Recently there have been significant advances TERAPIJA BOLA PEDIJATRIJSKIH BOLESNIKA. ANESTEZIOLOŠKI I ASPEKTI INTENZIVNOG LEČENJA

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1 UDK: PAEDIATRIC PAIN MANAGEMENT FOR ANAESTHETISTS AND INTENSIVISTS ID: Rad je saopšten na Međunarodnom simpozijumu Peti anglo srpski dani anestezije, održanom 4-6 oktobra 2012, u Beogradu. PAEDIATRIC PAIN MANAGEMENT FOR ANAESTHETISTS AND INTENSIVISTS Richard F. Howard Department of anesthesia and pain management, Great Ormond Street Hospital for Children, London, United Kingdom Summary. Pediatric patients are specific in every way, especialy regarding pain thresholds. This lecture provides an update for anaesthetists and intensivists. Effective pain assessment is central to the prevention and relief of pain. For precise and adequate pediatric patient management, level of pain they are expiriencing must be measured frequently, its intensity documented, and appropriate remedial action taken when needed. There are different types for describing pain level. Older children are able to use self-report scales such as the visual analogue scale (VAS) or numerical rating scale (NRS). These methods are not accurate in children who are too young to understand such concepts and cannot be used in infants, pre-verbal or non-verbal children. A number of detailed and helpful guidelines on the management of acute pain in children are available. Healthcare professionals should receive adequate training in the principles of postoperative pain management, institutional protocols and, also these guidelines must be available. Key words: management, pediatric, pain, measurement, acute Introduction Recently there have been significant advances in our understanding of pain mechanisms and evidence-based management of acute pain in infants and children. The aim of this lecture is to TERAPIJA BOLA PEDIJATRIJSKIH BOLESNIKA. ANESTEZIOLOŠKI I ASPEKTI INTENZIVNOG LEČENJA Richard F. Howard Odeljenje anestezije i terpaije bola, Great Ormond Street dečja bolnica, London, Velika Britanija Sažetak. Pedijatrijski bolesnici su specifični u svakom pogledu, a posebno po pitanju kupiranja bola. Ovaj rad pokazuje najnovije stavove, potrebne anesteziolozima i intenzivistima. Efektiva procena nivoa bola ključna je u prevenciji i otklanjanju bola. Za preciznu i adekvatnu terapiju bola pedijatrijskog bolesnika, neophodna je česta procena jačine bola. Dobijene rezultate treba dokumentovati i, kada je potrebno, preduzeti određene mere. Postoje različiti načini za izražavanje jačine bola. Starija deca mogu da koriste subjektivne skale, kao što su vizuelna analogna skala (VAS) ili numerička sbodovna skala (NRS). Ove metode ne mogu se koristiti kod dece koja ne mogu da razumeju koncepte ovih skala. Takođe, one ne mogu biti korišćene kod odojčadi i dece koja nisu progovorila. Dostupan je veliki broj vodiča za terapiju akutnog bola u dece. Lekari, koji se bave ovom tematikom, treba konstantno da se usavršavaju i da im terapijski vodiči budu dostupni. Ključne reči: terapija, pedijatrijski, bol, merenje, akutno provide an update for anaesthetists and intensivists on the following: 1. Developmental neurobiology of pain in children 2. Measurement of pain 3. Management of acute pain: a) Procedural pain and pain in ICU b) Postoperative pain. Adresa autora: Richard F. Howard, Great Ormond Street Hospital for Children, Great Ormond Street, London, WC1N 3JH United Kingdom, tel: , ich.ucl.ac.uk

2 24 SJAIT 2013/ Neurobiology of pain in children Neonates are known to be relatively more sensitive than older children and adults to nociceptive pain. Pain thresholds are lower at birth and they increase as a function of developmental age throughout infancy and childhood. Studies of thresholds to mechanical stimuli (touch, pressure) in infants from pre-term to 3 months of age show a clear linear relationship between the mechanical force needed to trigger a reflex withdrawal response and chronological age. This increased sensitivity is important; the physiological consequences of unmodified painful tissue damaging inputs at this age were first clearly demonstrated in human studies that measured the stress response to major surgery in neonates. A massive, robust and potentially harmful neuroendocrine stress response to pain, prevented by anaesthesia and analgesia, was found to occur, even at the youngest ages. In addition, it was shown that pain relief during and after surgery also improved important associated postoperative physiological outcomes such as respiratory function in these infants, highlighting the importance of analgesia in overall management strategies. Many aspects of maturation are subject to activity dependant developmental control and it has therefore been a concern that abnormal events such as severe pain in the neonatal period may alter normal development and lead to adverse long-term consequences to sensory processing mechanisms. In fact, surgery or injury such as repeated painful procedures in ICU in the neonatal period has been shown to change the response to subsequent pain months or even years later. In order to fully appreciate the actual and potential consequences of pain in the neonate it is necessary to understand how the infant processes nociceptive information and how these inputs are capable of altering CNS development 1. Pain Processing Mechanisms Nociceptors and sensory pathways are present from embryonic stages of development but they undergo considerable postnatal re-organization and functional change. Refinement of sensorymotor co-ordination and the development of complex integrative central processing functions, particularly in the brain, are known to take place throughout infancy, childhood and adolescence but some of the most important, rapid and profound changes occur during the neonatal period. CNS plasticity, or capacity for change and adaptation is probably never greater than during this period. In fact, such plasticity is essential for neural development and normal levels of activity in nociceptive pathways is one mechanism by which this process is controlled. Conversely, unmodified abnormally high levels of activity such as during surgery without anesthesia or severe pain without analgesia may be contributors to some of the longterm changes in pain perception. Newborn infants have lower response thresholds for touch, heat, and pain that gradually increase as the nervous system matures. These changes are mediated by alterations in the central connexions and function of nociceptors, and activity in modulatory pathways. Painful mechanical, thermal and chemical stimuli are normally detected by polymodal slow conducting C and fast A-delta fiber nociceptors whose cell bodies are located in the dorsal root ganglion (DRG) and whose central terminals are mostly found in nociceptive specific areas of the superficial dorsal horn of the spinal cord. A-delta fibers terminate directly on ascending projection neurons in lamina I, whereas C fibers generally terminate on interneurons located in lamina II. Fast conducting A-beta fibers mostly detecting innocuous touch and pressure terminate in deeper laminae of the cord. In early development these central terminals are relatively less well localised, and those of low threshold A-fibers overlap with C-fiber terminals in lamina ll thereby potentially activating nociceptive projection neurons when stimulated. A reduction in specificity due to this structural difference is augmented by lack of myelination and immature ion channel kinetics that alter neuronal conduction times and synaptic strength, leading to a more diffuse central response to peripheral stimuli. Intrinsic spinal cord and descending inhibitory controls are also less well organised and reduced in strength, and in contrast to the adult contralateral cutaneous inhibitory receptive fields are not matched to their corresponding excitatory fields. Cutaneous receptive fields, the area of skin that excites an individual sensory neuron when stimulated, are relatively larger and more overlapping at birth such that each stimulus is cable

3 PAEDIATRIC PAIN MANAGEMENT FOR ANAESTHETISTS AND INTENSIVISTS 25 of inducing a response in many more neurons at this time. This lack of specificity, organisation and control is mirrored in motor circuits such that output responses are also more diffuse and less well integrated spatially and temporally. Although little is currently known about nociceptive processing in higher centres of the brain, physiological studies in premature newborn infants have clearly shown that painful inputs are capable of producing measurable responses from at least 24 weeks post conception. Sensitisation, inflammatory and neuropathic pain Pain after surgery or significant tissue damaging trauma is the result of complex peripheral and central mechanisms of sensitisation. The fall in sensory thresholds that develop at the site of an injury is known as primary hyperalgesia, it is accompanied by a temporary reduction in thresholds in both the surrounding non-injured tissue and at distant sites known as secondary hyperalgesia. These post injury changes in sensitivity are characteristic of inflammatory pain, they usually resolve spontaneously in days or weeks as a normal part of the healing process; it responds fairly well to conventional analgesics, see below. If damage occurs to nerves or nervous tissue a state of more prolonged pain that is known as neuropathic pain may follow. Although neuropathic pain also involves sensitisation, unlike inflammatory pain it often does not resolve spontaneously and can be difficult to treat. Neuropathic pain is a component of many chronically painful conditions such as phantom limb pain, diabetic neuropathy, trigeminal neuralgia, complex regional pain syndrome (CRPS) and many others. Both sensitisation and the mechanisms underlying neuropathic pain are under intense research scrutiny with the aim of finding more effective analgesics. Many of these responses are different in children 2. Primary hyperalgesia at the site of an injury has been shown to occur from birth and although recovery seems to be more rapid, although a more prolonged inflammatory hyperalgesia has been demonstrated in neonates after repetitive injury. Secondary hyperalgesia appears to be less prominent at younger ages and is slower to develop. Neuropathic pain has not been reported in neonates or infants, even following severe nerve injuries, such as brachial plexus damage, that are know to be a potent cause in adults. Epidemiological studies Laboratory investigations have confirmed that nerve damage does not produce signs of neuropathic pain in early, recent studies have indicated that this may be due to immaturity of immune responses in the spinal cord involving microglia and peripheral cellular immunity known to maintain neuropathic pain in adults. Long-term effects of pain and analgesia There is also evidence that pain in the neonatal period can lead to augmented responses to pain some time later: Boys who underwent neonatal circumcision without analgesia showed an enhanced response to pain at 3 months during immunisation in comparison with those who did receive analgesia or were not circumcised. Infants who had abdominal surgery repeated in the same dermatome as a previous operation before 3 months of age showed increased pain responses and analgesic requirements. Even more minor events such as heelstick blood sampling are a significant cause of pain in the neonate. They too can lead to augmentation of the response to subsequent pain or may even be associated with more serious morbidity and poorer outcomes especially when repeated frequently in ICU. More complex and subtle effects have also been shown in cohorts of children who had neonatal surgery and ICU. A relative increase in temperature and touch thresholds near the site of surgery has been observed, but some children also have a more generalised decrease in temperature threshold. Although the precise mechanisms behind these observations are not known, it is clear that sensory development depends on a normal balance of sensory activity and if this is disrupted then abnormal patterns or even failure of normal maturation can occur. NMDA receptor activity has been shown to be important for normal sensory development in rat pups as chronic NMDA receptor blockade prevents the normal withdrawal of A-fibres from lamina II, and a consequent persistence of lower sensory thresholds. A number of drugs and chemical compounds may also cause long-term adverse effects when administered in the neonatal period over and above the altered pharmocokinetic or pharmacodynamic responses that are due to

4 26 SJAIT 2013/1-2 immaturity. Neuroapoptosis, or programmed cell death, is a component of normal maturation in which cells that do not form functional connexions are eliminated. Drugs that are NMDA antagonists and/or GABA agonists in particular have the potential to markedly increase apoptosis to such an extent that neural development is damaged leading to deficits in e.g. memory and learning. Although these effects have only been demonstrated in animal models to date, many general anaesthetics have been implicated including ketamine a potent nonspecific NMDA anatagonist that is also used as an analgesic. Clearly, these many factors impact on the assessment, measurement and management of pain such that considerable specialist knowledge and skills are needed in order to deliver developmentally appropriate care. 2. Measurement of pain Effective pain assessment is central to the prevention and relief of pain; pain should be assessed frequently, its intensity documented, and appropriate remedial action taken when needed. The outcome and effectiveness of pain management strategies should then be confirmed by re-assessment; thereby establishing a cycle of evaluation and treatment that should continue throughout the postoperative period. This requires training of health care professionals in the principles of acute pain assessment, including the selection and use of structured pain measurement tools that are suitable for the developmental age of the child and the context in which they are to be used. Basic principles of measurement Standardised pain measurement tools use various different methods of self-report or observations to quantify pain intensity. Older children are able to use self-report scales such as the visual analogue scale (VAS) or numerical rating scale (NRS) but these methods are not accurate in children who are too young to understand such concepts and cannot be used in infants and pre-verbal or non-verbal children. In order to overcome these obstacles a variety of scales have been devised using 3 basic methods of measurement: 1. Self-report (e.g. using diagrams or pictures) 2. Observations of behaviour 3. Observations of physiological parameters as some of these methods are relatively indirect, and not appropriate for all ages and all settings, a pain measurement tool should be scientifically validated prior to its adoption for clinical use. Children s self-report of pain is the preferred approach whenever possible, this is usually feasible in children older than 5 years. An observational measure should be used in conjunction with selfreport with 3-5 year olds because the evidence for the reliability and validity of self-report measures of pain intensity alone in this age group is quite limited and a number of potential problems and biases have been identified when children do not fully understand the scale or the concepts underpinning it. Physiological measures, such as changes in cardio-vascular or respiratory parameters are unreliable indicators of pain as they are very nonspecific and therefore prone to error. Their use in clinical practice is unproven and therefore they are not recommended as a sole modality, however physiological measures are sometimes used in combination with observations of behaviour in some composite pain assessment tools. Selection of appropriate measurement tools An evidence-based guideline The Recognition and Assessment of Acute Pain in Children from the UK Royal College of Nursing is available as a free online resource, it provides an evaluation of many currently available tools and advice on selecting appropriate tools Management of Acute Pain A number of professional and regulatory bodies have produced detailed and helpful guidelines on the management of acute pain in children. They include Practice Guidelines for Acute Pain Management in the Perioperative Setting from the American Society of Anesthesiologists 2012, that includes advice on the management of postoperative pain in children 4. Acute Pain Management: Scientific Evidence from the Australian and New Zealand College of Anaesthetists , and Good Practice in Postoperative and Procedural Pain from the Association of Paediatric Anaesthestists , are comprehensive, systematically developed, evidence-based guidelines on specific analgesic

5 PAEDIATRIC PAIN MANAGEMENT FOR ANAESTHETISTS AND INTENSIVISTS 27 Table 1. Measures for postoperative and procedure pain by age Child s age* Measure** Newborn-3 years old COMFORT or FLACC 4 years old FPS-R + COMFORT or FLACC 5-7 years old FPS-R 7 years old + VAS or NRS or FPS-R * assuming normal cognitive development **see 3 for explanation of tools and abbreviations strategies for postoperative pain and procedure pain in many different settings. Multi-modal analgesia, including two or more drugs combined with non-pharmacological strategies, is most likely to be effective for acute pain. Most frequently, a combination of opioids, NSAIDS, paracetamol and local analgesia are used to achieve comfort; these drugs act on different components of nociceptive pathways and therefore canprovide synergistic and complimentary effects. Since this approach was first suggested, the efficacy of combinations of analgesics and analgesic strategies have been shown in numerous studies of postoperative and procedural pain in children, although there have been few with sufficient sensitivity to demonstrate the individual contribution of a single analgesic 5,6. Non-pharmacological psychological and physical techniques such as reassurance, distraction and hypnosis, have proven effectiveness for brief procedural pain and also have a place as a supplement to analgesic drugs in the perioperative period by helping to allay fear and anxiety during potentially painful care such as blood sampling, placing, changing or removing naso-gastic tubes, bladder catheters, chest drains or sutures and during postoperative mobilisation. a. Pain in ICU Providing appropriate analgesia and sedation in children in ICU is often challenging. Multiple noxious stimuli including medical procedures and nursing care coupled with the presence of endotracheal tubes and need for mechanical ventilation, catheters, NG tubes, chest drains, surgical wounds are often present simultaneously. In spite of widespread recognition of the importance of managing pain, 44% of children who remembered their PICU admission, reported memories of painful experiences in a recent survey. Analgesic strategies should be tailored to the need of each individual, as inappropriate use of medication may have adverse consequences. Inadequate analgesia may have important short or long-term effects: Pain and consequent suffering can have an immediate detrimental effect on cardio-respiratory physiology and other body systems. Tissue injured in infancy and untreated pain are known to produce centrally mediated alterations in nociceptive pathways and changes in responses to mechanical and thermal stimuli that may alter the child s response to subsequent pain and surgery. However, higher doses of opioids and many analgesic drugs promote the development of tolerance and subsequent withdrawal phenomena. Opioids form the mainstay of analgesia in ICU due to their high efficacy, but the overall approach should be multimodal using both pharmacological and non-pharmacological means to reduce pain and pain responses. Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), infiltration of local anaesthetic (LA), or use of topical LA preparations can reduce opioid requirements. Morphine and fentanyl are the most commonly used opioids for both maintenance and breakthrough analgesia. Their analgesic effects are mediated mainly through μ and κ receptors located both peripherally and centrally while interaction at other receptors may contribute to adverse effects such as respiratory depression and nausea and vomiting. Potent lipid-soluble synthetic opioids such as fentanyl, remifentanil and sufentanil have additional benefits in that they modify the stress response. Children are also exposed to repeated procedural pain during their intensive care stay, including that associated with tracheal suctioning, blood sampling

6 28 SJAIT 2013/1-2 and placement of vascular cannulae, chest drain insertion and removal, and wound manipulation and dressing. Such invasive procedures are often performed without supplemental analgesia, particularly in neonates and young infants. Simply increasing background infusions will promote drug accumulation and tolerance, but may not provide the short-lived but intense analgesia required during such brief, highly noxious and damaging nociceptive inputs. The use of topical anaesthetic agents such as Ametop (4% w/w amethocaine base preparation) or EMLA (eutectic mixture of local anaesthetic agents lidocaine and prilocaine) is well established in pediatric practice. LAT gel (lidocaine adrenaline tetracaine gel) is a newer agent with a rapid onset of around 10 minutes. Subcutaneous infiltration of local anaesthetic (LA) prior to procedures such as chest drain, arterial or central line insertion can eliminate afferent pain conduction and should not be omitted, even in well sedated patients. Buffering LA solutions, for example lidocaine + bicarbonate (10:1), and using fine 30G needles also reduces the pain associated with infiltration. Non-pharmacological approaches such as nonnutritive sucking, tactile stimulation, swaddling and heel massage should be used in addition to pharmacological techniques whenever possible. In older children, psychological preparation by nursing staff, play therapists and families is important. In all circumstances, clinicians should ensure that the procedure is necessary and consider whether an alternative would be less painful e.g. venepuncture is less painful than heel lances. Personnel with the necessary skills and experience should perform procedures in an optimal environment and after sufficient time has elapsed for analgesic measures to be effective. There should be a clear plan of action should the analgesic strategy prove insufficient or the procedure fails. In neonates, the administration of oral sucrose solution has been shown to reduce pain scores following a variety of noxious events such as venepuncture, heel lance and nasogastric tube insertion. It is safe and easy to use and should be employed along with other non-pharmacological techniques, although the optimal dose remains unclear and its effectiveness in unstable or ventilated neonates may require further investigation. In children over 6 years, nitrous oxide (50-70% mix with oxygen) may be used to provide analgesia and sedation. The technique may be used as part of a strategy for procedures including chest drain removal, dressing changes and venepuncture, although it requires co-operation on the part of the child. Intranasal administration of highly potent opioids such as remifentanil or diamorphine can be given easily and quickly, following which it provides profound analgesia for around 15 minutes. b. Postoperative pain Healthcare professionals should receive adequate training in the principles of postoperative pain management, institutional protocols and guidelines must be available. Written information should be available for families describing options, risks and benefits of available techniques. Analgesia should be planned prior to surgery in conjunction with children, their families, and members of the peri-operative team. Pain assessment and analgesia should be appropriate to developmental age, surgical procedure and clinical setting: there is a wealth of evidence-based guidance to support postoperative pain care 4,5,6. In the initial period following surgery analgesia Figure 1. The reverse pain ladder

7 PAEDIATRIC PAIN MANAGEMENT FOR ANAESTHETISTS AND INTENSIVISTS 29 should be given regularly by the clock. Pain after minor surgical procedures can usually be treated by combinations of analgesics given orally. If analgesia must be given at home following surgery parents should receive instruction on what analgesia to give and when. Pain after major or complex surgery is likely to require specialised pain management techniques such as PCA, NCA or continuous epidural analgesia. Evidence for the indications and efficacy of specific techniques are available in detail in recent guidelines 6. management: Guidelines from the Association of Paediatric Anaesthetists. Paediatr Anaesth Vol 22, Suppl 1: Available at: pan issue-s1/issuetoc Conclusion This article showes basic principles of acute pain management in pediatric patients. In order to treat these patients properly, one must undrestand developmental neurobiology of pain in children. Effective pain assessment is central to the prevention and relief of pain. Pain can be measured by using diferent types of metods, and all of them should be ajusted depending on child s age. Management of acute pain can be slightly different, depending on the fact are we treating patient in the ICU, or are we dealing with postoperative pain. Anyways, Healthcare professionals should receive adequate training in the principles of acute pain management, institutional protocols and, also updated guidelines must be available. Reference list 1. Fitzgerald M, Walker SM (2009) Infant pain management: a developmental neurobiological approach. Nat Clin Pract Neurol 5: Fitzgerald M (2005) The development of nociceptive circuits. Nat Rev Neurosci 6: Royal College of Nursing (2009) Clinical Guidelines for the Recognition and Assessment of Acute Pain in Children. Available at: development/practice/clinicalguidelines/pain 4. Practice Guidelines for Acute Pain Management in the Perioperative Setting: An Updated Report by the American Society of Anesthesiologists Task Force on Acute Pain Management (2012). Anesthesiology 116: Macintyre PE, Schug SA, Scott DA, Visser EJ, Walker SM (2010) Acute Pain Management: Scientific Evidence (3 rd edition). 3rd edition ed. Melbourne: Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Available at: au/resources/books-and-publications/acutepain.pdf 6. Howard R, Carter B, Curry J, Jain A, Liossi C, et al. (2012) Good practice in postoperative and procedural pain