Current systems for administering N 2 O include continuous fl ow systems that deliver anywh ere from 0% to 70% N 2 O and older \200\230demand valve \200\231 systems that use a premix ed 50% mixture of N 2 O in oxygen. Demand valve systems require the patient to initiate neg a- tive pressure to open the inspiratory valve of the system (Farrell et al., 2008). Th is can be diffi cult for some toddlers and thus the continuous fl ow systems are preferable fo r the youngest patients. Scavenging systems should be available for N 2 O at any location t hat it is being delivered (Rowland et al., 1995). Recent studies have shown excellent safet y outcomes (no apnoea or airway interven- tions in over 5000 patient encounters) for 70% N 2 O administered by continuous fl ow to pediatric patients (Farrell et al., 2008; Zier and Liu, 2011). Ketamine can be given orally at a dose of 5 to 6 mg/kg. Onset of sedation occurs in 15 to 3 0 min and eff ects may be prolonged with this route \200\224 lasting 3 to 4 h (Rowland et al., 1995; Srinivasan et al., 2012). Intramuscular (IM) ketamine reaches peak blood levels and clinical eff ect in 5 min aft er a 3 to 5 mg/kg IM injection. Recovery from dissociatio n occurs within 15 to 30 min with coherence and purposeful neuromuscular activity returning in 30 to 120 min (Sanderson, 1997). Th ere are two formulations for ketamine \200\224 10 mg/ml and 100 mg/ml. Th e more concentrated formulation of ket- amine is preferred for IM a dministration. IM ketamine has been widely reported in the pediatric emergency medicine lit erature for sedation during painful procedures such as facial laceration repair, fracture r eduction, abscess incision and drainage, and foreign body removal (Bloomfi eld et al., 1993 ; Sanderson, 1997). Ketamine can also be given intramuscularly to uncooperative patients in whom IV or oral administration of ketamine or other sedatives is not pos- sible (Pershad e t al., 2007). Reversal agents Reversal agents should be available when performing sedation with a benzodi azepine or opioid. Flumazenil can be used to reverse the eff ects of benzodiazepines and sh ould be immedi- ately available when using benzodiazepines for sedation. A dose of 0.01 mg/ kg should be administered initially. Although rare, re-sedation may occur and additional do ses of fl umazenil may be required. Naloxone (Narcan ) is an opioid antagonist and can be given intravenously, intramuscularly , or subcutaneously. Th e drug should be given in a slowly titrated manner when possible. T h e standard preparation contains 0.4 mg/cc of naloxone. Th e dose for children is 0.1 mg/k g for children under 20 kg. Th e dose for children over 20 kg is 2 mg (Table 20.3 ). Ketamine may be given in small IV doses of 0.5 to 1 mg/kg to produce rapid and profound sed ation with analgesia. Peak concen- trations occur within 1 min and allow almost immediate i nduction of clinical eff ects and lasts 15 min if no additional doses are given (Clements a nd Nimmo, 1981). Painful procedures are tolerated well following administration of ketamine because of its profound analgesic properties. IV ketamine is ideal for painful procedures such as burn debridement, foreign body removal, abscess incision, and orthopedic procedures with a success rate over 98% (Baculard et al., 2007; Kienstra et al., 2004). Discharge Th e criteria for discharge from a sedated procedure should include stable vital signs; pain under control; a return to the level of con- sciousness that is similar to the baseline for that patient; adequate head control and muscle strength to maintain a patent a irway; nau- sea and/or vomiting should be controlled; and the patient should be adequately hydrated. Adverse events under ketamine sedation are similar regard- less of the route of administrat ion. Nausea and vomiting has been CHAPTER 20 procedural sedation 201 Table 20.3 Sedation regimens Propofol 50 \200\223200 mcg/kg/min IV Non-painful procedures Pentobarbital 3 \200\2236 mg/kg IV or PO Radiology imaging Midazolam 0.5 \200\2230.75 mg/kg PO 0.025 \200\2230.5 mg/kg IV 0.2 mg/kg intranasal Anxiolysis, premedication, procedural sedation along with a topical anesthetic or opioid Chloral hydrate 50 \200\223100 mg/kg PO Imaging, EEG, not commercially available in the US. Prolonged sedation Dexmedetomidine 0.5 \200\2232.0 mcg/kg bolus (over 10 min) followed by 1 \200\2232 mcg/kg/h infusion. For procedural sedation Propofol with fentanyl Fentanyl 1 \200\2232 mcg/kg IV with Propofol.5 \200\2231mg/kg boluses Painful procedures Midazolam with fentanyl Midazolam 0.020mg/kg IV Fentanyl 1 \200\2232mcg/kg IV Painful procedures Ketamine 3 \200\2234 mg/kg IM 1 \200\2232 mg/kg IV Painful procedures Even when these criteria are used children have been found to be discharged with residual s edation eff ects (Malviya et al., 2004). In particular, children who have received a large dose of long-acting sedation medications (such as chloral hydrate) are very prone to re-sed ation aft er vigorous eff orts are made to rouse them. Th ese patients should not be discha rged until they have demonstrated that they can maintain wakefulness for 15 min or more. undergo a large number of procedures and tend to focus on the process over time. Conclusion s: procedures result in fear and anxiety and may involve pain as well in children. Sedation is not always required, but may help eliminate unwanted long-term behavioral and psycholog ical outcomes from invasive procedures. Th e need for pharmacological intervention should b e determined by the developmental status, the level of anxiety, and context of the pro- ced ure. Th e formation of expert teams of providers is critical to optimal outcomes. Case example Presentation : an 8-year-old, 35-kg girl with acute lymphoblastic leukemia presents for a l umbar puncture with intrathecal chem- otherapy administration. Management : the child is he ld in mother \200\231s arms (as is her pref- erence) while an IV infusion begun. She is giv en 0.5 mcg/kg of fentanyl followed by 1 mg/kg of propofol as a slow IV push. As she starts to become sleepy she is placed in a left lateral decubi- tus position with nasal cannula ox ygen equipped with end-tidal CO 2 monitoring. A pulse oximeter and blood pressure cuff are also placed. Aft er 3 min she is deeply sedated as evidenced by no response to voice and mi nimal movement when 2 mg of 2% lidocaine is infi ltrated subcutaneously in the L3 to L4 int erspace. She receives no further sedation and does not move during the lumbar puncture proc edure. Heart rate is steady at 90 and her pulse oximeter remains at 98%. Breathing is parti ally obstructed and is easily improved with minimal jaw thrust \200\224 not required aft e r about 2 min. She wakes up 9 min aft er procedure is com- pleted and eats an ice lolly at that point. Comment : this case is an example of a painful procedure where an analgesic (fe ntanyl) is used in conjunction with the sedative (propofol). Th e combination results in de ep sedation which can (and does in this case) result in partial loss of airway tone requir- ing some airway manipulation. 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Eff ect of head posture on pediatric oropharyngeal structures: implications for a irway management in infants and children. Curr Opin Anaesthesiol , 22 , 396 \200\223399 . Zaman, K., Baqui, A. H., Yunus, M., Sack, R. B., Bateman, O. M., Chowdhury, H. R., et al. ( 1997). Acute respiratory infections in children: a community-based longitudinal study in ru ral Bangladesh . J Trop Pediatr , 43 , 133 \200\223137 . Zier, J. L. and Liu, M. (2011). Safety of high-concentration nitrous oxide by nasal mask fo r pediatric procedural sedation: experience with 7802 cases . Pediatr Emerg Care , 27 , 110 7 \200\2231112 . Von Ungern-Sternberg, B. S., Boda, K., Chambers, N. A., Rebmann, C., Johnson, C., Sly, P. D ., et al . (2010). Risk assessment for respiratory complications in pediatric anesthesia: a prospective cohort study. Lancet , 376 , 773 \200\223783 . Zier, J. L., Rivard, P. F., Krach, L. E., and Wendorf, H. R. (2008). Eff ectiveness of seda tion using nitrous oxide compared with enteral midazolam for botulinum toxin A injections i n children . Dev Med Child Neurol , 50 , 854 \200\223858 . Weinbroum, A. A., Szold, O., Ogorek, D., and Flaishon, R. (2001). Th e midazolam-induced pa radox phenomenon is reversible by fl umazenil . Epidemiology, patient characteristics and r eview of the literature. Eur J Anaesthesiol , 18 , 789 \200\223797 . CHAPTER 21 Neuropathic pain in children Suellen M. Walker Summary Lesions or disease of the somatosensory nervous system can produce neuropathic pain (NP). Typical features include spontane- ous or paroxysmal pain, oft en described as burni ng, shooting, like electric shocks, or pins and needles. NP does occur in childhood, but ag e at the time of injury may infl uence the risk of NP following traumatic nerve injuries. W hile conditions commonly associated with NP in adults may be less common in childhood (e.g. trigeminal neuralgia) other conditions (e.g. Fabry \200\231s disease and erythromela- lgia ), may present with pain in childhood and present a diagnostic challenge for pediatric prac titioners. \231 Children may have increased susceptibility to certain types of painful neurological injury (e.g. toxicity following mercury exposure; Celebi et al., 2008 ). NP may be considered as a clinical entity in its own right with a common pattern of symptom s and signs, oft en with similar man- agement irrespective of the underlying cause ( Table 21.1 ). In later sections of this chapter, NP associated with specifi c conditions in child ren will be outlined. Th e classifi cation of CRPS as a neuro- pathic pain condition is deb ated, but in this volume is included in Chapter 24 by Clinch. Pharmacological management of NP is oft en extrapolated from adult data (Attal et al., 2010 ; Dworkin et al., 2010 ; see Rastogi and Campbell, Chapter 48, this volume). Laboratory data regarding mechanisms and e ff ects of nerve injury in early life are discussed by Vega-Avelaria and Beggs (Chapter 7, this volume). Introduction Neuropathic pain (NP) has been defi ned as pain caused by a lesion or disease of the somatosensory nervous system (Jensen et al., 2011 ). Chronic pain is reported by up to 6% of children and adolescents (van Dijk et al., 2006 ), but the proportion with NP is n ot clear. However, children with neuropathic pain or complex regional pain syndrome (CRPS) comprise a signifi cant proportion of cases referred to pediatric chronic pain clinics (How ard, 2011 ; Martin et al., 2010 ). Epidemiological studies suggest a prevalence of chronic pain with neuropathic features of 3.3% to 8.2% in the adult population (Haanpaa et al., 201 1 ; Smith and Torrance, 2012 ); but conditions associated with NP in children diff er from those com- monly reported in adults (Borsook, 2012 ): Assessment and diagnostic features Current guidelines for the assessment and diagnosis of N P are designed for adults (Haanpaa et al., 2011 ), but are oft en extrapo- lated to older c hildren or adolescents features include: \231 Screening questionnaires to identify neuropathic pain include: LANSS, Leeds Assessme nt of Neuropathic Symptoms and Signs (Bennett, 2001 ); DN4, Douleur Neuropathique en 4 ques tions (Bouhassira et al., 2005 ); NPQ, Neuropathic Pain Questionnaire (Krause and Backonja, 2003 ); painDETECT (Freynhagen et al., 2006 ); and ID-Pain, identify Pain (Portenoy, 2006 ). Th e sensitiv- ity (66 \200\22391%) and specifi city (74 \200\22394%) of these tools fal l within reasonable ranges in adults (Bennett et al., 2007 ; Haanpaa et al., 2009 ) but the y have not yet been validated in children. \231 Many conditions associated with NP in adults are rare or not associated with signifi cant pain in children (e.g. Parkinson \200\231s dis- ease, Alzheimer \200\231s disease, po st-stroke pain). \231 Pain history including: evaluation of intensity (assessed by numerical rating scale or visual analog scale), quality (sensory descriptors), temporal aspects of pain (frequency , spontaneous/ paroxysmal or continuous, aggravating/relieving factors), and response to tr eatment. History remains the mainstay of diagnosis, and many children use descriptors that are considered \200\230typical \200\231 of NP, such as burning, shooting, radiating, burni ng, electricity-like, pain on contact, stabbing, pricking, tingling, pins and needles, and pinching (Krane and Heller, 1995 ; Wilkins et al., 1998 , 2004). However, young children ma y be unable to clearly describe their pain in these terms. \231 Th e incidence of post-herpetic neuralgia and trigeminal neural- gia is much lower in children (Hall et al., 2006 ). \231 Painful diabetic neuropathy is a feature of more prolonged dis- ease and is rarely r eported before 14 years of age (Hall et al., 2006 ), but sensory changes have been detected in children prior to onset of pain (Blankenburg et al., 2012 ). \231 Some NP conditions are increasingly recognized in children (e.g. CRPS, phantom limb pain, or NP following trauma or surgery; Walco et al., 2010 ). \231 NP may be the presenting symptom during childhood of spe- cifi c genetic conditions (e.g. Fabry \200\231s disease or erythromelalgia; Fischer and Waxman, 2010 ; Ramaswami, 200 8 ). \231 Sensory examination to verify the lesion of the somatosensory system (sensory, motor , and autonomic signs; allodynia and SECTION 4 pain in specific populations and diseases 206 Post-surgical neuropathic pain Neuropathic pain can occur acutely or as a feature of persis tent post- surgical pain in adults (Kehlet et al., 2006 ; Macintyre et al., 2010 ). Th ere has been limited prospective evaluation of postoperative NP in children, and most data come s from retrospective questionnaires. Table 21.1 Neuropathic pain conditions in children Classi \201 cation Examples Trauma \227\206 Post surgery \227\206 Phantom limb pain \227\206 Brachial plexus injury \227 \206 Peripheral nerve injury \227\206 Spinal cord injury Th e largest study (response rate 63%, n = 651) surveyed 18- to 19-year-olds who had underg one inguinal hernia repair before 5 years of age (Aasvang and Kehlet, 2007 ). Pain from the operated groin was reported by 13.5% of respondents; 5.2% had pain at rest with an average intensity of 2.5 (range 1 \200\2239 on 0 \200\22310 visual analog scale, VAS); and in 2% p ain was frequent and moderate or severe (VAS 6.3, range 4 \200\2239). Neuropathic descripto rs were reported by 53% and sensory descriptors by 72%, including tender, annoying, and sho ot- ing. Th ere was no diff erence in incidence if surgery was performed before 3 months of age. Pain was frequently precipitated by exercise and activity, and this led the authors t o conclude that a signifi cant component of the pain may arise from muscle and/or ligamento us sources rather than being predominantly neuropathic pain. Complex regional pain syndrome \227\206 Following trauma/fracture \227\206 No precipitating cause \227\206 Guillain \200\223Barr disease \227\206 Trigeminal neuralgia \227\206 Multipl e sclerosis Neurological and neuromuscular disease Metabolic disease \227\206 Fabry \200\231s disease \227\206 HIV/AIDS \227\206 Post-herpetic neuralgia Neuropathy following infection Eighty-eight of 91 patients who underwent thoracotomy for repair of coarctation of the aort a between 1965 and 1985 at ages between 0 and 25 years were assessed at an average time of 39.3 7.7 years following surgery (Kristensen et al., 2010 ). An increased propor- tion r eported pain for greater than 3 months following their sur- gery if it was performed at a l ater age: 1/31 at 0 to 6 years; 7/36 at 7 to 12 years, and 6/21 at 13 to 25 years. Th ree p atients, who had initial surgery between 7 and 25 years, still reported pain with neu- ropa thic descriptors at the surgery site. As the authors noted, this retrospective study is sub ject to signifi cant recall bias, particularly for those who had surgery before 6 years of age. Tumor \227\206 Nervous system tumor (neuro \201 bromatosis) \227\206 Invasion/compression by tumor \227\206 E \200 ect of treatment (e.g. post surgery, chemotherapy) \227\206 Erythromelalgia \227\206 Paroxysmal extreme pain disorder Genetic hyperalgesia; hypoaesthesia and hypoalgesia). Sensory abnor- malities on clinical examinati on are more diffi cult to elicit in infants and young children. Quantitative sensory testin g evalu- ates patterns of change in association with NP in adults (Maier et al., 2010 ), bu t pediatric use of this technique is oft en limited to research studies (Lebel et al., 2008 ;Sethna et al., 2007 ; see also Hermann, Chapter 40, this volume). Neuropathic pain was reported in six children (within a group of approximately 40) with cer ebral palsy undergoing multilevel surgery to reduce contractures (tendon release/lengthenin g/transfer) and/or improve sitting position or gait. Pain with neuropathic descriptors comm enced 4 to 9 days aft er surgery, was associated with allodynia in fi ve of six patients, a nd required referral and ongoing manage- ment in a chronic pain clinic (Lauder and White, 2 005 ). \231 Assessment of disability, quality of life, sleep, and mood. In adults, NP is associa ted with a greater disease burden than other forms of chronic pain, with eff ects on qualit y of life, impaired sleep, higher anxiety/depression scores, and increased use of health ca re and specialist services (Attal et al., 2011 ; Smith and Torrance, 2012 ). Th e impact of chronic pain on quality of life, mood, and disability is covered in many chapters througho ut this text, but relatively few pediatric series have evaluated the impact of NP per se on quality of life (Jan and Wilson, 2004 ). Early-onset localized pain in surgical scars was reported in three cases following surgery at 14 to 17 years. Symptom onset was delayed for 6 to 12 months in a further two cases foll owing surgery at 8 and 10 years respectively (Nayak and Cunliff e, 2008 ). Ulna nerve injury with sensory and/or motor signs occurred in 6% of children (average age 6 .5 years) having pins inserted for supracondylar fractures of the humerus. Recovery occurre d aft er a mean of 9.3 (range 6 \200\22336) weeks, but the presence or absence of associate d NP was not specifi cally reported (Eberl et al., 2011 ). \231 Additional tests may be indicated, although many are limited to research settings or specifi c cases (e.g. electroneuromyogra- phy, microneurography, functional brain imaging, skin biopsy). Investigations may be required to confi rm a specifi c underlying diagnosis (e.g. Fabry \200\231s disease) or to exclude other causes. In summary, neuropathic pain can occur following surgery in children, but additional larger studies are required to evaluate the prevalence and duration of symptoms, and also determi ne if sus- ceptibility is related to age at time of surgery. Neuropathic pain following trauma and surgery Laboratory models of traumatic peripheral ner ve injury have dem- onstrated a reduced susceptibility to neuropathic pain if the injury is performed at a younger age (fi rst 3 postnatal weeks in the rodent; see Vega-Avelaria and Beggs, Chapter 7; Walker, Chapter 3, this vol- ume). Clinical studies are also suggestive o f an increased likelihood of neuropathic pain following trauma or surgery at older ages.