Challenges in paediatric procedural sedation: political, economic, and clinical aspects.

British Journal of Anaesthesia 113 (S2): ii48–ii62 (2014)

doi:10.1093/bja/aeu387

PAEDIATRICS

Challenges in paediatric procedural sedation: political, economic, and clinical aspects K. P. Mason Department of Anaesthesia, Harvard Medical School, Boston Children’s Hospital, Boston, MA, USA

Editor’s key points † Delivery of paediatric sedation has expanded in the last decade. † In contrast, there have been few new sedatives developed, and many are not approved for children. † Current sedation guidelines are often contradictory, and vary both between and within specialty groups. † Large prospective outcome studies are necessary to determine optimal sedation practices.

Summary. Paediatric sedation has expanded in volume and demand over the past decade. In parallel with the increasing demand for and delivery of sedation by multi-specialty providers, conflicting political agendas have surfaced. With a limited selection of sedatives and few new sedatives to market over the past decade, some providers utilize agents that formerly were considered exclusive for administration by anaesthesiologists. This review highlights the important contributions to paediatric sedation over the past century. Considerations include the barriers and politics that impede progress and also future advances and contributions that may lie ahead. Keywords: paediatric anaesthesia; safety; sedation Accepted for publication: 2 October 2014

Paediatric sedation has expanded, over the past decade, in volume and demand. It is now being delivered by specialists of anaesthesia, emergency medicine, dentistry, gastroenterology, intensive care, paediatrics, pulmonology, cardiology, neurology, and nursing.1 – 3 In parallel with the increasing demand for and delivery of sedation by multi-specialty providers, conflicting political agendas have surfaced. With a limited selection of sedatives and few new sedatives to market over the past decade, some providers utilize agents that formerly were considered exclusive for administration by anaesthesiologists. Worldwide there is not consistent agreement on sedation practice and delivery. In some countries, government has interceded to regulate sedation delivery and reimbursement. For example, in the USA, deep sedation by registered nurses is no longer reimbursed under the Center for Medicaid and Medicare Services (CMS).4 Some specialty societies, notably those of emergency medicine, dentistry, anaesthesia, gastroenterology, and paediatric, have published their own sedation guidelines, recommendations, policies, and statements for the practice of sedation.5 – 11 The global challenge is the paucity of large, prospective, collaborative outcome studies. Without these studies, sedation providers are unable to determine which sedation practices are optimal for favourable outcomes. It may not be practical or realistic to standardize guidelines between different specialties. However, there are contradictions even within the same

specialty: specialty guidelines, recommendations and statements can be inconsistent between countries within the same continent.7 12 – 14 For example, in Europe there is disagreement between some countries on whether propofol should be restricted to delivery by anaesthesiologists.15 – 17 To advance the field of paediatric sedation over the next century, this author believes that large, multi-centre randomized controlled trials must be designed to guide optimal sedation practice, recognizing that sedation practice cannot always be the same between specialties. There are a range of topics that must be examined: provider skillset, credentialing, the role of simulation in training and maintaining proficiency, physiological monitoring, routes and methods of delivery, and the design and interpretation of clinical studies. Of foremost importance, we need to determine the best method of acquiring and maintaining sedation training and credentialing. This task is not straightforward because there are unresolved questions. Should the criteria for sedation competence differ between specialists (e.g. dental vs gastroenterology), sedatives (e.g. propofol vs dexmedetomidine), or targeted depth of sedation (e.g. moderate vs deep)? Many such questions must be considered when developing a training and sedation credentialing programme for sedation. Although there may be agreement on the undeniably necessary skills (establishing positive pressure ventilation, recognizing airway obstruction, etc.), there is no consensus on how to

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Paediatric procedural sedation

The past century in review: sedatives and their politics Many of the sedatives used today were first described over a century ago. In a retrospective review, drug overdosage, drug interactions, and administration of three or more sedatives were major contributors to critical incidents (death or permanent neurological injury).18 Overall, the majority of sedatives are used off-label in the paediatric population.19 Recently, the availability and utilization of some sedatives have been affected not only by their side effect profile, but also by politics and economics.

Chloral hydrate The first synthetic sedative-hypnotic, was discovered in 1832 and described as a ‘neues hypnoticum und anaestheticum’ (new hypnotic and anaesthetic) in 1869.20 Administered to children as early as 1893, chloral hydrate over a century later, remains the foundation of sedation for dental, neurological (electroencephalograms), radiological (magnetic resonance imaging, computerized tomography), intensive care and cardiac imaging (echocardiography) procedures worldwide.21 – 24 In the USA, the pharmaceutical producer of chloral hydrate will cease its manufacture. Some individual pharmacies and institutions have responded by compounding (creation of particular pharmaceutical product to fit the unique needs of

a patient) the chloral hydrate formulation. The economic effect of this production model has yet to be determined.25

Pentobarbital Pentobarbital, known by the brand name Nembutal, was first administered in the 1930s.26 As early as 1965, the use of pentobarbital was described for paediatric sedation.27 Despite its long half-life of up to 48 h, it has a high safety profile that continues to favour pentobarbital administration worldwide for sedation delivery, particularly by non-anaesthesiologists.23 24 Utilized predominantly by the i.v. route, only one company is approved by the Food and Drug Administration (FDA) to distribute the injectable form in the USA. Manufactured by a Danish pharmaceutical company, Lundbeck, pentobarbital has recently gained worldwide notoriety as being the drug administered in the USA for death by lethal injection. After legislation by the European Union banning export of medications intended for death by lethal injection, Lundbeck threatened to halt its distribution to the USA when intended for such purposes.28 29 Although both chloral hydrate and pentobarbital lack analgesic properties, their predictable and low rate of adverse events, respiratory depression, and failed sedation continue to favour their use.30 – 37 In public opinion, however, pentobarbital conjures negative and risky connotations.

Propofol Propofol, or 2,6-diisopropylphenol, was first used clinically as an anaesthetic in 1977. Propofol is an example of a medication that has fuelled the debate on which medications are appropriate for administration by non-anaesthesiologists. In June 2005, the American College of Gastroenterologists submitted a petition which was ultimately denied by the FDA to remove the warning that propofol be administered only by persons trained in the administration of general anaesthesia. At the time, less than a decade ago, this petition evoked emotionally charged arguments, both in defence and opposition, with the ultimate success of the American Society of Anesthesiologists (ASA) in their November 2005 testimony before the FDA to deny this request. The current package insert limits propofol administration to ‘persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure . . . (while) continuously monitored (patients) for early signs of hypotension, apnoea, airway obstruction, oxygen desaturation, or all’.38 Promoting unconsciousness, propofol inhibits release of the arousal-promoting histamine neurotransmitter in the cerebral cortex.39 Similar to pentobarbital, propofol also attracted public attention when it was intended for death by lethal injection. A public outcry lead the European Union in 2000 to threaten a ban on exportation of propofol to the USA should it be used for capital punishment, torture or other cruel, inhuman or degrading treatment, or punishment.40 Propofol’s association with the death penalty and its association with the death of the well-known music idol Michael Jackson, have created a negative stigma in the public eye.

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acquire and demonstrate proficiency. For example, the ability to establish effective mask ventilation and positive pressure ventilation is critical. Unanswered, however, is how these skills should be acquired, demonstrated and maintained. Should the proficiency of these skills be tailored to institution, specialty or socioeconomic setting? For example, in developing countries, the Mapleson A circuit may be the most appropriate equipment for administering positive pressure ventilation. There remain other unanswered questions: is the ability to perform tracheal intubation necessary in order to deliver deep sedation? Should all sedation providers be able to demonstrate competence in laryngeal mask airway (LMA) placement? If yes, how many tracheal intubations or LMA placements should a provider perform in order to be able to achieve acceptable competence? Should the ability to intubate children of different age ranges be demonstrated, especially considering that there is a notable difference in airway anatomy (cephalad and anterior larynx with large, floppy epiglottis in newborns) between some age groups? If yes, how many infants must be intubated in order to exhibit competence? Should there be ongoing requirements to perform a minimum number of intubations annually? With the recent emphasis on the use of capnography, should providers need to demonstrate an understanding and competence in evaluating capnogram traces? This review highlights important contributions to paediatric sedation over the past century and considers the barriers and politics that impede advancement and also the future advances and contributions that may lie ahead.

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Ketamine Ketamine was first approved in 1970 in the USA and is commonly administered by emergency medicine physicians for painful procedures, particularly in the paediatric population. First described in their literature in 1979, practice guidelines for ketamine administration have been published by the American College of Emergency Physician (ACEP).48 – 52 Worldwide it remains a commonly administered and essential medication, even recognized by the World Health Organization on their List of Essential Medicines for Children.53

Etomidate Etomidate was FDA approved for adults in 1982 and remains without paediatric labelling. Etomidate is associated with comparatively less hypotension and cardiovascular depression than occurs with most other sedatives and offers the advantage of rapid onset with a short elimination t1/2 of 2.6 h.54 55 Without analgesic properties, etomidate has been used for procedural sedation (often in combination with opioids), most commonly by emergency medicine physicians who do not have access to propofol for diagnostic imaging and brief procedures such as cardioversion, closed reduction of orthopaedic injuries, and abscess incision and drainage.56 Over the past decade, it has fallen into disfavour, both for adults and children, because of reports of increased mortality with continuous infusions and adrenal suppression with a subsequent decrease (for a minimum of 24 h) in plasma cortisol.57 – 62

Dexmedetomidine Dexmedetomidine was approved in the USA in 1999 and in Europe in 2011 for sedation of adults in the intensive care unit. Dosing recommendations differ between the USA and Europe.63 64 A highly specific alpha-2 adrenergic agonist, dexmedetomidine is unique because it preserves respiratory function and simulates natural non-rapid eye movement (non-REM) sleep which has also led to its utilization as a sedative for electroencephalography.65 – 70 Dexmedetomidine should be avoided in patients on digoxin as there is an association between this combination and cardiac arrest and severe bradycardia.63 71 Its off-label use for paediatric sedation has

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mostly been for radiological imaging.3 32 – 35 72 – 80 As a sole sedative in non-intubated children, higher than ‘recommended’ (package insert) doses of dexmedetomidine must be delivered with anticipation of possible haemodynamic shifts (arterial pressure, heart rate) and cardiovascular effects (change in stroke index, cardiac index, systemic vascular resistance).77 78 81 82

Sedation delivery politics, economics, policies, procedures, guidelines, and statements This review highlights the evolution of sedation in the USA, as the American Society of Anesthesiologists, American College of Emergency Physicians, American College of Gastroenterologists, Joint Commission, FDA and Center for Medicaid and Medicare services have been the most visible and prolific in their responses and contributions to evolving sedation practices. Historically, dentists, neurologists and anaesthesiologists have been providing procedural sedation for paediatric patients since the 1960s.83 – 88 Emergency medicine physicians began delivering sedation in the 1970s.48 In the 1990s, as more procedures began to be performed in areas outside of the operating theatre, sedation delivery expanded to other specialists—paediatricians, neurologists, hospitalists, pulmonologists, and nurses. As sedation has evolved over the decades, the specialty societies have created and updated guidelines, policies and statements intended not only to guide their own practice, but in some cases, the practice of others outside their specialty. One example of this is the ASA which published its first guidelines addressing the delivery of sedation by non-anaesthesia care providers in 1996. The ASA has subsequently presented updates, standards and statements on moderate and deep sedation, and on propofol delivery.89 – 94 The definition of deep sedation in the USA and Europe are similar: a drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully after repeated or painful stimulation.95 96 Apart from the ASA, other specialty (professional) societies have created guidelines for application by members of their own societies. In paediatrics, this began in the USA in 1983. Responding to the death of three children in a single dental office, the American Academy of Pediatrics published the first (with subsequent updates) guidelines for the sedation of children.97 – 102 The American College of Emergency Physicians, American Academy of Pediatric Dentistry (AAPD), American Dental Association, and American College of Gastrointestinal Endoscopy have independently published guidelines, some of which are evidence-based, to direct paediatric sedation by their members. Collectively, these guidelines span the breadth of sedation practice from pre-sedation assessment, the medical condition of the child, sedation environs, physiological monitoring, and recovery.7 8 14 100 103 – 112 In the USA, the government is also involved through its CMS. This government involvement, by affecting the reimbursement of sedation, has had significant ramifications on sedation delivery. As early as 2004, the Joint Commission intended to


Fospropofol is an alkylphenol-derived soluble prodrug of propofol, intended to offer benefits of reduced pain on injection, less risk of bacterial contamination, a larger therapeutic window with greater respiratory stability and a short terminal phase elimination half-life (t1/2) of 0.8 h.41 42 FDA approved in 2008 for Monitored Anaesthesia Care, fospropofol remains without paediatric labelling. To date, the majority of published experience has been limited to gastrointestinal endoscopies for adults, but also includes dental procedures and bronchoscopies.43 – 45 Despite a lack of significant adverse respiratory events, fospropofol’s side-effect profile of transient paresthesias in up to 69% and pruritus in up to 26% has limited its adoption as a sedative.46 47

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Volume of anesthesia services per 1 million enrollees

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increase in Medicare and commercial payments, respectively (Fig. 1).115 A review in 2013 estimated that worldwide, if anaesthesia delivery for gastrointestinal endoscopy procedures was able to prevent a sedation-related death, it would be at a cost of US $5 million per life-year saved.116 A computer assisted personalized sedation (CAPS) device (Sedasys. Ethicon Endo-Surgery, Cincinnati, OH, USA) was approved in January 2014 for non-anaesthesia delivery of propofol to healthy (ASA I and II) adults for routine endoscopy and oesophagogastroduodenoscopy procedures. With anaesthesia-administered sedation for routine endoscopy projected for 50% of the patients in 2015, this technology could have significant financial implications by reducing the current US $2 billion annual anaesthesia expenditures for such services.117 118 To date, there has not been an assessment of preventable morbidity, improved safety or difference in health care costs between anaesthesia and non-anaesthesia delivery of paediatric procedural sedation. Particularly in the low-risk (ASA I or II) patient, large multi-centre studies are needed to demonstrate whether there are differences in outcome with anaesthesia delivery.119 In the majority of Europe, there is also no consensus on sedation practice between or within specialties or individual countries: The Netherlands, Scotland and the UK have each recently published paediatric sedation guidelines.95 11 120 In the Netherlands, the Dutch Institute for Healthcare Improvement commissioned the 2011 Pediatric Guidelines for Procedural Sedation, Analgesia, or both at Locations Outside the Operating Theatre from the Netherlands Society of Anaesthesiologists and the Dutch Society of Pediatrics. In the UK, the National Institute for Health and Clinical Excellence developed in 2010

Payment for anesthesia services among commercially insured patients 8

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set the standard for sedation in any setting, when it first published (updated recently) a Comprehensive Accreditation Manual for Hospitals. In May 2010 (subsequently updated again in 2010 and 2011), the CMS had a significant impact on the delivery of sedation in the USA when it restricted reimbursement for deep sedation services to specific specialties. Appendix A of Revised Hospital Anesthesia Services Interpretive Guidelines—State Operations Manual limited administration of deep sedation to a qualified anaesthesiologist, a doctor of medicine or osteopathy (other than an anaesthesiologist), a dentist, oral surgeon, or podiatrist who is qualified to administer anaesthesia under State law, a certified registered nurse anesthetist (CRNA) or an anaesthesiologist’s assistant who is under the supervision of an anaesthesiologist who is immediately available if needed.113 Although those regulatory guidelines conflicted with guidelines published by some specialty societies, this policy initially shifted much of the sedation provision in the USA, and in many circumstances eliminated the delivery of deep sedation by registered and advanced practice nurses. A revision in 2011 sanctioned the institution to determine the qualifications of the sedation provideracknowledging that individual hospitals can establish their own policies in accordance with recognized guidelines of specialty societies.114 This revision was important because it removed government restriction on sedation provision and re-aligned them with national specialty guidelines. The economics of anaesthesia-delivered sedation in the USA is a topic of interest and concern. Between 2003 and 2009, anaesthesia services for gastrointestinal endoscopies increased by more than 50% for patients with commercial insurance. Anaesthesia services accounted for a two- and four-fold

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Training, credentialing and maintenance of sedation skills In the USA, the Joint Commission in 2007 made specific recommendations for training, specifying that providers be able to manage patients even from unintentionally achieved depths of sedation. Those delivering deep sedation, in particular, should be qualified to rescue and manage the cardiovascular, respiratory and airway complications that could accompany a general anaesthetic.124 Some societies have been proactive in their efforts to address the training needs of their members by publishing consensus statements and guidelines. This year gastroenterologists, in the USA, published a multisociety Sedation Curriculum for Gastrointestinal Endoscopy. This was a joint collaborative effort among four national gastroenterology societies to establish and maintain sedation proficiency.125 The American College of Emergency Physicians, ASA, American Dental Association, American Academy of Pediatrics, and American Academy of Pediatric Dentistry have also within the past few years published their own guidelines to address sedation training, delivery and credentialing of their members.6 90 91 92 99 101 104 126 127

Propofol-fuelled controversy Propofol continues to fuel worldwide controversy, with conflicting guidelines and statements being published, and sometimes retracted. In the USA, the past 5 yr have witnessed the introduction of guidelines for the delivery, skill-set, credentialing, and monitoring of propofol administration by the nonanaesthesiologists of the Societies of Gastrointestinal Endoscopy and Emergency Medicine.7 14 106 108 110 112 126 The ASA accepts non-anaesthesiologists for propofol delivery only when an anaesthesiologist is unavailable. In 2009, the ‘Statement on Safe Use of Propofol’ advised that involvement of an anaesthesiologist is optimal for patient care but, when not available, the non-anaesthesia provider must be qualified to rescue from ‘. . . a state of general anesthesia’.94

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This propofol controversy extends to Europe. In 2010, the European Society of Gastrointestinal Endoscopy, European Society of Gastroenterology and Endoscopy Nurses and Associates, and the European Society of Anaesthesiology reached a consensus when they published the Guideline for Propofol Administration by Non-Anesthesiologists.15 These guidelines were controversial and provoked an outrage amongst some anaesthesia societies throughout Europe. Eventually the European Society of Anaesthesiologists retracted its support for these propofol guidelines after the publication of a Consensus statement from 21 European National Societies of Anaesthesia that opposed this Guideline.16 17 Intended for adults, the aforementioned guidelines do not address children. In general, the majority of propofol delivery for procedural sedation in Europe is by anaesthesiologists, although it remains a topic of ongoing debate.17 128 129 In the Pacific rim area, the Australian and New Zealand College of Anaesthetists endorses propofol administration by non-anaesthesiologist medical or dental practitioners in their Guidelines on Sedation and/or Analgesia for Diagnostic and Interventional Medical, Dental or Surgical Procedures.130

Outcome studies of the safety of sedation Currently, there is no substantial data to restrict sedation delivery to one specialty. Large outcome studies (usually retrospective) and meta-analyses, present outcomes of nonanaesthesia providers. A large, multi-centre study of 130 000 sedations provided by paediatrician and non-paediatrician providers, presented a low rate of adverse events.131 Other large multi-centre studies have demonstrated similar outcomes between delivery by anaesthesiologists, intensive care medicine physicians, emergency medicine physicians, and paediatricians.132 Some specialties have independently published their own outcomes. For example, the emergency medicine literature presents a 3.9% overall incidence of airway and respiratory adverse events with ketamine. A meta-analysis of 8282 paediatric ketamine sedations, pooled from 32 studies, demonstrated that high i.v. doses, age ,2 yr or .13 yr, and co-administration of anticholinergics or benzodiazepines, independently predicted an increased risk of adverse events.133 Sedation delivery by dentists has become an area of scrutiny. Widely publicized office-deaths have identified significant risk to sedation in paediatric dental offices.134 135 It is estimated that there may be up to 250 000 paediatric dental sedations annually in the USA.136 Recently, two leading dental professional liability insurers in the USA reported that half of the events between 2003 and 2007 resulted in death or permanent brain damage in children ,3 yr of age.137 The USA continues to remain the country with the greatest volume of non-anaesthetist delivered propofol in the world. As experience mounts, more outcomes are published from different specialties: oxygen desaturation, airway obstruction and apnoea are the more common serious adverse events, occurring with an overall 2.3% incidence when delivered by emergency medicine physicians.2 138 Similar outcomes have


the Guidelines for Sedation for Diagnostic and Therapeutic Procedures in Children and Young People, and in 2013 the Academy of Royal Medical Colleges published Safe Sedation Practice for Healthcare Procedures with paediatric application.121 122 These guidelines are unique in that they recognized inhalation anesthetics (Sevoflurane) as appropriate for moderate and deep sedation by non-anaesthesiologists. To date, there are no sedation guidelines published specifically from Asian countries. Most of the Asian countries follow ASA, American College of Emergency Physicians, American Academy of Pediatrics, and Joint Commission guidelines. Some countries are currently embarking on creating their own sedation guidelines (Japan, China). In the South Pacific, the Australasian College for Emergency Medicine, and Australian and New Zealand College of Anaesthetists have published a ‘Statement on Clinical Principles for Procedural Sedation’.123 The South African Society of Anaesthesiologists published Paediatric Procedural Sedation and Analgesia Guidelines in 2011.5

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Drug shortages affect delivery of sedation Limited supplies and discontinuation of the manufacture of some sedatives are challenging the sedation provider to find alternative methods of sedation (drugs, routes, and methods).144 In 2012 and 2013, two of the major manufacturers of chloral hydrate in the USA notified the FDA that they would be discontinuing its manufacture, a business and not safety decision.145 In 2009, the USA experienced a shortage of propofol that prompted the FDA to temporarily allow the European formulation Fresenius Propoven 1% to be imported from the European Union despite its lack of formal FDA labeling and differences in formulation.146 Shortages of ketamine and etomidate, during periods when they were listed on the FDA Drug Shortage list, additionally challenged the provision of sedation in the USA.147 148 These shortages highlight the need to develop new sedatives, consider different routes and methods of administration, prioritize the need to pursue paediatric labelling for eligible sedatives, and be creative to determine solutions.

Role of simulation Future initiatives and developments in sedation should involve incorporation of simulation into training, credentialing and maintenance of sedation skills. The value of simulation dates back to World War I, when pilots, crew and air traffic controllers were trained with simulation.149 Simulation offers a hands-on experience, re-creating both relatively common (airway obstruction, laryngospasm, and bronchospasm), and rare (cardiovascular collapse, aspiration, and anaphylaxis) situations. Simulation can range from simple re-creation of clinical scenarios using human volunteers to expensive simulation centres with high-fidelity mannequins. Simulation training can be tailored to the specialist, patient population, procedure type, setting (hospital vs outpatient, ambulatory setting), and type of sedation administered. Simulation can not only develop the sedation provider’s management skills, but also identify methods to predict and prevent adverse events and develop teamwork. The ability to utilize, organize and direct a team is important in crisis management.150

Recent literature from different specialties demonstrates that simulation is important for training and can have long-lasting effects on the improvement of sedation-related skills.151 – 157 Future efforts should be made to identify the best means to incorporate simulation into the field of sedation, so that it is available, affordable and beneficial to all providers. Although there is widespread agreement that simulation is important, to-date there are no national or international recommendations or programmes to guide the application of simulation for sedation. A recent European initiative focuses on the role of training and competency in sedation: The European Society of Anaesthesiologists has recently presented an initiative to provide an updated evidence-based guideline on how to provide sedation in a safe way to children. This workgroup will use the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate the literature to develop evidence-based recommendations.158 The group will focus mainly on competencies that the sedation provider needs in order to make the procedure safe. If evidence is lacking, the consensus between experts will address the problem. It is hopeful that this initiative will guide and prioritize the skills necessary for safe sedation.

Do sedatives affect neurodevelopment? There remain unanswered, important questions regarding the safety of sedation. A topic of ongoing interest has been the potential effect of anesthetic agents on neonatal and infant neurodevelopment.159 160 Multi-centre studies are currently ongoing to determine whether there are long-term effects of certain anaesthetics. Studies in rodents and primates suggest that inhalation anesthetics and ketamine affect neuroapoptosis during sensitive times of brain development,161 – 164 but that dexmedetomidine may be neuroprotective.165 166 Currently the large, multi-centre studies designed to assess the effect of anesthetics on neurocognitive development, do not include commonly used sedatives such as dexmedetomidine, propofol, benzodiazepines, and ketamine.167 168 The sedation community must unite to design studies intended to evaluate the effect of some of the more commonly used sedatives on neuroapoptosis and cognitive development in infants and children. A relationship between neurocognitive outcome and sedative agents could guide not only the future delivery of sedation but also the choice on whether and when to perform non-urgent procedures on infants ‘at risk’.

Sedatives in development: new drugs, routes, delivery systems Over the past decade, there has only been one new sedative, dexmedetomidine, introduced worldwide, and no sedative with paediatric labelling. There is no current sedative that is ideal with respect to pharmacokinetics, pharmacodynamics, predictability, safety, patient satisfaction, and sedation profile. New sedatives, routes, and methods of delivery need to be explored. There are some sedatives in development that could offer benefits.

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been presented with more than 7000 propofol encounters by intensive care physicians (0.37% brief positive pressure ventilation, 0.03% intubation).139 Paediatric hospitalists report similar adverse event rates with 1649 propofol encounters (2 aspirations, 1 elective intubation in order to complete the procedure).140 141 Anaesthesiologists in Italy performed 17 999 sedations for paediatric gastrointestinal endoscopies, the majority administered as target controlled propofol infusions [targeted controlled infusion (TCI) propofol]. The 2.6% rate of adverse events was similar to those of nonanaesthesiologists.142 Data from 2527 patients in the Nordic countries who received nurse administered propofol showed a similarly low rate of significant adverse events (0.9% positive pressure ventilation, no tracheal intubations or cardiac arrest).143 To date, the data supports paediatric sedation with propofol by trained providers with well-defined protocols.

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SEDASYS integrates patient data (electrocardiogram, non-invasive blood pressure, capnography, respiratory rate, pulse oximetry, and patient responsiveness to verbal stimuli) into computerized programs in order to guide drug delivery. In the USA, it has been released on a limited basis since early 2014.187 Future studies are needed to determine whether this system could be applied or modified to paediatric use. A distant look into the future, reminiscent perhaps of Jules Verne in the 1800s when he fantasized of submarines and aircraft in 20 000 Leagues under the Sea and From the Earth to the Moon, respectively, might reveal applying pharmacogenetics to sedation practice. Pharmacogenetics has already been shown to have a role in the effect of propofol, dexmedetomidine, opioids, non-opioid analgesics, benzodiazepines, analgesic, sedative, and local anesthetic medications.188 – 195 In the future, knowledge of pharmacogenetics might enable tailored sedation to the genetic ‘fingerprint’ of a particular person.

Challenges to the advancement of paediatric sedation Children represent an at-risk population by virtue of the fact that many of the sedatives they receive are used off-label, having not undergone the necessary rigorous studies to meet approval for paediatric use. For example, ketamine, etomidate, chloral hydrate, pentobarbital, and dexmedetomidine are being administered off-label. The USA first addressed this disparity between adult and paediatric prescription with the Best Pharmaceuticals for Children Act of 2002. This Act incentivized drug companies to conduct FDA-requested paediatric studies by rewarding an additional 6 months of marketing exclusivity. The Pediatric Research Equity Act of 2003 defines conditions for which the FDA may require drug companies to conduct studies of their products.196 Despite these initiatives in the United States, there is a paucity of paediatric labelled sedatives. Midazolam received paediatric labelling in 1998 and propofol was the last sedative to obtain paediatric approval in 1999. The design of paediatric sedation studies for those pursuing paediatric labelling has become a topic of increasing interest by the FDA. In 2012, the FDA created a new Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) to develop evidence-based consensus recommendations for clinical trial designs, including efficacy and safety endpoints, for adult and paediatric procedural and intensive care unit sedation products. The SCEPTER group represents a multidisciplinary Steering Committee of sedation experts (clinical and researchers) from diverse medical specialties within the USA, Europe and Asia. The Committee includes anaesthesiologists, gastroenterologists, intensivists, emergency room physicians, and oral surgeons.197 The SCEPTER group has met twice and is actively working to advise the FDA on future sedation trial designs. It is hopeful that this initiative will not only encourage sedation trials but also, more importantly, ensure that the studies are optimal in design and outcome assessment. Currently, there is lack of conformity and agreement between specialists on sedation guidelines, recommendations


Most sedatives in development are pro-drugs of those currently available. For example HX0969W is a water-soluble pro-drug of propofol that releases propofol and gamma hydroxylbutyrate. Studies in rodents suggest that it has a longer onset time and shorter duration of action than fospropofol.46 169 HX0969W modified by adding a glycine or alanine to the structure, identified as HX0969-Gly-F3 and HX0969-Ala-HCl, has been tested in vitro. Initial studies suggest that without the phosphate ester, these prodrugs eliminate the paresthesias, pruritis and perineal burning that has been associated with propofol and fospropofol while producing quicker onset of action and an improved safety profile.170 Another agent in development is remimazolam. This is an ultra-short acting benzodiazepine that is currently undergoing trials as a procedural sedation agent. It appears from initial studies to have a more rapid onset and a shorter recovery time than midazolam.171 – 173 Derivatives of etomidate are in development, intended to modify the pyrrole ring responsible for adrenocortical suppression. Methoxycarbonyl(moc)-etomidate is reported to offer a stable haemodynamic profile, fast onset and rapid metabolism.174 Carboetomidate contains a five-membered pyrrole ring instead of an imidazole. The loss of the free imidazole nitrogen eliminates coordination interactions with heme irons, thereby reducing adrenal suppression.175 In vitro studies suggest that modifications to etomidate’s chiral centre reduce the adrenocortical suppression.176 177 Emulsified forms of inhalation anesthetics, available for i.v. delivery, might introduce a new approach to sedation. Emulsified isoflurane is being developed in China and currently has begun Phase I trials. Escalating doses have been shown to produce fast onset, increasing depths of sedation and fast recovery.178 179 New routes and methods of delivery, using either new or existing sedatives, might also offer benefits. For example, sublingual sufentanil with a profile similar to parenteral administration, is being developed.180 Intranasal and intramuscular dexmedetomidine, non-approved routes of delivery, have been described with success for the off-label paediatric patient population.68 181 – 184 New methods of sedation delivery using TCIs, a common method in Europe and Asia of delivering anaesthesia, could offer benefits. If the pharmacokinetics of a sedative are defined, as is already the case with propofol and remifentanil, it can be delivered to achieve a targeted blood concentration (brain) using validated pharmacokinetic models. Incorporating the bispectral index into the computer algorithm might offer an improved means of achieving and maintaining a targeted sedation depth.185 Currently TCI delivery pumps are approved and in use outside of the USA. Further development of paediatric models for TCI delivery, could provide a means of delivering sedation in a more precise, efficient and safe method. Future studies should focus on the benefits of TCI over manual titration of sedation. Currently, a computer-assisted personalized sedation device marketed as SEDASYS, has been developed and recently FDA approved (May 2013) for the moderate sedation of healthy adults during gastrointestinal endoscopy.173 186

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Step 1: Was there one or more adverse events associated with this sedation encounter? No, this form is now complete.

Yes, fill out remainder of form below.

Step 2: Please DESCRIBE the adverse events(s). Check all that apply. Minimal risk descriptors Vomiting / Retching Subclinical respriatory depressiona Muscle rigidity, myoclonus Hypersalivation Paradoxical responseb Recovery agitationc Prolonged recoveryd

Sentinel risk descriptors Oxygren desaturation, severe (60 s) Cardiovascular collapse/ shockg Cardiac arrest/absent pulse


Minor risk descriptors Oxygen desaturation (75–90%) for 25% from baseline.

g.

“Cardiovascular collapse/shock” is defined as clinical evidence of inadequate perfusion.

h. Examples of “escalation of care” include transfer from ward to intensive care, and prolonged hospitalisation. i. “Pulmonary aspiration syndrome” is defined as known or suspected inhalation of foreign material such as gastric contents into the respiratory tract associated with new or worsening respiratory signs. j.

“Sentinel” adverse events are those critical enough to represent real or serious imminent risk of serious and major patient injury. Once recognized, they warrant immediate and aggressive rescue interventions. Once clinically concluded, they warrant immediate reporting within sedation care systems, and the highest level of peer scrutiny for continuous quality improvement.

k.

“Moderate” adverse events are those that, while not sentinel, are serious enough to quickly endanger the patient if not promptly managed. Once clinically concluded, they warrant timely reporting within sedation care systems, and periodic peer scrutiny for continuous quality improvemet.

l.

“Minor” adverse events are those encountered periodically in most sedation settings, and that pose little threat given appropriate sedationist skills and monitoring.

m.

“Minimal” adverse events are those that alone present no danger of permanent harm to the patient.

Fig 2 Adverse sedation event-reporting tool199, by permission of Oxford University Press.

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Mason

Table 1 Objective risk assessment tool for sedation.201, with permission from John Wiley and Sons. Preliminary sample schematic: the choice of four levels here is arbitrary and for illustration purposes only; the final tool would contain the minimum number of discrete levels with independent predictive value. *Focused research would be required to validate the specific variables, parameters, and thresholds that predict the progressive levels of serious adverse event risk. Evaluation of capnography, for example, could include but not be limited to evaluation of waveform, frequency, pattern, numerical value on inspiration or expiration, or all. †To be determined at each level by consensus panel and would include but not be limited to recommendations on adjuvant personnel, i.v. access, availability of rescue medications and airway equipment Escalating risk of serious adverse event

Physiological monitoring parameters (singular or combination)*

Recommended provider skill set

Recommended resources†

1

≤1:10 000

Consistent with normal awake pattern and frequency

Ability to observe and interpret the agreed-upon physiological monitoring parameters

Appropriate for risk level

2

1:1000

Objective monitoring predicts this level of risk

Skills appropriate for maintaining sedation at this risk level and for rescuing from the subsequent level


3

1:100


Skills appropriate for maintaining sedation at this risk level and for rescuing from the subsequent level


4

≥1:10


Skills appropriate for maintaining a patient at this risk level


and practice. Of the 53 countries of Europe, only a handful have published sedation guidelines, most of which were only intended for specific specialties. This lack of conformity is partially a reflection of inadequate large, multicentre, multispecialist delivered sedation studies to provide outcomes that support the design of evidence-based guidelines. A first step to achieve these goals would be to establish a clear definition of specific sedation-related outcomes that could be applied to future studies. Currently, sedation studies are not uniform in their definition of outcomes. Terms such as hypoxia, apnoea, airway obstruction, oxygen desaturation, bradycardia, tachycardia, hypo/hypertension and failed sedation are outcomes with arbitrary, investigator-specified, definitions. The lack of universally accepted and utilized clear definitions for significant outcomes on hypoxia, hypotension and unplanned airway intervention, hampers the ability to objectively evaluate and compare outcome and sedation practice.198 The International Sedation Task Force (www.International SedationTaskForce.com) is comprised of sedation experts representing both adult and paediatric specialties from around the world. This Task Force reached a consensus on the definitions of sedation-related adverse events (Fig. 2) along with possible interventions that can be utilized to relieve them. Published in the British Journal of Anaesthesia,199 this consensus was translated to an open access, web-based Adverse Event Sedation Reporting Tool that is free of Protected Health Information, in compliance with the Health Information Portability and Accountability Act (HIPAA). This website, www.AESedationReporting.com, is accessible to all sedation providers –a means of collecting, organizing and accessing an individual’s data along with the collective data of all those who have contributed.199 Another initiative that could improve collection of objective data would be a reevaluation of the Sedation Continuum.96 An important limitation of the Sedation Continuum, albeit an accepted method to define the depth of sedation, is that it relies on subjective data. It requires that the patient be stimulated with verbal, tactile or painful stimuli in order to assess

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sedation depth. In many cases, stimulating a sedated child is impractical (child in a MRI scanner) and could awaken the child, thereafter compromising the ability to successfully complete the study or necessitating administration of additional sedatives for procedure completion. Using the Sedation Continuum as a measure of sedation, necessitating continuous reevaluation of sedation depth, is not always a practical expectation. Why is depth of sedation so important, other than to determine a patient’s ability to tolerate the stimulation of the procedure (audio, tactile and pain)? The Sedation Continuum has never been validated as being predictive of the risk of adverse outcomes. That there is a causal relationship between depth of sedation and outcome is currently being questioned by those in the anaesthesia community, many of whom support the need for a large, randomized trial to determine whether sedation depth dictates risk.200 Green and Mason have advocated adoption of a new objective scale, Objective Risk Assessment Tool for Sedation (ORATS), as a future means of assessing and predicting the risk of adverse events (Table 1). ORATS would use physiological data in conjunction with their newly proposed Comfort Assessment Tool for Sedation (CATS) in order to assess and stratify sedation risk.201 One such example is the current evaluation of the role of capnography to predict and reduce adverse events, with recent contributions to the literature.202 – 207 Although we believe that capnography will contribute to safer sedation care, to date there are no studies to support that capnography decreases the incidence of clinically relevant hypoxia and subsequent morbidity. Physiological monitors that use novel technologies, such as non-invasive cardiac output monitors, bispectral index, transcutaneous carbon dioxide and near-infrared spectroscopy (NIRS) monitors can all be incorporated into such a tool –an objective means of determining whether a particular monitor can identify, predict or reduce risk.82 208 – 215 Collection of large objectively obtained data using ORATS and CATS from multi-specialists globally is one example of an important and necessary first step to determining the variables


New levels (as yet unnamed)

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6

7

8

9 10

11

12

13 14

Authors’ contributions K.P.M. is the sole writer and researcher for this work.

15

Acknowledgement The author acknowledges Ms. Bailey Mannix, Boston Children’s Hospital, for her assistance in the preparation and editorial support of this paper.

16

Funding The author has received funding from Hospira for Investigator initiated clinical trials.

17

Declaration of interest None declared.

18

References 1

2

3

4

5

Cravero JP. Risk and safety of pediatric sedation/anesthesia for procedures outside the operating room. Curr Opin Anaesthesiol 2009; 22: 509–13 Cravero JP, Beach ML, Blike GT, Gallagher SM, Hertzog JH, Pediatric Sedation Research C. The incidence and nature of adverse events during pediatric sedation/anesthesia with propofol for procedures outside the operating room: a report from the Pediatric Sedation Research Consortium. Anesth Analg 2009; 108: 795–804 Mason KP. Sedation trends in the 21st century: the transition to dexmedetomidine for radiological imaging studies. Paediatr Anaesth 2010; 20: 265– 72 Services DoHH. Centers for Medicare & Medicaid Services Revised Hospital Anesthesia Services Interpretive Guidelines—state operations manual (SOM) Appendix A Ref: S&C-10-09-Hospital. 2010 Anesthesiologists SASo. Guidelines for the safe use of procedural sedation and analgesia for diagnostic and therapeutic procedures

19 20

21 22

23

24

in children, 2010. South African Journal of Anaesthesiology and Analgesia 2010; 16: (Suppl. 1) Association TAD. Guidelines for the Use of Sedation and General Anesthesia by Dentists—As adopted by the October 2007 ADA House of Delegates, 2007 Faigel DO, Baron TH, Goldstein JL, et al. Guidelines for the use of deep sedation and anesthesia for GI endoscopy. Gastrointest Endosc 2002; 56: 613–7 Godwin SA, Caro DA, Wolf SJ, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med 2005; 45: 177–96 Haddad S. Sedation by non-Anesthesiologists (Appendix A– G). Kingdom of Saudi Arabia: National Guard Health Affairs, 2010 Riphaus A, Bitter H. [Short version S3 guideline sedation for gastrointestinal endoscopy und medicolegal implications]. Z Gastroenterol 2012; 50: 407–10 Scottish Intercollegiate Guidelines N. SIGN Guideline 58: safe sedation of children undergoing diagnostic and therapeutic procedures. Paediatr Anaesth 2008; 18: 11 –2 Practice guidelines for sedation and analgesia by nonanesthesiologists. A report by the American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Anesthesiology 1996; 84: 459–71 FDA Docket Number 2005P-0267; Comments Opposing Citizen Petition Requesting Change in Propofol Labeling, 2005 Vargo JJ, Cohen LB, Rex DK, Kwo PY. Position statement: nonanesthesiologist administration of propofol for GI endoscopy. Gastrointest Endosc 2009; 70: 1053– 9 Dumonceau JM, Riphaus A, Aparicio JR, et al. European Society of Gastrointestinal Endoscopy, European Society of Gastroenterology and Endoscopy Nurses and Associates, and the European Society of Anaesthesiology Guideline: Non-anesthesiologist administration of propofol for GI endoscopy. Endoscopy 2010; 42: 960–74 Pelosi P. Retraction of endorsement: European Society of Gastrointestinal Endoscopy, European Society of Gastroenterology and Endoscopy Nurses and Associates, and the European Society of Anaesthesiology Guideline: Non-anesthesiologist administration of propofol for GI endoscopy. Endoscopy 2012; 44: 302; author reply Perel A. Non-anaesthesiologists should not be allowed to administer propofol for procedural sedation: a Consensus Statement of 21 European National Societies of Anaesthesia. Eur J Anaesthesiol 2011; 28: 580– 4 Cote CJ, Notterman DA, Karl HW, Weinberg JA, McCloskey C. Adverse sedation events in pediatrics: a critical incident analysis of contributing factors. Pediatrics 2000; 105: 805– 14 Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr 2005; 164: 552– 8 Liebreich O. Das Chloralhydrat Ein Neues Hypnoticum Und Anaestheticum Und Dessen Anwendung in Der Medicin. Berlin: Mu¨ller, 1869 Buck ML. Chloral hydrate use during infancy. Neonatal Pharmacol Quart 1992; 1: 31– 7 Twite MD, Rashid A, Zuk J, Friesen RH. Sedation, analgesia, and neuromuscular blockade in the pediatric intensive care unit: survey of fellowship training programs. Pediatr Crit Care Med 2004; 5: 521– 32 Prescilla R, Mason KP. Recent advances and contributions to procedural sedation with considerations for the future. Minerva Anestesiol 2014; 80: 844– 55 Gozal D, Mason KP. Pediatric sedation: a global challenge. Int J Pediatr 2010; 2010: 701257

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associated with sedation-related adverse events. A better appreciation of the risks and outcomes associated with various sedation techniques, patient populations, procedures and environs will aid in building a consensus for establishing evidence-based guidelines. The history and evolution of sedation parallels that of the innovator Walt Disney who evolved his first animated cartoon of 1920 to the 1955 inauguration of the first theme park in the world, which to date has hosted more than 650 million guests. The field of sedation has similarly grown and evolved to become its own unique multi-disciplinary field–the delivery of which has and will continue to evolve and improve to meet and exceed the growing demands and needs of children. Each child that we care for should stimulate similar to that response described by Walt Disney when he visited his theme park: ‘. . . whenever I go on a ride, I’m always thinking of what’s wrong with the thing and how it can be improved . . . times and conditions change so rapidly that we must keep our aim constantly focused on the future.’ Similarly, the future of sedation depends on a collaborative effort of all sedation providers to objectively evaluate their sedation practice and put aside the politics and economics, in order to unite to determine optimal sedation practice within and between specialties.

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44 Silvestri GA, Vincent BD, Wahidi MM. Fospropofol disodium for sedation in elderly patients undergoing flexible bronchoscopy. J Bronchol Interv Pulmonol 2011; 18: 15 –22 45 Yen P, Prior S, Riley C, Johnston W, Smiley M, Thikkurissy S. A comparison of fospropofol to midazolam for moderate sedation during outpatient dental procedures. Anesth Prog 2013; 60: 162–77 46 Cohen LB, Cattau E, Goetsch A, et al. A randomized, double-blind, phase 3 study of fospropofol disodium for sedation during colonoscopy. J Clin Gastroenterol 2010; 44: 345–53 47 Silvestri GA, Vincent BD, Wahidi MM, Robinette E, Hansbrough JR, Downie GH. A phase 3, randomized, double-blind study to assess the efficacy and safety of fospropofol disodium injection for moderate sedation in patients undergoing flexible bronchoscopy. Chest 2009; 135: 41 –7 48 Dailey RH, Stone R, Repert W. Ketamine dissociative anesthesia— emergency department use in children. JACEP 1979; 8: 57 –8 49 Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, review and implications. Ann Emerg Med 1990; 19: 1033–46 50 Green SM, Nakamura R, Johnson NE. Ketamine sedation for pediatric procedures: Part 1, a prospective series. Ann Emerg Med 1990; 19: 1024–32 51 Terndrup TE, Cantor RM, Madden CM. Intramuscular meperidine, promethazine, and chlorpromazine: analysis of use and complications in 487 pediatric emergency department patients. Ann Emerg Med 1989; 18: 528–33 52 Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med 2011; 57: 449–61 53 Organization WH. WHO Model List of Essential Medicines for Children, 2013 54 Gooding JM, Weng JT, Smith RA, Berninger GT, Kirby RR. Cardiovascular and pulmonary responses following etomidate induction of anesthesia in patients with demonstrated cardiac disease. Anesth Analg 1979; 58: 40 –1 55 Van Hamme MJ, Ghoneim MM, Ambre JJ. Pharmacokinetics of etomidate, a new intravenous anesthetic. Anesthesiology 1978; 49: 274–7 56 Baxter AL, Mallory MD, Spandorfer PR, et al. Etomidate versus pentobarbital for computed tomography sedations: report from the Pediatric Sedation Research Consortium. Pediatr Emerg Care 2007; 23: 690– 5 57 den Brinker M, Hokken-Koelega AC, Hazelzet JA, de Jong FH, Hop WC, Joosten KF. One single dose of etomidate negatively influences adrenocortical performance for at least 24 h in children with meningococcal sepsis. Intensive Care Med 2008; 34: 163–8 58 Donmez A, Kaya H, Haberal A, Kutsal A, Arslan G. The effect of etomidate induction on plasma cortisol levels in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1998; 12: 182–5 59 Ledingham IM, Watt I. Influence of sedation on mortality in critically ill multiple trauma patients. Lancet 1983; 1: 1270 60 Sokolove PE, Price DD, Okada P. The safety of etomidate for emergency rapid sequence intubation of pediatric patients. Pediatr Emerg Care 2000; 16: 18 –21 61 Malerba G, Romano-Girard F, Cravoisy A, et al. Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation. Intensive Care Med 2005; 31: 388– 92 62 Watt I, Ledingham IM. Mortality amongst multiple trauma patients admitted to an intensive therapy unit. Anaesthesia 1984; 39: 973–81


25 Dimitrovska Manojlovikj T, Trombeva D. PP-010 Introducing of compounded pediatric chloral hydrate syrup-drug deficiency solution. Eur J Hosp Pharm Sci Pract 2014; 21: A126 26 Fosburgh LC. From this point in time: some memories of my part in the history of anesthesia—John S. Lundy, MD. AANA J 1997; 65: 323– 8 27 Zuniga A. [Pre-anesthetic medication in pediatrics. Comparative clinical study of Ro-4– 5360, pentobarbital and a placebo with the double blind method and sequential analysis]. Rev Chil Pediatr 1965; 36: 420–5 28 Buhmann K. Damned if you do, damned if you don’t? The Lundbeck case of pentobarbital, the guiding principles on business and human rights, and competing human rights responsibilities. J Law Med Ethics 2012; 40: 206–19 29 Jolly D. Danish Company Blocks Sale of Drug for U.S. Executions. N Y Times 2011 30 Connor L, Burrows PE, Zurakowski D, Bucci K, Gagnon DA, Mason KP. Effects of IV pentobarbital with and without fentanyl on end-tidal carbon dioxide levels during deep sedation of pediatric patients undergoing MRI. Am J Roentgenol 2003; 181: 1691–4 31 Malviya S, Voepel-Lewis T, Tait AR, et al. Pentobarbital vs chloral hydrate for sedation of children undergoing MRI: efficacy and recovery characteristics. Paediatr Anaesth 2004; 14: 589– 95 32 Mason KP, Prescilla R, Fontaine PJ, Zurakowski D. Pediatric CT sedation: comparison of dexmedetomidine and pentobarbital. AJR Am J Roentgenol 2011; 196: W194–8 33 Mason KP, Sanborn P, Zurakowski D, et al. Superiority of pentobarbital versus chloral hydrate for sedation in infants during imaging. Radiology 2004; 230: 537–42 34 Mason KP, Zurakowski D, Connor L, et al. Infant sedation for MR imaging and CT: oral versus intravenous pentobarbital. Radiology 2004; 233: 723– 8 35 Mason KP, Zurakowski D, Karian VE, Connor L, Fontaine PJ, Burrows PE. Sedatives used in pediatric imaging: comparison of IV pentobarbital with IV pentobarbital with midazolam added. Am J Roentgenol 2001; 177: 427– 30 36 Rooks VJ, Chung T, Connor L, et al. Comparison of oral pentobarbital sodium (nembutal) and oral chloral hydrate for sedation of infants during radiologic imaging: preliminary results. Am J Roentgenol 2003; 180: 1125–8 37 Zgleszewski SE, Zurakowski D, Fontaine PJ, D’Angelo M, Mason KP. Is propofol a safe alternative to pentobarbital for sedation during pediatric diagnostic CT? Radiology 2008; 247: 528–34 38 Diprivan (Propofol) Package Insert. Lake Forest, IL: Hospira, Inc., 2009 39 Nelson LE, Guo TZ, Lu J, Saper CB, Franks NP, Maze M. The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci 2002; 5: 979–84 40 How the Use of Propofol in Executions Would Impact Patient Safety in the U.S., 2014. Available from http://propofol-info.com/ (accessed 12 June 2014) 41 LUSEDRA (fospropofol disodium) injection. Available from http:// dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8cc837aa-14f04809-9ca1-6cc7ff84646b (accessed 22 October 2014) 42 Moore GD, Walker AM, MacLaren R. Fospropofol: a new sedativehypnotic agent for monitored anesthesia care. Ann Pharmacother 2009; 43: 1802– 8 43 Bergese SD, Dalal P, Vandse R, et al. A double-blind, randomized, multicenter, dose-ranging study to evaluate the safety and efficacy of fospropofol disodium as an intravenous sedative for colonoscopy in high-risk populations. Am J Ther 2013; 20: 163 – 71

Mason


82 Wong J, Steil GM, Curtis M, Papas A, Zurakowski D, Mason KP. Cardiovascular effects of dexmedetomidine sedation in children. Anesth Analg 2012; 114: 193–9 83 Shane SM, Kessler S. Electricity for sedation in dentistry. J Am Dent Assoc 1967; 75: 1369– 75 84 Chambiras PG. Sedation in dentistry for children: narcotic action. Aust Dent J 1965; 10: 320–4 85 Eken EB, Palagonia GS. A new sedation for electroencephalograms of disturbed children in a general hospital. Arch Pediatr 1960; 77: 257– 60 86 Elman DS, Denson JS. Preanesthetic sedation of children with intramuscular methohexital sodium. Anesth Analg 1965; 44: 494–8 87 Healy TE, Edmondson HD, Hall N. Sedation for the mentally handicapped dental patient. Anaesthesia 1971; 26: 308– 10 88 White PT, Demyer W, Demyer M. Eeg Abnormalities in Early Childhood Schizophrenia: a double-blind study of psychiatrically disturbed and normal children during promazine sedation. Am J Psychiatry 1964; 120: 950– 8 89 Anesthesiologists ASo. Available from http://www.asahq.org/ForMembers/Standards-Guidelines-and-Statements.aspx (accessed 12 June 2014) 90 Anesthesiologists ASo. Granting Privileges for Deep Sedation to Non-anesthesiologist Sedation Practitioners, 2010 91 Anesthesiologists ASo. Practice guidelines for sedation and analgesia by non-anesthesiologists: an updated report by the American Society of Anesthesiologists task force on sedation and analgesia by non-anesthesiologists. Anesthesiology 2002; 96: 1004–17 92 Anesthesiologists ASo. Distinguishing Monitored Anesthesia Care (“MAC”) from Moderate Sedation/Analgesia (Concious Sedation), 2004 93 Anesthesiologists ASo. Standards for Basic Anesthetic Monitoring, 2010 94 Anesthesiologists ASo. Statement on Safe Use of Propofol, 2009 95 Sury M, Bullock I, Rabar S, Demott K, Guideline Development G. Sedation for diagnostic and therapeutic procedures in children and young people: summary of NICE guidance. Br Med J 2010; 341: c6819 96 Committee of Origin: Quality Management and Departmental Administration. Continuum of depth of sedation: definition of general anesthesia and levels of sedation/analgesia. Am Soc Anesthesiol 2004. Available from http://www.asahq.org/ForMembers/Clinical-Information/~/media/For%20Members/ documents/Standards%20Guidelines%20Stmts/Continuum% 20of%20Depth%20of%20Sedation.ashx (accessed 20 October 2014) 97 American Academy of Pediatrics Committee on F, Newborn, American Academy of Pediatrics Section on S, et al. Prevention and management of pain in the neonate: an update. Adv Neonatal Care 2007; 7: 151– 60 98 American Academy of Pediatrics. Committee on Psychosocial Aspects of C, Family H, Task Force on Pain in Infants C, Adolescents. The assessment and management of acute pain in infants, children, and adolescents. Pediatrics 2001; 108: 793–7 99 Cote CJ, Wilson S. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update. Pediatrics 2006; 118: 2587–602 100 Pediatrics AAo. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992; 89: 1110– 5 101 Pediatrics AAo. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: addendum. Pediatrics 2002; 110: 836– 8

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63 Precedex (Dexmedetomidine) Package Insert. Lake Forest, IL: Hospira, Inc., 2008 64 Dexdor (Dexmedetomidine) Package Insert. Espoo: Orion Corporation, 2014 65 Belleville JP, Ward DS, Bloor BC, Maze M. Effects of intravenous dexmedetomidine in humans. I. Sedation, ventilation, and metabolic rate. Anesthesiology 1992; 77: 1125– 33 66 Bloor BC, Ward DS, Belleville JP, Maze M. Effects of intravenous dexmedetomidine in humans. II. Hemodynamic changes. Anesthesiology 1992; 77: 1134–42 67 Mahmoud M, Sadhasivam S, Salisbury S, et al. Susceptibility of transcranial electric motor-evoked potentials to varying targeted blood levels of dexmedetomidine during spine surgery. Anesthesiology 2010; 112: 1364–73 68 Mason KP, Lubisch N, Robinson F, Roskos R, Epstein MA. Intramuscular dexmedetomidine: an effective route of sedation preserves background activity for pediatric electroencephalograms. J Pediatr 2012; 161: 927– 32 69 Mason KP, O’Mahony E, Zurakowski D, Libenson MH. Effects of dexmedetomidine sedation on the EEG in children. Paediatr Anaesth 2009; 19: 1175– 83 70 Souter MJ, Rozet I, Ojemann JG, et al. Dexmedetomidine sedation during awake craniotomy for seizure resection: effects on electrocorticography. J Neurosurg Anesthesiol 2007; 19: 38 –44 71 Berkenbosch JW, Tobias JD. Development of bradycardia during sedation with dexmedetomidine in an infant concurrently receiving digoxin. Pediatr Crit Care Med 2003; 4: 203–5 72 Mahmoud M, Gunter J, Donnelly LF, Wang Y, Nick TG, Sadhasivam S. A comparison of dexmedetomidine with propofol for magnetic resonance imaging sleep studies in children. Anesth Analg 2009; 109: 745–53 73 Mason KP, Lubisch NB, Robinson F, Roskos R. Intramuscular dexmedetomidine sedation for pediatric MRI and CT. Am J Roentgenol 2011; 197: 720–5 74 Mason KP, Robinson F, Fontaine P, Prescilla R. Dexmedetomidine offers an option for safe and effective sedation for nuclear medicine imaging in children. Radiology 2013; 267: 911–7 75 Mason KP, Turner DP, Houle TT, Fontaine PJ, Lerman J. Hemodynamic response to fluid management in children undergoing dexmedetomidine sedation for MRI. Am J Roentgenol 2014; 202: W574–9 76 Mason KP, Zgleszewski SE, Dearden JL, et al. Dexmedetomidine for pediatric sedation for computed tomography imaging studies. Anesth Analg 2006; 103: 57–62, table of contents 77 Mason KP, Zgleszewski SE, Prescilla R, Fontaine PJ, Zurakowski D. Hemodynamic effects of dexmedetomidine sedation for CT imaging studies. Paediatr Anaesth 2008; 18: 393– 402 78 Mason KP, Zurakowski D, Zgleszewski S, Prescilla R, Fontaine PJ, Dinardo JA. Incidence and predictors of hypertension during highdose dexmedetomidine sedation for pediatric MRI. Paediatr Anaesth 2010; 20: 516– 23 79 Mason KP, Zurakowski D, Zgleszewski SE, et al. High dose dexmedetomidine as the sole sedative for pediatric MRI. Paediatr Anaesth 2008; 18: 403– 11 80 Wu J, Mahmoud M, Schmitt M, Hossain M, Kurth D. Comparison of propofol and dexmedetomedine techniques in children undergoing magnetic resonance imaging. Paediatr Anaesth 2014; 24: 813– 8 81 Snapir A, Posti J, Kentala E, et al. Effects of low and high plasma concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy male subjects. Anesthesiology 2006; 105: 902– 10; quiz 1069–70

BJA

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123 Statement on clinical principles for procedural sedation. Emerg Med (Fremantle) 2003; 15: 205– 6 124 Operative or other high-risk procedures and/or the administration of moderate or deep sedation or anesthesia. Joint Commission on Accreditation of Healthcare Organizations. Comprehensive Accreditation Manual for Hospitals: the Official Handbook, 2007: PC-41 125 Vargo JJ, Delegge MH, Feld AD, et al. Multisociety sedation curriculum for gastrointestinal endoscopy. Am J Gastroenterol 2012; 76: e1– 25 126 O’Connor RE, Sama A, Burton JH, et al. Procedural sedation and analgesia in the emergency department: recommendations for physician credentialing, privileging, and practice. Ann Emerg Med 2011; 58: 365– 70 127 Green SM, Krauss B. Replacing the outmoded term “nonanesthesiologist”. Anesth Analg 2005; 100: 1862 128 Delaunay L, Gentili M, Cittanova ML, Delbos A, Lile A. Anaesthesia by non-anaesthesiologists: the Pandora Box is open! Eur J Anaesthesiol 2012; 29: 50– 1 129 Knape JT. Procedural sedation and analgesia and the propofol affair: a unique opportunity for anaesthesiology. Eur J Anaesthesiol 2012; 29: 51 –2 130 Guidelines on Sedation and/or Analgesia for Diagnostic and Interventional Medical, Dental or Surgical Procedures, 2010 131 Monroe KK, Beach M, Reindel R, et al. Analysis of procedural sedation provided by pediatricians. Pediatr Int 2013; 55: 17– 23 132 Couloures KG, Beach M, Cravero JP, Monroe KK, Hertzog JH. Impact of provider specialty on pediatric procedural sedation complication rates. Pediatrics 2011; 127: e1154–60 133 Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med 2009; 54: 158– 68 e1 –4 134 Lee HH, Milgrom P, Starks H, Burke W. Trends in death associated with pediatric dental sedation and general anesthesia. Paediatr Anaesth 2013; 23: 741–6 135 Healy M. After child surgery deaths, experts discuss the risks. USA Today 2014 136 Wilson S. Pharmacological management of the pediatric dental patient. Pediatr Dent 2004; 26: 131–6 137 Chicka MC, Dembo JB, Mathu-Muju KR, Nash DA, Bush HM. Adverse events during pediatric dental anesthesia and sedation: a review of closed malpractice insurance claims. Pediatr Dent 2012; 34: 231– 8 138 Mallory MD, Baxter AL, Yanosky DJ, Cravero JP, Pediatric Sedation Research C. Emergency physician-administered propofol sedation: a report on 25,433 sedations from the pediatric sedation research consortium. Ann Emerg Med 2011; 57: 462–8 e1 139 Vespasiano M, Finkelstein M, Kurachek S. Propofol sedation: intensivists’ experience with 7304 cases in a children’s hospital. Pediatrics 2007; 120: e1411– 7 140 Srinivasan M, Turmelle M, Depalma LM, Mao J, Carlson DW. Procedural sedation for diagnostic imaging in children by pediatric hospitalists using propofol: analysis of the nature, frequency, and predictors of adverse events and interventions. J Pediatr 2012; 160: 801–6 e1 141 Turmelle M, Moscoso LM, Hamlin KP, Daud YN, Carlson DW. Development of a pediatric hospitalist sedation service: training and implementation. J Hosp Med 2012; 7: 335–9 142 Agostoni M, Fanti L, Gemma M, Pasculli N, Beretta L, Testoni PA. Adverse events during monitored anesthesia care for GI endoscopy: an 8-year experience. Gastrointest Endosc 2011; 74: 266– 75 143 Slagelse C, Vilmann P, Hornslet P, Hammering A, Mantoni T. Nurse-administered propofol sedation for gastrointestinal


102 Pruitt AW, Anyan WR. Guidelines for the elective use of copncious sedation, deep sedation, and general anesthesia in pediatric patients. Pediatrics 1985; 76: 317–21 103 Guideline on use of anesthesia personnel in the administration of office-based deep sedation/general anesthesia to the pediatric dental patient. Pediatr Dent 2012; 34: 170–2 104 American Dental A. Guidelines for Teaching Pain Control and Sedation to Dentists and Dental Students, 2007 105 American Dental A. Guidelines for the Use of Sedation and General Anesthesia by Dentists, 2012 106 Godwin SA, Burton JH, Gerardo CJ, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med 2014; 63: 247– 58e18 107 Green SM, Roback MG, Miner JR, Burton JH, Krauss B. Fasting and emergency department procedural sedation and analgesia: a consensus-based clinical practice advisory. Ann Emerg Med 2007; 49: 454– 61 108 Lightdale JR, Acosta R, Shergill AK, et al. Modifications in endoscopic practice for pediatric patients. Gastrointest Endosc 2014; 79: 699– 710 109 Mace SE, Brown LA, Francis L, et al. Clinical policy: critical issues in the sedation of pediatric patients in the emergency department. Ann Emerg Med 2008; 51: 378– 99, 99e1–57 110 Miner JR, Burton JH. Clinical practice advisory: emergency department procedural sedation with propofol. Ann Emerg Med 2007; 50: 182– 7, 7e1 111 Miner JR, Heegaard W, Plummer D. End-tidal carbon dioxide monitoring during procedural sedation. Acad Emerg Med 2002; 9: 275–80 112 Waring JP, Baron TH, Hirota WK, et al. Guidelines for conscious sedation and monitoring during gastrointestinal endoscopy. Gastrointest Endosc 2003; 58: 317–22 113 Revised Hospital Anesthesia Services Interpretive Guidelines— State Operations Manual (SOM) Appendix A. Department of Health & Human Services, 2009 114 CMS Manual System: Pub. 100-07 State Operations Provider Certification. Department of Health & Human Services, 2010 115 Liu H, Waxman DA, Main R, Mattke S. Utilization of anesthesia services during outpatient endoscopies and colonoscopies and associated spending in 2003– 2009. JAMA 2012; 307: 1178– 84 116 Hassan C, Rex DK, Cooper GS, Benamouzig R. Endoscopist-directed propofol administration versus anesthesiologist assistance for colorectal cancer screening: a cost-effectiveness analysis. Endoscopy 2012; 44: 456– 64 117 Inadomi JM, Gunnarsson CL, Rizzo JA, Fang H. Projected increased growth rate of anesthesia professional-delivered sedation for colonoscopy and EGD in the United States: 2009 to 2015. Gastrointest Endosc 2010; 72: 580–6 118 Brill JV. Endoscopic sedation: legislative update and implications for reimbursement. Gastrointest Endosc Clin N Am 2008; 18: 665– 78, viii 119 Al-Awabdy B, Wilcox CM. Use of anesthesia on the rise in gastrointestinal endoscopy. World J Gastrointest Endosc 2013; 5: 1 –5 120 Summary of draft guidelines on sedation and/or analgesia (PSA) at Locations Outside the Operating Theatre. Part III: In Children Initiators: Netherlands Society of Anesthesiologists and Dutch Society of Pediatrics. Utrecht: Dutch Institute for Healthcare Improvement (Central Accompaniment Organization (CBO), 2011 121 Sedation in Children and Young People: Sedation for Diagnostic and Therapeutic Procedures in Children and Young People. London, 2010 122 Safe Sedation Practice for Healthcare Procedures: Standards and Guidance, 2013

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150

151

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154 155

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157

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165 Sanders RD, Xu J, Shu Y, et al. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology 2009; 110: 1077– 85 166 Hwang L, Choi IY, Kim SE, et al. Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus. Int J Mol Med 2013; 31: 1047–56 167 Vutskits L, Davis PJ, Hansen TG. Anesthetics and the developing brain: time for a change in practice? A pro/con debate. Paediatr Anaesth 2012; 22: 973–80 168 Flick RP, Nemergut ME, Christensen K, Hansen TG. Anestheticrelated Neurotoxicity in the young and outcome measures: the devil is in the details. Anesthesiology 2014; 120: 1303–5 169 Zhou Y, Yang J, Liu J, Wang Y, Zhang WS. Efficacy comparison of the novel water-soluble propofol prodrug HX0969w and fospropofol in mice and rats. Br J Anaesth 2013; 111: 825–32 170 Lang BC, Yang J, Wang Y, et al. An improved design of watersoluble propofol prodrugs characterized by rapid onset of action. Anesth Analg 2014; 118: 745–54 171 Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-controlled phase I single ascendingdose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics. Anesth Analg 2012; 115: 274–83 172 Rogers WK, McDowell TS. Remimazolam, a short-acting GABA(A) receptor agonist for intravenous sedation and/or anesthesia in day-case surgical and non-surgical procedures. IDrugs 2010; 13: 929–37 173 Zhang JQ, Meng FM, Xue FS. Is dexmedetomidine or remifentanil alone an optimal sedation scheme for awake intubation? J Anesth 2013; 27: 627–8 174 Cotten JF, Husain SS, Forman SA, et al. Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression. Anesthesiology 2009; 111: 240–9 175 Cotten JF, Forman SA, Laha JK, et al. Carboetomidate: a pyrrole analog of etomidate designed not to suppress adrenocortical function. Anesthesiology 2010; 112: 637–44 176 Murdoch JA, Grant SA, Kenny GN. Safety of patient-maintained propofol sedation using a target-controlled system in healthy volunteers. Br J Anaesth 2000; 85: 299–301 177 Pejo E, Santer P, Jeffrey S, GallinH, HusainSS, Raines DE. Analogues of Etomidate: modifications around Etomidate’s chiral carbon and the impact on in vitro and in vivo pharmacology. Anesthesiology 2014; 121: 290–301 178 Huang H, Li R, Liu J, Zhang W, Liao T, Yi X. A phase I, dose-escalation trial evaluating the safety and efficacy of emulsified isoflurane in healthy human volunteers. Anesthesiology 2014; 120: 614 – 25 179 Zhou C, Liu J. A novel intravenous general anesthetic—emulsified isoflurane: from bench to bedside. Front Med 2012; 6: 381– 7 180 Minkowitz HS, Singla NK, Evashenk MA, et al. Pharmacokinetics of sublingual sufentanil tablets and efficacy and safety in the management of postoperative pain. Reg Anesth Pain Med 2013; 38: 131–9 181 Li BL, Yuen VM, Song XR, et al. Intranasal dexmedetomidine following failed chloral hydrate sedation in children. Anaesthesia 2014; 69: 240– 4 182 Yuen VM, Hui TW, Irwin MG, Yao TJ, Wong GL, Yuen MK. Optimal timing for the administration of intranasal dexmedetomidine for premedication in children. Anaesthesia 2010; 65: 922–9 183 Yuen VM, Hui TW, Irwin MG, Yuen MK. A comparison of intranasal dexmedetomidine and oral midazolam for premedication in

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endoscopic procedures: first Nordic results from implementation of a structured training program. Scand J Gastroenterol 2011; 46: 1503–9 Weaver JM. Why are there so many drug shortages? Anesth Prog 2010; 57: 89–90 Drugs to be Discontinued. 2014. Available from http://www.fda. gov/Drugs/DrugSafety/DrugShortages/ucm050794.htm (accessed 13 June 2014) Fresenius Propoven 1% Emulsion for Injection or Infusion. Fresenius-Kabi Ltd, Runcorn Current Drug Shortages Index. 2014. Available from http://www. fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm (accessed 13 June 2014) Drug Shortages: Current Drugs. 2014. Available from http://www. ashp.org/drugshortages/current/ (accessed 13 June 2014) Nikolic MI, Sarter NB. Flight deck disturbance management: a simulator study of diagnosis and recovery from breakdowns in pilot-automation coordination. Hum Factors 2007; 49: 553– 63 Mercado da Aviacao. 2012. Available from http://www .mercadodaaviacao.com.br/cursos-apostilas/visualizar/crmevolution-faa-ingles/ (accessed 13 June 2014) Schinasi DA, Nadel FM, Hales R, Boswinkel JP, Donoghue AJ. Assessing pediatric residents’ clinical performance in procedural sedation: a simulation-based needs assessment. Pediatr Emerg Care 2013; 29: 447– 52 Tobin CD, Clark CA, McEvoy MD, et al. An approach to moderate sedation simulation training. Simul Healthc 2013; 8: 114–23 Babl FE, Krieser D, Belousoff J, Theophilos T. Evaluation of a paediatric procedural sedation training and credentialing programme: sustainability of change. Emerg Med J 2010; 27: 577– 81 Gaba DM. The future vision of simulation in healthcare. Simul Healthc 2007; 2: 126–35 Gaba DM. Adapting space science methods for describing and planning research in simulation in healthcare: science traceability and Decadal Surveys. Simul Healthc 2012; 7: 27 –31 Shavit I, Keidan I, Hoffmann Y, et al. Enhancing patient safety during pediatric sedation: the impact of simulation-based training of nonanesthesiologists. Arch Pediatr Adolesc Med 2007; 161: 740– 3 Siu LW, Boet S, Borges BC, et al. High-fidelity simulation demonstrates the influence of anesthesiologists’ age and years from residency on emergency cricothyroidotomy skills. Anesth Analg 2010; 111: 955–60 Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. Br Med J 2004; 328: 1490 Hudson AE, Hemmings HC. Are anaesthetics toxic to the brain? Br J Anaesth 2011; 107: 30– 7 Jevtouric-iodormic V, Absalom AR, Blomgrem K, et al. Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar. Br J Anaesth 2013; 111: 143– 51 Slikker W Jr, Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 2007; 98: 145– 58 Brambrink AM, Evers AS, Avidan MS, et al. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology 2010; 112: 834–41 Hansen TG, Henneberg SW. Neurotoxicity of anesthetic agents and the developing brain in rodents and primates: the time has come to focus on human beings. Anesthesiology 2010; 113: 1244– 5; author reply 5–6 Rappaport B, Mellon RD, Simone A, Woodcock J. Defining safe use of anesthesia in children. N Engl J Med 2011; 364: 1387–90

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201 Green SM, Mason KP. Stratification of sedation risk--a challenge to the sedation continuum. Paediatr Anaesth 2011; 21: 924–31 202 Yarchi D, Cohen A, Umansky T, Sukhotnik I, Shaoul R. Assessment of end-tidal carbon dioxide during pediatric and adult sedation for endoscopic procedures. Gastrointest Endosc 2009; 69: 877– 82 203 van Loon K, van Rheineck Leyssius AT, van Zaane B, Denteneer M, Kalkman CJ. Capnography during deep sedation with propofol by nonanesthesiologists: a randomized controlled trial. Anesth Analg 2014; 119: 49–55 204 Langhan ML, Chen L, Marshall C, Santucci KA. Detection of hypoventilation by capnography and its association with hypoxia in children undergoing sedation with ketamine. Pediatr Emerg Care 2011; 27: 394– 7 205 Deitch K, Miner J, Chudnofsky CR, Dominici P, Latta D. Does end tidal CO2 monitoring during emergency department procedural sedation and analgesia with propofol decrease the incidence of hypoxic events? A randomized, controlled trial. Ann Emerg Med 2010; 55: 258– 64 206 Slagelse C, Vilmann P, Hornslet P, Jorgensen HL, Horsted TI. The role of capnography in endoscopy patients undergoing nurseadministered propofol sedation: a randomized study. Scand J Gastroenterol 2013; 48: 1222–30 207 Kannikeswaran N, Chen X, Sethuraman U. Utility of endtidal carbon dioxide monitoring in detection of hypoxia during sedation for brain magnetic resonance imaging in children with developmental disabilities. Paediatr Anaesth 2011; 21: 1241– 6 208 Alswang M, Friesen RH, Bangert P. Effect of preanesthetic medication on carbon dioxide tension in children with congenital heart disease. J Cardiothorac Vasc Anesth 1994; 8: 415– 9 209 Bulow HH, Linnemann M, Berg H, Lang-Jensen T, LaCour S, Jonsson T. Respiratory changes during treatment of postoperative pain with high dose transdermal fentanyl. Acta Anaesthesiol Scand 1995; 39: 835– 9 210 Cerbo RM, Maragliano R, Pozzi M, et al. Global perfusion assessment and tissue oxygen saturation in preterm infants: where are we? Early Hum Dev 2013; 89(Suppl. 1): S44– 6 211 Fruchter O, Tirosh M, Carmi U, Rosengarten D, Kramer MR. Prospective randomized trial of bispectral index monitoring of sedation depth during flexible bronchoscopy. Respiration 2014; 87: 388–93 212 Padmanabhan P, Berkenbosch JW, Lorenz D, Pierce MC. Evaluation of cerebral oxygenation during procedural sedation in children using near infrared spectroscopy. Ann Emerg Med 2009; 54: 205–13 213 Rauch R, Welisch E, Lansdell N, et al. Non-invasive measurement of cardiac output in obese children and adolescents: comparison of electrical cardiometry and transthoracic Doppler echocardiography. J Clin Monit Comput 2013; 27: 187–93 214 Weiss M, Dullenkopf A, Kolarova A, Schulz G, Frey B, Baenziger O. Near-infrared spectroscopic cerebral oxygenation reading in neonates and infants is associated with central venous oxygen saturation. Paediatr Anaesth 2005; 15: 102–9 215 Yang KS, Habib AS, Lu M, et al. A prospective evaluation of the incidence of adverse events in nurse-administered moderate sedation guided by sedation scores or bispectral index. Anesth Analg 2014; 119: 43–8

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pediatric anesthesia: a double-blinded randomized controlled trial. Anesth Analg 2008; 106: 1715– 21 Yuen VM, Irwin MG, Hui TW, Yuen MK, Lee LH. A double-blind, crossover assessment of the sedative and analgesic effects of intranasal dexmedetomidine. Anesth Analg 2007; 105: 374–80 Le Guen M, Liu N, Bourgeois E, et al. Automated sedation outperforms manual administration of propofol and remifentanil in critically ill patients with deep sedation: a randomized phase II trial. Intensive Care Med 2013; 39: 454–62 Pambianco DJ, Vargo JJ, Pruitt RE, Hardi R, Martin JF. Computerassisted personalized sedation for upper endoscopy and colonoscopy: a comparative, multicenter randomized study. Gastrointest Endosc 2011; 73: 765–72 Sheahan CG, Mathews GM. Monitoring and delivery of sedation. Br J Anaesth 2014; 113 (Suppl. 2): ii37– ii48 Cohen M, Sadhasivam S, Vinks AA. Pharmacogenetics in perioperative medicine. Curr Opin Anaesthesiol 2012; 25: 419– 27 Ashenhurst JR, Bujarski S, Ray LA. Delta and kappa opioid receptor polymorphisms influence the effects of naltrexone on subjective responses to alcohol. Pharmacol Biochem Behav 2012; 103: 253 – 9 Hajj A, Khabbaz L, Laplanche JL, Peoc’h K. Pharmacogenetics of opiates in clinical practice: the visible tip of the iceberg. Pharmacogenomics 2013; 14: 575–85 Sadhasivam S, Chidambaran V. Pharmacogenomics of opioids and perioperative pain management. Pharmacogenomics 2012; 13: 1719–40 Saruwatari J, Matsunaga M, Ikeda K, et al. Impact of CYP2D6*10 on H1-antihistamine-induced hypersomnia. Eur J Clin Pharmacol 2006; 62: 995– 1001 Frolich MA, Zhang K, Ness TJ. Effect of sedation on pain perception. Anesthesiology 2013; 118: 611– 21 Loryan I, Lindqvist M, Johansson I, et al. Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia. Eur J Clin Pharmacol 2012; 68: 397–406 Sadhasivam S, Krekels EH, Chidambaran V, et al. Morphine clearance in children: does race or genetics matter? J Opioid Manag 2012; 8: 217– 26 Field MJ, Boat TF, eds. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC, 2012 New Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER), 2012. Available from http://www.acttion.org/news/9_25_12.html (accessed 13 June 2014) Warner ME, Warner MA. The value of sedation by anesthesia teams for complex endoscopy: perhaps not what you’d think. Anesth Analg 2014; 119: 222–3 Mason KP, Green SM, Piacevoli Q, International Sedation Task F. Adverse event reporting tool to standardize the reporting and tracking of adverse events during procedural sedation: a consensus document from the World SIVA International Sedation Task Force. Br J Anaesth 2012; 108: 13– 20 Leslie K, Short TG. Sedation depth and mortality: a large randomized trial is required. Anesth Analg 2014; 118: 903– 5

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