal morphine analgesia. Brain Res Dev Brain Res 1998;108: 239e54. 64. van Dijk M, Bouwmeester NJ, Duivenvoorden HJ, Koot HM, Tibboel D, Passchier J, et al. Efficacy of continuous versus intermittent morphine administration after major surgery in 0-3-year-old infants; a double-blind randomized controlled trial. Pain 2002;98:305e13. 65. Bouwmeester NJ, Hop WC, van Dijk M, Anand KJ, van den Anker JN, Tibboel D. Postoperative pain in the neonate: age-related differences in morphine requirements and metabolism. Intensive Care Med 2003;29:2009e15. 66. Dyke MP, Kohan R, Evans S. Morphine increases synchronous ventilation in preterm infants. J Paediatr Child Health 1995;31:176e9. 67. Moustogiannis AN, Raju TN, Roohey T, McCulloch KM. Intravenous morphine attenuates pain induced changes in skin blood flow in newborn infants. Neurol Res 1996;18:440e4. 68. Coffman BL, Rios GR, King CD, Tephly TR. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 1997;25:1e4. 69. Lynn AM, Nespeca MK, Bratton SL, Shen DD. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions. Pain 2000;88:89e95. 70. Bouwmeester NJ, van den Anker JN, Hop WC, Anand KJ, Tibboel D. Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants. Br J Anaesth 2003;90:642e52. 71. Bouwmeester NJ, Anand KJ, van Dijk M, Hop WC, Boomsma F, Tibboel D. Hormonal and metabolic stress responses after major surgery in children aged 0-3 years: a double-blind, randomized trial comparing the effects of continuous versus intermittent morphine. Br J Anaesth 2001;87:390e9. 72. Kart T, Christrup LL, Rasmussen M. Recommended use of morphine in neonates, infants and children based on a literature review: part 2dclinical use. Paediatr Anaesth 1997;7:93e101. 73. Gill AM, Cousins A, Nunn AJ, Choonara IA. Opiate-induced respiratory depression in pediatric patients. Ann Pharmacother 1996;30:125e9. 74. Lynn AM, Nespeca MK, Opheim KE, Slattery JT. Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993;77:695e701. 75. Wood CM, Rushforth JA, Hartley R, Dean H, Wild J, Levene MI. Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates. Arch Dis Child Fetal Neonatal Ed 1998;79:F34e9.
7 76. Hällström M, Koivisto AM, Janas M, Tammela O. Frequency of and risk factors for necrotizing enterocolitis in infants born before 33 weeks of gestation. Acta Paediatr 2003;92:111e3. 77. Carbajal R, Lenclen R, Jugie M, Paupe A, Barton BA, Anand KJ. Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates. Pediatrics 2005;115:1494e500. 78. Anand KJ, Hall RW, Desai N, Shephard B, Bergqvist LL, Young TE, et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet 2004;363:1673e82. 79. Simons SH, van Dijk M, van Lingen RA, Roofthooft D, Duivenvoorden HJ, Jongeneel N, et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA 2003;290: 2419e27. 80. Bellù R, de Waal KA, Zanini R. Opioids for neonates receiving mechanical ventilation. Cochrane Database Syst Rev; 2008. CD004212. 81. Perlman JM. Morphine, hypotension, and intraventricular hemorrhage in the ventilated premature infant. Pediatrics 2005;115:1416e8. 82. Grunau RE, Whitfield MF, Petrie-Thomas J, Synnes AR, Cepeda IL, Keidar A, et al. Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants. Pain 2009;143:138e46. 83. Ferguson SA, Ward WL, Paule MG, Hall RW, Anand KJ. A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood. Neurotoxicol Teratol 2012;34:47e55. 84. Vinall J, Miller SP, Chau V, Brummelte S, Synnes AR, Grunau RE. Neonatal pain in relation to postnatal growth in infants born very preterm. Pain 2012;153: 1374e81. 85. Somri M, Matter I, Parisinos CA, Shaoul R, Mogilner JG, Bader D, et al. The effect of combined spinal-epidural anesthesia versus general anesthesia on the recovery time of intestinal function in young infants undergoing intestinal surgery: a randomized, prospective, controlled trial. J Clin Anesth 2012;24: 439e45. 86. Somri M, Coran AG, Mattar I, Teszler C, Shaoul R, Tomkins O, et al. The postoperative occurrence of cardio-respiratory adverse events in small infants undergoing gastrointestinal surgery: a prospective comparison of general anesthesia and combined spinal-epidural anesthesia. Pediatr Surg Int 2011;27: 1173e8. 87. Somri M, Tome R, Yanovski B, Asfandiarov E, Carmi N, Mogilner J, et al. Combined spinal-epidural anesthesia in major abdominal surgery in high-risk neonates and infants. Paediatr Anaesth 2007;17:1059e65. 88. Bösenberg AT. Epidural analgesia for major neonatal surgery. Paediatr Anaesth 1998;8:479e83. 89. Bösenberg AT, Hadley GP, Wiersma R. Oesophageal atresia: caudo-thoracic epidural anaesthesia reduces the need for post-operative ventilatory support. Pediatr Surg Int 1992;7:289e91. 90. Shenkman Z, Hoppenstein D, Erez I, Dolfin T, Freud E. Continuous lumbar/ thoracic epidural analgesia in low-weight paediatric surgical patients: practical aspects and pitfalls. Pediatr Surg Int 2009;25:623e34. 91. Bösenberg AT, Jöhr M, Wolf AR. Pro con debate: the use of regional vs systemic analgesia for neonatal surgery. Paediatr Anaesth 2011;21:1247e58. 92. von Ungern-Sternberg BS, Regli A, Frei FJ, Hammer J, Schibler A, Erb TO. The effect of caudal block on functional residual capacity and ventilation homogeneity in healthy children. Anaesthesia 2006;61:758e63. 93. Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology 2000;93:858e75. 94. Wolf AR, Doyle E, Thomas E. Modifying infant stress responses to major surgery: spinal vs extradural vs opioid analgesia. Paediatr Anaesth 1998;8: 305e11. 95. Flandin-Bléty C, Barrier G. Accidents following extradural analgesia in children. The results of a retrospective study. Paediatr Anaesth 1995;5:41e6. 96. Ecoffey C, Lacroix F, Giaufré E, Orliaguet G, Courrèges P. Association des Anesthésistes Réanimateurs Pédiatriques d’Expression Française (ADARPEF). Epidemiology and morbidity of regional anesthesia in children: a follow-up one-year prospective survey of the French-Language Society of Paediatric Anaesthesiologists (ADARPEF). Paediatr Anaesth 2010;20:1061e9. 97. Bösenberg AT, Bland BA, Schulte-Steinberg O, Downing JW. Thoracic epidural anesthesia via caudal route in infants. Anesthesiology 1988;69:265e9. 98. Baidya DK, Pawar DK, Dehran M, Gupta AK. Advancement of epidural catheter from lumbar to thoracic space in children: comparison between 18G and 23G catheters. J Anaesthesiol Clin Pharmacol 2012;28:21e7. 99. van Niekerk J, Bax-Vermeire BM, Geurts JW, Kramer PP. Epidurography in premature infants. Anaesthesia 1990;45:722e5. 100. Valairucha S, Seefelder C, Houck CS. Thoracic epidural catheters placed by the caudal route in infants: the importance of radiographic confirmation. Paediatr Anaesth 2002;12:424e8. 101. Tsui BC, Seal R, Koller J. Thoracic epidural catheter placement via the caudal approach in infants by using electrocardiographic guidance. Anesth Analg 2002;95:326e30. 102. Schwartz D, King A. Caudally threaded thoracic epidural catheter as the sole anesthetic in a premature infant and ultrasound confirmation of the catheter tip. Paediatr Anaesth 2009;19:808e10. 103. Ueda K, Shields BE, Brennan TJ. Transesophageal echocardiography: a novel technique for guidance and placement of an epidural catheter in infants. Anesthesiology 2013;118:219e22.
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
8
S. Maitra et al.
104. Vas L, Naregal P, Sanzgiri S, Negi A. Some vagaries of neonatal lumbar epidural anaesthesia. Paediatr Anaesth 1999;9:217e23. 105. Breschan C, Krumpholz R, Jost R, Likar R. Intraspinal haematoma following lumbar epidural anaesthesia in a neonate. Paediatr Anaesth 2001;11:105e8. 106. Willschke H, Bosenberg A, Marhofer P, Willschke J, Schwindt J, Weintraud M, et al. Epidural catheter placement in neonates: sonoanatomy and feasibility of
ultrasonographic guidance in term and preterm neonates. Reg Anesth Pain Med 2007;32:34e40. 107. Lönnqvist PA. Regional anaesthesia and analgesia in the neonate. Best Pract Res Clin Anaesthesiol 2010;24:309e21. 108. Berde CB. Toxicity of local anesthetics in infants and children. J Pediatr 1993;122:S14e20.
Please cite this article in press as: Maitra S, et al., Acute perioperative pain in neonates: An evidence-based review of neurophysiology and management, Acta Anaesthesiologica Taiwanica (2014), http://dx.doi.org/10.1016/j.aat.2014.02.004
