Professor Andrew R Wolf

M D Frca

Dr Lara Jackman

Keywords: analgesia, cardiac, surgery, pain management Sedation, analgesia, pediatric, intensive care, cardiac, withdrawal

HAL is

General Principles

Infants and children admitted to the intensive care unit (ICU) require treatment for their primary disease and maintenance of bodily functions (fluid balance, energy intake, temperature control) to optimise recovery. Additional treatments provide analgesia, reduction of conscious level and when indicated, muscle relaxation. While this triad form the basis of classical anesthesia, in paediatric intensive care they are used for longer periods, often below the levels required for surgery and with different goals. This brings to the fore specific problems related to the drugs. These include differing pharmacokinetics and drug responses due to age and individual pathophysiology, tolerance and withdrawal, toxicity associated with long-term use, and the need to effectively monitor drug effect against delivery. Regrettably, administration of sedative drugs in the pediatric intensive care unit (PICU) is often approached in a generic way and as an afterthought, with more attention paid to the primary disease, which can lead to avoidable morbidity.

Undersedation and oversedation are both harmful. Inadequate sedation is unacceptable in a vulnerable child who may be unable to move or communicate distress due to use of muscle relaxants, while the unparalysed child may "fight" the ventilator leading to ineffective ventilation, accidental extubation or the loss of invasive access or monitors. In intensive care, agitation and inadequate sedation has been correlated with adverse short and longer-term outcome [START_REF] Tonner | Sedation and anlagesia in the intensive care unit[END_REF][START_REF] Kehlet | Effect of postoperative analgesia on surgical outcome[END_REF]. Recent data has highlighted that intensive care and surgery is associated with long-term dysregulation of nociceptive mechanisms, which may change behaviour and responses to future sensory and pain stimuli [START_REF] Walker | Long-term impact of neonatal intensive care and surgery on somatosensory perception in children born extremely preterm[END_REF]. By contrast, oversedation delays recovery, promotes tolerance to the drugs and leads to distressing symptoms on their withdrawal (agitation, seizures, hallucinations, psychosis, fever and tachycardia) [START_REF] Tobias | Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit[END_REF]. Maintaining ideal analgesia whilst at the same time promoting earlier extubation and PICU discharge can be difficult to achieve. Infants have an almost binary state of consciousness, (5) and a normally active three year old cannot easily be persuaded to remain quiescent for long periods in the ICU environment using non-pharmacological comforting measures alone. Furthermore, in the current healthcare environment, there are considerable consumer/parental pressures to ensure that all discomforts whether real or perceived are avoided. Recent advances in drug choices, patient monitoring and other therapeutic options, however, offer new prospects for the future.

Simplistically, analgesic drugs should be given for pain relief, sedative drugs for reduction of conscious level, and muscle relaxants used only for specific situations when paralysis is essential (e.g. low cardiac output states, when it may be necessary to anesthetise, paralyse and cool a child). However, there is some crossover in these roles: morphine has sedative properties, ketamine provides analgesia and anesthesia and even muscle relaxants may have an additive effect on reduction of conscious state through deafferentation [START_REF] Bonhomme | Muscle relaxation and depth of anaesthesia: where is the missing link?[END_REF]. Individual drugs have secondary properties which may be exploited therapeutically in specific situations, for example the use of high dose opioids in the management of pulmonary hypertension. Sedation and analgesia strategies need to be viewed as a collaborative effort between anaesthetist and intensivist in order to optimise the "postoperative recovery gradient" for the individual. For example, the perioperative strategy for an infant VSD may include on table or early extubation, within four hours, with continued sedation and analgesia to ensure that the infant can cope with the constraints of intensive care management. By contrast, the complex, postoperative neonate with a low cardiac output state, may have an ongoing requirement for high dose opioids, sedation and paralysis in PICU.

Analgesia ( Table 1 and2 1 and 2 near here Analgesic drugs comprise opioids, local anesthetic agents, prostaglandin synthetase inhibitors (NSAID's), acetaminophen, ketamine and alpha-2 agonists (clonidine and dexmedetomidine). Opioids remain the primary analgesic agents after cardiac surgery because of their high efficacy. Co-analgesia with NSAID's and acetaminophen plays a key role in reducing opioid requirements and side effects [START_REF] Hiller | The Analgesic Efficacy of Acetaminophen, Ketoprofen, or Their Combination for Pediatric Surgical Patients Having Soft Tissue or Orthopedic Procedures[END_REF], which is particularly useful for fast track surgery.

) ---------------------------------------------------------------------------------------------------------------- Table
Opioids have properties other than analgesia that can be exploited in the care of the critically ill child. Potent opioids such as fentanyl, sufentanil and remifentanil delivered at doses higher than that required simply for analgesia can obtund hemodynamic and adverse hormonal and metabolic responses in the critically ill. Studies by Anand and others demonstrated that highdose opioids used during surgery were associated with reduced stress response, nitrogen loss, postoperative complications and mortality [START_REF] Anand | Halothane-morphine compared with high dose sufentanil for anaesthesia and postoperative analgesia in neonatal cardiac surgery[END_REF][START_REF] Gruber | Stress response in infants undergoing cardiac surgery: a randomised study of fentanyl bolus, fentanyl infusion and fentanyl-midazolam infusion[END_REF][START_REF] Hickey | High-dose fentanyl reduces intraoperative ventricular fibrillation in neonates with hypoplastic left heart syndrome[END_REF] This led to a view that high-dose opioid analgesia, which aims to obtund measured responses to surgery are key to good outcome in the high-risk surgical infant. Less is known, however, about the benefits of high dose opioids has been shown to be beneficial in the prevention and treatment of specific situations such as a pulmonary hypertensive crisis in the at risk infant [START_REF] Hickey | Blunting of stress responses in the pulmonary circulation of infants by fentanyl[END_REF], and may benefit patients with a low cardiac output state, or those with a critically balanced pulmonary to systemic shunt. Data is limited, however, outside these specific areas.

Control of stress responses can be achieved at much lower doses than those used in the earlier studies and exposure to high dose opioids such as fentanyl (50mcg . kg -1 or higher) is associated with hypotension [START_REF] Duncan | Infant stress responses in the pre bypass phase of open heart surgery: a comparison of different fentanyl doses[END_REF]. The issue of benefits versus side effects of opioids in the critical care setting have been highlighted by the results of the "NEOPAIN" study [START_REF] Anand | Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial[END_REF] in the preterm neonate. The findings have been subject to considerable debate but suggest that in preterm neonates given morphine in a more liberal fashion than controls, observed comfort was improved at the expense of systemic hypotension. This was associated with increased risk of significant short and long-term neurological injury and adverse outcomes. Whilst management of the newborn is a special case, the inference in PICU is clear: provision of opioids mandates careful management to avoid hemodynamic instability whatever dose is provided. Children with severe cardiovascular compromise need careful hemodynamic monitoring and the availability of supportive therapy when first exposed to intense analgesia.

Neonates have both pharmacodynamic and pharmacokinetic susceptibility to sedatives and opioids, which may deter the clinician from providing effective dosing. However, unless effective plasma concentrations of the drug have already been achieved during surgery, initial loading doses may be required in the ICU. By contrast, in older infants and young children it can be difficult to maintain comfort and a relatively quiescent state without large drug doses, often in combination with multiple sedative agents. This reflects increased volume of distribution, with high clearance, that may equal or exceed that of adults, and a relative pharmacodynamic drug resistance. It is not until adolescence that responses and handling of the drugs approaches that of the adult.

Pharmacokinetics of the opioids are not only age-dependant but also affected by cardiac failure and cardiopulmonary bypass (CPB) surgery. Studies with morphine and remifentanil have shown that after cardiac surgery (14-15) there is a combination of an increase in volume of distribution and fall in drug clearance. Care therefore must be taken to provide adequate drug loading early on, whilst individualising continuous infusions over time to reflect All opioids are associated with tolerance, resulting in increasing requirements to maintain adequate analgesia/sedation. This is accelerated by high-dose opioid techniques during anesthesia, which can cause "acute tolerance", an effect which has been shown to be more pronounced in shorter acting, higher potency opioids, such as fentanyl and remifentanil [START_REF] Guignard | Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement[END_REF].

Neonates undergoing ECMO require five times the initial fentanyl infusion rate by day six to achieve an equivalent level of sedation, due to a combination of enhanced elimination [START_REF] Arnold | Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion[END_REF] and pharmacodynamic tolerance [START_REF] Greeley | Changes in sufentanil pharmacokinetics within the neonatal period[END_REF].

Morphine is more water soluble than fentanyl, with slow onset and offset, and pronounced sedative effects, which facilitates effective analgesia following anesthesia. Loading doses of 100-200 µg . kg -1 , followed by infusions of 10-60 µg . kg . hr -1 , provide reliable analgesia.

Excessive sedation, respiratory depression, nausea and vomiting can be problematic. Patientcontrolled analgesia, using a low background can be highly effective in older children, with nurse-controlled analgesia an option for the younger child.

Fentanyl is a potent opioid, with rapid onset and offset after short-term infusion (hours) due to its lipid solubility and extensive peripheral uptake. After lengthy infusions (days), recovery can be prolonged due to its relatively long elimination half-life. Whilst analgesia can be achieved with doses of 1-5 µg . kg . hr -1 , infusion rates of 10-20 µg . kg . hr -1 , may be beneficial in infants with low cardiac output states, critically balanced pulmonary and systemic circulations, or pulmonary hypertension, to reduce metabolic demands and obtund hemodynamic responses to stimuli. 5-10µg . kg -1 boluses may be required for procedures such as endotracheal suctioning and physiotherapy. High doses may provide complete anesthesia and sedation for neonates, whilst older infants and children also require an hypnotic agent.

Alfentanil is highly protein bound, resulting in a small volume of distribution. It undergoes rapid hepatic metabolism to inactive compounds [START_REF] Bower | Comparative pharmacokinetics of fentanyl and alfentanil[END_REF]. Although less potent than fentanyl, its rapid onset and offset lend it to short-term anesthesia and analgesia. Remifentanil is a synthetic opiate, offering potent analgesia, with rapid, predictable offset, making it potentially attractive for perioperative analgesia in the pediatric cardiac patient. Its short elimination half-life, of three to ten minutes, after single injection, is relatively ageindependent and not affected by renal and hepatic function, as it is metabolised by plasma and tissue cholinesterases [START_REF] Ross | Pharmacokinetics of remifentanil in anesthetised pediatric patients undergoing elective surgery or diagnostic procedures[END_REF]. Peripheral accumulation does not occur, hence the half-life remains independent of infusion duration, allowing rapid offset, which remains predictable, despite reduction in clearance associated with CPB [START_REF] Davis | The effects of cardiopulmonary bypass on remifentanil kinetics in children undergoing atrial septal defect repair[END_REF]. Effective plasma concentrations can be rapidly achieved by continuous infusion at doses of 0.05-0.4µg . kg . min 1 , with higher doses of 1µg . kg . min 1 , required to obtund stress responses [START_REF] Weale | Effect of remifentanil infusion rate on stress response to the pre-bypass phase of pediatric cardiac surgery[END_REF]. It has limited sedative effects, necessitating use with an hypnotic.

Despite its desirable properties, its role in postoperative pain management remains to be established, with cost and drug tolerance [START_REF] Vinik | Rapid development of tolerance to analgesia during remifentanil infusion in humans[END_REF], restricting its utility to relatively short-term analgesia. Furthermore, its potency and effects on ventilation, limit its use in spontaneously breathing children and sick neonates, who can develop bradycardia and hypotension on initial exposure [START_REF] Weale | Effect of remifentanil infusion rate on stress response to the pre-bypass phase of pediatric cardiac surgery[END_REF]. In a study of 'fast track' pediatric cardiac surgery, it lacked superiority over fentanyl in terms of recovery and was associated with a significant reduction in heart rate [START_REF] Friesen | A comparison of remifentanil and fentanyl for fast track paediatric cardiac surgery[END_REF]. It has potential utility for procedural analgesia, in ventilated patients in PICU. Given as a single intranasal dose it provides an excellent pharmacokinetic profile providing analgesia for 15 minutes. This approach avoids fluctuant levels and the attendant side effects of single intravenous dose or infusion of remifentanil. Verghese et al. have reported this technique for intubation during inhalational anaesthesia with 5% sevoflurane after a single dose of 4µg . kg -1 of remifentanil [START_REF] Verghese | The effect of intranasal administration of remifentanil on intubating conditions and airway responses after sevoflurane induction of anaesthesia in children[END_REF]. This exiting new approach would allow modulation of analgesia for procedures such as physiotherapy and endotracheal tube change, without having to modify existing infusions or break into the intravenous circuit to give additional bolus doses.

Once the alimentary route is effective, there is some evidence that oral opioid administration results in reduced longer-term tolerance [START_REF] Nestler | Molecular basis of long-term plasticity underlying addiction[END_REF][START_REF] Eisch | Opiates inhibit neurogenesis in the adult rodent dentate gyrus[END_REF][START_REF] Pu | Hippocampal long-term potentiation is reduced by chronic opiate treatment and can be restored by re-exposure to opiates[END_REF]. Certainly, the use of enteral drug administration reduces the infection-risk associated with long-term intravenous access and line manipulations [START_REF] Pronovost | An intervention to decrease catheter-related bloodstream infections in the ICU[END_REF] and should be used wherever possible. Morphine undergoes considerable first pass metabolism by the liver, if absorbed through the alimentary system, resulting in considerably greater dose-requirements than by intravenous routes, with total

Local Analgesia Techniques

Afferent pain conduction can be eliminated with effective local anesthesia, with minimal side effects. Simple local anesthetic techniques can provide an important adjunct to any analgesia or sedation regimen, by reducing the background drug requirement and that for procedural analgesia. Local anesthesia can be given by a wide variety of routes which include topical, infiltration, peripheral nerve block or central continuous block (epidural or spinal). Topical anesthesia is used regularly on the general paediatric wards and in the emergency department (ED). The use of these agents in PICU is often ignored except in non-intubated patients. The pain associated with venous cannulation is sufficiently distressing, even in a moderately sedated child, to necessitate additional sedation. If agents such as Ametop and EMLA are routinely applied in advance of an anticipated procedure, the use of intravenous analgesia and sedation can be minimised. Newer, faster acting agents are now available, including lidocaine-adrenaline-tetracaine gel (LAT gel), which is effective in as little as 10 minutes [START_REF] Benabent | Suture of skin lacerations using LAT gel (lidocaine, adrenaline, tetracaine)][END_REF][START_REF] Ernst | Topical lidocaine adrenaline tetracaine (LAT gel) versus injectable buffered lidocaine for local anaesthesia in laceration repair[END_REF]. This agent is finding increasing favor in the ED for wound suturing, with good effect. It has been suggested that its use should be extended to other areas, such as PICU, due to its rapid onset of action and excellent analgesic effects. Care does need to be given, however, to site of use, due to the adrenaline component.

Regional anesthesia for cardiac surgery remains in the domain of a few enthusiasts rather than as a mainstream technique. A variety of retrospective publications using caudal, epidural or spinal techniques have suggested value in the management of children after cardiac surgery, but the data remains limited and largely uncontrolled [START_REF] Thammasitboon | Epidural analgesia promotes immediate tracheal extubation without complications in infants, children and young adults after cardiac surgery[END_REF][START_REF] Peterson | A report of two hundred twenty cases of regional anesthesia in pediatric cardiac surgery[END_REF][START_REF] Hammer | A retrospective examination of regional plus general anesthesia in children undergoing open heart surgery[END_REF]. A prospective randomised trial of spinal anesthesia with an indwelling catheter, demonstrated reduced stress responses and lower blood lactate concentrations compared to a high dose conventional opioid technique in children under three years undergoing major cardiac surgery [START_REF] Humphreys | Spinal anesthesia with an indwelling catheter reduces the stress response in pediatric open heart surgery[END_REF]. A similar technique to that described is currently being used by our group to provide stress reduction in the operating theatre, facilitate early extubation and minimise the requirement for systemic analgesia. 3 near here ___________________________________________________________________________ Different drugs fulfil these roles to varying extents. Benzodiazepines, for example, provide anterograde amnesia, with reduced or complete unconsciousness at different doses, whilst phenothiazines and butyrophenones (chlorpromazine and haloperidol), used as major tranquillising drugs in schizophrenia, have psychotropic properties that render the patient disinterested in activity. Some analgesic drugs reduce both pain and consciousness: ketamine provides analgesia and a dissociative anesthesia/sedation, clonidine produces analgesia and a calmed relaxed state, and morphine has additional sedative properties. Therefore, choice of a sedative regimen needs to be tailored to the individual rather than generic.

Neonates are a special group, in that morphine alone can often provide sufficient analgesia and sedation. Outside this period, however, an analgesic and a sedative drug are almost always necessary. Where neuromuscular blockade is required, a sedative drug given at an adequate dose, becomes mandatory to prevent awareness.

In the past, patients in adult ICU have been given an opioid in combination with a low dose of anesthetic agent to ensure pain relief, hemodynamic stability and tolerance to the constraints of ITU. The potentially lethal side effects of anesthetic drugs used over days have only emerged after reviews of death rates and analysis of recurring adverse events. These [START_REF] Sanders | Sedation and immunomodulation[END_REF][START_REF] Galley | Immunomodulation by anaesthetic, sedative and analgesic agents: does it matter?[END_REF], adrenocortical suppression by etomidate [START_REF] Fraser | The effect of etomidate on adrenocortical function in dogs before and during hemorrhagic shock[END_REF] and more recently, mitochondrial dysfunction with propofol, in both adults and children [START_REF] Vasile | The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome[END_REF].

As with opioids, delivery via the enteral route may avoid complications associated with intravenous delivery, provided enteric function is intact. Many of the sedative agents are well absorbed and tolerated enterally, including benzodiazepines, clonidine and chloral hydrate.

An additional advantage to oral sedation is it can be weaned gradually and continued following discharge from ICU if necessary.

Early Extubation

Early extubation, with good analgesia that allows rapid mobilisation and recovery, is likely to be beneficial in terms of reducing postoperative complications, although the results of more general outcome studies remain inconclusive [START_REF] Kehlet | Effect of postoperative analgesia on surgical outcome[END_REF][START_REF] Scott | A prospective randomised study of the potential benefits of thoracic epidural anesthesia and analgesia in patients undergoing coronary artery bypass grafting[END_REF]. It should be added that a precondition of early extubation, is that the postoperative repair and cardiovascular function are adequate to support an awake, mobilising infant. Accelerated convalescence confers benefits in both medical and economic terms, in that earlier discharge from the ICU improves throughput.

The last 10 years has seen a widespread acceptance of fast track pediatric surgery, with rapid extubation not only for simple cases but also more complex procedures [START_REF] Vricella | Ultra fast track in elective congenital cardiac surgery[END_REF][START_REF] Heinle | Early extubation after cardiac operations in neonates and young infants[END_REF]. There may be specific advantages in immediate extubation for some cardiac conditions. For example those with single ventricle physiology (following Glenn shunt/ Fontan repair), and Fallot's Tetralogy, when reduced intrathoracic pressure, associated with spontaneous breathing, improves pulmonary blood flow and oxygenation [START_REF] Shekerdemian | Cardiopulmonary interactions after Fontan operations[END_REF].

A variety of techniques have been described, including the use of regional analgesia, however the difficulties lie not with on table extubation but with managing pain and sedation in ICU.

Children need to remain sufficiently sedated after surgery to prevent restlessness with attempts to remove vital monitoring or invasive catheters. In the authors' experience, this usually necessitates a combination of both analgesia (opioids, acetaminophen and NSAIDs) and sedation (a benzodiazepine or alpha-2 agonist). Excessive use of potent opioids during surgery promotes acute tolerance, leading to a requirement for increased analgesia after surgery [START_REF] Guignard | Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement[END_REF]. The debate on whether "pharmacological restraint" is always preferable to limited physical restraint, such as bandages around the hands, arm splints or even true restraint, remains unresolved, and provokes strong views. Continuing anesthesia for a short time after surgery in PICU allows time to assess the surgical repair, and ensure that the patient has been optimised prior to extubation. Several techniques have been described, including infusions of propofol, (5) and remifentanil with midazolam, (15) that allow a controlled emergence. The use of propofol in PICU remains contentious due to the issues surrounding 'Propofol Infusion Syndrome' [START_REF] Vasile | The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome[END_REF][START_REF] Wolf | Propofol infusions in children: when does an anaesthetic tool become an intensive care liability[END_REF]. Despite these concerns, and its contraindications for use by regulatory authorities in the USA and UK, it continues to be used short-term, at low dose (<4mg . kg . hr -1 ) for specific cases. Patients on a propofol infusion should be closely monitored for rising lactate, acidosis, reduced urine output or dysrythmias.

Remifentanil combined with low dose midazolam provides very reliable analgesia and sedation for early extubation. Recent studies have shown that there is a good correlation with drug infusion rate, plasma level and COMFORT score [START_REF] Rigby-Jones | Remifentanil-midazolam sedation for pediatric patients receiving mechanical ventilation after cardiac surgery[END_REF]. Before withdrawal of remifentanil, a loading dose of opioid is needed to maintain analgesia.

Sedation and Analgesia in the Long-stay Patient

As the management of the cardiac surgical patient continues to improve, the need to ventilate infants over days and weeks has diminished. However, those with residual problems, that cannot be improved immediately by further intervention or who remain marginal for cardiac or non-cardiac reasons, may enter a phase of chronic sedation and ventilation as their issues resolve. Examples include those with cardiac failure, pulmonary hypertension, lung or airway disease or ongoing sepsis. These patients are the most at risk from drug tolerance and subsequent withdrawal. Some agents are considered more problematic than others: the incidence of withdrawal with midazolam has been reported as frequently as 35%. Limiting midazolam infusion to 100mcg . kg . hr -1 reduces the likelihood of withdrawal but stopping the drug slowly does not reduce the risk. [START_REF] Jenkins | UK. Current United Kingdom sedation practice in pediatric intensive care[END_REF].

Techniques that can be used in PICU to limit the problems associated with long-term sedation include:

1. Drug cycling: changing pharmacological drug groups routinely to reduce the emergence of tolerance 2. Sedation holidays: temporary cessation of sedative drugs to evaluate emergence. In adult intensive care percutaneous tracheostomy is often performed at an early stage. This allows the patient to be ventilated whilst awake with minimal sedation, allowing the patient to breath with support ventilator modes, cough and clear their own secretions more effectively, reducing the risks of nosocomial chest infections. Unfortunately, this technique cannot be applied in children because of the technical issues associated with smaller airways and the continuing need for sedation. Surgical tracheostomy and insertion of a long-term indwelling central venous catheter can, however, allow the patient who requires longer term ventilator support to be managed with little or no sedation Neuromuscular blockade can be useful in patients that are difficult to ventilate, such as for inverse ventilatory ratios, high frequency oscillation, or to deliberately hyper or hypoventilate them depending on their underlying pathology [START_REF] Playfor | Consensus guidelines for sustained neuromuscular blockade in critically ill children[END_REF]. It continues to be used in children that require hypothermia due to dysrythmia or to reduce metabolic rate and oxygen demand.

Neuromuscular blockade is used more commonly than in adult ICU, but as a specialty we are now using it less frequently [START_REF] Merriman | The techniques used to sedate ventilated patients. A survey of methods used in 34 ICUs in Great Britain[END_REF], with recent reports estimating the use of long-term neuromuscular blockade in 14-16% of ventilated days in PICU [START_REF] Martin | Prospective documentation of sedative, analgesic, and neurouscular blocking agent use in infants and children in the intensive care unit: A multicenter perspective[END_REF]. Avoidance of prolonged use is preferable due to the risks of critical care polyneuropathy [START_REF] Tabarki | Critical illness neuromuscular disease: Clinical, electrophsiological, and prognostic aspects[END_REF] and drug accumulation, which may result in delayed extubation.

Withdrawal phenomena remain a major concern in those patients who have received sedation over many days. Symptoms can include sweating, tachycardia, hypertension, agitation, posturing, withdrawal, vomiting and diarrhoea. Occasionally this prompts concerns of, and investigation for, cardiac, neurological or gastrointestinal disease. The alpha-2 agonist clonidine, chlorpromazine, and haloperidol can be used effectively to moderate these effects and the patients discharged to wards on a weaning oral regimen over a period of 7-14 days.

Concerns remain about abrupt cessation of clonidine and the risk of rebound hypertension.

Assessment of Pain and Sedation

Sedation is administered to critically ill children according to predicted requirement. This may not, however, reflect actual requirements, with significant individual variation. Several scales, assessing behavioral and/ or physiological measures have been developed and validated for this purpose. These include 'The COMFORT Scale', an objective measure of distress in ventilated pediatric patients, validated in all age groups [START_REF] Ambuel | Assessing distress in pediatric intensive care enviroments: the COMFORT scale[END_REF][START_REF] Van Dijk | The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0 to 3-year-old infants[END_REF]. It comprises 8 variables, each rated 1-5: alertness, calmness/agitation, respiratory response, physical movement, heart rate, blood pressure, muscle tone and facial tension, the scale ranging from 0-40, with a target range of 17-26. As with other scoring systems it is limited by interobserver variability, provides only intermittent data and cannot be used in the context of neuromuscular (NMJ) blockade. Cardiovascular responses are also difficult to assess in patients who are paced.

Neurophysiological methods and auditory evoked potentials have been evaluated in the research domain. Bispectral Index (BIS) monitoring utilizes data from electroencephalogram (EEG) to measure depth of anesthesia. This technique assumes changes in frequency are related and looks for phase coupling among frequency bands (biocoherance) [START_REF] Raimer | Bispectral Index Monitoring in the PICU[END_REF][START_REF]Bispectral electroencephalographic monitoring[END_REF]. In awake individuals, there is minimal synchronisation due to multiple signal generators within the brain, wheras during sleep, there is less activity and the EEG reflects coupling between signal generators [START_REF] Raimer | Bispectral Index Monitoring in the PICU[END_REF][START_REF]Bispectral electroencephalographic monitoring[END_REF]. A dimensionless value, 'the BIS number', is calculated, which ranges from 0-100, 0 indicating an isoelectric state, with 100 correlating with a fully awake individual. Values of 40-60 are seen with general anesthesia [START_REF] Rampril | A primer for EEG signal processing in anesthesia[END_REF]. While it may provide an accurate assessment of depth of sedation for single agents such as midazolam, propofol and volatile agents, this is not the case for opiates or ketamine [START_REF] Shields | Clinical Utility of the Bispectral Index score when compared to the University of Michigan Sedaton Scale in assessing the depth of outpatient pediatric sedation[END_REF][START_REF] Aneja | Sedation monitoring of children by the Bispectral Index in the paediatric intensive care unit[END_REF]. Furthermore, Messner et al., demonstrated BIS Index to decline, with NMJ blockade in awake volunteers, suggesting it may not identify those inadequately sedated under muscle relaxant [START_REF] Messner | The Bispectral index declines during neuromuscular block in fully awake persons[END_REF]. The BIS monitor is age-dependant (58) and currently there is insufficient evidence to support routine use of the BIS monitor, or any other neurophysiological sedation scoring technique, in PICU [START_REF] Playfor | The use of bispectral index monitors in paediatric intensive care[END_REF].

Future prospects

The concept of using the volatile agents for longer-term sedation on ICU's in not a new one.

Barriers in the past have been ways to safely deliver the drug (vaporisers) as well as protecting the staff and environment (scavenging systems). A few ICU ventilators in the past such as the servo 900c were able to provide a plug on vaporiser to deliver isoflurane to the critically ill patient, but these are now generally obsolete. Adult data has shown that isoflurane can be an effective and practical sedative drug in the intensive care unit when combined with opioids with few side effects [START_REF] Millane | Isoflurane and propofol for long-term sedation in the intensive care unit. A crossover study[END_REF][START_REF] Spencer | Isoflurane for prolonged sedation in the intensive care unit; efficacy and safety[END_REF]. More recently, Meiser and others have shown the rapidly eliminated inhalational agent desflurane to have characteristics that make it superior to other more conventional agents [START_REF] Meiser | Desflurane compared with propofol for postoperative sedation in the intensive care unit[END_REF]. The data in PICU is very limited. The early 10 patient study by Arnold et al. (63) used relatively high doses of isoflurane as a single agent in patients who had already become tolerant to opioids. Their results showed that while the drug was effective, there was a high incidence (50%) of tolerance agitation and dystonia on withdrawal of the drug. More recent reports, particularly for treatment of status asthmaticus, as part of a more balanced sedative regimen, have been more encouraging [START_REF] Wheeler | Isoflurane therapy for status asthmaticus in children: A case series and protocol[END_REF][START_REF] Shanker | Isoflurane therepy for severe refractory status asthmaticus in children[END_REF]. However there is major lack of good prospective data to evaluate the potential of these drugs in PICU.

The renewed interest in gaseous sedative agents is likely to continue with developments of new delivery systems within ICU. Early studies with xenon show great potential in the clinical areas of the developing neonate and neurological injury [START_REF] Bedi | Use of xenon as a sedative for patients receiving critical care[END_REF][START_REF] Sanders | Xenon: elemental anaesthesia in clinical practice[END_REF]. Unlike many PICU sedative agents, including midazolam, ketamine and other volatile anesthetic agents, xenon has been shown in animal models to provide anesthesia and sedation without producing apoptosis [START_REF] Ma | Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain[END_REF]. Further studies have found that xenon can offer protection from hypoxic injury. Hobbs et al. demonstrated that rat pups exposed to hypoxic injury had a significantly better outcome with the combination of cooling to 32°C and xenon. The functional improvement with this regimen was almost complete, sustained long-term, and accompanied by greatly improved histopathology [START_REF] Hobbs | Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischaemia[END_REF]. Chakkrapani and colleagues demonstrated similar neuroprotective benefits of xenon, with synergistic effects seen with hypothermia in asphyxiated newborn piglets [START_REF] Chakkarapani | Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigs[END_REF]. Issues still remain if this drug is to become viable in PICU.

It is rare, expensive and requires a closed system of delivery, which necessitates the developmet of new ventilatory systems.

F

  of general pediatric intensive care. Certainly, high dose opioid administration

  clearance, particularly in the setting of low cardiac output, and hepatic or renal impairment. Accumulation of the active metabolite of morphine, morphine-6-glucuronide, in renal failure, can lead to excessive and long-lasting sedation that delays extubation.

  to be increased by a factor of five to ten in order to achieve the same level of analgesia.

  broad term when used in the context of PICU. It may facilitate several goals including: 1. Unconsciousness (virtual anesthesia) or reduction in conscious level 2. Reduced awareness 3. Loss of explicit and implicit memory 4. Compliance with the need to lie in a confined space, attached to monitors and invasive lines 5. Prevention of distress during procedures such as physiotherapy, radiological scanning or minor surgical intervention, which may require enhanced levels Table

  -pharmacological techniques: oral sucrose, reducing environmental stress (noise, light, interruption of day-night cycle), swaddling etc 4. Transfer to oral sedation where possible

  of sedation, with titration of analgesic and sedative drugs, is important to ensure comfort and avoid adverse outcomes, associated with under or over-sedation.

Table 1 : Opioid Analgesia

 1

	o r
	P
	e
	e r
	R
	e
	v i e
	w

Table 2 : Non-Opioid Analgesia

 2 * These drugs are used extensively outside their product licence but within recommended guidelines from the Royal College of Paediatrics and Child Health. Prevention and Control of Pain in Children 1997: BMJ Publishing Group, London

	Drug	Benefits	Dose		Comments
	Benzodiazepines	Amnesic benefit in	Intravenous infusion:		High risk of withdrawal
	Midazolam	addition to sedation	max 200µg . kg . hr -1		with prolonged use or high
					doses (>100µg . kg . hr -1 ).
			Intranasal:
			0.1mg . kg -1 each nostril	Helps control seizures
	Lorazepam	Oral drug useful in			Risk of respiratory
		midazolam withdrawal		depression -particularly
					with repeated doses
	Diazepam	Status epilepticus	Rectal:
		(rectal)	Neonate: max 2.5mg
			1 month-2years: 5mg
			2-12 years: 5-10mg
	Propofol	F r rapid wake up o Short term action -	12-18 years: 10mg max 4mg . kg . hr -1 Titrate to effect Intravenous infusion:		Hypotension
		Check for rising lactate or acidosis, limit infusion duration e P	Risk of propofol infusion syndrome. Lipid load with infusion. Contraindicated by FDA
	Phenothiazines hydrochloride) (Chlorpromazine	Dissociated sedation	Oral or IV: e r 500µg . kg -1		Risk of extrapyramidal side effects
	Butyrophenones (Haloperidol)	Dissociated sedation	Intravenous infusion: R		Risk of extrapyramidal side effects
			1month-12 years: e 25-85µg . kg -1 over 24
			hours 12-18 years: 1.5-5mg over 24 hours v i e
	Clonidine	Withdrawal Analgesic properties	Intravenous infusion: 0.5-3.0 µg/kg/min	Can cause hypotension and w bradycardia
		with opiate-sparing	Oral:		Rebound hypertension
		effect	2-5µg . kg -1 4-hourly		described in adults
	Volatile agents	Rapid clearance for	Dose titrated to effect		Can be useful for
		quick wake up			bronchospasm and seizures
			Depends on delivery
			system and gas flows		Requires vapouriser and
					scavenger systems
	Chloral hydrate	Well tolerated	Oral or rectal:		Delayed clearance in
			25-50 mg . kg -1		neonates -be wary with
					regular dosing
					22

Table 3 : Sedative Drugs

 3

Pediatric Anesthesia


Dr Sarah Barnett
email: sarahfbarnett@googlemail.com

Dr Claire Moloney

Dr Robert Bingham

MBBS Frca Consultant

Keywords: Apert syndrome, peri-operative complications, mid-face hypoplasia, obstructive sleep apnoea, airway management Apert syndrome, peri-operative complications, mid-face hypoplasia, obstructive sleep apnoea, airway management

Objectives: To perform a retrospective, anaesthesia case note review in children with Apert Syndrome.

Aim: To identify peri-operative complications in this group of patients.

Background: Apert syndrome is a rare autosomal dominant disorder characterized by craniosynostosis, craniofacial anomalies, and severe symmetrical syndactyly (cutaneous and bony fusion) of the hands and feet. Children with this syndrome require general anaesthetics for a number of different operations and procedures. Our institution has records of 71 children with Apert syndrome. Analysis of their general anaesthetic records was undertaken and the incidence of perioperative complications was investigated.

Methods: A retrospective case note review was performed on 61 children with Apert syndrome over a 14 year period. There were a total of 509 general anaesthetics administered to these children during this period of time.

Results: There were a total of 31 peri-operative respiratory complications occurring in 21 patients (6.1% of the total cases). 23 of these complications were supraglottic airway obstruction (4.5% of total cases).

Conclusions:

We found there to be a low incidence of major peri-operative major complications in this group of patients. Nevertheless, a significant proportion of these children have obstructive sleep apnoea and may develop supraglottic airway obstruction on induction and emergence from anaesthesia due to the associated mid-face anatomical abnormalities.

Introduction

Apert syndrome is a rare disorder which generally occurs sporadically, although an autosomal dominant inheritance has been described [START_REF] Mantilla-Capacho | Apert syndrome with preaxial polydactyly showing the typical mutation Ser252Trp in the FGFR2 gene[END_REF]. It is evident at birth, and accounts for 4.5% of all cases of craniosynostosis (premature fusion of one or more cranial sutures). Further craniofacial abnormalities include hypertelorism, midface hypoplasia and choanal stenosis. Neurological and intracranial anomalies can include ventriculomegaly, hydrocephalus [START_REF] Quintero-Rivera | Intracranial anomalies detected by imaging studies in 30 patients with Apert syndrome[END_REF] and developmental delay [START_REF] Cohen | The central nervous system in the Apert syndrome[END_REF].

The other dominant clinical feature is symmetrical syndactyly of the fingers [START_REF] Wilkie | Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome[END_REF] and feet (cutaneous and bony fusion) generally tending to affect the upper limb more severely than the lower limb [START_REF] Cohen | Hands and feet in the Apert syndrome[END_REF].

There have also been reports of associated congenital cardiac and renal defects. There is fusion of the cervical spine in 68% of cases of Apert syndrome, mainly at C5-C6, distinguishing it from Crouzons syndrome where the fusion is usually at the C2-C3 level [START_REF] Kreiborg | Cervical spine in the Apert syndrome[END_REF].

These features have clinical relevance to anaesthetists as some degree of upper airway obstruction due to reduced nasopharyngeal volume and choanal patency is certain. Obstructive sleep apnoea is present in almost 50% [START_REF] Bannink | Obstructive sleep apnea in children with syndromic craniosynostosis: long-term respiratory outcome of midface advancement[END_REF] and cor pulmonale may result [START_REF] Kaplan | Clinical assessment and multispecialty management of Apert syndrome[END_REF]. There have also been descriptions of complete or partial cartilage sleeve abnormalities of the trachea, which has been postulated to cause lower airway compromise [START_REF] Cohen | Upper and lower airway compromise in the Apert syndrome[END_REF].

Children with this syndrome require general anaesthetics for a number of different operations and procedures. It has been suggested that they have a much higher incidence of peri-operative respiratory complications, particularly bronchospasm, than other children [START_REF] Elwood | Respiratory complications during anaesthesia in Apert syndrome[END_REF]. There is very little published data looking specifically at peri-operative outcomes in children with Apert syndrome.

Reviews and reports tend to group them together with other craniofacial syndromes [START_REF] Mallory | Anaesthetic management in facial bipartition surgery: the experience of one centre[END_REF][START_REF] Sculerati | Airway management in children with major craniofacial anomalies[END_REF][START_REF] Uppington | Anaesthesia for major craniofacial surgery: a report of 23 cases in children under four years of age[END_REF], so specific complications may be masked. Our institution has records of 71 children with Apert syndrome diagnosed clinically and genetically. Analysis of their general anaesthetic records was undertaken and the incidence of peri-operative complications was investigated.

Methods

Following ethical and audit committee advice a retrospective case note review was performed on 71 children with Apert syndrome at Great Ormond Street Hospital. Eight case notes were untraceable during the period of time due to filing and tracking errors and therefore omitted from the series and a further 2 sets of case notes had no records of anaesthesia. The anaesthetic charts from the case notes of the remaining 61 children were analysed for the 14 year period from 1995 until 2009. Details of patient demographics and the procedures undertaken were collated. The patient's preoperative respiratory status was recorded, specifically looking for a sleep study diagnosis of obstructive sleep apnoea, a history of asthma or wheeze, tracheostomies, and previous respiratory admissions. Intra-operative airway management and complications were documented, and the postoperative period was evaluated.

Results

There were a total of 509 general anaesthetics administered to 61 children (38 males and 23 females) during this 14 year period of time. Their ages ranged from 1 day to 15 years old, and they were classified as ASA II (n=77) and ASA III (n=431), with operation duration ranging from 10 minutes to over 4 hours.

The most frequent reason for a general anaesthetic was an orthopaedic procedure (Table 1.). Within the 224 operations undertaken 115 of these were for a change of dressing. There were 46 major craniofacial operations, the majority of which were posterior vault expansions, frontal remodelling and biparietal distractions (Table 2.). The remaining minor craniofacial procedures included adjustments and removals of 'RED (Rigid Extraction Device) frames'. we were unable to clarify the exact age of the children when they were diagnosed, their ages when presenting for surgery ranged from 6 weeks to 14 years. Two of these children, aged 11 and 12, were receiving home CPAP. Eight out of the nine adenotonsillectomy patients in this series were having the procedure in an attempt to ameliorate OSA. Only 5 of the patients had a history of asthma or being 'wheezy' in the past. Three of these children were taking regular inhalers for the condition. Six children had a tracheostomy, at some point during their lives. The indication for four of these children was temporary insertion because of craniofacial surgery. One child had a tracheostomy at the age of 2 weeks to assist prolonged ventilatory requirements. One child had a definitive tracheostomy for severe obstructive sleep apnoea. Fifteen children had known choanal atresia, and one child had congenital subglottic stenosis. Eight of the children had been admitted to hospital with respiratory symptoms since birth, and on sixteen occasions the patients had experienced a recent upper respiratory tract infection prior to their anaesthetic (Table 3

.).

Atropine was prescribed before 216 anaesthetics and sedation was given before 44 procedures. The majority of times, no premedication was given (n=293). A majority of the anaesthetics were initiated with a gas induction (251 vs. 58 intravenous). Maintenance of anaesthesia was with volatile agents in all but one of the anaesthetics where total intravenous anaesthesia (TIVA) was used. The patients received positive pressure ventilation for 225 of the anaesthetics, and in the remaining 284 cases the child breathed spontaneously throughout the procedure.

The airway was managed in a variety of ways -face mask (n=68, SV=66, PPV=2), laryngeal mask (n=206, SV=206), tracheal tube (n=199, SV=2, PPV= 197) and tracheostomy (n=36, SV=10, PPV=26).

The children were easy to intubate in the majority of cases with a Cormack and Lehane grade I (n=181), grade II (n=15) and grade III (n=3). There were no children with a grade IV view. There were 2 cases where the laryngeal mask did not provide a good seal; one was managed with tracheal intubation and the other with a face mask. In 98 of the 199 occasions, an age appropriate tracheal tube size was used according to the formula: tracheal tube size (internal diameter in millimetres) = (age/4) +4. In 68 instances a larger tube size was required, and a smaller tracheal tube was placed in 28 cases. There were 5 anaesthetics where the tube size was not documented (Table 4.).

Peripheral access was documented in 457 of the anaesthetics. On 52 occasions there was no intravenous access. There were 45 arterial lines and 30 central venous catheters placed.

The majority of orthopaedic operations were upper limb procedures and brachial plexus blocks (n=80) were commonly performed. Limited abduction of the upper arm and 'winging' of the scapula in Apert syndrome makes axillary brachial plexus block difficult to perform and ultrasound guidance is helpful. The remaining regional blocks were caudal epidurals (n=3), and an ankle block (n=1). There were a total of 31 peri-operative respiratory complications occurring in 21 patients (6.1% of the total cases). 23 of these complications were supra-glottic airway obstruction (4.5% of total cases), which were easily resolved with simple airway manoeuvres, adjuncts or positive end expiratory pressure (PEEP) (Table 5.). There was only one documented incidence of wheeze, which followed fentanyl and erythromycin administration and was clinically felt to be allergy related although no treatment was required. The child was 3 years old, having syndactyly release surgery and was breathing spontaneously through a laryngeal mask. The child had a recent URTI but subsequent anaesthetic charts documented this event as an antibiotic allergy. Other problems were: desaturation due to secretions down the tracheal tube, resolved with suctioning (x1); Laryngospasm Five children had a past medical history of asthma/wheeze and 3 of these were taking regular inhalers for the condition; the patient who experienced wheeze under anaesthesia was not one of this cohort. Thirty-six patients had a formal sleep study diagnosis of obstructive sleep apnoea but only 9 of these had documented peri-operative supraglottic airway obstruction. Only 3 children with a recent URTI had documented peri-operative respiratory complications; 1 (described previously) associated with wheeze and allergy; 1 with tracheal tube secretions and the other with supraglottic airway obstruction.

There was one patient with a major bleed following a bipartition distraction, who required unexpected admission to the PICU for ongoing management. Two children vomited, one on induction and the other on emergence, but neither resulted in aspiration.

The majority of patients returned to the ward/ HDU environment after their operations (n=494) with only 15 admissions to the PICU/NICU post-operatively.

Discussion

Although a retrospective case note review may well under-report complications, we are confident that major problems requiring treatment will have been captured. Overall, we found there to be a low incidence of major peri-operative respiratory complications in this group of patients and in contrast to a previous publication [START_REF] Elwood | Respiratory complications during anaesthesia in Apert syndrome[END_REF], we found the incidence of bronchospasm to be extremely low at 0.2% and there were no cancellations of surgery due to respiratory complications.

The lower airway abnormalities described in the literature did not cause excessive problems in our cohort, tracheal tube size was either age appropriate or greater in 83.4% of the group and only one [START_REF] Cohen | Upper and lower airway compromise in the Apert syndrome[END_REF]. In one child, there was desaturation related to partial obstruction of the tracheal tube by secretions and although this was easily resolved, we note that this complication has been reported previously [START_REF] Basar | An intraoperative unexpected respiratory problem in a patient with Apert syndrome[END_REF]. Tracheobronchial secretions may also cause lower airway obstruction and mimic bronchospasm, which may account for some of the cases previously described.

Our results showed that our group of patients were far more likely to experience supra-glottic rather than infra-glottic obstruction. It may be that this was under-reported in our data, as minor degrees of supra-glottic obstruction may not have caused the anaesthetist or patient substantial problems and may have seemed unworthy of reporting. Simple airway manoeuvres and adjuncts usually rectified any upper airway obstruction documented. The majority of upper airway obstructions occurred on induction of anaesthesia. There were only four incidences of postoperative obstructions. A common supposition would be to assume the incidence of postoperative problems occurs more frequently with longer intubations and prolonged surgery. Our results do not support this statement. The majority of the supraglottic obstructions occurred when the child was scheduled to have 'shared airway' surgery such as Ear, Nose and Throat (ENT) and dental procedures. Perioperative airway complications were encountered infrequently in the major craniofacial operations. Just over half of the incidents of supraglottic obstruction arose in children under the age of 2 years, which is not unexpected. We find it re-assuring to have collected data which demonstrates that if supra-glottic airway obstruction does occur, laryngoscopy and intubation is generally easy. It should be noted however, that although surgical mid-face advancement improves the cosmetic appearance, it results in a marked deterioration of laryngoscopic view and this may cause unexpected difficulties [START_REF] Morris | Difficult tracheal intubation following midface distraction surgery[END_REF]16].

Our data demonstrates that patients with Apert syndrome may require many anaesthetics of relatively short duration. A large proportion of the anaesthetics were of less than 30 minutes and In 52 of the anaesthetic charts there was no peripheral vascular access. This was a deliberate policy intended to preserve valuable vascular access sites during hand dressing changes. An intraosseous device was immediately available for all these cases but was never required.

In our cohort of patients the peri-operative problems occurred in 21 children (34%), which is a similar incidence to Elwood et al. who reported respiratory complications in 33% of patients [START_REF] Elwood | Respiratory complications during anaesthesia in Apert syndrome[END_REF].

Very few of the complications were serious and none resulted in cancellation of the procedure so it is important that a population of patients are not incorrectly labelled as 'high risk'. Nevertheless a significant proportion of these children have obstructive sleep apnoea and may develop supraglottic airway obstruction on induction and emergence from anaesthesia due to the mid-face anatomical abnormalities associated with this syndrome and the anaesthetist must be prepared to deal with this.

The authors have no financial or other interests to declare.

Payment by Purchase Order

If you are asking your university or institution to pay we require purchase order details I attach order number dated

Please now return all pages of your completed form as a scanned electronic file (preferred option), or by fax or post to the production editor for your journal. Contact details can be found in the instructions for authors.

  had a sleep study diagnosis of obstructive sleep apnoea pre-operatively. Although

  in situ prior to 19 anaesthetics in 4 children. Another 6 children had a nasal prong placed at the end of their operations.

  requiring re-intubation (x1); Self resolving stridor in recovery (x1); Post-operative upper airway clot after micro-laryngo-bronchoscopy (x1); Coughing on induction (x1); Obstruction of nasal prong on postoperative ward leading to respiratory arrest and PICU admission (x1); Desaturation and after monoblock distraction (x1), which was successfully treated with naloxone and furosemide.

  documented congenital sub-glottic stenosis

  large proportion of cases where the patient was breathing spontaneously either with a face-mask or laryngeal mask airway.

  Frawley G, Heggie A. Difficult tracheal intubation induced by maxillary distraction devices in craniosynostosis syndromes. Paediatr Anaesth. 2002 Mar;12(3):227-34.

*

  Quick cost lookup table for colour figures irt print and online: Card (MasterCard/VISA/American Express) Blackwell Publishing accepts payment in three major currencies: Pounds Sterling, United States Dollars and the Euro. Please indicate which currency you would like to pay in Pounds Sterling (£) G / United States Dollars* (US$) Q / Euros* (€) Q (tick one) Conversions from US$ or € will be made at our monthly rate. Please debit my credit card number: Verification ID Number:Name on cardThis can be found on your credit card (Visa/MasterCard have 3 numbers and Amex has 4) payment by credit card can only be accepted if all sections are completed. Please use BLOCK CAPITALS where possible.

Table 4 .

 4 Age appropriate tracheal tube sizes (based on the formula: Tracheal tube internal diameter (mm) = age/4 + 4).

	Tube size	Numbers	Percentage
	Age appropriate 98/199	49.2%
	Larger size	68/199	34.2%
	Smaller size	28/199	14.1%
	Unclear	5/199	2.5%

Table 5 .

 5 Details of patients who experienced supraglottic airway obstruction.

	Patient Age	Known	Surgery	Duration	Timing of	Manipulation	Definitive
			preoperative		of	obstruction	of airway to	airway for
			Upper		surgery		overcome	proceedure
			Airway				obstruction
			obstruction?
	1.	3 yrs	Yes -OSA	Tonsillectomy	60 mins	Induction	Oropharyngeal	Tracheal tube
				and			airway
				Adenoidectomy
	2.	19	No	Fronto-orbital	6 hrs	Induction	Oropharyngeal	Tracheal tube
		mths		remodelling			airway
	3a.	8	Yes -OSA	Change of	20 mins	Induction	Oropharyngeal	Face mask and
		mths		dressing			airway and	oropharyngeal
							PEEP	airway
	3b.	9	Yes -OSA	Change of	20 mins	Induction	Oropharyngeal	Face mask and
		mths		dressing			airway	oropharyngeal
								airway
	3c.	9	Yes -OSA	Tonsillectomy	30 mins	Induction	Oropharyngeal	Tracheal tube
		mths		and			airway
				Adenoidectomy
	4a.	12 yrs Yes -OSA.	Dental	2 hrs 45	Induction	Jaw support	Tracheal tube
			Nocturnal	extractions	mins		and suction
			CPAP
	4b.	9 yrs	Yes -OSA	Tonsillectomy	1 hr 15	Induction	Jaw support	Tracheal tube
				and	mins
				Adenoidectomy,
				EUA ears
	5.	14 yrs No	Correction of	40 mins	Induction	PEEP	Tracheal tube
				fixed flexion
				deformity of
				hand
	6.	4	Yes -	Adenoidectomy,	60 mins	Induction	Jaw support	Tracheal tube
		mths	OSA/choanal	EUA postnasal
			atresia	space
	7.	5	Yes -	Frontal	4 hrs	Induction	LMA	Tracheal tube
		mths	OSA/choanal	remodelling
			atresia
	8.	5 yrs	Yes -OSA	Adenoidectomy	40 mins	Induction	Jaw thrust	Tracheal tube
	9.	14 yrs Yes -OSA	Syndactyly	1 hr	Emergence Oropharyngeal	Tracheal tube
				repair			airway until
							awake
	10a.	9	Yes -	Nasal prong and	20 mins	Induction	Oropharyngeal	LMA
		mths	OSA/choanal	dilation			airway and
			atresia				nasal prong
	10b.	2 yrs	Yes -OSA	CT Head	10 mins	Induction	Oropharyngeal	LMA
		10					airway
		mths
	11a.	4	No	Cleft palate	1 hr 30	Induction	Oropharyngeal	Tracheal tube
		mths		repair	mins		airway
	11b.	9	No	Syndactyly	3 hrs 30	Induction	Oropharyngeal	Tracheal tube
		mths		repair	mins		airway
	12.	12	No	Grommets	10 mins	Induction	Oropharyngeal	LMA

Table 1 .

 1 Type of surgery.

Table 2 .

 2 Major craniofacial reconstructions.

Table 3 .

 3 Patient demographics.

Table 4 .

 4 Age appropriate tracheal tube sizes (based on the formula: Tracheal tube internal diameter

	(mm) = age/4 + 4).

Table 5 .

 5 Details of patients who experienced supraglottic airway obstruction.

	Colour Work Agreement Form
	Form No: SN_Sub2000_P_CoW
	F o r
	P
	e e
	r
	R e
	v i e
	w

Please now complete this table (Remember: only one 'X' per figure).

Acknowledgements

We would like to thank the craniofacial nurse specialists Andrea White and Kathy Truscott for their help obtaining the list of patients.

ILEY-

If you have any problems or queries please contact the Production Editor for guidance (details can be found in the Instructions for Authors)

If you have submitted a manuscript that contains colour figures, it is the policy of the journal for authors to meet the full cost of colour reproduction. Blackwell Publishing require you to complete this form. Please fill in your contact details and then complete the table as instructed. Note: this form must be filled in for all manuscripts that have been submitted with colour work, even if you subsequently choose not to publish either in print or online in colour.

We are unable to process your manuscript until we receive your instructions so please return this form as quickly as possible!

WHAT YOU NEED TO DO

Please complete the table on page 2, placing an 'X' in the relevant column for each figure.

The costs are shown at the top of each column. Please calculate the total cost for each category at the foot of the table, and then add VAT if applicable (see below).

All customers MUST quote their VAT numbers

Customers in the UK: add VAT at 17.5%.

Customers elsewhere in the EU: