Clinical Policy: Critical Issues in the Sedation of Pediatric Patients in The

PEDIATRICS/CLINICAL POLICY

Clinical Policy: Critical Issues in the Sedation of Pediatric Patients in the Emergency Department From the EMSC Panel (Writing Committee) on Critical Issues in the Sedation of Pediatric Patients in the Emergency Department: Sharon E. Mace, MD, Chair, American College of Emergency Physicians (ACEP) Lance A. Brown, MD, MPH (ACEP) Lisa Francis, BSN, RN (Society of Pediatric Nurses) Steven A. Godwin, MD (ACEP) Sigrid A. Hahn, MD (ACEP) Patricia Kunz Howard, PhD, RN, CEN (Emergency Nurses Association) Robert M. Kennedy, MD (American Academy of Pediatrics) David P. Mooney, MD (American Pediatric Surgical Association) Alfred D. Sacchetti, MD (ACEP) Robert L. Wears, MD, MS, Methodologist (ACEP) Randall M. Clark, MD (American Society of Anesthesiologists)

Other members of the EMSC Panel included: Approved by the ACEP Board of Directors, October 5, 2007 Ramon W. Johnson, MD (ACEP Board Liaison) Supported by the Emergency Nurses Association, Rhonda R. Whitson, RHIA (Clinical Policies Manager, October 5, 2007 ACEP) Endorsed by the Society of Pediatric Nurses, November Tuei Doong (Vice President, The Nakamoto Group, Inc) 3, 2007 Jenni Nakamoto-Yingling (President, The Nakamoto Endorsed by the American Pediatric Surgical Group, Inc) Association, December 20, 2007

Karen Belli (Public Policy and Partnerships Specialist, Organizational representation does not imply EMSC) endorsement of this document by that organization. Tasmeen Singh, MPH, NREMT-P (Executive Director, National Resource Center, EMSC) This clinical policy was developed by a multidisciplinary Tina Turgel (Nurse Consultant, EMSC) panel and funded by Project #HHSH240200515109P of the Emergency Medical Services for Children Program, Maternal and Child Health Bureau, Health Resources and Services Administration, US Department of Health and Human Services.

Policy statements and clinical policies are the ofﬁcial policies of the American College of Emergency Physicians and, as such, are not subject to the same peer review process as articles appearing in the print journal. Policy statements and clinical policies of ACEP do not necessarily reﬂect the policies and beliefs of Annals of Emergency Medicine and its editors.

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[Ann Emerg Med. 2008;51:378-399.] INTRODUCTION Procedural sedation is the technique of administering PREFACE sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant Emergency physicians routinely provide sedation and procedures while maintaining cardiorespiratory function.16 analgesia, monitor the respiratory and cardiovascular status, and Analgesia is usually a component of procedural sedation manage critically ill patients of all ages.1-3 The provision of safe particularly for painful procedures. Procedural sedation and and effective sedation and analgesia is an integral part of analgesia yields a depressed level of consciousness while allowing emergency medicine practice and a component of the core 4-6 the patient to maintain independent control of the airway and curriculum for emergency medicine residency programs. oxygenation by preserving the protective airway reflexes. Failure to adequately treat a patient’s pain can have negative Moderate sedation/analgesia, previously “conscious sedation,” is consequences, the event potentially affecting later physiologic a drug-induced depression of consciousness during which responses and behaviors. Appropriately treating pain and anxiety patients respond purposefully to verbal or light tactile decreases patient suffering, facilitates medical interventions, stimulation while maintaining protective airway reflexes.18,20,22 increases patient/family satisfaction, improves patient care, and Deep sedation/analgesia is a drug-induced depression of 7-10 may improve patient outcome. consciousness during which patients are not easily aroused, and Providing effective and safe procedural sedation in the may need airway and/or ventilatory assistance but may respond emergency department (ED) is a multifactorial process purposefully to repeated or painful stimulation.19,20,22 General beginning with the preprocedural patient assessment and anesthesia, in contrast, is a state of drug-induced loss of continuing through intraprocedural monitoring and consciousness in which patients are not arousable and often postprocedure evaluation. Setting up the proper environment have impaired cardiorespiratory function needing and selecting the most appropriate pharmacologic and support.19,20,22 The terminology “moderate sedation,” “deep nonpharmacologic agents are keys to successful procedural sedation,” and “general anesthesia” may not apply to dissociative sedation.1,11-15 There are many drugs that can be used for sedation. In dissociative sedation, as with ketamine, a trancelike procedural sedation and analgesia. In addition, there are various cataleptic state occurs with both profound analgesia and nonpharmacologic modalities that can be used for procedural amnesia while maintaining protective airway reflexes, sedation and analgesia.13-15 The choice of a particular agent or spontaneous respirations, and cardiopulmonary stability.23 In modality is influenced by many factors.12 These include patient children, deep or dissociative sedation is usually required for 24 characteristics (eg, age, comorbidity, special health care needs) painful procedures. and the procedure to be performed (painful or painless, Because individuals vary in their responses to a given dose of duration, etc).12 Appropriate monitoring and assessment are a specific sedative, practitioners providing procedural sedation critical for safe and effective procedural sedation and and analgesia require the skills needed to provide analgesia.3,11,16,17 airway/respiratory management and cardiovascular support. A previous clinical policy focused on medications for Health care providers administering procedural achieving sedation and analgesia in pediatric patients sedation/analgesia should be proficient in the skills needed to undergoing procedures in the ED.12 This clinical policy deals rescue a patient at a level greater than the desired level of with 2 additional sedation drugs, nitrous oxide and chloral sedation. Thus, if moderate sedation is desired, the practitioner hydrate; a nonpharmacologic agent for sedation, sucrose; as well should be able to provide the skills needed for deep sedation, and if deep sedation is intended, the practitioner should be as preprocedural fasting or nulla per os (NPO) status, and competent in the airway management and cardiovascular discharge criteria. support involved in general anesthesia.17 Such skills are a Multiple documents about procedural sedation have been requirement of emergency medicine training programs and an issued by various professional organizations, including The Joint essential component of emergency medicine practice.3-5 Commission, the American Academy of Pediatrics (AAP), the American Society of Anesthesiologists (ASA), and the American METHODOLOGY 12,16-22 College of Emergency Physicians (ACEP). This clinical policy was created after careful review and The goal of this panel is to eliminate the bias from the critical analysis of the medical literature. Multiple searches of recommendations by creating a document that is, to the degree MEDLINE and the Cochrane database were performed. possible, evidence-based. With some aspects of procedural Specific key words/phrases used in the searches are identified 16 sedation, there is a relative deficiency of high-quality data. under each critical question. All searches were limited to This policy is not intended to set standards for individual English-language sources, human studies, and years 1976 to institutions or practitioners and cannot address every topic 2006. References obtained on the searches were reviewed by about pediatric procedural sedation but does give data for panel members (title and abstract) for relevance before inclusion answering key management issues using an evidence-based in the pool of studies to be reviewed. Abstracts and articles were approach. reviewed by panel members, and pertinent articles were selected.

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These articles were evaluated, and those addressing the There are certain circumstances in which the questions considered in this document were chosen for grading. recommendations stemming from a body of evidence should Additional articles were reviewed from the bibliographies of not be rated as highly as the individual studies on which they studies cited. Panel members also supplied articles from their are based. Factors such as heterogeneity of results, uncertainty own knowledge and files. about effect magnitude and consequences, strength of prior The panel used the ACEP clinical policy development beliefs, and publication bias, among others, might lead to such a process; this policy is based on the existing literature; where downgrading of recommendations. literature was not available, consensus of panel members was This policy is not intended to be a complete manual on used. The draft was sent to all of the participating organizations pediatric sedation issues but rather a focused examination of for comments during the expert review stage of development. critical issues that have particular relevance to the current All articles used in the formulation of this clinical policy were practice of emergency medicine. graded by at least 2 panel members for strength of evidence and It is the goal of the panel to provide an evidence-based classified by the panel members into 3 classes of evidence on the recommendation when the medical literature provides enough basis of the design of the study, with design 1 representing the quality information to answer a critical question. When the strongest evidence and design 3 representing the weakest medical literature does not contain enough quality information evidence for therapeutic, diagnostic, and prognostic clinical to answer a critical question, panel members believe that it is reports, respectively (Appendix A). Articles were then graded on equally important to alert emergency physicians to this fact. 6 dimensions thought to be most relevant to the development of Recommendations offered in this policy are not intended to a clinical guideline: blinded versus nonblinded outcome represent the only diagnostic and management options that the assessment, blinded or randomized allocation, direct or indirect emergency physician should consider. The panel clearly outcome measures (reliability and validity), biases (eg, selection, recognizes the importance of the individual physician’s detection, transfer), external validity (ie, generalizability), and judgment. Rather, this guideline defines for the physician those sufficient sample size. Articles received a final grade (Class I, II, strategies for which medical literature exists to provide support III) on the basis of a predetermined formula taking into account for answers to the crucial questions addressed in this policy. Scope of Application. This guideline is intended for design and quality of study (Appendix B). Articles with fatal physicians administering procedural sedation and analgesia to flaws were given an “X” grade and not used in the creation of pediatric patients in hospital-based EDs. this policy. Evidence grading was done with respect to the Inclusion Criteria. This guideline applies to pediatric specific data being extracted and the specific critical question patients less than or equal to 18 years of age who are in a being reviewed. Thus, the level of evidence for any one study hospital ED and have conditions necessitating the alleviation of may vary according to the question, and it is possible for a single anxiety, pain, or both. article to receive different levels of grading as different critical Exclusion Criteria. This guideline excludes patients greater questions are answered. Question-specific level of evidence than 18 years of age. grading may be found in the Evidentiary Table available online at http://www.annemergmed.com, and online at http://www.acep.org on the Clinical Policies page. CRITICAL QUESTIONS Clinical findings and strength of recommendations regarding 1. Should pediatric patients undergo a period of patient management were then made according to the following preprocedural fasting to decrease the incidence of criteria: clinically important complications during procedural Level A recommendations. Generally accepted principles sedation in the ED? for patient management that reflect a high degree of clinical certainty (ie, based on strength of evidence Class I or Patient Management Recommendations overwhelming evidence from strength of evidence Class II Level A recommendations. None specified. studies that directly address all of the issues). Level B recommendations. Procedural sedation may be Level B recommendations. Recommendations for patient safely administered to pediatric patients in the ED who have management that may identify a particular strategy or range of had recent oral intake. management strategies that reflect moderate clinical certainty Level C recommendations. None specified. (ie, based on strength of evidence Class II studies that directly Key words/phrases for literature searches: preprocedural address the issue, decision analysis that directly addresses the fasting, NPO, gastric emptying agents, vomiting, aspiration, issue, or strong consensus of strength of evidence Class III procedural sedation. studies). Recommendations concerning preprocedural fasting in both Level C recommendations. Other strategies for patient pediatric and adult sedation are based on a rare but real risk of management that are based on preliminary, inconclusive, or pulmonary aspiration. Definitive sedation guidelines based on conflicting evidence, or in the absence of any published sound evidence are lacking because of a paucity of ED studies literature, based on panel consensus. about preprocedural fasting. The ASA fasting guidelines,

380 Annals of Emergency Medicine Volume , .  : April  Clinical Policy adopted by the AAP, are consensus-based, extrapolated from patient population, classified as ASA physical status I or patients undergoing general anesthesia.25 As noted in these II.26,30,37-39,41,42 guidelines, “Published evidence is silent on the relationship Documentation of clinically significant or subclinical between fasting times, gastric volume, or gastric acidity and the aspiration events during procedural sedation and analgesia is risk of emesis/reflux or pulmonary aspiration in humans.” extremely limited. Only 1 study reports any incidents of Although these recommendations may be appropriately cautious aspiration.43 The adverse event occurred in 2 pediatric patients, when considering patients who are undergoing elective general both of whom met NPO criteria for fasting. These patients were anesthesia, controversy exists as to whether these guidelines are deeply sedated with opioid-barbiturate combinations, one for a applicable to the pediatric ED population. radiologic procedure and the other for bronchoscopy. Both An important distinction between procedural sedation and required only supplemental oxygen and observation. A review of analgesia in the ED and general anesthesia in the operating the literature reveals no other reported cases of aspiration as a room involves the preservation of airway reflexes. In result of procedural sedation and analgesia in the ED. Given the moderate sedation, airway reflexes are generally maintained. rare occurrence of aspiration, to date no single study is These reflexes, although normally present, are less reliably adequately powered to determine the incidence of aspiration maintained in deep sedation. However, in general anesthesia, during ED procedural sedation. airway reflexes are significantly blunted or completely Multiple factors have been investigated in an attempt to suppressed, thus increasing the potential risk of aspiration.26- identify risk factors for aspiration in the general anesthesia population. These questions include the relationship between 30 Dissociative agents such as ketamine and inhalational agents such as nitrous oxide have a different mechanism of aspiration and gastric contents, motility, and acidity. To date, action and do not blunt the airway reflexes to the same no benefit from the routine addition of antacids and other pharmacologic motility regimens preoperatively has been degree as other sedatives. Therefore, the description for the 25,32 continuum of sedation that ranges from anxiolysis to general demonstrated. Concerning NPO status, 2 Class I44,45 and 2 Class II anesthesia may not accurately reflect the minimal effect of studies46,47 evaluated gastric fluid volume and pH after various these agents on protective airway mechanisms. fasting periods. In one of the Class I studies, Maekawa et al44 Aspiration is a rare but well-documented associated risk in found no difference in gastric fluid volume, pH, lipid patients undergoing general anesthesia. The incidence of homeostasis, or glucose levels with NPO periods of 2, 4, and 12 aspiration in pediatric patients has been reported to be 1:978 hours after drinking apple juice. The other Class I study and 1:2,632 patients in 2 pediatric specific studies by Warner et compared NPO after midnight with clear liquids up to 3 hours al28 and Borland et al.29 When both emergent and elective preoperatively and demonstrated no difference between groups’ patients of all ages are reviewed, the incidence decreases to less gastric fluid volume or pH.45 These findings are supported by a than 1:3,500.30-32 During emergency surgery, the incidence of Class II study by Ingebo et al46 that used endoscopic suction reported aspiration increases to 1:895 in adults and general after intravenous sedation. The duration of fasting after clear population patients27 and as frequent as 1:373 patients in the 28 fluid ingestion ranged from 0.5 to 24 hours, with a mean period Warner et al pediatric study. The timing of reported of 6.7ϩ/-5.3 hours. There was no significant difference in aspiration events is most commonly seen during induction, gastric fluid volumes or pH between the groups with the laryngoscopy, and extubation (50% to 78%, 30% to 36%, and following fasting times: 30 minutes to 3 hours, more than 3 4% to 33%, respectively), which does not apply to procedural hours to 8 hours, and more than 8 hours.46 27-29 sedation and analgesia. Further, inhalational anesthetics can There are limited data about clearance of solids alone. A be emetogenic, with documented postoperative nausea and Class II adult study evaluated 8 healthy adult female volunteers vomiting described in up to one third of all surgical who received a light meal and underwent gastric 33,34 patients. In contrast, pediatric patients undergoing ultrasonography, followed by nasogastric placement for gastric procedural sedation and analgesia are not intubated and have a volume monitoring.47 A gastric emptying study with much lower incidence of nausea and vomiting, varying from paracetamol was then performed. Although 3 patients cleared 26,35-40 0.3% to 10%. 120 minutes after the meal, it took 240 minutes for all patients A significant relationship has been demonstrated to exist to be solid free. between aspiration during general anesthesia and the patient’s A total of 8 studies were found that evaluated the effect of ASA physical status.29 Physical status classes of III and IV have fasting versus nonfasting on adverse events in pediatric patients been shown to have a significantly increased risk of aspiration undergoing procedural sedation.26,35,37,38,42,43,48,49 Five Class compared to that of ASA I and II patients (1:418 versus II26,35,37,42,43 and 3 Class III38,48,49 studies evaluating NPO 1:1,341).29 Warner et al28 found a greater safety range, with status were reviewed. These studies recorded a total of 4,814 only a 1:7,945 risk of aspiration in pediatric patients with ASA I patient encounters, with 2 documented episodes of clinically and II physical status classes. The majority of reported pediatric apparent pulmonary aspiration. As noted above by Hoffman et ED procedural sedation and analgesia occurs in a healthier al,43 both of these patients were fasted. On pooling of these

Volume , .  : April  Annals of Emergency Medicine 381 Clinical Policy data, the incidence of clinically apparent pulmonary aspiration Patients less than 6 months of age who were fasted for during sedation may reflect an incidence of less than 1:2,000 greater than 2 hours experienced a significantly higher pediatric patient encounters. incidence of inadequate sedation (Pϭ.03) than patients Two studies evaluated the NPO status for solids and liquids. fasted for less than 2 hours.48 In a Class III study, Keiden et In a Class II study by Agrawal et al,26 only 44% (396/905 al49 evaluated children undergoing a hearing test who were patients) met published ASA/AAP guidelines. There was no sedated with chloral hydrate. This retrospective cohort study significant difference in adverse events, including emesis, extracted data from 2 hospitals using different fasting between patients meeting or not meeting established guidelines. guidelines. At one hospital (group 1), fasting guidelines were The median time for fasting duration in patients with emesis strictly enforced, whereas the second hospital (group 2) was 6.8 hours (interquartile range [IQR] 5.1 to 9.5 hours) for enforced no fasting guidelines prior to sedation. The average solids and 5.8 hours (IQR 3.6 to 8.1 hours) for clear liquids. fasting period was significantly longer in patients with Median fasting duration for solids increased with age and strictly enforced fasting guidelines than in the second group ranged from 4.2 hours (IQR 2.4 to 6.3 hours) in patients of patients who had no fasting guidelines (5.7 ϩ/- 1.7 versus younger than 6 months (nϭ14) to 7.3 hours (IQR 5.5 to 9.7 2 ϩ/- 0.2 hours; PϽ0.001). Patients who followed fasting hours) in patients older than 36 months (nϭ644). The median guidelines demonstrated a significantly higher failure rate in fasting duration for clear liquids also increased with age. The achieving sedation with an equivalent first dose of chloral duration increased from 4.1 hours in patients younger than 6 hydrate compared with the second group of unfasted patients months (IQR 2.4 to 6.3 hours) to 6.4 hours (IQR 4.4 to 8.6 (21% versus 11%; Pϭ0.03). The higher failure rate resulted hours) in patients older than 36 months. The authors suggested in patients requiring higher medication dosages (83 ϩ/- 31 that given that 56% of patients did not meet criteria and no versus 61 ϩ/- 21 mg/kg; PϽ0.01) for adequate sedation and increase in adverse events was found, that noncompliance with remaining sedated for longer periods (103 ϩ/- 42 versus 73 ASA/AAP guidelines does not appear to be a contraindication ϩ/- 48 minutes; P Ͻ0.001), resulting in a later discharge.49 for procedural sedation.26 In another Class II study, Babl et al35 As previously noted, the only documented cases of aspiration identified 155 of 220 children (71.1%; 95% confidence interval were discussed in a Class II study by Hoffman et al.43 In this [CI] 64.5% to 77.0%) who did not meet fasting guidelines for study, however, adherence to NPO guidelines did not affect solids. Thirty-seven (20.6%; 95% CI 15.0% to 27.3%) children overall risk of complications (11 of 309 NPO guidelines did not meet fasting guidelines for clear liquids. The median followed [3.6%], 95% CI 1.8% to 6.2% versus 29 of 651 NPO fasting duration was 4.4 hours (IQR 3 to 6.5 hours) for solids guidelines not followed [4.5%], 95% CI 3.0% to 6.3%; odds and 4 hours (IQR 2.2 to 6.3) for liquids. Again, there was no ratio [OR] 0.79; Pϭ.64) and did not decrease the risk of significant difference in emesis rate between patients meeting hemodynamic and respiratory complications (9 of 309 NPO and not meeting fasting guidelines.35 guidelines followed [2.9%], 95% CI 1.3% to 5.5% versus 18 of Few patient data sets are available with numbers involving 651 NPO guidelines not followed [2.8%], 95% CI 1.6% to fasting of less than 2 hours. In a Class II study involving a 4.3%; OR 0.97; NS). The complication risk was insignificantly pediatric ED sedation databank, authors extracted data about different in patients without documented NPO status (3 of 45 fasting status, sedation, and adverse events.37 The fasting [6.7%], 95% CI 1.4% to 18.3% versus 37 of 915 [4.0%], 95% time was documented in 1,555 of 2,085 (74.6%) patients. CI 2.9% to 5.5%; OR 1.68; Pϭ.43). The occurrence of Median fasting time before sedation was 5.1 hours (range 5 sedation failures was significantly higher in patients who met minutes to 32.5 hours). No significant difference was found NPO criteria (20 of 921 [2.2%], 95% CI 1.3% to 3.3% versus in adverse events when patients were compared with fasting 2 of 443 [0.5%], 95% CI 0.05% to 1.6%; OR 4.4; Pϭ.016). times in 2-hour time blocks up to greater than 8 hours (0 to The authors suggest that this loss of effective sedation may be a 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, Ͼ8 hours, result of increased agitation as a result of hunger in these and undocumented). A total of 156 of 1,555 (7.5%) patients children.43 experienced emesis. One hundred fifty patients were fasted In conclusion, there is no evidence suggesting a correlation for less than 2 hours, with 10 (6.7%) of these patients between fasting, emesis, and pulmonary aspiration in healthy experiencing emesis. A total of 391 patients were fasted for 2 pediatric patients undergoing procedural sedation in the ED. to 4 hours, with 40 (10.2%) episodes of documented Overall it is important to note that although many studies do emesis.37 In a Class III study of children undergoing include patients who were not fasted before their procedure, it is echocardiography, 334 children were divided into 2 groups possible that clinicians may have been considering other treated with chloral hydrate.48 The first group of 140 undisclosed factors that selectively affect NPO times prior to patients was fasted for less than 2 hours, with a mean of 80 procedural sedation. This selection bias is difficult to identify in minutes. A second group of 184 patients was fasted for the studies but may more closely represent current clinical practice. greater than 2 hours, with a mean of 225 minutes. There Given the many variables present even in the best-designed were no major adverse outcomes in either group, as well as studies, clinical judgment should always weigh the risk and no differences in rates of emesis between groups (Pϭ.74). benefits for each patient.50

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2. Is nitrous oxide effective and safe for providing pediatric effects, eg, imagining flying, significantly enhances the drug’s 52 procedural sedation in the ED? efficacy. N2O has both opioid agonist and N-methyl-D- A previous clinical policy focused on the efficacy and safety of aspartate (NMDA) glutamate receptor antagonist effects.53,54 In etomidate, fentanyl/midazolam, ketamine, methohexital, healthy patients, N2O has minimal cardiovascular or respiratory pentobarbital, and propofol for achieving sedation and analgesia in effects;55-57 however, it may enhance the depressed response to pediatric patients undergoing procedures in12 Seethe AppendixED. hypoxia and hypercarbia induced by other agents.55-59 Onset

C for the recommendations from the previous clinical policy. and offset of effects occur within 5 minutes, and N2O does not require vascular access or painful administration. Patient Management Recommendations for Nitrous Oxide For more than a century and with few adverse events, 30% to Level A recommendations. Nitrous oxide at 50% 70% N2O has been widely used to reduce distress in children 60 concentration can be used with concurrent local anesthesia for during dental procedures. A 50% concentration of N2O has safe and effective procedural sedation in healthy children also been used for management of acute pain in adults in out- 61,62 undergoing painful procedures. of-hospital and ED settings. The demand valve-equipped Level B recommendations. A gas scavenging system should fixed 50% N2O delivery apparatus commonly available in EDs be used for protection of health care providers when is difficult for children to activate, but patients of all ages easily administering nitrous oxide. use the continuous-circuit devices, some of which deliver up to 63 Level C recommendations. 70% N2O. (1) Nitrous oxide at 60% to 70% concentration may be used Numerous studies in children undergoing dental procedures with concurrent local anesthesia for safe and effective in dental offices detail the effectiveness of N2O in reducing procedural sedation in healthy children undergoing painful anxiety and distress,64-71 but relatively few studies have been procedures. conducted in children undergoing painful procedures in the (2) Nitrous oxide may be combined with other sedative ED. Sixty-one articles concerning use of nitrous oxide for analgesic agents to augment sedation, but patients receiving procedural sedation in children were identified. Local anesthesia these combinations should be carefully monitored for was routinely used as an adjunct. After grading, 44 articles were deepening sedation, respiratory depression, and other included in this analysis.

adverse events. Suturing-related distress in children was reduced by N2Oin2 (3) Nitrous oxide may be less effective in reducing procedure- Class I,72,73 2 Class II,74,75 and 1 Class III76 ED-based studies. related distress in younger children compared with older Luhmann et al72 found that children aged 2 to 6 years had children. lower distress scores during wound cleaning, supplemental

(4) Nurses trained in principles of nitrous oxide sedation, lidocaine injection, and suturing when they received 50% N2O including the speciﬁc nitrous oxide administration device, instead of oral midazolam in addition to standard topical may safely administer nitrous oxide to healthy children anesthetic, video cartoon viewing, and bedside parent.

while under the supervision of an emergency physician or Combining midazolam with N2O did not further reduce other appropriately trained and credentialed specialist in distress. Children who received N2O alone were less likely to the ED. experience minor adverse effects (ataxia, dizziness, crying), other The evidentiary basis for the efficacy and safety of a given than vomiting, in the ED and within 24 hours. Vomiting drug may differ. Considering that significant adverse events are occurred more frequently with N2O (10% with N2O, 2% with ϩ 73 generally rare, it is likely that there is stronger evidence for N2O midazolam). Burton et al also found reduced distress 74 efficacy than for safety. When assigning one overall with 50% N2O during suturing. Gamis et al, using 30% recommendation for a given drug based on combining these 2 N2O, found less distress with N2O in children older than 8 distinct attributes (efficacy and safety) of the drug, the lowest years but only a trend in that direction in younger children. most conservative level of evidence has been designated. Distress during fracture reduction in children was also 77 reduced with use of N2O in 1 Class I study, 4 Class II 78-81 82 Efficacy of Nitrous Oxide studies, and 1 Class III study conducted in the ED or 77 ϩ Key words/phrases for literature searches: nitrous oxide, orthopedic clinic. Luhmann et al found that N2O lidocaine procedural sedation; age 1-18 years. hematoma block (HB) for fractures was as effective in reducing

Nitrous oxide (N2O) is a relatively weak dissociative distress as intravenous ketamine during forearm fracture anesthetic gas that provides mild to moderate procedural reductions in children aged 5 to 17 years. Recovery was much ϩ anxiolysis, analgesia, and amnesia in a linear dose-response faster for N2O HB (16 minutes versus 83 minutes). 51 pattern. When used for sedation, N2O is blended with oxygen Comparable decreases in distress during fracture reduction with (N2O/O2) and generally denoted, as in this guideline, as N2O, 50% N2O were also found versus intravenous regional 79 78 without acknowledgment of the O2 blend. Use of local anesthesia or intramuscular meperidine and promethazine. anesthesia and imagery to prepare patients for the gas’s clinical Hennrikus et al80 and Wattenmaker et al82 noted decreased

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81 levels of distress with 50% N2O alone. Hennrikus et al found this question found no radiopaque dye on chest radiograph after that subsequent addition of a HB further reduced distress. the dye was placed in the posterior pharynx of 50 children 95 Use of N2O also reduced children’s distress during other undergoing dental procedures with 20% to 65% N2O or in 91 painful procedures such as lumbar puncture, abscess drainage, 14 adult volunteers sedated with 50% N2O for 5 minutes. cyst/nevi excision, bone marrow aspiration, dressing change, However, traces of dye were found on chest radiograph in 2 of 64,75,83-86 and intravenous catheter placement in 6 Class II 10 volunteers sedated with 50% N2O for more than 10 studies and 1 Class III87 study conducted in various outpatient minutes. The clinical signiﬁcance of this micro-aspiration is 96 settings. Recovery from N2O sedation, when noted, was unclear. Whether the combination of N2O with other reported to be very rapid.71-73,75,77-79,88 sedative or analgesic medications increases the risk for aspiration

Depth of sedation with a specific concentration of N2O may and other adverse events is unknown. vary.89 In a Class II study, Babl et al35 found that with 50% to Emesis was the most common adverse event reported. In 2 72,77 35,73,74,79-81 78 70% N2O, 86% of children were moderately, 7% deeply, and Class I, 6 Class II, and 1 Class III trials, the 7% poorly sedated during ED procedures. A Class I study by frequency of emesis with 50% N2O varied from a high of 26% Burton et al73 found deep sedation in 12% of children during (6% during the procedure) when co-administered with oral suturing, and a Class I study by Luhmann et al77 and Class II oxycodone77 to 10%,72 6%,73 or none when administered studies by Hennrikus et al80,81 found 2% to 9% of children alone.74,78-81 No clinically apparent aspiration was noted in 35 poorly sedated with 50% N2O during fracture reduction. these studies. Babl et al found that vomiting occurred in 7% Sedation also may significantly deepen when other sedative or of pediatric patients during N2O administration in the ED. analgesic agents are co-administered with N2O. Several studies Emesis did not appear to be associated with the length of noted as secondarily observed outcomes, that although N2O was fasting, type of procedure, depth of sedation, or length of still effective when compared with placebo, increasing distress administration. Other commonly reported minor adverse was observed with decreasing age, especially in children less than effects include nausea, dizziness, euphoria, and 6 to 8 years of age.69,74,86,87 The relationship between dysphoria.35,72,73,77,87,99 Most reported resolution of these effectiveness of N2O and age needs further evaluation using effects within 5 minutes of cessation of N2O administration. continuous-circuit devices easily used by young children. Hypoxemia was found to occur rarely with N2O administration in healthy patients, in part because N2O was Safety of Nitrous Oxide blended with oxygen. When end-tidal carbon dioxide (ETCO2) Key words/phrases for literature searches: nitrous oxide, was measured, mild respiratory depression was found to occur procedural sedation; age 1-18 years. when N2O was co-administered with other sedative or analgesic When N2O was used alone or in combination with local medications. Class II safety studies conducted in the operating anesthesia in healthy (ASA Physical Status class I and class II) room prior to general anesthesia noted increasing ETCO2 with children, no major cardiopulmonary adverse events (apnea, increasing concentrations of N2O in children who had also significant hypoxia, hypotension, or bradycardia) were reported received oral chloral hydrate57 or oral midazolam 0.7 mg/kg56 in the studies examined, including two35,90 in which 50% to but not 0.5 mg/kg.55 These studies are consistent with the

70% N2O without additional systemic sedative or analgesic finding that young children sedated with oral midazolam 0.5 ϩ medication was administered by specially trained nurses to ASA mg/kg 50% N2O for facial laceration repair had no significant I or II ED patients.35,64-66,68,70-96 A Class III report respiratory effects.72 Although there have been concerns about summarizing patient data sheets on 35,828 administrations of diffusion hypoxia with cessation of N2O administration, in a N2O, 82% of which were given to children, found that 9 Class II study, comparison of room air versus O2 for “wash out” (0.03%) serious adverse events (somnolence, vomiting, after 30 minutes of 40% N2O found no clinically significant bradycardia, vertigo, headache, nightmares, sweating) were difference in oxygen saturations.93 Finally, studies in healthy 97 possibly attributed to the 50% N2O. However, no clinical children undergoing elective dental procedures found no information about these cases was presented, nor about 18 significant adverse events when N2O was combined with other others with more serious events (apnea, desaturation, low-dose sedative medications;64,66,68 it is not clear whether laryngospasm, convulsions, and a cardiac arrest) thought not to these medication combinations are safe for procedural sedation have been caused by the N2O. Deaths associated with N2O use in children in the ED. have been due to inadvertent administration of 100% nitrous Chronic exposure to environmental N2O may have adverse oxide, with subsequent hypoxia. As reviewed by Duncan and effects on health care providers, but infrequent brief contact 98 Moore, these tragedies point out the essential need for with N2O is likely safe for individual patients, with the clinicians to understand all aspects, including mechanical, of the exception of rare patients deficient in enzymes associated with gas delivery device being used. methionine synthesis or deficient in vitamin B12, in whom N2O No study was large enough to determine the risk of clinically may cause central nervous system injury.100 A Class III survey of significant pulmonary aspiration during inhalation of N2O, female dental assistants found 60% reduction in fertility with because of the rarity of this event. Focused attempts to answer greater than 5 hours per week of exposure to unscavenged N2O;

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101 no effect was found if the N2O was scavenged. Subsequent there are still a number of unanswered questions about the use analysis of that data also found a relative risk of 2.6 for of sucrose for pain relief in infants. Biological and contextual spontaneous abortion if female dental assistants were working factors affect sucrose’s effectiveness and contribute to difficulty 102 with unscavenged N2O. A Class III survey of midwives in determining the optimal dose and effect magnitude. Patient found no association between N2O use at delivery and fertility factors include the infant’s gestational age and postnatal age, except in those assisting at greater than 30 deliveries a baseline level of alertness, overall health, and previous painful month.103 No association was found with spontaneous experiences. Contextual factors include comfort measures used abortions.104 Another Class III survey of dentists and their along with sucrose during the procedure, such as holding by a assistants found that users with “heavy exposure” to N2O were nurse or parent or using pacifiers. The “pharmacologic” more likely to report numbness, tingling, or muscle variables related to sucrose involve not only the concentration weakness.105 and volume given but also the method of administration (by 3. Can oral sucrose be used to reduce infant distress due to syringe or pacifier and whether on the anterior or posterior minor, painful procedures in the ED? tongue), frequency of administration, and time of administration before the painful procedure. Questions also Patient Management Recommendations remain about the efficacy of sucrose in older infants. Published Level A recommendations. Oral sucrose can be used to trials have most commonly enrolled preterm and term neonates. reduce signs of distress due to minor, painful procedures in Fewer studies have included older infants, limiting the preterm and term neonates (less than 28 days old). conclusions that can be drawn about this group. It is also Level B recommendations. unclear how well findings from the commonly studied neonatal (1) Effective doses for neonates range from 0.1 mL of 24% to 2 intensive care unit (NICU) or well-baby population extrapolate mL of 50% sucrose (with the most commonly studied dose to the ED; only 1 trial actually took place in the ED.108 The being 2 mL of 24% sucrose). ED generally sees an overall healthier population, with fewer (2) Oral sucrose can be used in combination with sucking (ie, a preterm infants than the NICU, but, unlike the well-baby pacifier) to improve its efficacy. nursery, sees infants with acute illnesses. Additionally, the (3) Oral sucrose may be safely administered to full-term painful stimulus studied in some trials is not relevant to the ED neonates and infants. (eg, circumcision), whereas other common ED procedures, such Level C recommendations. as bladder catheterization or lumbar puncture, were rarely or (1) Sucrose appears to be less effective in infants between 1 never evaluated. month and 6 months of age. Some uncertainty is also inherent in the measurement of an (2) Effective doses for infants between 1 month and 6 months infant’s perception of pain. Most studies measured various of age may range from 0.75 mL of 50% to 2 mL of 75% behavioral or physiologic markers of distress or a combination sucrose. thereof. A commonly used outcome measure is infant crying, (3) Effective doses for very-low-birth-weight, preterm infants which has intuitive “face validity.” However, the best may be as low as 0.05 mL of 24% sucrose. quantitative measure of crying (percentage of time crying, (4) Oral sucrose should be given approximately 2 minutes duration of the cry, total time crying, etc) has yet to be before an invasive procedure. determined. Vital signs have also been used. For example, (5) Oral sucrose may be safely given to low-birth-weight, tachycardia and a decrease in oxygen saturation have been preterm neonates. identified as indirect evidence that pain is occurring.109 Key words/phrases for literature searches: sucrose, behavioral Physiologic variables may be affected by many factors other than distress, pain, infants, neonates, procedural sedation; age 0-1 pain and are therefore nonspecific. In an attempt to improve the year. sensitivity, reliability, and validity of infant pain assessment, Sucrose has been widely studied as a nonpharmacologic numerous composite measures incorporating behavioral, intervention to reduce pain in young infants undergoing minor, physiologic, and contextual markers have been developed and invasive procedures. The AAP, in their guideline “The Relief of validated. Validated composite scales that were used in the trials Pain and Anxiety in Pediatric Patients in Emergency Medical reviewed in this section include the Neonatal Infant Pain Scale Systems,” recommends that oral sucrose be used as an adjunct (NIPS),110 the Neonatal Facial Coding Scale (NFCS),111 the for limiting procedural pain in neonates and infants younger Douleur Aigue chez le Nouveau-ne (DAN),112 and the than 6 months of age, and suggests that it may be more effective Premature Infant Pain Profile (PIPP),113 the latter of which when given in combination with a pacifier.106 The Cochrane takes gestational age into account. Overall, the heterogeneity of Collaboration performed a systematic review of the topic for outcome measures used, variability regarding when the neonates and concluded that sucrose is safe and effective for measurements are taken (during or after the procedure), and the reducing pain caused by a single, painful event (eg, heel lance or variable reliability of the measures themselves have made direct venipuncture).107 comparisons among studies difficult. Despite a large body of literature published on the subject, The following discussion reviews the published literature to

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127,131 128,129 determine the efficacy of oral sucrose in reducing signs of pain no effect on heart rate, SaO2, or cerebral blood or distress in infants. Overall, studies were well-designed, flow.129 An additional 11 Class III studies investigating the randomized controlled trials that were blinded unless precluded analgesic efficacy with various invasive procedures in term and/ by the intervention. Many had fairly small sample sizes (Ͻ100 or preterm infants were identified.114,132-141 Most found some infants), resulting in wide CIs, and limiting external validity. reduction in measures of distress caused by painful procedures. Studies were downgraded for various methodological weaknesses, as detailed in the Evidentiary Table (available Efficacy in older infants online at http://www.annemergmed.com, and online at Fewer studies have evaluated the analgesic effect of sucrose in http://www.acep.org on the Clinical Policies page), or if their older infants. Overall sucrose appears to be less effective than in design did not directly answer the critical question. Although neonates, but there may be a modest reduction in crying time glucose, breast milk (which contains 7% lactose), and some with higher doses of sucrose in 2-, 4-, and 6-month-olds. Three nonsucrose sweeteners may also act through the same Class II trials evaluated sucrose for intramuscular vaccinations in mechanism, this discussion is limited to sucrose. an outpatient setting.123,142,143 Barr et al142 compared 0.75 mL of 50% sucrose versus water in infants receiving intramuscular Efficacy of sucrose in neonates immunizations at 2 months of age and then again at 4 months. The Class I Cochrane meta-analysis calculated a weighted They found no difference in percentage of time spent crying mean difference (WMD) and CI for several outcome during injection, but a smaller percentage of time crying during measures.107 PIPP scores were pooled for 3 studies that used the 60 seconds after injection in the sucrose group (69% versus doses ranging from 0.1 mL to 0.5 mL of 24% sucrose.114-116 83%; PϽ0.05). In another study, Lewindon et al143 compared PIPP scores can range from 0 (no pain) to 18 for term, or 21 for an unusually high concentration of sucrose (2 mL of 75%) preterm, infants (maximal pain). The WMD was highly against water in 2-, 4-, and 6-month-olds. Mean total crying statistically significant for sucrose relative to control at 30 time was reduced from 59 to 36 seconds (Pϭ0.00008) and seconds (-1.64; 95% CI –2.47 to –0.81; Pϭ0.0001) and 60 mean first cry duration decreased from 42 to 29 seconds seconds after heel stick (-2.0; 95% CI –3.08 to –1.05; (Pϭ0.0004) in the sucrose group. Of interest, although nurses Pϭ0.0001). The authors also pooled data for change in heart perceived infant distress to be lower in the sucrose group, rate from 2 studies and found that there was no significant parents did not perceive a difference in the level of infant change with doses ranging from 2 mL of 25% to 30% sucrose at distress between the 2 groups. Allen et al,123 on the other hand, 1 minute (WMD 0.90; 95% CI –5.81 to 7.61) or 3 minutes found no difference in crying time between the 12% sucrose (WMD -6.20; 95% CI –15.27 to 2.88) after heel stick.117,118 group versus water in any age category (2 weeks to 18 months). Results for preterm and term infants were not considered Another study, which differed from the others in that it separately in this systematic review. compared 25% sucrose plus nonnutritive sucking, plus holding Ten Class II, randomized, controlled trials evaluated the against control, found that total crying time and first cry effect of sucrose on behavioral and/or physiologic indicators of duration were reduced in the treatment group, but there was no pain, or composite pain scores, in full term neonates. Results of effect on heart rate.144 Parents preferred the intervention, and both primary and secondary outcome measures are described nurses found the intervention to be no more difficult than here.117-126 Although some of the trials below had multiple control. treatment arms in addition to sucrose, only comparisons of The only trial to take place in the ED enrolled infants less sucrose versus water or placebo are described. The majority of than 91 days of age who required bladder catheterization during trials found a reduction in crying in the sucrose group during their evaluation.108 In this Class II trial, there was no difference heelstick or venipuncture,117,119-122 whereas a minority found between the placebo and 24% sucrose for any of the 3 primary no effect.123,124 Pain scores (including DAN and facial outcome measures: composite behavioral scale (DAN score), expression scores) were lower in the sucrose group in some percentage of infants crying during catheter insertion, and time trials124,125 but not in others.118,120 Response of vital signs to to return to behavioral baseline. A post hoc subgroup analysis painful stimulus was variable; some trials found a decrease in found a difference in the neonates but no difference in the 31- heart rate in the sucrose group,119,122 but most trials found no to 60- and 61- to 90-day age groups. The duration of the consistent difference in heart rate,117,120,126 respiratory rate,119 painful procedure was considerably longer than the noxious 118,119 120,121 SaO2, or vagal tone among treatment groups. stimuli evaluated in the other studies and may have affected the Five Class II trials looked at sucrose in preterm infants. observed efficacy of sucrose. Crying time was consistently reduced with sucrose in this age group.127-131 Three trials that evaluated behavior using the Dose of sucrose NFCS or a “composite behavioral scale” found that scores were Several studies have directly compared the efficacy of various lower in the treatment group.128,130,131 Physiologic effects again doses of sucrose. In a Class II trial, Abad et al127 found a were mixed; several studies found a lower heart rate128,129 and reduction in crying from 63 seconds in the 12% group to 19 respiratory rate129 in the treatment group, whereas others found seconds in the 24% group (versus 73 seconds in controls;

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Pϭ0.0256). In another Class II trial, Haouari et al118 compared expressions of pain compared with controls. Reis et al144 2 mL of 12.5%, 25%, and 50% sucrose in full-term infants and compared the combination of sucrose, nonnutritive sucking, found a significant reduction in the primary outcome measure, and holding versus water in older infants and found a reduction postprocedural crying time, only in the 50% group versus in crying in the treatment group. controls (Pϭ0.02). Blass and Shah,145 in a Class III study, compared a range of sucrose doses, 2 mL of 6%, 12%, and Safety of sucrose 17%, given over 2 minutes before heel stick. Looking at crying Overall, adverse events appear to be uncommon and minor. per unit time, they found no dose-response curve. Guala et Eight trials including more than 800 infants commented that al,126 in a Class II trial, compared 33% and 50% sucrose in no adverse effects of sucrose administration had been 108,114,124-126,138,139,144 116 full-term infants and found no difference in heart rate. noted. Only Gibbins et al noted any Ramenghi et al139 compared 25% and 50% sucrose (among adverse events: 3 episodes of desaturation in the treatment other interventions) in a Class III trial and found that although group receiving oral sucrose through a syringe, 2 episodes in the sucrose was superior to water in reducing crying time and pacifier group, and none in the combined sucrose plus pacifier behavior scores, there was no difference in efficacy between the group. These events were too infrequent to perform statistical 25% and 50% groups. Thus, these individual trials did not analysis. As reported in the Cochrane review, no intervention show consistent evidence of a dose-response curve, although the was required. One infant choked on the water and pacifier but higher doses more consistently had a positive effect. recovered within 10 seconds. Unfortunately, as the authors of the Cochrane review note, the A single, older study that was investigating the use of inconsistency of dosing across trials (both in amount and nutritional supplementation in very-low-birth-weight infants Ͻ concentration given) preclude pooling of data to determine the ( 1.3 kg) administered frequent doses of calcium lactate in a Ͼ minimal effective or optimal dose of sucrose.107 Doses 20% sucrose vehicle (with an osmolality of 1,700 mOsm/kg H2O), and found an increased risk of necrotizing investigated and found to be effective in older infants were 146 generally higher than those in neonates. enterocolitis. This raised concerns about the use of sucrose in at-risk infants. Although most subsequent studies Timing of sucrose administration administrating sucrose for analgesia have been designed to evaluate efficacy rather than safety, Stevens et al,114 in a study of Only 1 trial was specifically designed to evaluate the optimal 122 very-low-birth-weight, preterm infants, did not report an timing of sucrose administration before a procedure. In this increased risk of necrotizing enterocolitis with a pacifier Class III study, Blass and Shah145 compared 2 mL of 12% containing 0.1 mL of 24% sucrose. Necrotizing enterocolitis is sucrose at 30, 60, 90, 120, and 240 seconds before heel stick. generally not a risk in the ED population. The study included healthy newborns, but the number of subjects enrolled in this subsection of this 2-part study was not 4. Is chloral hydrate effective and safe for providing clearly stated. The group given sucrose 120 seconds before the procedural sedation in children in the ED? procedure cried significantly less than all other groups This critical question about chloral hydrate was included for (PϽ0.03). Most subsequent studies have administered sucrose completeness because of its use in some practice settings. A previous approximately 2 minutes before the invasive procedure. clinical policy focused on the efficacy and safety of etomidate, fentanyl/midazolam, ketamine, methohexital, pentobarbital, and Efficacy in combination with other comfort measures propofol for achieving sedation and analgesia in pediatric patients 12 In many of the studies evaluating the efficacy of sucrose, 1 or undergoing procedures in the TheseED. recommendations about more of the arms included other non-pharmacologic comfort the safety and efficacy of chloral hydrate do not imply superiority to measures, such as a pacifier or holding. Three Class II116,121,125 the above medications. See Appendix C for the recommendations and 2 Class III studies134,138 found that the combination of from the previous clinical policy. sucrose (with variable dosing including 2 mL of 12%, 0.5 mL of 24%, or 2 mL of 30%) plus nonnutritive sucking tended to be Patient Management Recommendations for Chloral Hydrate more effective than sucrose and/or a pacifier alone. In 1 Class Level A recommendations. III study in very-low-birth-weight, preterm infants, Stevens et (1) Chloral hydrate may be used to provide effective procedural 114 al did not find a difference between the sucrose plus pacifier sedation in pediatric patients undergoing painless diagnostic group and the water plus pacifier group. Another Class III study studies. However, children receiving chloral hydrate should found sucrose plus a pacifier to be more effective than water be properly monitored and managed by appropriately plus a pacifier in preterm infants during portions of the retinal trained personnel due to the risk of respiratory depression examination of prematurity, considered a ”highly invasive” and hypoxia. procedure.137 (2) Chloral hydrate should not be considered a first-line agent Two Class II studies compared sucrose plus holding versus in children older than 48 months because of decreased sucrose or holding alone during heel stick.120,131 Both found efficacy as compared with younger children. that sucrose and sucrose plus holding reduced crying or facial Level B recommendations. None specified.

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Level C recommendations. effects were delayed. Two of the 3 Class I studies with greater (1) Chloral hydrate has the potential for resedation and may than 92% efficacy used 75 mg/kg as their initial dose, with a produce residual effects up to 24 hours after administration. third study using 70 mg/kg or 100 mg/kg.148,150,151 In Class II (2) Chloral hydrate may be used safely and effectively in studies with greater than 90% efficacy, dosages varied from 50 properly monitored children who have congenital cardiac mg/kg to 100 mg/kg.147,153,154,156 anomalies and are undergoing painless diagnostic Sedation failure rates are decreased when a second dose of procedures. chloral hydrate (up to a maximum of2gor100mg/kg, (3) Chloral hydrate should not be used in children with whichever is lowest) is given. First dose/second dose success neurodevelopmental disorders due to an increased incidence rates for chloral hydrate are Class I 60%/93%,148 64%/92%,149 of adverse effects and decreased efficacy as compared with Class III 89%/98%,170 88%/90%,160 and 84.5%/94.5%.49 healthy children. Reports of success rates that listed just second doses included (4) Pediatric patients receiving chloral hydrate should not be Class III 98%,159 99.3%,162 98.7%,163 and 99.5%165 (with intentionally fasted because of increased procedural sedation hydroxyzine also given if age Ͼ1 year).165 failure rates. Multiple doses of chloral hydrate were required to achieve The evidentiary basis for the efficacy and safety of a given high levels of efficacy in some studies. In the only Class I study drug may differ. Considering that significant adverse events are designed to identify the optimal dose of chloral hydrate, 28% of generally rare, it is likely that there is stronger evidence for children initially sedated with 70 mg/kg required supplemental chloral hydrate compared with 13% of children initially efficacy than for safety. When assigning one overall 149 recommendation for a given drug based on combining these 2 receiving 100 mg/kg. distinct attributes (efficacy and safety) of the drug, the lowest Adequate sedation occurred in 64% of patients receiving an most conservative level of evidence has been designated. initial dose of 70 mg/kg versus 87% for an initial 100 mg/kg dose. After subsequent dosing, 92% of children in the 70 mg/kg Efficacy of Chloral Hydrate group and 100% of those in the 100 mg/kg group were Key words/phrases for literature searches: chloral hydrate, successfully sedated. They developed the following formula to procedural sedation; age 1-18 years. determine the optimal dose of chloral hydrate according to age ϭ ϩ 149 Chloral hydrate is a sedative hypnotic agent first introduced and weight: Dose (mg/kg) 56 (0.8xage in months). In a into clinical practice in the middle 1800s. The drug may be Class II study, a lower dose yielded higher sedation failure rates, administered orally or rectally and has been described as an whereas higher doses increased the incidence of adverse 153 anxiolytic adjunct for dental procedures and as a single or reactions. combined sedative agent for painless diagnostic studies. The oral In addition to the total dose of chloral hydrate administered, preparation is reported as having a bitter unpalatable taste that chloral hydrate’s efficacy is affected by age, the patient frequently requires administration in a flavored vehicle to population (special health care needs or not), and other factors. disguise its taste. In 1 Class II study, 30% of children would not Failed sedations were noted to increase with increasing 147,153,154,158,160,167,168,170,171,173 accept the chloral hydrate orally and required rectal age. In 2 Class II studies, administration, and 30% of the remaining 108 patients vomited failed sedations were most common in children older than 48 147,154 immediately after oral administration of the drug, yet there were months. The efficacy of chloral hydrate in a Class II study no complications or serious adverse effects and successful decreased with increasing age from 98% in children younger 154 sedation occurred in 95% of the patients.147 than 12 months to 74% in children 6 to 11 years of age. The efficacy of chloral hydrate as a sedative for diagnostic or Sedation failure rates were greater than 15% for age older than 7 therapeutic procedures was 92% to 100% in 4 Class I years, less than 7.5% for age up to 7 years, and less than 5% for studies,148-151 85% to 100% in 8 Class II studies,147,152-158 and age younger than 3 years.153 A Class III study found that chloral 80% to 100% in 12 Class III studies.49,159,160-169 hydrate sedation was successful in 84% of children greater than Two studies were done in the ED: 1 Class I study with 100% or equal to 3 years of age versus 99% of children less than 3 effectiveness151 and 1 Class III study with 88% effectiveness.167 years of age.166 A Class III ED study found the following first In other studies, chloral hydrate sedation was used for the dose/second dose success rates based on age: 0 to 0.9 years 98%/ performance of a diagnostic imaging study (computed 100%, age 1 to 1.9 years 84%/91%, 3 years 76%/85%.167 In tomography [CT] or magnetic resonance imaging [MRI] another Class III study, the sedation failure rate for children scan),149-156,158-160,162-165,168-171 echocardiogram,147,148,157,166 older than 4 years was higher (20% versus 12.5%) than for electroencephalogram (EEG),172 hearing testing,49 various younger children.160 A study of hospital-wide procedural procedures (CT, MRI, bone scan, EEG, other),160,168,173 sedation in children noted that those who had failed procedures radiation therapy,161 and dental procedures.174 with chloral hydrate were significantly older (3.6 years) than The dose of chloral hydrate administered generally varied children who were successfully sedated (2.6 years).173 between 50 and 100 mg/kg, with most studies providing the It is unclear from the literature whether these failures with option of administering additional doses if adequate clinical increasing age are related to deficiencies with chloral hydrate or

388 Annals of Emergency Medicine Volume , .  : April  Clinical Policy whether older children who require sedation for diagnostic study did demonstrate a 5% decrease in saturation in 6% of studies may be more likely to have neurodevelopmental patients, which was more prominent in children with genetic problems that make their sedation more difficult. disorders.166 A Class II study demonstrated no difference in Studies found a decreased efficacy of chloral hydrate sedation cyanotic and acyanotic children sedated with chloral in certain patient populations. Chloral hydrate’s success rate was hydrate.147 only 80% in children with central nervous system disorders in a Three studies reported clinical effects the day after Class II study153 and 73% in children with neurologic disorders sedation.157,170,175 One Class II study noted grogginess and (versus 4% for “normal” children) in a Class III study.160 irritability in children younger than 6 months of age, and Another article (Class III) found that “most failed” sedations grogginess, irritability, and motor instability in children 6 with chloral hydrate occurred in “children with seizure disorders months to 2 years of age.157 One Class III study reported or retardation.”168 Failure to achieve adequate sedation occurred unsteadiness in 68% and hyperactivity in 29% of sedated in 71% of patients with a genetic disorder (Class II study).147 children the day after treatment.170 A second Class III study Olson et al172 found that only 9% of sedations with chloral comparing chloral hydrate and midazolam noted motor hydrate for EEGs were unsuccessful but that 65.9% of those imbalance in 31% of children receiving chloral hydrate who could not be adequately sedated had a history of compared with 18% of the midazolam group (PϽ0.05).175 In developmental delay or autism. In contrast to patients with the same study, agitation was noted in 18% of the chloral neurodevelopmental disorders or genetic syndromes, children hydrate group compared with 8% of the midazolam group with congenital heart disease, including those with cyanotic (PϭNS). For both the chloral hydrate and midazolam groups, heart disease, do not have a higher sedation failure rate or only 48% returned to baseline activity within 8 hours, although increased adverse effects with chloral hydrate.147,148,157,166 89% were at baseline at 24 hours.157,170,175 There are other factors that may affect chloral hydrate’s A single Class I study demonstrated the occurrence of efficacy. One Class III study49 and 1 Class II study157 vomiting, excitation, and nausea in 21% of children sedated demonstrated that the fasting state of a child affected the dose of with 2 different doses of chloral hydrate, 70 mg/kg or 100 mg/ chloral hydrate, with fed children demonstrating a quicker onset kg.149 There was no difference in incidence of these effects and a lower dose than fasted children. The greater dose between the 2 dosage groups. requirement in fasted children was thought to be related to the One Class III study did demonstrate that chloral hydrate longer duration to onset, which also resulted in a longer patients were more likely to achieve an unintended deeper level duration of action.49,157 In one Class II study, the efficacy of of sedation than occurred with other sedation agents.43 chloral hydrate was increased when timed to coincide with nap However, this study provided no data on the specific dosing, times.157 personnel, or circumstances of the chloral hydrate use and did In direct comparison studies, chloral hydrate demonstrated not report any need for rescue intubation or permanent comparable or superior efficacy to oral midazolam and neurologic deficits in these children.43 In another anecdotal pentobarbital.148,150,151,155,156,158,162-164,174 study, 13 deaths or severe neurologic injuries were found after chloral hydrate administration.176 None of these severe adverse Safety of Chloral Hydrate events occurred in the ED setting. The cases were identified in a Key words/phrases for literature searches: chloral hydrate, review of US Food and Drug Administration records or surveys procedural sedation; age 1-18 years. of specialists, with no information reported on monitoring or Three Class I studies demonstrated the presence of side effects qualifications of personnel performing the procedures. Five of such as vomiting (9% to 18%) and paradoxical excitement (0% to these patients were dental patients; 5 were undergoing 2%) in children sedated with chloral hydrate, but no cardiac or radiologic procedures; 2 were cardiology procedures; and 1, an respiratory adverse effects were reported.149-151 audiology procedure. In the 7 cases in which chloral hydrate was In 5 Class II studies the following was reported: vomiting 2% the single agent administered, 4 patients received an overdose. to 30%, paradoxical excitement 1% to 6%, and desaturation Significant preexisting medical problems were noted in 8 of the 0% to 4%.147,153,154,156,158 In 4 Class III studies, vomiting 13 patients. No information on the total number of cases occurred in 0% to 2%, paradoxical excitement in 0% to 15%, sedated was presented.176 This one report176 is in contrast to the prolonged sedation in 0% to 1%, and desaturation in 0% to many formal Class I, II, and III studies involving chloral 7.6%.162,163,165,169 In all instances the hypoxia was responsive hydrate that demonstrated no significant adverse events and in to positional maneuvers or supplemental oxygen. particular no deaths or severe neurologic injuries. In a single study of 7 neonates with pulmonary hypertension Two studies found significant decreases in the oxygen or persistent fetal circulation, desaturation occurred in 57%; saturation occurring with chloral hydrate in half of patients with treatment with additional oxygen was used in some infants but genetic disorders: 50% of patients with Down’s syndrome in the none required BVM support or intubation.155 Class II Coskun et al147 study and 54% in the Class III Napoli In 3 studies of children undergoing echocardiograms, no et al166 study. adverse effects were noted in one study,148 whereas another In contrast to patients with genetic syndromes or neurologic

Volume , .  : April  Annals of Emergency Medicine 389 Clinical Policy disorders, children with congenital heart disease, including those Key words/phrases for literature searches: discharge, with cyanotic heart disease, are not at particular risk with chloral procedural sedation; age 1-18 years. hydrate sedation.157 Most children who have undergone procedural sedation in One particular concern with chloral hydrate is its potential the ED are discharged home. Determining discharge readiness is for resedation because of its long half-life. Cote et al176 and a process that takes place in each of these discharged cases. The Malviya et al175 note the possibility of resedation, in which the intent of this process is to ensure that a child will not experience infant or child appears to have recovered and meets discharge serious or life-threatening adverse events at home, where criteria but then is resedated because of circulating active immediate medical intervention is not available. The balance metabolites and residual drug. between safety and practicality results in a tension between Furthermore, the response to chloral hydrate’s sedative effects prolonged observation and premature discharge. The ideal in a given patient may be varied and unpredictable. In a solution would be a universally applicable, evidence-based set of telephone follow-up of 376 children who received sedation for clinical criteria that, if met, would ensure safe discharge from diagnostic radiology studies, 89% received chloral hydrate and the ED at the earliest possible time. Unfortunately, we have yet 11% received midazolam as the primary sedative. After to identify such a set of criteria. discharge, medical advice was sought for 15 children (4%). Recommended criteria have been published by a number of Three children required a visit to the ED for prolonged or organizations, such as the ASA,22 the AAP,24 the Canadian excessive sedation. All of these children had received a Association of Emergency Physicians,1 and the Australasian recommended dose of chloral hydrate (61 mg/kg to 77 mg/kg) College for Emergency Medicine.190 None of these are evidence as a sole sedative. In one child, the procedure had been aborted based. Comprehensive review of the literature evaluating clinical because of inadequate sedation in the hospital, yet the child indicators/discharge criteria has failed to yield well-supported became difficult to arouse at home.175 measures of discharge readiness after pediatric procedural A study of procedural sedation in a pediatric ED at a sedation.170,176,187,191-200 children’s hospital used chloral hydrate in 122 patients (10% We identified 2 studies directly addressing pediatric-specific of their procedural sedation regimens) and reported no criteria for postsedation discharge readiness from an outpatient adverse events with chloral hydrate and no serious setting. The first is a Class III study of 29 children who complications in their 1,180 patients.177 A hospital-wide underwent echocardiography facilitated by chloral hydrate study of 1,140 children undergoing procedural sedation also (nϭ27) or midazolam/diphenhydramine (nϭ2) sedation given revealed no long-term sequelae.173 orally.197 All children were ASA physical status classification III The use of chloral hydrate has been controversial, with some due to congenital cardiac diseases. These authors used Bispectral critics of the opinion that it should be banned.178,179 Serious Index monitoring and 2 clinical scoring systems: the University complications180-185 and deaths32,176,186-189 have been of Michigan Sedation Scale201 and a modified Maintenance of associated with chloral hydrate. Like other sedative hypnotic Wakefulness Test.202 The authors concluded that incorporating agents, chloral hydrate has the potential for central nervous these 2 clinical scoring systems into discharge decisionmaking system depression, suppression of respiratory activity, direct or prolonged the observation time (from a mean of 16 minutes to hypoxia-induced arrhythmias, and airway obstruction secondary a mean of 75 minutes) but resulted in discharged children to skeletal muscle relaxation. However, many of the adverse having Bispectral Index scores closer to baseline measurements patient outcomes reported with chloral hydrate occurred in than when traditional criteria were used. There are several reports in which proper patient monitoring or clinician problems with the applicability of this study to the ED. The competence was not documented. In all graded studies included population studied was medically complicated and likely to be in this analysis, chloral hydrate did not demonstrate any of the dissimilar to most children in most EDs. The children catastrophic patient outcomes found above. Proper patient underwent a relatively painless procedure, whereas many monitoring and improved physician training may account for procedures in the ED are painful and require higher doses of the improved results in the more recent studies of chloral sedation agents, which can complicate discharge readiness. hydrate use. Bispectral Index scoring has not been adequately validated as a surrogate marker for discharge readiness, nor has it been shown 5. What clinical indicators support safe discharge after to be more useful than clinical observation.203 Bispectral Index pediatric procedural sedation in the ED? monitoring is not applicable in cases involving ketamine Patient Management Recommendations sedation.204 The modified Maintenance of Wakefulness Test Level A recommendations. None specified. proposed by the authors requires a 20-minute period in a Level B recommendations. None specified. “soporific environment (ie, dim, quiet room),” an environment Level C recommendations. No universally applicable, unlikely to be present in many EDs. evidence-based set of clinical indicators has been established. In the other Class III study, Newman et al205 found there Emergency physicians, in conjunction with their institutions, were no serious adverse events beyond 25 minutes after the final should develop criteria for safe discharge. medication administration if a serious adverse event did not

390 Annals of Emergency Medicine Volume , .  : April  Clinical Policy occur within the first 25 minutes. However, the heterogeneity of Mace SE, Ducharme J, Murphy M, eds. Pain Management and this study population, the different sedative agents used, and the Sedation: Emergency Department Management. New York, NY: McGraw Hill; 2006:7-14. various routes of administration make universal time-based 9. American Academy of Pediatrics and Canadian Paediatric recommendations difficult. Society. Prevention and management of pain and stress in the It is likely that discharge decisionmaking will remain a neonate. Pediatrics. 2000;105:454-461. complex process. The factors likely to influence this decision 10. Anand KJ. Clinical importance of pain and stress in preterm include the pharmacologic properties of the sedation agent or neonates. Biol Neonate. 1998;73:1-9. agents chosen, the route of administration, the procedure 11. Glauser J. Documentation and standard forms for use during procedural sedation in the emergency department. In: Mace SE, performed, preexisting medical conditions or ASA physical Ducharme J, Murphy M, eds. Pain Management and Sedation: status classification, the use of reversal agents, the occurrence of Emergency Department Management. New York, NY: McGraw adverse events during the procedure, individual patient factors Hill;2006:22-30. (eg, age, metabolism, polypharmacy, obesity), and the social 12. Mace SE, Barata IA, Cravero JP, et al. EMSC Grant Panel Writing circumstances of the child. Further study may yield generally Committee on Pharmacologic Agents Used in Pediatric Sedation and Analgesia in the Emergency Department. Clinical policy: applicable clinical discharge criteria. Professional organization evidence-based approach to pharmacologic agents used in consensus guidelines have been developed to assess discharge pediatric sedation and analgesia in the emergency department. readiness and may be used to develop institutional protocols or Ann Emerg Med. 2004;44:342-377. guidelines. 13. Zempsky WT, Cravero JP, for the American Academy of Pediatrics Committee on Pediatric Emergency Medicine and This clinical policy may also be found at: Section on Anesthesiology and Pain Medicine. Relief of pain and http://www.acep.org anxiety in pediatric patients in emergency medical systems. http://www.jenonline.org (June 2008) Pediatrics. 2004;114:1348-1356. http://www.pedsnurses.org/ and 14. Brown L, Minasyan L. Nonpharmacologic interventions. In: Mace SE, Ducharme J, Murphy M, eds. Pain Management and As a link at http://www.eapsa.org/ Sedation: Emergency Department Management. New York, NY: When this document is cited, the following citation format is McGraw Hill; 2006:398-403. 15. Rogovik AL, Goldman RD. Hypnosis as treatment for pain. In: suggested: Mace SE, Brown LA, Francis L, Godwin SA, Hahn Mace SE, Ducharme J, Murphy M, eds. Pain Management and SA, Howard PK, Kennedy RM, Mooney DP, Sacchetti AD, Sedation: Emergency Department Management. New York, NY: Wears RL, Clark RM. EMSC Panel on Critical Issues in the McGraw Hill; 2006:390-397. Sedation of Pediatric Patients in the Emergency Department. 16. American College of Emergency Physicians. Clinical policy for Clinical policy: critical issues in the sedation of pediatric procedural sedation and analgesia in the emergency department. Ann Emerg Med. 1998;31:663-677. patients in the emergency department. Ann Emerg Med. 2008; 17. Godwin SA, Caro DA, Wolf SJ, et al. American College of 51:378-399, e1-e57. Emergency Physicians Subcommittee (Writing Committee) on Procedural Sedation and Analgesia in the Emergency REFERENCES Department. Clinical policy: procedural sedation and analgesia 1. Innes G, Murphy M, Nijssen-Jordan C, et al. Procedural sedation in the emergency department. Ann Emerg Med. 2005;45:177- and analgesia in the emergency department. Canadian 196. Consensus Guidelines. J Emerg Med. 1999;17:145-156. 18. Joint Commission on Accreditation of Healthcare Organizations. 2. American College of Emergency Physicians. Rapid sequence Hospital Accreditation Standards. Oakbrook Terrrace, IL: Joint intubation. Ann Emerg Med. 1997;29:573. Commission Resources, Inc; 2004:163-166, 206, 287-288. 3. Glauser J, Mace SE. Procedural sedation in the emergency 19. American Academy of Pediatrics. Guidelines for monitoring and department: regulations as promulgated by the Joint management of pediatric patients during and after sedation for Commission on Accreditation of Healthcare Organizations and diagnostic and therapeutic procedures. Pediatrics. 1992;89: establishment of procedural sedation policy within the 1110-1115. emergency department. In: Mace SE, Ducharme J, Murphy M, 20. American Academy of Pediatrics. Guidelines for monitoring and eds. Pain Management and Sedation: Emergency Department management of pediatric patients during and after sedation for Management. New York, NY: McGraw-Hill; 2006:15-21. diagnostic and therapeutic procedures: Addendum. Pediatrics. 4. Core Content Task Force II. The model of the clinical practice of 2002;110:836-838. emergency medicine. Ann Emerg Med. 2001;37:745-770. 21. American Society of Anesthesiology. Practice guidelines for 5. Task Force on the Core Content for Emergency Medicine sedation and analgesia by non-anesthesiologists. Revision. Core content for emergency medicine. Ann Emerg Med. Anesthesiology. 1996;84:459-471. 1997;29:792-811. 22. American Society of Anesthesiology Task Force on Sedation and 6. Hostetler MA, Auinger P, Szilagyi PG. Parenteral analgesic and Analgesia by Non-Anesthesiologists. Practice guidelines for sedative use among ED patients in the United States: combined sedation and analgesia by non-anesthesiologists. results from the National Hospital Ambulatory Medical Care Survey Anesthesiology. 2002;96:1004-1017. (NHAMCS) 1992-1997. Am J Emerg Med. 2002;20:139-143. 23. Green SM, Krauss B. The semantics of ketamine. Ann Emerg 7. American Academy of Pediatrics and American Pain Society. The Med. 2000;36:480-482. assessment and management of acute pain in infants, children, 24. Cote CJ, Wilson S. Work Group on Sedation. Guidelines for and adolescents. Pediatrics. 2001;108:793-797. monitoring and management of pediatric patients during and 8. Mace SE, Murphy M. Pain management and procedural sedation: after sedation for diagnostic and therapeutic procedures: an definitions and clinical emergency department management. In: update. Pediatrics. 2006;118:2587-2601.

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25. American Society of Anesthesiologists Task Force on Academy of Pediatrics/American Society of Anesthesiologists Preoperative Fasting. Practice guidelines for preoperative fasting process model. Pediatrics. 2002;109:236-243. and the use of pharmacologic agents to reduce the risk of 44. Maekawa N, Mikawa K, Yaku H, et al. Effects of 2-, 4- and 12- pulmonary aspiration: application to healthy patients undergoing hour fasting intervals on preoperative gastric fluid pH and elective procedures. Anesthesiology. 1999;90:896-905. volume, and plasma glucose and lipid homeostasis in children. 26. Agrawal D, Manzi SF, Gupta R, et al. Preprocedural fasting state Acta Anaesthesiol Scand. 1993;37:783-787. and adverse events in children undergoing procedural sedation 45. Splinter WM, Schaefer JD. Unlimited clear fluid ingestion three and analgesia in a pediatric emergency department. Ann Emerg hours before surgery in children does not affect volume or pH of Med. 2003;42:636-646. stomach contents. Anaesth Intensive Care. 1990;18:522-526. 27. Warner MA, Warner ME, Weber JG. Clinical significance of 46. Ingebo KR, Rayhorn NJ, Hecht RM, et al. Sedation in children: pulmonary aspiration during the perioperative period. adequacy of two-hour fasting. J Pediatr. 1997;131:155-158. Anesthesiology. 1993;78:56-62. 47. Soreide E, Hausken T, Soreide JA, et al. Gastric emptying of a 28. Warner MA, Warner ME, Warner DO. Perioperative pulmonary light hospital breakfast. A study using real time ultrasonography. aspiration in infants and children. Anesthesiology. 1999;90:66- Acta Anaesthesiol Scand. 1996;40:549-553. 71. 48. Ghaffer S, Haverland C, Ramaciotti C, et al. Sedation for 29. Borland LM, Sereika SM, Woelfel SK, et al. Pulmonary aspiration pediatric echocardiography: evaluation of preprocedure fasting in pediatric patients during general anesthesia: incidence and guidelines. J Am Soc Echocardiogr. 2002;15:980-983. outcome. J Clin Anesth. 1998;10:95-102. 49. Keidan I, Gozal D, Minuskin T, et al. The effect of fasting 30. Green SM, Krauss B. Pulmonary aspiration risk during practice on sedation with chloral hydrate. Pediatr Emerg Care. emergency department procedural sedation—an examination of 2004;20:805-807. the role of fasting and sedation depth. Acad Emerg Med. 2002; 50. Green SM, Roback MG, Miner JR, et al. Fasting and emergency 9:35-42. department procedural sedation and analgesia: a consensus- 31. Mellin-Olsen J, Fasting S, Gisvold SE. Routine preoperative based clinical practice advisory. Ann Emerg Med. 2007;49:454- gastric emptying is seldom indicated. A study of 85,594 461. anaesthetics with special focus on aspiration pneumonia. Acta 51. Parbrook GD. The levels of nitrous oxide analgesia. Br J Anaesthesiol Scand. 1996;40:1184-1188. Anaesth. 1967;39:974-982. 32. Engelhardt T, Webster NR. Pulmonary aspiration of gastric 52. Benedetti C, Chapman CR Colpitts YH, et al. Effects of nitrous contents in anaesthesia. Br J Anaesth. 1999;83:453-460. oxide concentration on event-related potentials during painful 33. Kovac AL. Prevention and treatment of postoperative nausea tooth stimulation. Anesthesiology. 1982;56:360-364. and vomiting. Drugs. 2000;59:213-243. 53. Gillman MA. Analgesic (sub anesthetic) nitrous oxide interacts 34. Tramer MR, Reynolds DJ, Moore RA, et al. Efficacy, dose- with the endogenous opioid system: a review of the evidence. response, and safety of ondansetron in prevention of Life Sci. 1986;39:1209-1211. postoperative nausea and vomiting: a quantitative systematic 54. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, et al. Nitrous review of randomized placebo-controlled trials. Anesthesiology. oxide (laughing gas) is an NMDA antagonist, neuroprotectant 1997;87:1277-1289. and neurotoxin. Nat Med. 1998;4:460-463. 35. Babl FE, Puspitadewi A, Barnett P, et al. Preprocedural fasting 55. Litman RS, Berkowitz RJ, Ward DS. Levels of consciousness and state and adverse events in children receiving nitrous oxide for ventilatory parameters in young children during sedation with procedural sedation and analgesia. Pediatr Emerg Care. 2005; oral midazolam and nitrous oxide. Arch Pediatr Adolesc Med. 21:736-743. 1996;150:671-675. 36. Egelhoff JC, Ball WS Jr, Koch BL, et al. Safety and efficacy of 56. Litman RS, Kottra JA, Berkowitz RJ, et al. Breathing patterns and sedation in children using a structured sedation program. AJR levels of consciousness in children during administration of Am J Roentgenol. 1997;168:1259-1262. nitrous oxide after oral midazolam premedication. J Oral 37. Roback MG, Bajaj L, Wathen JE, et al. Preprocedural fasting and Maxillofac Surg. 1997;55:1372-1377. adverse events in procedural sedation and analgesia in a 57. Litman RS, Kottra JA, Verga KA, et al. Chloral hydrate sedation: pediatric emergency department: are they related? Ann Emerg the additive sedative and respiratory depressant effects of Med. 2004;44:454-459. nitrous oxide. Anesth Analg. 1998;86:724-728. 38. Kennedy RM, Porter FL, Miller JP, et al. Comparison of fentanyl/ 58. Everett GB, Allen GD. Simultaneous evaluation of midazolam with ketamine/midazolam for pediatric orthopedic cardiorespiratory and analgesic effects of nitrous oxide-oxygen emergencies. Pediatrics. 1998;102:956-963. inhalation analgesia. J Am Dent Assoc. 1971;83:129-133. 39. Green SM, Rothrock SG, Lynch EL, et al. Intramuscular ketamine 59. Stewart, RD, Gorayeb MJ, Pelton GH. Arterial blood gases for pediatric sedation in the emergency department: safety before, during, and after nitrous oxide: oxygen administration. profile in 1,022 cases. Ann Emerg Med. 1998;31:688-697. Ann Emerg Med. 1986;15:1177-1180. 40. McDowall RH, Scher CS, Barst SM. Total intravenous anesthesia 60. Ruben H. Nitrous oxide analgesia in dentistry. Its use during 15 for children undergoing brief diagnostic or therapeutic years in Denmark. Br Dent J. 1972;132:195-196. procedures. J Clin Anesth. 1995;7:273-280. 61. O’Sullivan I, Benger J. Nitrous oxide in emergency medicine. 41. Godambe SA, Elliot V, Matheny D, et al. Comparison of Emerg Med J. 2003;20:214-217. propofol/fentanyl versus ketamine/midazolam for brief 62. Stewart RD. Nitrous oxide sedation/analgesia in emergency orthopedic procedural sedation in a pediatric emergency medicine. Ann Emerg Med. 1985;14:139-148. department. Pediatrics. 2003;112:116-123. 63. Luhmann JD, Kennedy RM, Jaffe DM, et al. Continuous-flow 42. Bassett KE, Anderson JL, Pribble CG, et al. Propofol for delivery of nitrous oxide and oxygen: a safe and cost-effective procedural sedation in children in the emergency department. technique for inhalation analgesia and sedation of pediatric Ann Emerg Med. 2003;42:773-782. patients. Pediatr Emerg Care. 1999;15:388-392. 43. Hoffman GM, Nowakowski R, Troshynski TJ, et al. Risk reduction 64. Averley PA, Girdler NM, Bond S, et al. A randomized controlled in pediatric procedural sedation by application of an American trial of paediatric conscious sedation for dental treatment using

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intravenous midazolam combined with inhaled nitrous oxide or alternative to conscious sedation? J Pediatr Surg. nitrous oxide/sevoflurane. Anaesthesia. 2004;59:844-852. 2004;39:495-499. 65. Berge TI. Acceptance and side effects of nitrous oxide oxygen 84. Ekbom K, Jakobsson J, Marcus C. Nitrous oxide inhalation is a sedation for oral surgical procedures. Acta Odontol Scand. safe and effective way to facilitate procedures in paediatric 1999;57:201-206. outpatient departments. Arch Dis Child. 2005;90:1073-1076. 66. Houpt MI, Kupietzky A, Tofsky NS, et al. Effects of nitrous oxide 85. Henderson JM, Spence DG, Komocar LM, et al. Administration on diazepam sedation of young children. Pediatr Dent. 1996;18: of nitrous oxide to pediatric patients provides analgesia for 236-241. venous cannulation. Anesthesiology. 1990;72:269-271. 67. Houpt MI, Limb R, Livingston RL. Clinical effects of nitrous oxide 86. Kanagasundaram SA, Lane LJ, Cavalletto BP, et al. Efficacy and conscious sedation in children. Pediatr Dent. 2004;26:29-36. safety of nitrous oxide in alleviating pain and anxiety during 68. McCann W, Wilson S, Larsen P, et al. The effects of nitrous painful procedures. Arch Dis Child. 2001;84:492-495. oxide on behavior and physiological parameters during 87. Annequin D, Carbajal R, Chauvin P, et al. Fixed 50% nitrous conscious sedation with a moderate dose of chloral hydrate and oxide oxygen mixture for painful procedures: a French survey. hydroxyzine. Pediatr Dent. 1996;18:35-41. Pediatrics. 2000;105:1-6. 69. Weinstein P, Domoto PK, Holleman E. The use of nitrous oxide 88. Keidan I, Zaslansky R, Weinberg M, et al. Sedation during in the treatment of children: results of a controlled study. JAm voiding cystourethrography: comparison of the efficacy and Dent Assoc. 1986;112:325-331. safety of using oral midazolam and continuous flow nitrous 70. Wilson K, Welbury RR, Girdler NM. A randomized, controlled, oxide. J Urol. 2005;174:1598-1601. crossover trial of oral midazolam and nitrous oxide for paediatric 89. Sundin RH, Adriani J, Alam S, et al. Anxiolytic effects of low dental sedation. Anaesthesia. 2002;57:860-867. dosage nitrous oxide-oxygen mixtures administered continuously 71. Wilson KE, Girdler NM, Welbury RR. Randomized, controlled, in apprehensive subjects. South Med J. 1981;74:1489-1492. cross-over clinical trial comparing intravenous midazolam 90. Frampton A, Browne GJ, Lam LT, et al. Nurse administered sedation with nitrous oxide sedation in children undergoing relative analgesia using high concentration nitrous oxide to dental extractions. Br J Anaesth. 2003;91:850-856. facilitate minor procedures in children in an emergency 72. Luhmann JD, Kennedy RM, Porter FL, et al. A randomized clinical department. Emerg Med J. 2003;20:410-413. trial of continuous-flow nitrous oxide and midazolam for sedation 91. Cleaton-Jones P. The laryngeal-closure reflex and nitrous oxide— of young children during laceration repair. Ann Emerg Med. oxygen analgesia. Anesthesiology. 1976;45:569-570. 2001;37:20-27. 92. Dollfus C, Annequin M, Adam M, et al. Analgesia with nitrous 73. Burton JH, Auble TE, Fuchs SM. Effectiveness of 50% nitrous oxide for painful procedures in pediatric hematology-oncology. oxide/50% oxygen during laceration repair in children. Acad Ann Pediatr (Paris). 1995;42:115-121. Emerg Med. 1998;5:112-117. 93. Dunn-Russell T, Adair SM, Sams DR, et al. Oxygen saturation 74. Gamis AS, Knapp JF, Glenski JA. Nitrous oxide analgesia in a and diffusion hypoxia in children following nitrous oxide pediatric emergency department. Ann Emerg Med. 1989;18:177- sedation. Pediatr Dent. 1993;15:88-92. 181. 94. Gerhardt RT, King KM, Wiegert RS. Inhaled nitrous oxide versus 75. Keidan I, Zaslansky R, Yusim Y, et al. Continuous flow 50:50 placebo as an analgesic and anxiolytic adjunct to peripheral nitrous oxide: oxygen is effective for relief of procedural pain in intravenous cannulation. Am J Emerg Med. 2001;19:492-494. the pediatric emergency department. Acute Pain. 2003;5:25-30. 95. Roberts GJ, Wignall BK. Efficacy of the laryngeal reflex during 76. Bar-Meir E, Zaslansky R, Regev E, et al. Nitrous oxide oxygen—nitrous oxide sedation (relative analgesia). Br J administered by the plastic surgeon for repair of facial Anaesth. 1982;54:1277-1280. lacerations in children in the emergency room. Plast Reconstr 96. Rubin J, Brock-Utne JG, Greenberg M, et al. Laryngeal Surg. 2006;117:1571-1575. incompetence during experimental “relative analgesia” using 77. Luhmann JD, Schootman M, Luhmann SJ, et al. A randomized 50% nitrous oxide in oxygen. A preliminary report. Br J Anaesth. comparison of nitrous oxide plus hematoma block versus 1977;49:1005-1008. ketamine plus midazolam for emergency department forearm 97. Onody P, Gil P, Hennequin M. Safety of inhalation of a 50% fracture reduction in children. Pediatrics. 2006;118:e1078- nitrous oxide/oxygen premix. A prospective survey of 35,828 e1086. administrations. Drug Safety. 2006;29:633-640. 78. Evans JK, Buckley SL, Alexander AH, et al. Analgesia for the 98. Duncan GH, Moore P. Nitrous oxide and the dental patient: a reduction of fractures in children: a comparison of nitrous oxide review of adverse reactions. J Am Dent Assoc. 1984;108:213- with intramuscular sedation. J Pediatr Orthop. 1995;15:73-77. 219. 79. Gregory PR, Sullivan JA. Nitrous oxide compared with 99. Gall O, Annequin D, Benoit G, et al. Adverse events of premixed intravenous regional anesthesia in pediatric forearm fracture nitrous oxide and oxygen for procedural sedation in children. manipulation. J Pediatr Orthop. 1996;16:187-191. Lancet. 2001;358:1514-1515. 80. Hennrikus WL, Simpson RB, Klingelberger CE, et al. Self- 100. Selzer RR, Rosenblatt DS, Laxova R, et al. Adverse effect of administered nitrous oxide analgesia for pediatric fracture nitrous oxide in a child with 5, 10-methylenetetrahydrofolate reductions. J Pediatr Orthop. 1994;14:538-542. reductase deficiency. N Engl J Med. 2003;349:45-50. 81. Hennrikus WL, Shin AY, Klingelberger CE. Self-administered 101. Rowland AS, Baird DD, Weinberg CR, et al. Reduced fertility nitrous oxide and a hematoma block for analgesia in the among women employed as dental assistants exposed to high outpatient reduction of fractures in children. J Bone Joint Surg. levels of nitrous oxide. N Engl J Med. 1992;327:993-997. 1995;77-A:335-339. 102. Rowland AS, Baird DD, Shore DL, et al. Nitrous oxide and 82. Wattenmaker I, Kasser JR, McGravey A. Self-administered spontaneous abortion in female dental assistants. Am J nitrous oxide for fracture reduction in children in an emergency Epidemiol. 1995;141:531-538. room setting. J Orthop Trauma. 1990;4:35-38. 103. Ahlborg G Jr, Axelsson G, Bodin L. Shift work, nitrous oxide 83. Burnweit C, Diana-Zerpa JA, Nahmad MH, et al. Nitrous oxide exposure and subfertility among Swedish midwives. Int J analgesia for minor pediatric surgical procedures: an effective Epidemiol. 1996;25:783-790.

Volume , .  : April  Annals of Emergency Medicine 393 Clinical Policy

104. Axelsson G, Ahlborg G Jr, Bodin L. Shift work, nitrous oxide 125. Carbajal R, Chauvet X, Couderc S, et al. Randomised trial of exposure, and spontaneous abortion among Swedish midwives. analgesic effects of sucrose, glucose, and pacifiers in term Occup Environ Med. 1996;53:374-378. neonates. BMJ. 1999;319:1393-1397. 105. Brodsky JB, Cohen EN, Brown BW Jr, et al. Exposure to nitrous 126. Guala A, Pastore G, Liverani ME, et al. Glucose or sucrose as oxide and neurologic disease among dental professionals. an analgesic for newborns: a randomized controlled blind trial. Anesth Analg. 1981;60:297-301. Minerva Pediatr. 2001;53:271-274. 106. Zempsky WT, Cravero JP, American Academy of Pediatrics 127. Abad F, Diaz NM, Domenech E, et al. Oral sweet solution Committee on Pediatric Emergency Medicine and Section on reduces pain-related behaviour in preterm infants. Acta Paediatr. Anesthesiology and Pain Medicine. Relief of pain and anxiety in 1996;85:854-858. pediatric patients in emergency medical systems. Pediatrics. 128. Acharya AB, Annamali S, Taub NA, et al. Oral sucrose analgesia 2004;114:1348-1356. for preterm infant venepuncture. Arch Dis Child Fetal Neonatal 107. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in Ed. 2004;89:F17-18. newborn infants undergoing painful procedures. Cochrane 129. Bucher HU, Moser T, von Siebenthal K, et al. Sucrose reduces Database Syst Rev. 2004;(3):CD001069. pain reaction to heel lancing in preterm infants: a placebo- 108. Rogers AJ, Greenwald MH, Deguzman MA, et al. A randomized, controlled, randomized and masked study. Pediatr Res. 1995; controlled trial of sucrose analgesia in infants younger than 90 38:332-335. days of age who require bladder catheterization in the pediatric 130. Ramenghi LA, Evans DJ, Levene MI. ”Sucrose analgesia”: emergency department. Acad Emerg Med. 2006;13:617-622. absorptive mechanism or taste perception? Arch Dis Child Fetal 109. Porter FL, Wolf CM, Miller JP. Procedural pain in newborn Neonatal Ed. 1999;80:F146-147. infants: the influence of intensity and development. Pediatrics. 131. Johnston CC, Stremler RL, Stevens BJ, et al. Effectiveness of 1999;104:e13. oral sucrose and simulated rocking on pain response in preterm 110. Lawrence J, Alcock D, McGrath P, et al. The development of a neonates. Pain. 1997;72:193-199. tool to assess neonatal pain. Neonatal Netw. 1993;12:59-66. 132. Ramenghi LA, Griffith GC, Wood CM, et al. Effect of non-sucrose 111. Grunau RV, Craig KD. Pain expression in neonates: facial action sweet tasting solution on neonatal heel prick responses. Arch and cry. Pain. 1987;28:395-410. Dis Child Fetal Neonatal Ed. 1996;74:F129-131. 112. Carbajal R, Paupe A, Hoenn E, et al. APN: evaluation behavioral 133. Blass EM. Milk-induced hypoalgesia in human newborns. scale of acute pain in newborn infants. Arch Pediatr. 1997;4: Pediatrics. 1997;99:825-829. 623-628. 134. Blass EM, Hoffmeyer LB. Sucrose as an analgesic for newborn 113. Stevens B, Johnston C, Petryshen P, et al. Premature Infant infants. Pediatrics. 1991;87:215-218. Pain Profile: development and initial validation. Clin J Pain. 135. Harrison D, Johnston L, Loughnan P. Oral sucrose for procedural 1996;12:13-22. pain in sick hospitalized infants: a randomized-controlled trial. J 114. Stevens B, Johnston C, Franck L, et al. The efficacy of Paediatr Child Health. 2003;39:591-597. developmentally sensitive interventions and sucrose for relieving 136. Herschel M, Khoshnood B, Ellman C, et al. Neonatal procedural pain in very low birth weight neonates. Nurs Res. circumcision. Randomized trial of a sucrose pacifier for pain 1999;48:35-43. control. Arch Pediatr Adolesc Med. 1998;152:279-284. 115. Johnston CC, Stremler R, Horton L, et al. Effect of repeated 137. Mitchell A, Stevens B, Mungan N, et al. Analgesic effects of oral doses of sucrose during heel stick procedure in preterm sucrose and pacifier during eye examinations for retinopathy of neonates. Biol Neonate. 1999;75:160-166. prematurity. Pain Manag Nurs. 2004;5:160-168. 116. Gibbins S, Stevens B, Hodnett E, et al. Efficacy and safety of 138. Mohan CG, Risucci DA, Casimir M, et al. Comparison of sucrose for procedural pain relief in preterm and term neonates. Nurs Res. 2002;51:375-382. analgesics in ameliorating the pain of circumcision. J Perinatol. 117. Isik U, Ozek E, Bilgen H, et al. Comparison of oral glucose and 1998;18:13-19. sucrose solutions on pain response in neonates. J Pain. 2000; 139. Ramenghi LA, Wood CM, Griffith GC, et al. Reduction of pain 1:275-278. response in premature infants using intraoral sucrose. Arch Dis 118. Haouari N, Wood C, Griffiths G, et al. The analgesic effect of Child Fetal Neonatal Ed. 1996;74:F126-128. sucrose in full term infants: a randomised controlled trial. BMJ. 140. Rushforth JA, Levene MI. Effect of sucrose on crying in response 1995;310:1498-1500. to heel stab. Arch Dis Child. 1993;69:388-389. 119. Abad F, Diaz-Gomez NM, Domenech E, et al. Oral sucrose 141. Stang HJ, Snellman LW, Condon LM, et al. Beyond dorsal penile compares favourably with lidocaine-prilocaine cream for pain nerve block: a more humane circumcision. Pediatrics. 1997; relief during venepuncture in neonates. Acta Paediatr. 2001;90: 100:E3. 160-165. 142. Barr RG, Young SN, Wright JH, et al. “Sucrose analgesia” and 120. Gormally S, Barr RG, Wertheim L, et al. Contact and nutrient diphtheria-tetanus-pertussis immunizations at 2 and 4 months. J caregiving effects on newborn infant pain responses. Dev Med Dev Behav Pediatr. 1995;16:220-225. Child Neurol. 2001;43:28-38. 143. Lewindon PJ, Harkness L, Lewindon N. Randomised controlled 121. Greenberg CS. A sugar-coated pacifier reduces procedural pain trial of sucrose by mouth for the relief of infant crying after in newborns. Pediatr Nurs. 2002;28:271-277. immunisation. Arch Dis Child. 1998;78:453-456. 122. Ors R, Ozek E, Baysoy G, et al. Comparison of sucrose and 144. Reis EC, Roth EK, Syphan JL, et al. Effective pain reduction for human milk on pain response in newborns. Eur J Pediatr. 1999; multiple immunization injections in young infants. Arch Pediatr 158:63-66. Adolesc Med. 2003;157:1115-1120. 123. Allen KD, White DD, Walburn JN. Sucrose as an analgesic agent 145. Blass EM, Shah A. Pain-reducing properties of sucrose in human for infants during immunization injections. Arch Pediatr Adolesc newborns. Chem Senses. 1995;20:29-35. Med. 1996;150:270-274. 146. Willis DM, Chabot J, Radde IC, et al. Unsuspected 124. Ogawa S, Ogihara T, Fujiwara E, et al. Venepuncture is hyperosmolality of oral solutions contributing to necrotizing preferable to heel lance for blood sampling in term neonates. enterocolitis in very-low-birth-weight infants. Pediatrics. 1977;60: Arch Dis Child Fetal Neonatal Ed. 2005;90:F432-436. 535-538.

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147. Coskun S, Yuksel H, Onag A. Chloral hydrate in children 166. Napoli KL, Ingall CG, Martin GR. Safety and efficacy of chloral undergoing echocardiography. Indian J Pediatr. 2001;68:319- hydrate sedation in children undergoing echocardiography. 322. J Pediatr. 1996;129:287-291. 148. Wheeler DS, Jensen RA, Poss WB. A randomized, blinded 167. Lichenstein R, King JC, Bice D. Evaluation of choral hydrate for comparison of chloral hydrate and midazolam sedation in pediatric sedation. Clin Pediatr. 1993;32:632-633. children undergoing echocardiography. Clin Pediatr. 2001;40: 168. Weir MR, Segapeli JH, Tremper JL. Sedation for pediatric 381-387. procedures. Mil Med. 1986;151:181-184. 149. Marti-Bonmati L, Ronchera-Oms CL, Casillas C, et al. 169. Sanborn PA, Michna E, Zurakowski D, et al. Adverse Randomised double-blind clinical trial of intermediate- versus cardiovascular and respiratory events during sedation of high-dose chloral hydrate for neuroimaging of children. pediatric patients for imaging examinations. Radiology. 2005; Neuroradiology. 1995;37:687-691. 237:288-294. 150. Malviya S, Voepel-Lewis T, Tait AR, et al. Pentobarbital vs 170. Kao SC, Adamson SD, Tatman LH, et al. A survey of post- chloral hydrate for sedation of children undergoing MRI: efficacy discharge side effects of conscious sedation using chloral and recovery characteristics. Pediatr Anesth. 2004;14:589-595. hydrate in pediatric CT and MR imaging. Pediatr Radiol. 1999; 151. D’Agostino J, Terndrup TE. Chloral hydrate versus midazolam for 29:287-290. sedation of children for neuroimaging: a randomized clinical 171. Bissett GS III, Ball WS Jr. Preparation, sedation, and monitoring trial. Pediatr Emerg Care. 2000;16:1-4. of the pediatric patient in the magnetic resonance suite. Semin 152. Thompson JR, Schneider S, Ashwal S, et al. The choice of Ultrasound CT MR. 1991;12:376-378. sedation for computed tomography in children: a prospective 172. Olson DM, Sheehan MG, Thompson W, et al. Sedation of evaluation. Radiology. 1982;143:475-479. children for electroencephalograms. Pediatrics. 2001;108:163- 153. Ronchera-Oms CL, Casillas C, Marti-Bonmati L, et al. Oral 165. chloral hydrate provides effective and safe sedation in 173. Malviya S, Voepel-Lewis T, Tait AR. Adverse events and risk paediatric magnetic resonance imaging. J Clin Pharm Ther. factors associated with the sedation of children by 1994;19:239-243. nonanesthesiologists. Anesth Analg. 1997;85:1207-1213. 154. Greenberg SB, Faerber EN, Aspinall CL, et al. High-dose chloral 174. Reeves ST, Wiedenfeld KR, Wrobleski J, et al. A randomized hydrate sedation for children undergoing MR imaging: safety and double-blind trial of chloral hydrate/hydroxyzine versus efficacy in relation to age. AJR Am J Roentgenol. 1993;161:639- midazolam/acetaminophen in the sedation of pediatric dental 641. outpatients. ASDC J Dent Child. 1996;63:95-100. 155. McCarver-May DG, Kang J, Aouthmany M, et al. Comparison of 175. Malviya S, Voepel-Lewis T, Prochaska G, et al. Prolonged chloral hydrate and midazolam for sedation of neonates for recovery and delayed side effects of sedation for diagnostic neuroimaging studies. J Pediatr. 1996;128:573-576. imaging studies in children. Pediatrics. 2000;105:E42. Available 156. Pereira JK, Burrows PE, Richards HM, et al. Comparison of at: http://www.pediatrics.org/cgi/content/full/105/3/e42. sedation regiments for pediatric outpatient CT. Pediatr Radiol. 176. Cote CJ, Karl HW, Notterman DA, et al. Adverse sedation events 1993;23:341-344. in pediatrics: analysis of medications used for sedation. 157. Lipshitz M, Marino BL, Sanders ST. Chloral hydrate side effects Pediatrics. 2000;106:633-644. in young children: causes and management. Heart Lung. 1993; 177. Pena BMG, Krauss B. Adverse events of procedural sedation 22:408-414. and analgesia in a pediatric emergency department. Ann Emerg 158. Malviya S, Voepel-Lewis T, Eldevik OP, et al. Sedation and Med. 1999;34:483-491. general anaesthesia in children undergoing MRI and CT: adverse 178. Wang HE. Clinical policy on pediatric procedural sedation. Ann events and outcomes. Br J Anaesth. 2000;84:743-748. Emerg Med. 2005;45:564-565. 159. Hubbard AM, Markowitz RI, Kimmel B, et al. Sedation for 179. Nazziola E, Sharma AN, Hoffman RS. Sedation and analgesia for pediatric patients undergoing CT and MRI. J Comput Assist procedures in children [letter]. N Engl J Med. 2000;343:302- Tomogr. 1992;16:3-6. 303. 160. Rumm PD, Takao RT, Fox DJ, et al. Efficacy of sedation of 180. Anyebuno MM, Rosefeld CR. Chloral hydrate toxicity in a term children with chloral hydrate. South Med J. 1990;83:1040- infant. Dev Pharmacol Ther. 1991;17:116-120. 1043. 181. Biban P, Baraldi E, Pettenazzo A, et al. Adverse effect of chloral 161. Seiler G, De Vol E, Khafaga Y, et al. Evaluation of the safety hydrate in two young children with obstructive sleep apnea. and efficacy of repeated sedations for the radiotherapy of young Pediatrics. 1993;92:461-463. children with cancer: a prospective study of 1033 consecutive 182. Hirsch IA, Zauder HL. Chloral hydrate: a potential cause of sedations. Int J Radiat Oncol Biol Phys. 2001;49:771-783. arrhythmias. Anesth Analg. 1986;65:691-692. 162. Rooks VJ, Chung T, Connor L, et al. Comparison of oral 183. Munoz M, Gomez A, Soult JA, et al. Seizures caused by chloral pentobarbital sodium (Nembutal) and oral chloral hydrate for hydrate sedative doses. J Pediatr. 1997;131:787-788. sedation of infants during radiologic imaging: preliminary 184. Rokicki W. Cardiac arrhythmias in a child after the usual dose of results. AJR Am J Roentgenol. 2003;180:1125-1128. chloral hydrate. Pediatr Cardiol. 1996;17:419-420. 163. Mason KP, Sanborn P, Zurakowski D, et al. Superiority of 185. Young JB, Verdermolen LA, Pratt CM. Torsade de pointes: an pentobarbital versus chloral hydrate for sedation in infants unusual manifestation of chloral hydrate poisoning. Am Heart J. during imaging. Radiology. 2004;230:537-542. 1986;112:181-184. 164. Chung T, Hoffer FA, Connor L, et al. The use of oral 186. Casken H, Odabas D, Unerune A, et al. Respiratory arrest due pentobarbital sodium (Nembutal) versus oral chloral hydrate in to chloral hydrate in an infant. J Emerg Med. 2003;24:342- infants undergoing CT and MR imaging—a pilot study. Pediatr 343. Radiol. 2000;30:332-335. 187. Coté CJ, Notterman DA, Karl HW, et al. Adverse sedation events 165. Vade A, Sukhani R, Dolenga M, et al. Chloral hydrate sedation in pediatrics: a critical incident analysis of contributing factors. of children undergoing CT and MR imaging: safety as judged by Pediatrics. 2000;105:805-814. American Academy of Pediatrics guidelines. AJR Am J 188. Gaulier JM, Merle G, Lacassie E, et al. Fatal intoxications with Roentgenol. 1995;165:905-909. chloral hydrate. J Foresic Sci. 2001;46:1507-1509.

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189. Justak JT, Pallasch T. Death after chloral hydrate sedation: 198. Mason KP, Zurakowski D, Connor L, et al. Infant sedation for report of case. J Am Dent Assoc. 1988;116:345-348. MR imaging and CT: oral versus intravenous pentobarbital. 190. Australasian College for Emergency Medicine, Australian and Radiology. 2004;233:723-728. New Zealand College of Anaesthetists, Faculty of Pain Medicine, 199. Sandler NA, Hodges J, Sabino M. Assessment of recovery Joint Faculty of Intensive Care Medicine. Statement on clinical in patients undergoing intravenous conscious sedation principles for procedural sedation. Emerg Med (Fremantle). using bispectral analysis. J Oral Maxillofac Surg. 2001;59: 2003;15:205-206. 603-611. 191. Baiocchi M, Rinaldi V, Zanette G, et al. Quality control of 200. Takarada T, Kawahara M, Irifune M, et al. Clinical recovery time sedation for diagnostic radiological procedures in paediatric from conscious sedation for dental outpatients. Anesth Prog. patients (waiting for guidelines). Minerva Anestesiol. 2002;68: 2002;49:124-127. 911-917. 201. Malviya S, Voepel-Lewis T, Tait AR, et al. Depth of sedation in 192. Cote CJ. Discharge criteria for children sedated by children undergoing computed tomography: validity and reliability nonanesthesiologists. Is “safe” really safe enough? of the University of Michigan Sedation Scale (UMSS). Br J Anesthesiology. 2004;100:207-209. Anaesth. 2002;88:241-245. 193. Glasier CM, Stark JE, Brown R, et al. Rectal thiopental sodium for sedation of pediatric patients undergoing MR and other 202. Mitler MM, Gujavarty KS, Browman CP. Maintenance of imaging studies. AJNR Am J Neuroradiol. 1995;16:111-114. wakefulness test: a polysomnographic technique for 194. Gudlin DJ, Winch AE, Kochevar W. Conscious sedation. J Soc evaluation treatment efﬁcacy in patients with excessive Pediatr Nurs. 1997;2:143-147. somnolence. Electroencephalogr Clin Neurophysiol. 1982;53: 195. Holzman RS, Cullen DJ, Eichhorn JH, et al. Guidelines for 658-661. sedation by nonanesthesiologists during diagnostic and 203. McDermott NB, VanSickle T, Motas D, et al. Validation of the therapeutic procedures. J Clin Anesth. 1994;6:265-276. bispectral index monitor during conscious and deep sedation in 196. Lepere AJ, Slack-Smith LM. Average recovery time from a children. Anesth Analg. 2003;97:39-43. standardized intravenous sedation protocol and standardized 204. Wu CC, Mok MS, Lin CS, et al. EEG-bispectral index changes discharge criteria in the general dental practice setting. Anesth with ketamine versus thiamylal induction of anesthesia. Acta Prog. 2002;49:77-81. Anaesthesiol Sin. 2001;39:11-15. 197. Malviya S, Voepel-Lewis T, Ludomirsky A, et al. Can we improve 205. Newman DH, Azer MM, Pitetti RD, et al. When is a patient safe the assessment of discharge readiness? A comparative study of for discharge after procedural sedation? The timing of adverse observational and objective measures of depth of sedation in effect events in 1,367 pediatric procedural sedations. Ann children. Anesthesiology. 2004;100:218-224. Emerg Med. 2003;42:627-635.

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Appendix A. Literature classiﬁcation schema.* Design/Class Therapy† Diagnosis‡ Prognosis§ 1 Randomized, controlled trial or Prospective cohort using a Population prospective cohort meta-analyses of randomized trials criterion standard

2 Nonrandomized trial Retrospective observational Retrospective cohort Case control

3 Case series Case series Case series Case report Case report Case report Other (eg, consensus, review) Other (eg, consensus, review) Other (eg, consensus, review)

*Some designs (eg, surveys) will not fit this schema and should be assessed individually. †Objective is to measure therapeutic efficacy comparing Ն2 interventions. ‡Objective is to determine the sensitivity and specificity of diagnostic tests. §Objective is to predict outcome including mortality and morbidity.

Appendix B. Approach to downgrading strength of evidence. Downgrading Design/Class 123 None I II III 1 level II III X 2 levels III X X Fatally ﬂawed X X X

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Appendix C.Recommendations from the 2004 clinical VII. Does the addition of midazolam as an adjunct to policy.12 ketamine for procedural sedation for children in the ED reduce recovery agitation or vomiting? I. Is etomidate effective for providing procedural Level A recommendations. The addition of midazolam sedation in children in the ED? as an adjunct to ketamine for procedural sedation for Level A recommendations. None specified. children in the ED does not decrease the incidence of Level B recommendations. None specified. emergent reactions. Level C recommendations. Etomidate is an effective Level B recommendations. The addition of midazolam agent for procedural sedation in the pediatric patient as an adjunct to ketamine for procedural sedation for population within the ED. children decreases the incidence of emesis. Level C recommendations. None specified. II. Is etomidate safe for providing procedural sedation in VIII. Is methohexital effective for providing procedural children in the ED? sedation in children in the ED? Level A recommendations. None specified. Level A recommendations. None specified. Level B recommendations. None specified. Level B recommendations. Methohexital administered Level C recommendations. Etomidate is a safe agent by either the intravenous, intramuscular, or rectal routes for procedural sedation in the pediatric patient population can provide effective sedation for children undergoing within the ED. painless diagnostic studies. III. Are fentanyl and midazolam effective for providing Level C recommendations. None specified. procedural sedation in children in the ED? IX. Is methohexital safe for providing procedural sedation Level A recommendations. None specified. in children in the ED? Level B recommendations. Intravenous use of fentanyl Level A recommendations. None specified. and midazolam is effective for pediatric sedation during Level B recommendations. Methohexital can be painful procedures in the ED. safely used for procedural sedation but may require Level C recommendations. None specified. head positioning, supplemental oxygen, and occasional IV. Is the use of fentanyl and midazolam safe for providing bag-valve-mask ventilatory support. procedural sedation for painful procedures in children Level C recommendations. None specified. in the ED? X. Is pentobarbital effective for providing procedural Level A recommendations. None specified. sedation in children in the ED? Level B recommendations. The combination of Level A recommendations. None specified. fentanyl and midazolam appears to result in a greater risk Level B recommendations. Pentobarbital alone is of respiratory depression; therefore, the clinician should effective in producing cooperation for painless diagnostic take particular care to monitor the patient for signs of procedures. Best sedation results are seen in children respiratory depression and should have appropriate younger than 8 years. training and support to treat apnea. Level C recommendations. None specified. Level C recommendations. None specified. XI. Is pentobarbital safe for providing procedural sedation in children in the ED? V. Is ketamine effective for providing procedural sedation Level A recommendations. None specified. in children in the ED? Level B recommendations. Pentobarbital can be safely Level A recommendations. Ketamine is effective either used for procedural sedation but may require head as a sole agent or in combination with a benzodiazepine positioning, supplemental oxygen, and occasional bag-valve- for brief painful procedures in children. mask ventilatory support. Level B recommendations. None specified. Level C recommendations. None specified. Level C recommendations. None specified. XII. Is propofol effective for providing procedural sedation VI. Is ketamine safe for providing procedural sedation in in children in the ED? children in the ED? Level A recommendations. None specified. Level A recommendations. Ketamine can be safely Level B recommendations. Propofol combined with used for procedural sedation in children in the ED, but opiate agents is effective in producing cooperation for may require head positioning, supplemental oxygen, painful therapeutic or diagnostic studies. occasional bag-valve-mask ventilatory support, and Level C recommendations. Propofol alone, without measures to address laryngospasm. the concomitant use of opiate agents, is likely to be Level B recommendations. None specified. effective in producing sedation for painless diagnostic Level C recommendations. None specified. studies in ED patients.

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Appendix C (continued). XIII.Is propofol safe for providing procedural sedation in children in the ED? Level A recommendations. None speciﬁed. Level B recommendations. Propofol combined with opiate agents can be safely used for procedural sedation but may require head positioning, supplemental oxygen, and occasional bag-valve-mask ventilatory support. Level C recommendations. Propofol alone, without the concomitant use of opiate agents, can be safely used for procedural sedation but may require head positioning, supplemental oxygen, and occasional bag-valve-mask ventilatory support.

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Evidentiary Table. Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/Comments Class Modality Measure/Criterion Standard Agrawal et 2003 Prospective, Consecutive patients Observational protocol to ASA physical status class I: Inadequate power to II al26 observational requiring procedural detect adverse events 785 (77%), class II: 188 (19%), determine differences in study sedation during 11 mo; including desaturation, class III: 41 (4%), no class IV aspiration after emesis; 905/1,014 patients had prolonged sedation, or V, 56% of patients not nonblinded sedation adequate fasting airway complications, fasted; no difference in adverse recorders (ED nurses caring documentation; age 5 days emesis, and aspiration events between fasted and for patients); no follow-up to 31 y, median age 5.4 y; unfasted groups; 77 adverse of patients after ED 580(57%) male; no gastric events occurred in 68/1,014 discharge although patients emptying agents or anti- patients (6.7%; 95% CI 5.2% had to be deemed back to emetic medications were to 8.4%); all adverse events normal before discharge documented although were minor and successfully from the ED; no data on patients receiving treated; adverse events why physicians waited or medications for intractable occurred in 32/396 (8.1%) did not wait; could be vomiting were excluded patientswho met and 35/509 physicians self selected (6.9%)patients who did not (bias) meet fasting guidelines; median fasting duration for patients withemesis was 6.8 h for solids and 5.8 h for clear liquids; emesis occurred in 15 (1.5%)patients; 11/15 patients with emesis were sedated with ketamine; median age for emesis 11.1 y vs 5.3 y for patients without emesis; odds ratio for emesis with ketamine was 3.2 (P=.04); there were no episodes of aspiration   :  . , April  Volume   :  . , April

 Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/Comments Class Modality Measure/Criterion Standard Green and 2002 Review Review of pulmonary Design; risk of aspiration during III Krauss30 aspiration risk during ED ED procedural sedation appears procedural sedation to be extremely low; there is no compelling evidence that mandates specific times for presedation fasting for solids or liquids Babl et al35 2005 Prospective Incidence of adverse events Prospectively Fasting status documented in 71% of patients undergoing ED II observational with preprocedural fasting documented adverse 218 patients (99.1%); procedural sedation did not meet study for nitrous oxide procedural outcomes defined as orthopedic procedures 45%, fasting guidelines; no sedation in theED;220 minor and serious; lacerations 21%, vascular association between children underwent painful serious affects included access 18%; 86% moderate, preprocedural fasting and procedures; 82%got 70% but were not limited to 7% deep, 7% poorly sedated; emesis; no serious adverse nitrous oxide; 18% got 50% airway compromise, ASA guidelines met for solids events; 60 patients missed in nitrous oxide; 12% also got desaturation, and in 29%, clear liquids in 79%; chart review butfound no morphine; ages 14 mo to 17 aspiration 46 minor events occurred in 37 difference from study subjects; y;median age 8 y 3 mo, patients (17%); no aspiration; inadequate power to determine 60% boys; 209 (95%) emesis in 6% meeting and 7% differences in aspiration after patients were ASA class I or not meeting fasting guidelines emesis; no data on physicians as II, 11 (5%) were class III, no for solids; no correlation to why they waited or did not class IV or V; authors between fasting status and wait, could be physicians self performed follow-up calls vomiting; no major adverse selected (bias) with 207 patient families to events; 5% of patients in Annals document any late sequelae; follow-up calls admitted to no gastric emptying agents vomiting after returning home of or anti-emetic medications

mrec Medicine Emergency were documented lnclPolicy Clinical 399.e2 399.e3 Policy Clinical Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/Comments Class Modality Measure/Criterion Standard Egelhoff 1997 Retrospective 6,006 pediatric outpatients of a Sedation complications, 65% of patients received Design of study the largest III et al36 cohort radiology department; ages 1 and rate of successful pentobarbital with 38% receiving limitation; not designed to mo to 18 y; retrospective sedation fentanyl as well; 35% received specifically evaluate fasting review for safety and efficacy chloral hydrate; 4 required guidelines with the sedation during the overnight hospitalization because imaging study; fasting of CNS depression with no guidelines: 3 h for liquids and sequelae; no cardiovascular or solids in children <1 y and 8 h respiratory arrest occurred; 48 with no solids and 4 h with no patients experienced transient liquids for children 12 mo and respiratory depression; 63% older; milk was a solid; the3 (N=3,783) were contacted for drugs used were chloral follow-up; delayed complications hydrate, pentobarbital, and in 29 (0.77%) children, with fentanyl; no gastric emptying excessive vomiting in 20(0.53%) agents or anti-emetic patients and no hospitalizations; medications documented sedation failure was about 1%   :  . , April  Volume   :  . , April  Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Roback et 2004 Retrospective 2,497 patients received procedural Incidence of vomiting, No aspiration episodes; Retrospective review of II al37 review of sedation and analgesia; 412 patients aspiration, or respiratory incidence of adverse events prospectively collected data; prospective were excluded for receiving oral or events not related to NPO time; fasting time documented in database intranasal drugs (n=95) or for 150 patients fasted <2 h; only ¼ of patients; brings bronchoscopy by nonemergency 391 patients fasted 2-4 h; into question the validity of physicians (n=317); a total of 2,085 adverse events included the results; type of ingestion patients received parenteral sedation desaturations (169 [8.1%]), of last meal (liquid, solid) by emergency physicians; ages: 19 vomiting (156 [7.5%]), apnea not documented; days to 32.1 y (median age 6.7 y); (16 [0.8%]), and documentations may not fasting time documented in1,555 laryngospasm (3 [0.1%]); have detected key (74.6%) patients, 60.2% of these 1,096/2,085 sedations for information as nursing may male; median fasting time before fracture or dislocation not have been as thorough sedation was 5.1 h (range 5 min to reduction, 411 patients for because it was for a data 32.5 h); various medications used laceration repair, and 95 base and not a study including ketamine, patients for radiologic initially; variety of ketamine/midazolam, midazolam, procedures; others were medications and doses; fentanyl/midazolam, and mixture of predominantly adequacy of sedation not morphine/midazolam; no gastric painful procedures noted; other medical emptying agents or anti-emetic conditions? medications documented; comparisons were made on the incidence of adverse events according

Annals to length of preprocedural fasting; all unpremedicated patients included; all patients taking known gastric motility of agents excluded; ASA physical status mrec Medicine Emergency not documented lnclPolicy Clinical 399.e4 399.e5 Policy Clinical Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/Comments Class Modality Measure/Criterion Standard Kennedy 1998 Prospective, 260 patients; age 5–15 y Recorded data included Safety: mean time to last oral intake and Well-done randomized III et al38 single- requiring orthopedic time of last meal and sedation for subjects who vomited was controlled trial not specifically blinded, procedures in ED; ASA adequacy of sedation; 4.4 +/- 2.5 h, compared with 5.0 +/- 2.4 designed to identify issues randomized, status I–II; videotaped safety assessed by h who did not; no aspirations associated with preprocedural controlled blinded assessment of objective monitoring; documented; ketamine/midazolam had fasting such as solids versus trial sedation events; compared efficacy assessed by 9- more vomiting in 7-day period after liquids and their specific times ketamine/midazolam point facial affective procedure (4% versus 0%) (P=.03); of ingestion; only orthopedic versus scale, parents 10 cm hypoxia in 6% of ketamine/midazolam procedures; results fentanyl/midazolam; VAS, orthopedist group versus 25% in the may not apply to younger dosing regimens: satisfaction VAS, and fentanyl/midazolam group (P=.001); patients; single-blind study; midazolam 0.1 mg/kg, OSBD-R scored breathing cues needed 1% for ketamine/midazolam is more maximum 2.5 mg every 3 by blindedobservers ketamine/midazolam versus 12% in efficacious for sedation than min until sedated; fentanyl and blinded treating fentanyl/midazolam (P=.001), and fentanyl/midazolam for 0.5 mg/kg every 3 min physicians oxygen required in 10% orthopedic procedures with until decrease response to ketamine/midazolam versus 20% less hypoxia and airway verbal/painful stimuli fentanyl/midazolam (P=.04); 2 patients maneuvers; versus ketamine 0.5 mg/kg in ketamine/midazolam group required ketamine/midazolam every 3 min (up to 2 assisted mask ventilation versus0 is associated with fewer mg/kg)+glycopyrrolate 5 patients in fentanyl/midazolam group; respiratory complications, but mg/kg up to 250 mg efficacy: ketamine/midazolam had better respiratory support may be efficacy measured by lower distress needed with either regimen; scores during procedure and increased vomiting in weeks after orthopedic physician satisfaction; sedation slightly more common OSBD-R for ketamine/midazolam was with ketamine/midazolam lower than with fentanyl/midazolam (4% versus 0%) 1.08+1.12 vs 2.70+2.16 (P<.0001)   :  . , April  Volume   :  . , April 

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Basset 2003 Prospective Consecutive case series of 393 propofol Vital signs, need for ASA classifications: 379 (96%) Depth of sedation not II et al42 observational sedations for painful orthopedic airway assistance, patients ASA I; 13 (4%) patients objectively observed; fasting cohort procedures in tertiary care pediatric fasting time, procedure ASA II; 50 (13%) patients with was not the focus of the hospital ED; one patient with an ocular time, sedation time fasting protocol violations with study although study burn also included; opioid premed shortened fasting times were violations were documented; administered 1 min before propofol identified; 31 (8%) were fasted no comparison group and no delivery; sedation forms; no gastric for less than 3 h for liquids; clear differentiation of NPO; emptying agents or anti-emetic adverse events included: 1 only 13% with fasting medications documented episode of postsedation emesis, period <3 h; otherwise 3 h decrease in blood pressure in 331 cutoff within guidelines for (84%) children, 23 (6%) with clear liquids; does not bradycardia, 3 (0.8%) patients delineate solids versus required brief bag-valve-mask; liquids in final numbers no patient required endotracheal intubation; no clinically significant aspirations Annals of mrec Medicine Emergency lnclPolicy Clinical 399.e6 399.e7 Policy Clinical Annals Evidentiary Table (continued).

of Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/Comments Class

mrec eiieVolume Medicine Emergency Modality Measure/Criterion Standard Hoffman 2002 Retrospective 960 prospectively coded NPO status and drugs Fasting question: Fasting question: according to Fasting et al43 cohort sedation records; NPO used; type 1 deep sedation in 215 (22%) with the authors the effect of NPO II criteria not met in 309/960 complications included only 65 (7%) documented planned status on sedation outcome (32%) patients; in 45 of sedation failure; type 2 deep sedation; adherence to NPO could not be adequately ______these (15%), NPO status not complications included guidelines did not affect overall risk assessed in this study because documented; all others such as of complications 11/309 (3.6%) inadequate NPO time was Chloral ASA physical status: 501 respiratory and hemo- versus 29/651 (4.5%), and did not identified a priori as a risk Hydrate patients ASA I, 353 patients dynamic instability decrease the risk of type 2 factor, which should have ASA II, 56 patients ASA III, complications 9/309 (2.9%) versus altered the sedation plan; Efficacy 14 patients ASA IV, and 2 18/651 (2.8%); complication risk alternatively, sedation of N/A patients ASA V; ASA was insignificantly different in infants and young children may status I or II in 89% of patients without documented NPO be more difficult when they are Safety III patients; age <2 y in 508 status 3/45 (6.7%) vs 37/915 (4.0%); hungry (53%) sedation failure was significantly higher in patients who met NPO Chloral hydrate question: no criteria 20/921 (2.2%) vs 2/443 individual analysis of chloral (0.5%); sedation failure was equal in hydrate cases to adjust for targeted conscious and targeted procedures, ages, or types of deep sedation; 2 aspiration events cases; no specification of occurred in patients who met NPO severity of adverse events; no criteria and were deeply sedated dosages, no ASA status; with opioid-barbiturate retrospective review of quality combinations, 1 for radiologic improvement records; no fixed procedure, the other for procedure bronchoscopy; both patients required postprocedure care with overnight oxygen administration; aspiration incidence was 3.1% of patients who were deeply sedated or 0.21% overall

Chloral hydrate question: complication rate 3.8% in chloral hydrate group; chloral hydrate more

  :  . , likely to develop inadvertent deep sedation (OR 11.6; P<0.001) or adverse event (OR 2.1; P<0.05) April  Volume   :  . ,

Evidentiary Table (continued).

April Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion

 Standard Maekawa et 1993 Prospective, 105 healthy children ages 1-14 y under- Gastric volume, serum No difference in Apple juice, not other clear I al44 randomized, going elective surgery broken into3 glucose, ketones, gastric fluid fluids nonblinded NPO time periods: 2, 4, and 12 hours; prior triglycerides, NEFA, volume or pH and the children were given set volume of apple and cortisol levels glucose level; juice; all ASA I physical status; gender fewer ketone was not documented; gastric aspirates taken bodies and NEFA through an orogastric tube from patients in 2 h NPO immediately after intubation; all patients patients were unpremedicated; all patients taking known gastric motility agents were excluded

Splinter and 1990 Prospective, 122 healthy children ages 2-12 y Gastric fluid volume No difference Does not evaluate NPO I Schaefer45 randomized, single undergoing elective operation were either and pH between the 2 less than 3 h; both solid blinded NPO from midnight or allowed clear groups’ gastric and liquid ingestion within liquids up to 3 h preoperatively; no fluid volume or pH current AAP/ASA difference in gender or ASA status (exact guidelines numbers not reported); stomach contents aspirated by gastric tube following intubation

Ingebo et al46 1997 Prospective Prospective observational study of 285 Gastric volume and pH No difference in Compared data to II observational pediatricpatients ages 1 to 18.6 y; gastric gastric volume or historical standards; does contents were collected by endoscopic pH was found with not specifically look at suction immediately after intravenous different NPO time from ingestion of sedation; duration of fasting after clear times milk and solids prior to Annals fluid ingestion ranged from .5 to 24 h, sedation; only 3 patients mean of 6.7+5.3 h; 49 patients fasted fasted less than 2 h; broad

of exactly 2 h, 3 patients fasted less than 2 h; patient ages; potential for patients were on a variety of unnamed increased gastric emptying mrec Medicine Emergency medications, some used to treat gastric effect from unnamed reflux; patients were instructed to not take patient medications any medications once milk and solids were discontinued lnclPolicy Clinical 399.e8 399.e9 Policy Clinical Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Soreide et 1996 Prospective, 8 healthy female adults (median age Presence of solids; It took 240 min for Adult women; only 8 subjects II al47 observational 37 y) ate a light meal and underwent nasogastric fluid all patients to be experiment gastric ultrasounds at timed intervals volume; serum solids free; antral to determine the presence of solids, paracetamol area returned to and then a nasogastric placement to concentration; gastric normal and check for fluid volume; a gastric antral area paracetamol level emptying study with paracetamol was peaked before all performed solids were gone Ghaffer et 2002 Retrospective Pediatric patients receiving Adequacy of sedation, Increase (NS) in Retrospective design; chloral III al48 observational echocardiograms were retrospectively minor and major inadequate sedation hydrate used as sedative; analyzed; 334 patients under the age complication rate in longer NPO echocardiograms are not of 3 y were divided into 2 groups and group; patients <6 painful, may be inadequate treated with chloral hydrate 80 mg/kg; mo with longer for ED procedures; no follow- group 1 (140 patients) had fasting fasting times had up on patients after treatment times <2 h (average 80 min), whereas decreased efficacy group 2 (184 patients) had fasting compared with times more than 2 h (average 225 shorter fasting times min); a subgroup of children <6 mo of (P=.03); no major age was analyzed; no gastric complications in emptying agents or anti-emetic either group; overall medications were documented 9% minor although 10% of patients were given complication rate; diphenhydramine (1 mg/kg) no difference in minor complications between the 2 groups   :  . , April  Volume   :  . ,

Evidentiary Table (continued).

April Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion

 Standard Keidan et 2004 Retrospective 200 infants ages 1 to 26 mo NPO time, dose Average fasting period was Limited to chloral hydrate; Fasting al49 cohort undergoing hearing tests with chloral required, need for significantly longer in fasted may not be generalizable to III hydrate (50-60 mg/kg with option for redosing, sedation patients than in nonfasted painful procedures, no additional 25 mg/kg if needed) time; efficacy patients (5.7 vs 2 h; standardized data collection Chloral sedation at one of 2 hospitals; one determined by P<0.001); fasted patients form; no follow-up attempts, hydrate hospital’s protocol adhered to fasting completion of study had significantly higher child could have vomited Efficacy guidelines and one hospital followed sedation failure rate with the after leaving hospital; sample III no fasting guidelines; patients were first dose of chloral hydrate size too small to detect Safety redosed as needed; ASA physical compared with nonfasted aspiration; chloral hydrate III status and gender were not identified; patients (21% vs 11%; was less effective in children no gastric emptying agents or anti- P=0.03), needed higher with longer NPO time who emetic medications documented doses (83 mg/kg vs 61 needed more redosing and mg/kg; P<0.01), were experienced more prolonged sedated for longer periods sedation (103 min vs 73 min; P<0.001), and were discharged later; no significant difference in adverse events

Litman et 1996 Nonrandomized Premedicated with oral midazolam 0.5 Levels of sedation Sedation proportional to Study in operating room; Efficacy 55 al trial; 20 mg/kg; given 15%, 30%, 45%, then (response to standard concentration of N2O; short time at each II patients, 11 60% N2O for 4 min each non-noxious stimuli); sedation scores significantly concentration may be too boys, 9 girls; changes in respiratory higher at 60% N2O than all short to see cumulative Safety fasted children rate, ETCO2, oxygen other N2O concentrations effects; no painful II

Annals ages 1-3 y; no saturation, upper (P<.02); at 60% N2O 1/3 stimulation; small number ASA listed; airway obstruction, patients eachnot sedated, elective respiratory impedance conscious sedation, or deep of outpatient plethysmography sedation; 1 unresponsive to mrec Medicine Emergency surgery intravenous insertion; no change in respiratory rate, ETCO2, or oxygen saturations with increasing concentration N2O; 1 had emesis; no hypoxemia lnclPolicy Clinical 399.e10 399.e11 Policy Clinical Annals

Evidentiary Table (continued). of Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class mrec eiieVolume Medicine Emergency Modality Measure/Criterion Comments Standard Litman et al561997Nonrandomized Oral midazolam 0.7 mg/kg Levels of sedation (response All oxygen saturations Study in operating Efficacy trial; 34 patients, then 40% N2O (mixed with to standard stimuli); >92%, no significant upper room; no painful II mean age 3.8 y, 19 <30% oxygen) for 15 min; changes in respiratory rate, airway obstruction; ETCO2 stimulation, small boys; healthy, excluded patients with ETCO2, oxygen saturation, ↑ to >45 in 4 patients after sample size; patients Safety fasted children, conditions that might upper airway obstruction, N2O begun with upper airway II restorative dental increase upper respiratory respiratory impedance (hypoventilation); overall, abnormalities excluded surgery under obstruction, eg, enlarged plethysmography no clinically significant general anesthesia; tonsils difference in oxygen age range 1-9 y saturations/ETCO2/VT, or VT/TI; sedation levels for midazolam alone (before N2O given) vs midazolam plus N2O were: unsedated 14 vs 12, conscious sedation 19 vs 17, deep sedation 1 vs 3, general anesthesia 0 vs 1 Litman et 1998 Nonrandomized Premedicated with 70 mg/kg Levels of sedation (response No oxygen saturation Study in operating Efficacy 57 a1 trial; 32 patients; oral chloral hydrate; 1 h to standard stimuli); <92%; ETCO2 >45 in 77% room; patient II mean age 3.9 y; later, began 30% then 50% changes in respiratory rate, on room air with chloral administered ≤30% age range 1-9 y; N2O using anesthesia circuit ETCO2, oxygen saturation, hydrate alone, 94% on oxygen with the N2O, Safety fasted; ASA I/II; that limited FiO2 to ≤30% upper airway obstruction, 30%+chloral hydrate ie, N2O not blended II 16 males, 16 respiratory impedance (P=0.007), 97% on 50%+ with oxygen; fasted females; outpatient plethysmography chloral hydrate (P=0.02); 4 children; small sample dental procedures had partial upper airway size obstruction with 30%; after chloral hydrate alone: 25% not sedated, 31% conscious sedation, 44% deep sedation; after 30% N2O, 6% not sedated, 94% conscious sedation; after

  :  . , 50% N2O, 3% not sedated, 94% conscious sedation, 3% general anesthesia (1 patient) April  Volume   :  . , April Evidentiary Table (continued).  Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Averley et 2004 Prospective, Intravenous midazolam to Primary outcome successful 40% N2O no better than air Dental procedures; Efficacy 64 al blinded, effect with air, 40% N2O, or completion of dental (P=0.07); successful randomization to air II randomized, 40% N2O plus sevoflurane procedure with child completion of dental stopped midtrial; may controlled trial; responsive to verbal procedure in 54% with air, have weakened Safety anxious patients, commands; Wong-Baker 80% with N2O, and 93% comparison of N2O to III ages 6-14 y, in scale by patient; standard with N2O plus sevoflurane; air dental clinic, behavioral and sedation N2O significantly sedated by scales by dentist; standard improved behavior during anesthesiologists; vital signs, ETCO2/N2O, IV starts; all were 697 healthy capnography, oxygen responsive; no significant children, ASA I/II, saturation adverse events; 6 vomited mean age 9.5 y; 44.6% male (311/697) 55.4% females (386/697) 65 Berge 1999Nonrandomized Maximum of 65% N2O Standard assessment tool One emesis: no major Dental study; Efficacy trial; anxious administered by oral for anxiety of patient; adverse events; ASA II and subjective outcome III children and adults surgeon for dental/oral primary outcome: very anxious patients more measure; about one- for elective oral surgical procedures; local procedure completed likely unsuccessful; N2O fourth patients were Safety surgical procedures anesthetic used without problems per oral effective adjunct to local adults II in dental suite; 241 surgeon; standard vital anesthesia; 8.2% minor sedations in 194 signs monitored, oxygen adverse effects, easily

Annals patients, 48% saturation treated males, 183 ASA I, 11 ASA II, mean of age 14.5 y (3-46 y), mrec Medicine Emergency 77% <19 y; median N2O concentration 50% lnclPolicy Clinical 399.e12 399.e13 Policy Clinical Annals

of Evidentiary Table (continued). mrec eiieVolume Medicine Emergency Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Houpt et al66 1996 Blinded, Oral diazepam 0.5 mg/kg Standardized sedation Groups similar for Dental study; Efficacy randomized, then either 50% N2O for 20 scale by chair-side sleepiness, movement, patients restrained II crossover trial in min followed by 100% observers and from crying; with 50% N2O, 71% healthy anxious oxygen or 100% oxygen for videotapes; successful of patients very good or Safety children; 24 20 min then 50% N2O sedation (“enabled ability excellent vs 31% with II patients, mean age to carry out procedure”); 100% oxygen; successful 32 mo, for dental vital signs, oxygen sedation (lack of crying or procedures; all saturation movement that interrupted patients restrained, treatment) in 83%; overall fasted >4 h; no ASA sedation with N2O better or gender listed 56% of time, same 31%, worse 13% 67 Houpt et al 2004 Nonrandomized 50% N2O for 5 min before Observations after 5 min With N2O, “90% relaxed Dental study; Efficacy trial; healthy dental procedures in healthy 50% N2O: behavior behavior,” 95% liked small significant III children requiring children (Frankel scale), effects, 70% felt good, 2% effect on dental restoration in psychomotor effects felt bad, 86% felt different; psychomotor ability, Safety dental clinic; 59 (Bender Visual Motor no difference by uncertain of clinical N/A patients, mean age Gestalt Test), and age/previous experience; no importance 7.7 y, (age range 4- perceptions of 50% N2O significant difference in 13 y); 36 males, 23 effects increased errors with females, no ASA psychomotor test between listed age groups McCann et 1996 Placebo-controlled, 50% N2O or 100% oxygen Standard behavior scales No significant physiologic Dental study; Efficacy al68 double blinded, in anxious children, sedated (OSUBRS); vital signs, or behavioral differences pretreatment with III randomized, with 40 mg/kg chloral oxygen saturation and between N2O and oxygen sedatives unable to controlled trial; hydrate and 2 mg/kg ETCO2 (when co-administered with analyze effect of N2O Safety crossover hydroxyzine chloral hydrate/hydroxy); alone; small number III comparison for trends of less increase in patients (N=20) dental procedures, heart rate during anesthesia 40 visits, mean age injection; greater increase in 45 mo (age ETCO2, lower behavioral range=36-60 mo); scores under N O;   :  . , 2 ASA, gender not significant variability in given responsiveness to N2O April  Volume   :  . , April Evidentiary Table (continued).

 Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Weinstein et 1986 Blinded, crossover Up to 40% N2O vs up to Behaviors videotaped and N2O increased patients’ Dental study; Efficacy 69 al design; 101 anxious 40% N2 in anxious children then scored with standard positive response to no data on safety I patients, mean 7.7 y; undergoing dental format; vital signs suggestion and effect of age range 3-12 y; procedures reassurance; greater effect in Safety ASA and gender not older patients; more N/A listed inappropriate movement in younger patients with N2O Wilson et al70 2002 Randomized, Oral midazolam 0.5 mg/kg Blood pressure, heart rate, No difference in vital signs; Dental study; only Efficacy controlled, crossover or 30% N2O oxygen saturation, sedation N2O with higher oxygen 30% N2O studied; II trial; 44 patients, and behavioral scores every saturations (P<0.001); less unclear who scorers mean age 12.5 y; 5 min; standardized time to maximum sedation were; appears to have Safety range 10-16 y; 16 anxiety levels and (P<0.001), faster recovery been unblinded study II male, 30 female (2 satisfaction scores (P<0.001); midazolam had dropouts from deeper sedation, greater study); ASA I; amnesia for painful events children NPO ≥2 h, (P<0.001); both reduced undergoing dental anxiety for second visit extractions Wilson et al71 2003 Randomized, cross- Intravenous midazolam Standardized behavior and Median time to maximum Dental study; only Efficacy over, controlled titrated to effect (mean dose sedation scales; vital signs; sedation 8 min for 30% N2O studied; II trial; 40 patients, 2.8 mg) or 30% N2O oxygen saturation midazolam, 6 min for N2O anxiety and mean 13.2 y; age (P<0.001); for recovery 52 behavioral range 12-16 y; ASA min for midazolam, 23 min assessments by Safety I/II; nothing by for N O (P<0.0001); similar unblinded scorer II Annals 2 mouth ≥2h, minimal changes in vital undergoing signs/oxygen saturations; of orthodontic dental depth of sedation and mrec Medicine Emergency extractions amnesia similar for both midazolam and N2O; 51% preferred midazolam, 38% N2O, 11% no preference lnclPolicy Clinical 399.e14 399.e15 Policy Clinical Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Luhmann et 2001 Partially blinded, Oral midazolam, 50% N2O OSBD-R from videotapes Less distress with N2O Small sample size for Efficacy 72 al prospective, or midazolam+N2O and VAS by observers for during lidocaine injection, serious adverse events I randomized, (control=no sedation) during distress; recovery time; cleaning, suturing; controlled trial; 204 ED facial laceration repair; vital signs, oxygen (P=0.0001, each interval); Safety patients, mean age fasted ≥2 h; local anesthetics saturation; adverse events midazolam+N2O not better I 4.1 y; age range 2-6 used defined than N2O alone; no major y; 66% boys; ASA I adverse events; minor (92%), ASA II (8%) adverse events (ataxia) more frequent with midazolam except vomiting (10% with N2O) 73 Burton et al 1998 Double-blinded, 50% N2O vs 100% oxygen CHEOPS at bedside, Study stopped when planned Small sample size; use Efficacy randomized, (continuous flow apparatus) anxiety scale, patient co- halfway review found of mask with oxygen I placebo-controlled during laceration repair in operation; vital signs, significant efficacy: N2O in controls may have trial in ED; 30 anxious children 2-7 y; NPO oxygen saturation reduced behavioral distress increased patient Safety patients enrolled, ≥2 h; local anesthetic used and anxiety (P<0.001, anxiety, thus II mean age 3.8 y, 17 each); 1 patient (6%) enhancing apparent got N2O; ASA and vomited, 2 (12%) were N2O benefit gender not listed deeply sedated, 4 (24%) had transient dizziness; no major adverse events 74 Gamis et al 1989 Prospective, double- 30% N2O vs oxygen placebo CHEOPS before and Patients >8 y had less Small sample size; Efficacy blinded, for children 2-16 y of age during repair; subjects distress during suturing (P< N2O 30%; use of mask II randomized, undergoing laceration monitored with vital signs, 0.05); patients <8 y had with oxygen in controlled trial in repair; local anesthesia used oxygen saturation trend toward less distress controls may have Safety ED; 34 patients, with N2O but did not reach increased patient II mean age around 7 significance; no emesis, anxiety, thus y; 15 received N2O hypoxia, oversedation, or enhancing apparent adverse events N2O benefit   :  . , April  Volume   :  . ,

April Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class  Modality Measure/Criterion Comments Standard 75 Keidan et al 2003 Nonrandomized 50% N2O during procedure, Pain 10-point VAS by 55 children (4 refusals); Small sample for Efficacy trial in consecutive administered by anesthetist anesthetist, ED physician, ages 0.5-15 y completed safety regarding major II nonfasted children RN, and parent during procedures (intravenous, adverse events in ED undergoing procedure; major and lumbar puncture, laceration Safety painful procedures minor adverse events repairs, fracture reduction, II recorded; vital signs and burn management, joint oxygen saturation aspiration), some augmented by local anesthesia; procedure time mean 7 min; pain scores mean 1.4/10 for <3 y; 0.2/10 for >3 y; vomiting 9%; euphoria 7%; prolonged recovery in 1; no significant adverse events Bar-Meir et 2006 Nonrandomized, 50% N2O vs nothing during Efficacy measured by 60 children, mean age 3-4 y; Nonblinded trial; small Efficacy al76 nonblinded suturing of facial lacerations FLACC scale and need for 2/3 boys; FLACC (distress) sample size for safety III alternating trial in by plastic surgeon in ED; restraint; safety measured scores less with addition of regarding major nonfasted children N2O initially administered by heart rate, oxygen N2O during infiltration and adverse events Safety in the ED by surgeon, then by RN or saturation changes, major suturing (P<0.01); no major II parent; patient monitored by and minor adverse effects adverse effects, 11% had RN vomiting Luhmann et 2006 Partially blinded 50% N2O+lidocaine Procedural Behavior Less distress for Respiratory distress Efficacy 77 al randomized hematoma block or Checklist (from N2O/hematoma block not measured by I controlled trial; 102 intravenous ketamine 1 videotapes); time of (P=0.02) but change very ETCO2; use of local Annals patients, mean age 9 mg/kg, glycopyrrolate 5 recovery; VAS for small for both groups; anesthetic y; 60% boys; ASA ug/kg+midazolam 0.1 observed pain/ recovery time much less for Safety I or II; age range 5- mg/kg, maximum 2 mg for distress/satisfaction; vital N O/hematoma block I of 2 17 y reduction of forearm signs, oxygen saturation; (P<0.0001); minor adverse mrec Medicine Emergency fractures in ED; both groups adverse events in ED and 1 effects more frequent for received oral oxycodone; day afterward ketamine/midazolam in ED fasted ≥2 h (P=0.0003) and at 24 h (P=0.04); all easily managed lnclPolicy Clinical 399.e16 399.e17 Policy Clinical Annals

of Evidentiary Table (continued). mrec eiieVolume Medicine Emergency Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard 78 Evans et al 1995 Prospective 50% N2O (fixed dose) CHEOPS during reduction No difference in CHEOPS Orthopedic clinic Efficacy randomized (N=15) vs intramuscular (at bedside); patient (~9.5/13) during reduction patients; small sample II controlled trial meperidine 2 mg/kg/ memory/satisfaction scores or memory/satisfaction size; mixed fracture in children 4-16 y promethazine 1 mg/kg (done at first follow-up); scores at 30 min post- types; no oxygen Safety with fractures in (N=15) for fracture monitoring vital signs, reduction; recovery time 30 saturations III orthopedic clinic; reduction observation, no oximetry min (N2O) versus 83 min 30 patients, 4-15 y; (meperidine/ average age 10 y; promethazine) (P< 0.01); 19 boys; ASA not no nausea, vomiting, or listed hypoxia

Gregory and 1996 Nonrandomized 50% N2O vs intravenous Completion of reduction; Mean Wong-Baker Faces Small sample size Efficacy 79 Sullivan (alternating), regional anesthesia (Bier postreduction subjects score 3.5/6 for N2O, 3.6/6 (N=14) in each group, II prospective trial for block); no additional pain or completed Wong-Baker for Bier block; similar total 28 patients forearm fracture sedative medications within Faces Scale for pain, results for VAS; Safety reduction in 4 h summing all aspects of successful reduction in II children ≥4 y; 28 treatment of fracture; 27/28 fractures; 1 technical patients; in N2O patients >8 y and providers failure with Bier block; no group mean age 7.9 also completed pain VAS; nausea, vomiting, y; Bier block mean vital signs, oxygen desaturation, or adverse age 9.3 y; 16 boys, saturation event; 41 min total time for 12 girls; ASA not N2O vs 61 min for Bier listed; ED setting block (P<0.0003)

Hennrikus et 1994 Nonrandomized Fixed 50% N2O; no CHEOPS by observing 5 patients failed analgesia Efficacy al80 trial; unfasted additional pain or sedative physician; pain recalled by (no effect); average II children >4 y for medications subject (4-point scale); CHEOPS 9/13 (moderate reduction of closed vital signs, oxygen pain), 46% ≥10 (significant fractures in ED; 54 saturation pain); recalled pain: 42% Safety patients; 36 boys,18 moderate-to-severe; no II girls; no ASA listed; vomiting, desaturation; 2

  :  . , average age 8.8 y; unsuccessful reductions fractures because of residual malalignment April  Volume   :  . ,

Evidentiary Table (continued). April Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments  Standard Hennrikus et 1995 Prospective, Fixed 50% N2O and CHEOPS by observing 3 children with no effect; Nonblinded Efficacy al81 nonrandomized lidocaine fracture hematoma physician; pain recalled by 52% CHEOPS ≤6 (no pain); II trial; block; no additional pain or subject on 10-point Faces 13% CHEOPS ≥10 (severe 100 patients, sedative medications scale; vital signs, oxygen pain); 81% amnestic for Safety average age 9 y, saturation hematoma block and II mostly forearm reduction; no vomiting, no fractures; unfasted adverse event; 3 children >4 y for unsuccessful reductions due reduction of closed to residual malalignment; fractures in ED; age higher proportion failures range 4-17 y; 68 with displaced radius/ulna boys, 32 girls; no fracture ASA listed

Wattenmaker 1990 Prospective cohort, Fixed 50% N2O for fracture Informal analgesia Fractures: 18 angulated or Small sample size, Efficacy et al82 nonrandomized reduction in ED; fractures effectiveness scale (severe, displaced forearm, 2 informal observer pain III trial, chosen expected to require moderate, minimal, no displaced proximal scale unpremedicated single reduction attempt pain); vital signs phalangeal, 1 angulated Safety children >4 y; 22 tibia/fibula; 1 displaced III patients, average humerus; 20/22 fractures age 10 y; range 4-15 reduced; 52% minimal, 38% y; ASA and gender moderate, 10% no pain; not listed 60% recalled no pain; no complications with N2O Burnweit et 2004 Nonrandomized 50% N2O administered by Wong-Baker Faces Scale 150 children ages 1-20 y, Selection criteria for Efficacy Annals al83 trial in selected specially trained RN; by patient to measure pain mean age 9.8 y; 57% girls; patients not stated; II healthy children 1- EMLA then buffered before, during, and after 40 had excision of small sample for safety 20 y of age, lidocaine 1% with procedure; vital signs and nevi/cysts, 34% had abscess regarding major Safety of undergoing minor epinephrine local anesthetic; oxygen saturation incision and drainage; mean adverse events II mrec Medicine Emergency painful procedures parent at bedside monitored throughout Wong-Baker scores <0.5/6 by pediatric surgeon during procedure; 2 in outpatient “minor vomited, 2 others nauseated operating room” (3% total); no major adverse events lnclPolicy Clinical 399.e18 399.e19 Policy Clinical Annals Evidentiary Table (continued).

of Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class

mrec eiieVolume Medicine Emergency Modality Measure/Criterion Comments Standard Ekbom et 2005 Randomized EMLA + N2O titrated to Pain VAS by patient 5 min N2O + EMLA resulted in Fasted, planned Efficacy al84 controlled trial in 50 50% for intravenous after cannulation, parent fewer attempts, less pain, procedures; weak II children, mean age placement and patient global same overall time, and indirect measure of 13 y, and crossover evaluation on 5-point greater satisfaction (all distress Safety trial in 20 anxious linear scale, RN overall P<0.001) compared to II children, mean age assessment of distress on EMLA alone; 90% of 11 y; all ASA I, 3-point scale, time and patients who experienced ages 6-18 y; nothing number of attempts for both treatments preferred by mouth >4 h, cannulation, changes in N2O+EMLA over EMLA undergoing venous heart rate and oxygen alone; no significant adverse cannulation in saturations, other adverse events, 1 patient with brief outpatient clinic effects tinnitus Henderson 1990 Blinded, placebo- 50% N2O, 70% N2O, 100% CHEOPS pain score No pain behavior in 56% Fasted patients in the Efficacy 85 et al controlled, oxygen, or air for analgesia during intravenous with 50% N2O (P<0.05); no operating room; small II randomized, during venous cannulation attempt by blinded pain behavior in 77% with sample size; 1 group controlled trial in before elective surgery; no observer; vital signs, 70% N2O (P<0.05) vs 16% (air) had no mask, Safety children 3 wk to 18 preanesthetic medications oxygen saturation with oxygen, 15% with air; other 3 groups had II y of age; 165 ASA I given adverse events (excitement, mask patients; gender not dysphoria, nausea, listed restlessness, opisthotonic movements in 1 child) in 28% with 70% N2O; no adverse events in other groups (P<0.05) Kanagasund- 2001 Nonrandomized 50-70% N2O; imagery, OSBD-R multiple phases: N2O maintained low levels Oncology clinic Efficacy aram et al86 trial, oncology distraction, etc, taught defined adverse events; of distress during patients II clinic patients; 90 preprocedure; parents depth of sedation analyzed procedures; younger children patients, mean age 7 present; no premedications by ages: 1-5, 5-10, >11 y; had greater distress Safety y; fasted children; vital signs, oxygen (P=0.001); deepest II painful procedures: saturation level of sedation=awake intravenous start, (able to communicate) in bone marrow 93%; vomiting in 8%, aspiration, lumbar desaturation <95% in 9%   :  . , puncture, or dressing change; no gender or ASA listed April  Volume   :  . ,

Evidentiary Table (continued). April Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class

 Modality Measure/Criterion Comments Standard Annequin et al87 2000 Prospective cohort; Standard questionnaire Self-assessment of Overall median pain VAS No oxygen Efficacy multicenter; 31 centers; after each N2O pain (VAS) by patients 9/100 by patients, 1/10 by saturation, no III N2O provided outside administration for 2 mo; >6 y and by nurses for RNs and parents; staff categorization of operating room fixed 50% N2O during all ages, occurrence of satisfaction 88%; minor adverse effects; no Safety (outpatient clinics, lumbar puncture/bone standard behavioral adverse effects in 37% standard protocol for II hemato-oncology, ED); marrow aspirations in reactions, satisfaction (euphoria 20%, N2O administration, ages ≤18 y; 1,019 hemato-oncology clinic by providers, nausea/vomiting 4%, deep use of adjunct sedations; ages ≤18 y, patients, lacerations in monitored vital signs, sedation 2%); no serious medications or median 6.4 y; 51% ED patients; local direct observation adverse effects patient monitoring lumbar puncture/bone anesthetics typically marrow aspirations in used hemato-oncology patients; 21% lacerations in ED; gender and ASA not listed Keidan et al882005Randomized, Oral midazolam (N=24) or Sedation AVPU scale, Efficacy of sedation, Elective radiologic Efficacy controlled trial; 47 continuous flow 50% N2O FLACC score (non- anxiolysis, amnesia procedure: voiding II patients, mean age 6 y; (N=23) during elective blinded), OSBD, VAS, comparable; N2O patients cystourethrography; ages 3-15 y; 89% girls; voiding defined adverse required less restraint fasted children; small Safety 85% ASA I; setting: cystourethrography; fasted events; vital signs, P(=0.01); recovery for sample size II radiology unit children oxygen saturation N2O significantly faster (P<0.001); adverse effects minimal 89

Annals Sundin et al 1981 Nonrandomized trial in N2O titrated to effect to Blood pressure, heart Concentration of N2O to Adult volunteers, Efficacy 20 healthy non- study anxiolytic effects of rate, ECG, salivary and achieve anxiolytic effect relatively low anxiety III pregnant volunteers of N2O blood cortisol, ranged from 25%-65%, at baseline; of both sexes 18-60 y of standardized sensation averaging 35%-40%; no nasal administration Safety mrec Medicine Emergency age; ASA not listed to pain (sandpaper), analgesic effect found at with room air III degree of sedation, anxiolytic level; report of entrained; small psychologic screening anxiolysis correlated with sample size inventory salivary cortisol, diastolic blood pressure lnclPolicy Clinical 399.e20 399.e21 Policy Clinical

Annals Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class of Modality Measure/Criterion Comments mrec eiieVolume Medicine Emergency Standard 90 Frampton et al 2003 Nonrandomized trial in 50-70% N2O administered State of consciousness, 224 children (113 <5 y) Patients with upper Efficacy consecutive healthy by specially trained RN respirations, airway completed (1 failure due respiratory infection, N/A children in ED, >12 patency, and oxygen to vomiting); procedures respiratory symptoms, mo of age, fasted >2 h, saturation monitored; included laceration asthma, or received Safety undergoing painful pain or distress not repair/wound intravenous opioids or II procedure measured; major and management, intravenous sedatives were minor adverse events placement, lumbar excluded for sedation; defined and recorded puncture, fracture small sample for safety reduction, burn regarding major management; mean N2O adverse events administration time 14 min; one 18-mo old with recent bronchiolitis had brief tachypnea without decrease in oxygen saturation, 8% had vomiting, 1% had dysphoria 91 Cleaton-Jones 1976 Prospective cohort After 5 min of 50% N2O Dye on chest No physiologic changes; Small sample size; Efficacy (healthy, nonfasted while supine on a radiograph at 1 and 5 no dye seen in larynx, subjects not having N/A dental students); 14 radiograph table, 10 mL of min after swallowing trachea, or lungs; dye dental procedure; brief students, ages 22-29 y, radiopaque dye was placed dye; vital signs seen in lower esophagus N2O Safety mean 23.6 y: ASA and on the posterior tongue and of all III gender not listed swallowed 92 Dollfus et al 1995 Prospective cohort; 50% N2O (fixed dose, self Efficacy: pain 10-point 8 patients refused mask; Hematology/ Efficacy cancer patients in administration) for lumbar VAS by patient if >5 y for 29 pairs of self- oncology clinic III oncology clinic, many puncture/bone marrow and by observer using evaluation: lumbar patients; comparison to had several N2O aspiration; patients fasted 4-point scale; operator puncture pain 7.96 procedure without N2O Safety sedations at different ≥4 h, no premedication; satisfaction scale; without vs 1.49 with dependent on memory III times; 87 patients, 200 EMLA, then lidocaine compared to memory N2O, bone marrow of previous procedure procedures; average injected at site of previous pain for aspiration pain 7.44 age 8.5 y (9 mo-18 y); lumbar puncture/bone without vs 1.86 with N2O ASA class and gender marrow aspiration (P<0.0001); operator not listed without N2O (VAS satisfaction 97%; minor   :  . , estimates) to those adverse effects in 27%, with N2O transient (euphoria/dysphoria 21, vomiting 3); no major

April adverse events  Volume   :  . , April Evidentiary Table (continued).

 Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Dunn-Russell et 1993 Prospective crossover Compared initial 5 min of Oxygen saturation at Mean time of 40% N2O Dental study: no pre- Efficacy al93 trial in children recovery with 100% oxygen 15-second intervals exposure was 28-29 min; or concurrent N/A requiring 2 dental versus room air after 40% for 5 min after oxygen saturations additional procedures; 24 ASA I N2O sedation; fasted ≥2 h stopping of N2O fluctuated <1% for both medications, only Safety patients ages 3.4-9.4 groups; statistically but not 40% N2O studied II y, mean 5.6 y; gender clinically significant not listed

Gerhardt et 2001 Double-blinded, 50% N2O vs 100% oxygen Change in subject 11 subjects, 1 withdrew Only adults studied, Efficacy al94 placebo-controlled, for reduction of pain and VAS (100 mm) for because of dizziness with small sample size III randomized, controlled anxiety during venous pain and anxiety N2O; mean pain less with (N=10) trial; crossover design; cannulation (18 gauge) in between baseline and N2O (VAS 10 for N2O, 31 Safety healthy adult healthy adult volunteers IV cannulation; for control) (P=0.01), and N/A volunteers 18-50 y, measured after each anxiety (0.5 for N2O, 15 ASA gender not listed; cannulation for control) less with N2O ED military teaching (P=0.02) hospital Roberts and 1982Nonrandomized, Children undergoing dental Chest radiograph No respiratory problems in Dental procedures; Efficacy 95 Wignall prospective procedures, nonsedated vs findings of intra- days or weeks no standard N2O N/A comparison; 50 sedated with N2O titrated to pulmonary dye; posttreatment; neither concentration children, mean ages 13 effect (for anxious patients): respiratory symptoms group aspirated dye Safety

Annals y 2 mo sedated, 12 y 9 N2O concentration varied posttreatment II mo controls, age range 20%-65% (23 patients got 4-18 y; ASA and <50%); radiopaque dye of gender not listed placed on posterior tongue mrec Medicine Emergency after sedation before drilling, halfway through procedure, and at end before recovery lnclPolicy Clinical 399.e22 399.e23 Policy Clinical Annals

of Evidentiary Table (continued). mrec eiieVolume Medicine Emergency Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard 96 Rubin et al 1977Prospective, crossover During 50% N2O sedation Chest radiograph to In 2 of 10 (20%), dye seen Dental study Efficacy trial; 10 healthy, for more than 10 min water look for aspirated dye in lungs on chest simulated; N/A fasted, nonpregnant sprayed to simulate dental read by radiologist radiograph after N2O; no very small sample female adult procedure, then 15 mL of blinded to study dye seen after procedure size; 20% with Safety volunteers, ages 18-21 radiopaque dye dripped over purpose; pulse without N2O; not aspiration may be II y 2 min onto back of tongue; monitored statistically significant clinically significant process repeated 1 week (0.4

  :  . , laryngospasm, seizures reported but thought not due to N2O April  Volume   :  . , April 

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Gall et al992001Prospective cohort, 18-mo review of Major adverse events 7,511 patients (2,095 in Unclear how patients Efficacy multicenter (46 standardized records of 50% defined: airway ED for laceration repair, monitored, eg, N/A institutions), most in N2O in children obstruction, fracture reduction, oxygen saturations, EDs and oncology desaturation, apnea, abscess incision and vital signs Safety clinics; age ≤18 y, cardiovascular drainage); 75 (1%) failed II gender and ASA not changes, loss of sedation; major adverse listed verbal contact events 0.33%, all brief, no airway interventions; increased major adverse event if patient age <1 y (P=.001) or if opioid+benzodiazepine also given (P=.04) Annals of mrec Medicine Emergency lnclPolicy Clinical 399.e24 399.e25 Policy Clinical Annals

of Evidentiary Table (continued).

mrec eiieVolume Medicine Emergency Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Rowland et 1992 Retrospective cohort Questionnaire of full-time Relationship between Each h of exposure to Actual exposure to Efficacy 101 al female dental assistants who exposure to N2O and unscavenged N2O per N2O not measured; N/A had been pregnant within fertility (number of week corresponded to 6% recall bias past 4 y not due to birth menstrual cycles reduction in conception Safety (for control failure; 418 (91% without contraception with each menstrual health care response rate); ages 18-39 y, needed to become cycle; no relation to providers) randomly chosen from pregnant) scavenged N2O; 60% III California Registry reduction in fertility with ≥5 h per week exposure to unscavenged N2O; 50% of pregnancies spontaneously aborted with unscavenged ≥5 h per week vs 8% with scavenged N2O Rowland et 1995 Retrospective cohort Questionnaire of full-time Relationship between 101 pregnancies (7%) Actual exposure to Efficacy 102 al female California dental exposure to N2O and ended in spontaneous N2O not measured; N/A assistants who had been spontaneous abortion: higher risk of recall bias pregnant within past 4 y not abortions; person- spontaneous abortion if Safety (for due to birth control failure; week model working with health care current pregnancies through unscavenged N2O≥3 h providers) week 20 included 4,856 per week; relative risk III (69%) responded 2.6; no increase with scavenged N2O Ahlborg et 1996 Retrospective survey in Queried working conditions Per-cycle probability 3,358 responses (84%); Recall bias; survey Efficacy al103 1989 of all Swedish within past 5 y, including of becoming pregnant midwives working nights response dependent; N/A midwives born in 1940 exposure to N2O, and calculated; ratio of or 2 or 3 shift rotations only successful or later number of menstrual cycles exposed to had decreased fertility pregnancies queried; during most recent unexposed to N2O compared to day-shift- inability to conceive Safety (for successful attempt to compared only workers; no effect of not included health care become pregnant N2O except in those providers) assisting at >30 deliveries III   :  . , per month when N2O was used; no correlation with use of scavenging April  Volume   :  . , April

 Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Axelsson et 1996 Retrospective; survey in Queried working conditions, Association between 3,358 responses (84%); Recall bias, survey Efficacy 104 al 1989 of all Swedish including exposure to N2O work conditions, no association found response dependent; N/A midwives born in 1940 during deliveries; midwives’ including exposure to between N2O use and many could not recall or later spontaneous abortions for N2O, and midwives’ spontaneous if scavenger device Safety (for pregnancies between 1980- spontaneous abortions (OR 0.95), used health care 1988; current and ectopic abortions; exposure including use during first providers) pregnancies and women to N2O classified as trimester III with ≥5 spontaneous none, used in ≤50% abortions excluded of deliveries, or used in >50% of deliveries 105 Brodsky et al 1981 Questionnaire of N2O 15,000 each, N2O user and Answers grouped >18,000 responses (>70% Recall bias; Efficacy user and nonuser nonuser dentists and their into (1) nerve specific each group); for dentists responder bias (more N/A dentists and their assistants, randomly symptom (eg, and assistants, vs no or symptoms reported if assistants randomly selected; asked about h per sciatica), (2) light exposure, “heavy responder concerned Safety (for selected from national week use of N2O during past nonspecific nerve exposure” associated with N2O causes problems health care registry 10 y and any symptoms of symptom (eg, group 2 symptoms and responder has provider) adverse effects; answers numbness, (nonspecific neurologic regular N2O III blindly reviewed; exposure paresthesia, symptoms) (P<0.01), and exposure) to N2O during 10 y defined: weakness), (3) group 3 symptoms <3,000 h=light, >3,000 symptoms secondary (specific neurologic h=heavy (3,000 h=6 h per to specific diseases diagnosis) (P=0.05); week for decade); rates (eg, multiple for assistants, group 1

Annals adjusted for mercury sclerosis, pernicious symptoms also associated exposure anemia), (4) (P=0.04) miscellaneous (eg, of migraine headache, mrec Medicine Emergency stroke), and (5) no neurologic complaints lnclPolicy Clinical 399.e26 399.e27 Policy Clinical Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Stevens et al107 2004 Meta-analysis Evaluated 21 randomized Numerous outcome Pooled PIPP scores across 3 Well-executed meta- I controlled trials (1,616 measures were randomized controlled trials were analysis; excluded patients) to determine the evaluated, and where reduced in neonates given sucrose several studies for efficacy, effect of dose, and possible, WMD with at 30 seconds after heel lance relatively minor flaws safety of oral sucrose in 95% CI were (WMD -1.64, 95% CI -2.47 to - in accordance to their neonates calculated for 0.81) and at 60 seconds after heel methodology, continuous outcome lance (WMD -2.05, 95% CI -3.08 however, these studies measures to -1.02); pooled results for change would not have in heart rate across 2 randomized contradicted their controlled trials found no conclusions difference at 1 min or 3 min post– heel lance Rogers et al108 2006 Randomized Compared 2 cc of 24% Primary outcome Although there was a trend toward This is the only trial II controlled trial sucrose or water 2 min measures were: reduced signs of distress with that takes place in the before bladder change in the sucrose, there was no significant ED, and the only one catheterization in infants composite DAN difference between the 2 groups for that uses bladder born >34 wk (n=80, 51 score from baseline change in DAN score, percentage catheterization as the males, 29 females, PNA to point of maximal of patients crying, and time to painful stimulus; the range 3-90 days); ED study catheter insertion, return to baseline behavior; post study was downgraded percentage of patients hoc subgroup analysis found a because although there crying during significant reduction in all outcome is some evidence that procedure, and time measures in the 1-to 30-day age sucrose is less to return to baseline group (DAN score 2.9 vs 5.3, effective in older age behavior P=0.035; percentage crying 29% vs groups, the study was 79%, P=0.008; return to baseline not designed and 10 vs 37 seconds, P=0.04) powered for age- specific subgroup analysis; no adverse events were noted   :  . , April  Volume   :  . , Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments

April Standard Stevens et 1999 Randomized Compared pacifier with 0.1 Primary outcome Mean PIPP scores were: control 9.8, Lack of III

 al114 controlled trial cc of 24% sucrose, pacifier measure was PIPP prone 10.3, pacifier with water 8.4, generalizability to the (crossover with water, or prone scores pacifier with sucrose 7.9 (P<0.0001); ED because of very- design) positioning vs control during post hoc analysis revealed a significant low-birth-weight, heel stick in very-low-birth- difference between the pacifier with preterm infants; also weight, preterm neonates sucrose and control (P<0.0001) multiple treatment (n=122, 70 males, 52 females, groups, not all relevant gestational age 28-29 wk, to this critical PNA 3-13 days); NICU study question; no group received oral sucrose alone; no adverse events observed Johnston et 1999 Randomized Compared a single dose of Outcome measure The group with repeated doses had Limited III al115 controlled trial 0.05 cc of 24% sucrose vs was pain as measured significantly lower postprocedural PIPP generalizability to ED repeated doses of 0.05 cc of on the PIPP scores compared with placebo (P<0.05); as study population 24% sucrose delivered before, composite scale the group with a single dose had lower was preterm infants during, and after the PIPP scores than placebo, but the receiving ongoing care procedure, vs water in differences did not achieve statistical in the NICU preterm neonates in the NICU significance (P=0.07) undergoing heel stick (n=48, gestational age 30-31 wk, PNA 6-7 days); NICU study Gibbins et 2002 Randomized Compared 0.5 cc of 24% Primary outcome Mean PIPP scores differed among the Limited external II al116 controlled trial sucrose plus non-nutritive measure was sucrose and non-nutritive sucking group validity; findings in sucking, water plus non- efficacy, as measured (8.16 at 30 seconds, 8.78 at 60 seconds), this study population nutritive sucking, or sucrose by the PIPP pain the sucrose alone group (9.77 at 30 (premature infants alone in preterm and term score that includes seconds, 11.20 at 60 seconds), and the receiving care in

Annals neonates after heel stick; physiologic, non-nutritive sucking with water group NICU) may not SNAP-PE severity of illness behavioral, and (10.19 at 30 seconds, 11.20 at 60 generalize to neonates score ranged from 4.00 to contextual measures, seconds), P<0.001; post hoc analysis in the ED; did not have of 4.68 (n=190, 94 males, 96 and takes into found that the sucrose plus non-nutritive “no treatment” control mrec Medicine Emergency females, mean gestational age account gestational sucking group had lower scores than the group because of 33-34 wks, mean PNA age; the study also other treatment groups; sucrose alone ethical considerations; approximately 3 days); NICU assessed safety, and non-nutritive sucking with water the study was not study evaluating the were not significantly different from powered to detect the incidence of adverse each other; adverse events (5 episodes of influence of

events desaturation and 1 of choking) were too gestational age on the Policy Clinical rare to perform statistical comparisons efficacy of sucrose among the groups 399.e28 399.e29 Policy Clinical Annals

Evidentiary Table (continued). of Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class mrec eiieVolume Medicine Emergency Modality Measure/Criterion Comments Standard Isik et al117 2000 Randomized Compared 2 cc of 30% Outcome measures: Mean crying time: 61 seconds in the No primary outcome II controlled trial sucrose, 30% glucose, 10% crying time during 3- 30% sucrose group, 103 seconds in the measure clearly glucose or water 2 min before min period after heel 10% glucose group, 95 seconds in the defined; also multiple heel stick in healthy, full-term lance, maximum 30% glucose group, and 105 seconds in comparisons were neonates (n=113, 56 males, heart rate, percentage the control group (P=0.02 overall, made at various time 57 females, median change in heart rate P=0.002 for sucrose versus water); there points without using gestational age 40 wk, from baseline at min was a lower percentage change in heart repeated measures median PNA 2 days); 1, 2, and 3, and heart rate in the sucrose group at 2 min analysis; did not report university hospital setting rate recovery time postprocedure (P=0.05); differences in adverse events maximum heart rate and heart rate recovery time did not differ among groups Haouari et 1995 Randomized Compared 2 cc of 12.5%, Primary outcome There was a significant reduction in With only 15 infants II al118 controlled trial 25%, and 50% sucrose measure was duration crying time (from 135 seconds to 45 per treatment group, solution vs control in full- of crying during the seconds) and duration of first cry (from the study may have term, healthy newborns first 3 min after heel 95 seconds to 20 seconds) in the 50% been underpowered to undergoing heel stick (n=60, stick; additional sucrose group compared with controls determine the 29 males, 31 females, median outcome measures (both P=0.02); no differences in change minimum effective gestational age 38-39 wk, included duration of in Sp02 or facial expression among the sucrose dose; did not median PNA 3-4 days); first cry, percentage groups report adverse events postnatal ward setting change in heart rate and SpO2 after heel stick, and change in facial expression on 5-point scale Abad et 2001 Randomized Compared the effect of water, Primary outcome Sucrose reduced crying time relative to A subset of infants II al119 controlled trial EMLA cream, 2 cc of 24% measure was placebo (P=0.001); EMLA plus sucrose (n=4) was enrolled oral sucrose, or both EMLA reduction in audible also reduced crying time relative to twice and was quasi- and sucrose in reducing the crying time water (P=0.008); overall, there was a randomized to a pain of venipuncture in postprocedure; significant change in heart rate different treatment stable, full-term neonates secondary outcome (increase), respiratory rate (increase), group for the second (n=51, 38 males, 13 females, measure was change and SaO2 (decrease) to venipuncture, but venipuncture

  :  . , mean gestational age 38.6- in vital signs (heart only heart rate actually differed among 40.0 wk, mean PNA 1.8-2.0 rate, respiratory rate, treatment groups; it was significantly days); neonatal unit setting and SaO2) lower in the sucrose group (P=0.03) and EMLA plus sucrose group (P=0.04) April  Volume   :  . , April 

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Gormally et 2001 Randomized Compared the effect of 0.75 Outcome measures: There was a significant reduction in mean Multiple main II al120 controlled cc of 24% sucrose alone, percentage of time percentage of time crying in the sucrose outcome measures; trial holding alone, sucrose plus crying during min 1, group compared with water (P<0.05); the also, initially NFCS holding, vs control in 2, and 3 of the effect of holding on crying was not was one of the planned reducing pain during heel procedure, the Pain significant; in contrast, holding caused a outcome measures but stick in healthy, full-term Concatenation Score, significant reduction in the Pain because of difficulties newborns (n=85, 38 males, heart rate, and vagal Concatenation Score (P<0.02), but sucrose seeing and grading 47 females, mean tone did not; heart rate and vagal tone did not facial expressions, it gestational age 39.5 wk, differ significantly among groups was changed to the mean PNA 53-63 h); Pain Concatenation community hospital setting Score; heel stick was performed by 1 of 8 nurses; mean duration of procedure was similar across groups, but the number of heel squeezes required to obtain blood was higher in the sucrose- alone group, which

Annals subsequent ANCOVA analysis identified as a possible confounder; of did not report adverse mrec Medicine Emergency events lnclPolicy Clinical 399.e30 399.e31 Policy Clinical Annals

Evidentiary Table (continued). of Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class mrec eiieVolume Medicine Emergency Modality Measure/Criterion Comments Standard Greenberg121 2002 Randomized Compared pacifier plus Outcome measures: Duration of cry differed significantly No primary outcome II controlled water, pacifier plus table duration of cry, among groups (P=0.001); the P value of the measure identified; not trial sugar (sucrose), 2 cc of vagal tone index difference between the 12% sucrose group all P values reported; 12% sucrose by syringe, or as calculated from (85 seconds) and control (133 seconds) was 12% sucrose might control during heel stick in heart rate variability, not reported; post hoc analysis found that have been suboptimal healthy, full-term neonates and salivary cortisol infants in the pacifier plus table sugar concentration for (n=84, 38 males, 46 group had shorter duration of cry (46 comparison; clinically females, gestational age seconds) than the pacifier plus water group relevant and practical >37 wk, mean PNA 18 h); (126 seconds, P=0.006), and the control research question as moderate-sized hospital group (P=0.001); vagal tone index differed table sugar easily study significantly among groups (P=0.005); post stored and readily hoc analysis group found that the pacifier available; did not plus table sugar group had a significantly report adverse events lower index than control during the procedure and certain postprocedural time periods; no differences in salivary cortisol levels among groups Ors et al1221999Randomized Compared 2 cc of 25% Outcome measures: Median crying time in the sucrose group Non-ED population; II controlled sucrose, human milk, or crying time, was shorter than in the milk or water group no primary outcome trial water prior to heel stick in percentage change (36 seconds vs 62 seconds vs 52 seconds, measure was identified healthy, full-term neonates in heart rate, and P=0.0009); median heart rate recovery time (n=102, 49 males, 53 time to “recovery” in the sucrose group was shorter than in the females, median of normal heart rate milk or water group (72 seconds vs 112 gestational age 39-40 wk, seconds vs 124 seconds, P=0.004); median PNA 1.6 days); percentage change in heart rate was university hospital study significantly lower in the sucrose groups at 1 min, 2 min, and 3 min (P=0.008, P=0.01, P=0.002) Allen et al123 1996 Randomized Compared effect of 2 cc of Outcome measure: Among 2-wk-olds, both the sucrose group Number of patients in II controlled 12% sucrose vs water or reduction in and the water group cried less than the no- the treatment vs trial no intervention prior to “audible distress intervention group after intramuscular control groups was not intramuscular vaccinations vocalization” per injection (P<0.01, P<0.01 for pairwise specified; one of the in healthy, full-term 2-wk 15 second interval comparison, respectively); neither the water few articles to assess   :  . , to 18-mo-old infants after the nor sucrose group cried less than the no sucrose in older infants (n=285); ambulatory immunization intervention group in the 2-, 6-, 9-, 15-, or pediatric clinic setting procedure 18-mo-old groups April  Volume   :  . ,

Evidentiary Table (continued). April Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments  Standard Ogawa et al124 2005 Randomized Compared heel stick or Outcome measure: Oral sucrose significantly reduced NCFS Primary study question II controlled venipuncture with or pain at specified scores during blood sampling by heel was whether trial, 2x2 without 1 cc of 50% points throughout and stick (58 seconds vs 47 seconds, venipuncture or heel design sucrose in healthy full- after the procedures P<0.01), and while the bleeding was stick was more painful term neonates (n=100, 52 as measured using the being stopped (52 seconds vs 32 for neonates; no males, 48 females, mean NCFS scale and cry seconds, P<0.01); sucrose did not adverse effects were gestational age 39-40 wk, duration significantly affect NCSF scores during observed in any of the PNA approximately 5 blood sampling by venipuncture; oral infants days); NICU study sucrose reduced neither the duration nor incidence of crying in the heel stick or venipuncture group Carbajal et 1999 Randomized Compared no treatment, Primary outcome Mean pain scores: Relatively small II al125 controlled water, 2 cc of 30% measure was pain as 7 no treatment, number of patients per trial glucose, 2 cc of 30% measured by the 7 water, group resulted in wide sucrose, a pacifier, or 30% DAN scale 5 glucose, CIs around estimates sucrose plus a pacifier in a 5 sucrose, of treatment effect; convenience sample of 2 pacifier, observers could not be normal, full-term neonates 1 pacifier and sucrose; compared with blinded to presence of undergoing venipuncture water, the median reduction in pain with pacifier, and these (n=150, 88 males, 62 sucrose was 2 (95% CI 0-4; P=0.01); groups showed the females, median compared with a pacifier, the median greatest effect; no gestational age 39-40 wk, reduction in pain score with sucrose plus adverse events were median PNA 3-4 days); a pacifier was 1 (95% CI 0-2; P=0.06) noted in any group maternity ward setting Guala et al126 2001 Randomized Compared 2 cc of 5%, Primary outcome Differences among groups were not The only outcome II Annals controlled 33%, or 50% sucrose measure was heart statistically significant; no adverse measure was heart trial solutions vs control prior rate before, during, effects were observed rate, which does not to heel stick in healthy, and after the appear to be a very of full-term newborns procedure consistent or sensitive mrec Medicine Emergency (n=140, gestational age 38- measure of degree of 41 wk, PNA 4 days); pain; it would be postnatal ward setting preferable to use composite outcome measure lnclPolicy Clinical 399.e32 399.e33 Policy Clinical Annals

Evidentiary Table (continued). of Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class mrec eiieVolume Medicine Emergency Modality Measure/Criterion Comments Standard Abad et al127 1996 Randomized Compared 2 cc of water, 2 Outcome measures: Time spent crying was significantly Limited external II controlled cc of 12% sucrose, or 2 cc time spent audibly different among groups: 72.9 seconds in validity; findings in trial of 24% sucrose prior to crying, and change in the control group, 63.1 seconds in the this study population venipuncture in healthy, vital signs (heart rate, 12% sucrose group, and 19.1 seconds in (premature infants preterm neonates (n=28, 15 respiratory rate, and the 24% sucrose group (P=0.026); post receiving longer-term males, 13 females, median SpO2) hoc analysis revealed that 24% sucrose care in NICU) may not gestational age 34.4 wk, group cried significantly less than 12% generalize to neonates median PNA 4 days); sucrose and controls (P<0.05); of vital presenting to the ED NICU study sign outcomes, only heart rate was found to differ significantly among groups, with a lower heart rate at all time points in the 12% sucrose group Acharya et 2004 Randomized Compared 2 cc of 25% Outcome measures: Duration of first cry was 34 seconds Limited external II al128 controlled sucrose versus water prior crying time, NFCS, shorter in the sucrose group (95% CI 16- validity; findings in trial to venipuncture in healthy, heart rate, and SpO2 51) and total duration of crying was 41 this study population (crossover preterm infants (n=39, 22 seconds shorter (95% CI 19-62); NFCS (premature infants design) males, 17 females, mean increased less in the sucrose group receiving longer-term gestational age 30.5 wk, between baseline and after venipuncture care in NICU) may not mean PNA 27.2 days); (mean difference 2.4; 95% CI 1.3-3.5); generalize to neonates NICU study mean heart rate increase from baseline to presenting to the ED; after venipuncture was lower in the no infant developed sucrose group by 4.2 (95% CI 0.3-8.0); necrotizing no difference in SpO2 enterocolitis Bucher et al129 1995 Randomized Compared 2 cc of 50% Primary outcome Mean heart rate increase after the heel Limited external II controlled sucrose or water given measures: change in stick was 34 in the sucrose group and 51 validity to ED trial prior to heel stick in heart rate from in the water group (P=0.005); percentage population; all patients (crossover healthy, preterm infants baseline, and duration of time crying during the whole were premature in an design) (n=16, gestational age 27- of crying; secondary intervention was lower in the treatment inpatient, intermediate 34 wk, corrected PNA at outcome measures: group (72% vs 94%; P=0.002); recovery care setting time of study 33-36 wk); other physiologic time in sucrose group was significantly (gestational age <35 intermediate care setting variables (including shorter as measured by heart rate wk); did not report cerebral blood flow) (P=0.05) and respiratory rate (P=0.05); adverse events

  :  . , and duration of there was no difference in effect on crying cerebral blood flow, oxygen saturation, and PCO2; blinded nurses could not distinguish sucrose from water group April  Volume   :  . , April Evidentiary Table (continued).  Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Ramenghi et 1999 Randomized Compared 25% sucrose or Primary outcomes: a There was significant reduction of Although designed II al130 controlled water orally or by composite, behavioral score (5 vs 9, P=0.002) and primarily to address trial nasogastric tube 2 min behavioral response percentage crying time (6 vs 22 seconds, the question of the (crossover before heel stick (n=30, score of 15 points, P=0.006) in the intraoral sucrose group vs efficacy of design) median gestational age 34- and percentage of intraoral water; no significant difference in nasogastric 35 wk, median PNA 3-4 time crying during 5- behavioral score or crying time when either administration of days) min observation solution was administered by nasogastric sucrose, this study period tube also compared the efficacy of intraoral sucrose vs water; external validity is limited by the fact that the study sample was comprised of preterm neonates being fed by nasogastric tube Johnston et 1997 Randomized Compared 0.05 cc 24% Primary outcome Both sucrose and sucrose plus rocking Limited II al131 controlled sucrose, simulated rocking, measures: reduced facial expressions of pain (P<0.02) generalizability to trial or both, vs placebo in physiologic (heart but did not have an effect on heart rate; no ED as study preterm, very-low-birth- rate and SpO2) and significant difference between sucrose and population was very- weight neonates behavioral (“facial sucrose plus rocking low-birth-weight undergoing heel stick; actions”) infants in NICU; used Annals mean SNAP-PE score conservative dosing ranged from 7.9 to 8.3 of sucrose in this (n=85, 42 males, 43 population, which has of females, mean PCA 31 wk, been recommended mrec Medicine Emergency mean PNA 5 days); NICU by some authors; study adverse events not reported lnclPolicy Clinical 399.e34 399.e35 Policy Clinical Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Ramenghi et 1996 Randomized Compared 2 cc of 50% Outcomes measures: There was no difference in pain score at Use of unvalidated III al132 controlled sucrose, 25% sucrose, 5-point scale time of heel stick, but it was higher in outcome measure; pain trial nonsucrose sweetener, or (determined by the the water group than in other groups at 3 score was significantly water 2 min before heel presence of facial min (2 vs 0 in other groups; P=0.05); higher in water group stick in healthy term expressions and there was significant reduction in before heel stick, infants (n=60, median crying), crying during median duration of first cry and total potentially influencing gestational age 38-39 wk, and after the percentage of time spent crying in all postprocedure pain median PNA 3-4 days) procedure, and groups relative to water (P=0.02, scores duration of first cry; P=0.02); percentage change in heart rate heart rate was also was significantly higher at 3 min recorded postprocedure in the 50% sucrose and nonsucrose sweetener group vs water (P=0.009) Blass1331997Randomized Compared heel stick after Outcome measure: Sucrose and Similac were more effective Sample size was small III controlled receiving either water, 2 cc percentage of crying than water in reducing the amount of given the large number trial of 12% sucrose, protein, during the procedure crying during heel stick (P=0.015, of treatment groups; lactose, dilute fat, and during recovery P=0.038); water, Similac, and lactose also, the study sought concentrated fat, were the only interventions that did not to assess a question of fat/lactose, Similac or Ross reduce crying during the recovery more academic than Special Formula (n=72, 30 period; no P value is provided for the clinical interest; many males, 42 females, effect of sucrose during the recovery of the substances gestational age not period tested are impractical specified but enrolled for common use “normal newborns,” PNA 22-40 h); community hospital setting   :  . , April  Volume   :  . , April 

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Blass and 1991 Randomized 2 distinct sections of study; Outcome measure for 12% sucrose reduced crying during and Essentially 2 studies in III Hoffmeyer134 controlled both enrolled normal, full- the first section was after heel stick compared with water 1 publication trial term neonates, PNA 28-54 percentage of time (P<0.01); pacifiers with sucrose were evaluating sucrose h; the first section spent crying during significantly more effective than from a syringe in the compared sucrose (2 cc of the procedure and the pacifiers with water in reducing crying heel stick section and 12%) with water before 3-min recovery during circumcision (P<0.05); pacifiers sucrose from pacifier heel stick (n=24); the period; outcome with either liquid were significantly in the circumcision second section compared: measure for the more effective than no intervention section; this resulted in no intervention, nipple second section was (P<0.001) smaller sample sizes with water, or nipple duration of crying for each component of dipped in 24% sucrose during each phase of the study; number of during circumcision (n=30, the procedure infants randomized to 30 males); neonatal control vs treatment nursery setting group not stated; circumcision is not an ED procedure Annals of mrec Medicine Emergency lnclPolicy Clinical 399.e36 399.e37 Policy Clinical Annals of

mrec eiieVolume Medicine Emergency Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Harrison et 2003 Randomized Compared 1 cc 33% Outcome measures: Pain as indicated by the facial score was No primary outcome III al135 controlled sucrose (after publication, 4-point subset of the lower at heel lance (P=0.02) and at 1 and measure defined; the trial solution was found to NFCS, crying 2 min postprocedure (P=0.04, P=0.046) outcome measures contain 33% sucrose, not (duration of first cry, in the sucrose group; there was no were compared at 25% as initially reported) duration of crying difference during heel squeeze and at the multiple time points or water prior to heel stick during the procedure, third min postprocedure, no difference in without statistical in sick infants who had a and duration of crying during the procedure, nor was correction; mean NTISS score ranging crying during there a difference in duration of first cry, generalizability to ED from 8.4 to 10.1 (n=128, recovery), heart rate, but postprocedural crying was reduced patients is limited; this 85 males, 43 females, and SpO2 in the sucrose group (P=0.01); no was a population of mean gestational age difference in heart rate or oxygen sick inpatients; more approximately 36 wk, saturation between the groups than 50% had surgery, mean PNA 17-23 days); more than 85% were neonatal unit and cardiac receiving enteral feeds; unit settings pacifier use was at discretion of the treating nurse and was higher in the sucrose group; post hoc analysis did not identify this as a confounder; despite randomization, the placebo group was more ill, as per an illness severity score; post hoc regression analysis revealed that this may have led to an underestimation of the effect of sucrose;   :  . , adverse events not reported April  Volume   :  . , Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments April Standard Herschel et 1998 Randomized Compared 50% sucrose in Primary outcome Elevation was greater throughout the External validity III  al136 controlled a pacifier, dorsal penile measures: change in procedure in the control group than in limited by the fact that trial nerve block, or control (no heart rate, and SpO2 either treatment group (P<0.001); mean circumcision is not an treatment) during during the procedure changes in heart rate from baseline were ED procedure; only circumcision in healthy, and recovery; data 37 in the control group, 27 in the sucrose physiologic outcome full-term, male newborns loss due to movement group, and 10 in the dorsal penile nerve measures were used, (n=119, mean gestational was also compared block group (P<0.001); no difference in and there was age 39 wk, mean PNA 24- SpO2 among the groups; relative risk of difficulty in recording 27 h); general care nursery data loss due to movement in the sucrose SpO2 during setting group compared with control was 0.26 procedure; no (95% CI 0.18–0.36) behavioral measures of pain were recorded; adverse events not reported Mitchell et 2004 Randomized Compared 3 staggered Outcome measure: The PIPP score was significantly Limited III al137 controlled doses of 0.1 cc of 24% PIPP score reduced in the sucrose group only during generalizability to ED trial sucrose or water by the active eye examination phase (8.8 vs setting because pacifier before and during 11.4; P=0.0077) not during preparation population was eye examination for (eye drop application) or recovery preterm, low-birth- retinopathy of prematurity weight infants in very preterm infants; all undergoing a infants received topical procedure that is not anesthetic and a pacifier performed in the ED (n=30, 7 males, 23 and is considered to be females, mean gestational “severely invasive” age 26-27 wk, mean PNA 8 wk); NICU study

Annals 138 Mohan et al 1998 Randomized Compared a pacifier Outcome measure: SpO2 for the sucrose group differed External validity III controlled containing 2 cc of 24% physiologic significantly from the water-pacifier compromised, trial sucrose, EMLA cream, indicators (heart rate, group across all time points (P=0.03); circumcision not an of EMLA plus sucrose blood pressure, SpO2) heart rate and blood pressure did not ED procedure; control mrec Medicine Emergency pacifier, vs a water-dipped and duration of differ between the sucrose group and group (pacifier with pacifier for healthy, full- crying/duration of control; all treatment groups cried less water) excluded from term males undergoing procedure than the “control” (P<0.01); patients randomization process; circumcision (n=80, receiving EMLA and EMLA plus unclear whether gestational age 37-42 wk, sucrose cried significantly less than the outcome assessment PNA 1.6 to 2.3 days); sucrose group (P<0.01) was blinded Policy Clinical well-baby nursery setting 399.e38 399.e39 Policy Clinical Annals Evidentiary Table (continued).

of Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class

mrec eiieVolume Medicine Emergency Modality Measure/Criterion Comments Standard Ramenghi et 1996 Randomized Compared 1 cc of 25% Outcome measures: The duration of first cry was Limited external III al139 controlled sucrose vs water prior to duration of first cry, significantly shorter in the sucrose group validity, enrolled only trial heel stick in healthy, percentage cry over 5 (12 vs 23 seconds, P=0.004), as was the premature infants; the (crossover preterm infants (n=15 with min, heart rate, and percentage cry over 5 mins (16.6 facial expression scale design) each subject measured changes in facial seconds vs 6 seconds, P=0.018); heart outcome measure is of twice, median gestational expressions on a 4- rate did not differ significantly; mean questionable reliability age 33 wk, median PNA 2 point scale pain scores were lower in the sucrose and validity; no days) group at 1 and 3 min poststimulus adverse effects were seen Rushforth and 1993 Randomized Compared 2 cc of 7.5% Outcome measure: There was no difference in crying Dose was likely too III Levene140 controlled sucrose vs water prior to duration of crying between the groups low to show effect trial heel stick in full-term infants (n=52, 20 males, 32 females, median gestational age 38-39 wk, median PNA 6 days) Stang et 1997 Randomized During circumcision Outcome measures: The padded chair group and the sucrose Lack of III al141 controlled compared group I: a behavior as measured pacifier group showed less behavioral generalizability to the trial padded chair for by the Brazelton distress overall than the other groups ED, circumcision is circumcision, with a dorsal Behavioral State (P<0.05); the sucrose group cried not an ED procedure; penile nerve block and a Scale at time points significantly less 2 min after the dorsal nonstandard outcome pacifier; group II: the throughout the penile nerve block (0.003) and during measure limits standard restraint board, procedure, and the circumcision itself (P=0.002); comparison with other dorsal penile nerve block plasma cortisol cortisol levels did not differ among studies with buffered lidocaine, measured 30 min groups and a pacifier; group III: after the procedure standard restraint board, dorsal penile nerve block, and a pacifier dipped in 24% sucrose; and group IV: standard restraint, dorsal penile nerve block, and a pacifier (n=80, 80   :  . , males, mean gestational age 39.5 wk, mean PNA 35.1 h); community hospital setting April  Volume   :  . , April 

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Barr et al142 1995 Randomized Compared 0.75 cc of 50% Outcomes included: There was no difference in crying during Limited external II controlled sucrose vs water in healthy percentage of time the procedure, but sucrose significantly validity, findings in trial 2- and 4-mo-olds receiving crying (“audible reduced postinjection crying compared this healthy outpatient intramuscular vaccinations negative with water (83% vs 69%, P<0.05); population may not (n=57, 31 males, 26 vocalizations and overall, crying was greater in younger generalize to infants females); ambulatory facial grimace”) than older infants, but there did not presenting to the ED; pediatric clinic setting during and appear to be a difference in effectiveness one of the few articles postinjection, of sucrose between the different age to assess sucrose in relationship of age to groups older infants response, and whether effect was on pain response during procedure or during recovery period Lewindon et 1998 Randomized Compared 2 cc of 75% Primary outcome All measures of cry were shorter in the Unusually high dose of II al143 controlled sucrose vs water in healthy measures: crying, sucrose group, including duration of first sucrose; subjective trial infants born at >34 wk duration of first cry, cry (42 vs 29 seconds; P<0.0003), sum Oucher Scale was presenting for sum total crying, and total crying (59 vs 36 seconds; validated as a self- immunization at 2, 4, and 6 start to finish crying; P<0.000008), total crying time (69 vs 43 reporting pain scale for mo (n=107, 56 males, 51 the Oucher Scale was seconds; P<0.00002); nurses perceived a older children, not as it

Annals females); outpatient clinic used so that nurses lower level of distress according to was used in this study; setting and caregivers could Oucher Scale in the sucrose group, but “usual” parental subjectively assess caregivers did not differ in their cuddling practice was of infant distress perception of infant distress observed for all mrec Medicine Emergency neonates lnclPolicy Clinical 399.e40 399.e41 Policy Clinical Annals of Evidentiary Table (continued). mrec eiieVolume Medicine Emergency Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Reis et al144 2003 Randomized Infants undergoing Primary outcome First cry duration was 19 seconds in the Effect of sucrose could III controlled intramuscular vaccinations measures: first cry sucrose group vs 58 seconds in the not be separated from trial (4 injections), comparing and total cry duration control group (95% CI for treatment the effect of the other 25% sucrose from a bottle from the beginning of effect -11 to -42); total cry duration was interventions; parents 2 min before the procedure the procedure; 92 seconds vs 188 seconds (95% CI for and nurses who with continued “oral change from baseline treatment effect -1 to -38); no difference participated in stimulation” plus parental to maximum heart in change in heart rate; parents preferred providing the holding vs no intervention rate was also the intervention, as measured by a VAS; intervention could not (n=116, 59 males, 57 assessed; secondary nurses showed no preference regarding be blinded to treatment females, mean age 9.5 wk); outcome measures: ease of administration group; investigators primary care center setting parental and nurse were blinded to preference audiotaped cry assessment, which was the primary outcome measure Blass and 1995 Non- 2 distinct sections of study; Outcome measure: Authors report “sucrose was an effective Essentially 2 studies: III Shah145 randomized the first section compared “% of crying per unit analgesic agent” (P<0.03); from the the first designed to controlled 2 cc of 0.17, 0.34, or 0.51 time” during figures, it appears that 0.34 M and 0.51 elucidate dose- trial M sucrose, water, or no procedure and for M sucrose was more effective than 0.17 response curve and the intervention given during 2 subsequent 3 min M or water in reducing crying during second to define the min prior to heel stick; heel stick, and there was no difference temporal second section looked at postprocedure, although P values are not characteristics of 0.34 M sucrose given 30, reported; infants who received the antinociceptive effect 60, 90, 120, and 240 sucrose 120 seconds before heel stick of sucrose; number of seconds before heel stick; cried significantly less than those who infants assigned to both enrolled healthy received the sucrose earlier or later control vs each newborns, gestational age treatment group not and PNA not specified stated; total number in (n=72, 46 males, 26 either component of females); community the study not specified; hospital setting protocol for treatment   :  . , group selection was not specified April  Volume   :  . , April 

Evidentiary Table (continued). StudyYearDesign Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Coskun et al147 2001 Prospective 360 patients age 2 wk to 8 y, Efficacy determined Chloral hydrate “23% refused oral drug Efficacy observational undergoing echocardiography; 2 by completion of successful sedation because of bitter taste, 30% of II study doses of chloral hydrate: age <2 y or study 95%; desaturation 3%; the remaining patients vomited with cyanotic heart disease 50-75 hypoxia in patients after oral drug administration; Safety mg/kg, others 75-100 mg/kg with genetic disorders a significant decrease of II but not cardiac oxygen saturation was problems recorded in half the patients with Down syndrome; failure of adequate sedation occurred in 71% (10/14) of patients with a genetic disorder (12 Down syndrome, 2 fragile x syndrome)” Wheeler et al148 2001 Randomized, 40 children <5y of age undergoing Objective scoring Chloral hydratedeep Echocardiography not common Efficacy controlled echocardiography; chloral hydrate 75 system for sedation; sedation 93% vs ED procedure I trial; blinded mg/kg vs midazolam 0.5 mg/kg objective criteria for midazolam 36% monitoring of vital (P=0.001); no change Safety signs in time to onset of II sedation but chloral

Annals hydrate longer duration of action (37.4 min vs 80.6 min) of mrec Medicine Emergency lnclPolicy Clinical 399.e42 399.e43 Policy Clinical Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study YearDesign Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Marti-Bonmati et 1995 Randomized, 97 children received either 70 mg/kg Efficacy defined as Adequate sedation with Age, weight, and diagnosis Efficacy al149 blinded, or 100 mg/kg chloral hydrate for successful initial dose of chloral influenced efficacy; “older I prospective MRI imaging completion of study hydrate in 64% of the and heavier children and dosage study with 95% of images 70 mg/kg group and those with white matter Safety free of motion 87% of the 100 mg/kg disease are more likely not I artifact group (P<0.05); to be satisfactorily additional doses of sedated” chloral hydrate brought groups up to 92% and 100% success; time to sedation was 28 min in lower-dose group and 21 min in higher-dose group (P<0.05); time to awakening did not differ between dosage groups; adverse events, including vomiting and nervousness in 21% of patients, but not statistically different between dosage groups; no cardiorespiratory depression   :  . , April  Volume   :  . ,

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/Comments Class April Modality Measure/Criterion Standard  Malviya et al1502004Randomized, 70 children randomized to chloral Formalized grading Sedation scores Efficacy blinded, hydrate 75 mg/kg or pentobarbital system for quality of significantly higher for I controlled trial 2-5 mg/kg intravenous; patients MRI studies and pentobarbital (P<0.01); could be supplemented with sedation scores time to onset shorter for Safety intravenous midazolam pentobarbital (P=0.001) I but time to discharge was similar for 2 groups; in chloral hydrate group 37% required intravenous midazolam compared to 9% of pentobarbital group; sedation success was 97% for chloral hydrate and 91% for pentobarbital (P=NS); desaturation in 11% of chloral hydrate and 17% of pentobarbital (P=NS); major motion artifact in 4% chloral hydrate; postdischarge h until return to baseline 11 for chloral hydrate, 17 for pentobarbital (P<0.05) D’Agostino and 2000 Randomized, 33 children aged 0-93 mo sedated Efficacy determined Adequate sedation in Efficacy Terndrup151 controlled, for outpatient imaging study by completion of 100% chloral hydrate I blinded study received either chloral hydrate 75 study compared to 50% Annals mg/kg or midazolam 0.5 mg/kg midazolam (P<0.05); Safety need for supplemental I

of medication 9% of chloral hydrate group and 55% of mrec Medicine Emergency midazolam group (P<0.05); duration of sedation notstatistically different: 95 min for chloral hydrate vs 76 min

for midazolam Policy Clinical 399.e44 399.e45 Policy Clinical Annals of mrec eiieVolume Medicine Emergency Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Thompson et 1982 Randomized, 582 patients randomized tochloral Sedation defined by Failure 15% for No objective standards for Efficacy al152 controlled trial hydrate 80 mg/kg, AMPS, or general successful completion chloral hydrate, 12% efficacy; no data on chloral II anesthesia with endotracheal of CT without motion for AMPS; hydrate safety intubation for CT study artifact complications not Safety reported for each N/A group but 3.5% overall Ronchera-Oms 1994 Nonrandomized, 596 elective MRI patients; chloral Efficacy determined Mean dose 64 mg/kg; “15% failure rate in older Efficacy et al153 observational hydrate dose not specified by quality of MRI and 76.2% successful after children (>7 y), <5% failure II study motion artifacts first dose, 94.1% rate in younger children successful after total (<36 mo); effectiveness Safety dose; 9.9% adverse around 80% inchildrenwith II reactions; nausea and encephalic white matter vomiting most alterations, medullary common; more tumors/syringohydromyelia” frequent in older children Greenberg et 1993 Prospective, 300 children ages 1 mo to 11 y, who Efficacy by Efficacy: 91% “Success rate=96% (age ≤48 Efficacy al154 observational received 100 mg/kg chloral hydrate completion of study completed MRI mo) versus 81% for age >48 II study for MRI; efficacy and safety overall, children <48 mo” correlated by age mo 96%, children 4- Safety 11 y 81%; failure rate II increased proportionately with increasing age from 2% in infants to26% in children 6-11 y (P<0.0005); respiratory depression more common in children <24 mo   :  . , (6.7%) (P=0.05) April  Volume   :  . , April 

Evidentiary Table (continued). Study YearDesign Intervention(s)/Test(s)/ Outcome Results Limitations/Comments Class Modality Measure/Criterion Standard McCarver- 1996Randomized, 7 term neonates undergoing CT Specific sedation All infants fell asleep Small number of unique Efficacy May et al155 blinded, and single photon emission CT 2 definitions used with single dose of patients II crossover study days apart; chloral hydrate (75 chloral hydrate compared mg/kg) given for first study, with only 42% of Safety midazolam (0.2 mg/kg) for midazolam infants; 57% III second study; all infants had of infants in both groups meconium aspiration syndrome desaturated and persistent pulmonary hypertension Pereira et al156 1993 Retrospective 2,178 patients; ages newborn to Efficacy defined by Good or adequate studies Efficacy examination of 17 y; sedation for outpatient CT scoring system based were obtained in 96.4% II prospectively imaging; options included chloral on quality of images of chloral hydrate collected data hydrate 50-80 mg with option for patients, 97.7% of Safety supplemental dose of 25-40 intramuscular II mg/kg), intravenous pentobarbital pentobarbital, 96.9%of (2.5 mg/kg, 1.25 mg/kg, 1.25 intravenous pentobarbital, mg/kg protocol), intramuscular and 70.7% of CM-3 pentobarbital (5-6 mg/kg), or patients; duration meperidine, chlorpromazine, and including induction time promethazine (CM-3) was 92 min for chloral hydrate, 115 min for

Annals intramuscular pentobarbital, 63 min for intravenous pentobarbital, of and 111 min for CM-3 mrec Medicine Emergency patients (P<0.001) lnclPolicy Clinical 399.e46 399.e47 Policy Clinical Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Lipshitz et 1993 Prospective, 140 children, 0-36 mo undergoing Side effects (ataxia, No increase in hypoxia in No objective efficacy Efficacy al157 observational echocardiography; mean dose chloral excitement), delayed children cyanotic at criteria II study hydrate 87 mg/kg; objective to evaluate sedation, light sleep, baseline; beginning and effects of age, food, and nap schedule behavioral changes sedated saturations highly Safety on chloral hydrate sedation; follow-up were assessed correlated (P<0.0001); II parental survey at 24 h effect of delivery of medication increased when timing procedure with nap time; paradoxical excitement in 18%, 3 children never fell asleep; variables associated with paradoxical excitement and/or ataxia were older age (P<.001) and had a higher total dose (P=0.0003), successful sedation=97.9% Malviya et 2000 Retrospective 922 children ages birth to 18 y sedated Quality of diagnostic Chloral hydrate was 96% Did not report specifics of Efficacy al158 examination of for CT or MRI were compared with scans was evaluated effective in permitting chloral hydrate vs other II prospectively 140 children undergoing the same as adequacy of completion of scans agents collected data studies under general anesthesia sedation compared to 91% for Safety benzodiazepine (P<0.02); II mean dose of chloral hydrate was 60.1 mg/kg; oxygen desaturation in 3% of chloral hydrate patients, and 1% required airway interventions   :  . , April  Volume   :  . , April

Evidentiary Table (continued).  Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Hubbard et 1992 Observational 407outpatients (aged 1 day to 18 y) Of the 34 patients who They did not separate the Efficacy al159 study sedated for CT or MRI, 265 received had transient oxygen various sedations and III chloral hydrate (mean dose 80 mg/kg), saturation decrease, 49% complications/failed 25% required a second dose of chloral had some “disease that sedations, although the Safety hydrate; 115 received nembutal, 27 compromised their majority (65%) of patients III patients received other sedatives airway,” including received chloral hydrate rhinitis, sinusitis, mandibular hypoplasia, Down syndrome, and obesity; certain patients were difficult to sedate; these were children with mental retardation, patients receiving chemotherapy, and patients habituated to sedation; patients on antiseizure medication required higher sedation doses; successful chloral hydrate sedation=98% Rumm et 1990 Prospective, 50 children undergoing diagnostic Effective sedation Single dose success Children with neurologic Efficacy al160 observational study (CT, MRI, EEG, bone scan, defined by successful rate=86%; no disorders had a much III

Annals study other); mean initial dose=58 mg/kg completion of complications or side greater (27% vs 4%) diagnostic test with a effects in any patients, failure rate than “normal” Safety sedation score of at although 2 of the 7 children; no complications III of least 3 of 4 on 4-point “failures” of sedation or side effects, yet note 2 mrec Medicine Emergency scale at completion of “vomited a considerable of 7 failures vomited their test portion of their initial medication dose” lnclPolicy Clinical 399.e48 399.e49 Policy Clinical Annals of mrec eiieVolume Medicine Emergency Evidentiary Table (continued). Study YearDesign Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Seiler et al161 2001Observational Children undergoing radiation therapy Satisfactory sedation for Small number; high ECOG Efficacy study for cancer, age 9 mo to 9 y; 148 treatment: chloral hydrate status III or IV, selected III sedations were done; dose 75-100 60%, meperidine 60%, patient population (sick mg/kg by mouth or per rectal initially, midazolam 82%; unable cancer patients) Safety repeat 25 mg/kg dose if lower 75 to treat: chloral hydrate III mg/kg dose was used initially up to a 20%, meperidine 13%, maximum of 2 g; mean dose 100 midazolam 5%; no mg/kg (range 10-167 mg/kg); chloral serious complications; hydrate was used in 30 procedures, “chloral hydrate was the midazolam in 78, meperidine in 15, least successful with at other sedatives in 25 least 1 complication occurring in23% (7/30),” vomiting 13% (4/30), pulse >160 beats/min 10% (3/30) Rooks et 2003 Nonrandomized, Review of prospectively collected data Efficacy determined Efficacy 99.7%; adverse No formalized scoring Efficacy al162 observational on 675 infants who received oral by completion of events pentobarbital system for efficacy; non- III study pentobarbital (initial dose 4 mg/kg) or study 1.6%, chloral hydrate randomized chloral hydrate (50 mg/kg) for radiology 1.7% Safety studies (MRI, CT, other) III Mason et 2004 Retrospective 1,316 infants <1 y receiving oral Efficacy defined as Time to sedation (17-18 No formalized scoring Efficacy al163 review of sedation for radiology imaging studies; successful min) and discharge system III prospectively chloral hydrate dose 50 mg/kg, completion ofstudy similar (102-103 min); collected data pentobarbital 4 mg/kg success rate for chloral Safety hydrate was 98.7% and III for pentobarbital was 99.5% (P=NS); complications including hypoxia more common in chloral hydrate group (2.7%) vs pentobarbital   :  . , group (0.5%) (P=0.01) April  Volume   :  . , April 

Evidentiary Table (continued). Study YearDesign Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Chung et al164 2000 Prospective 54 infants ages 2-13 mo, undergoing Efficacy defined by Sedation success 100% Parents selected sedative Efficacy observational radiology imaging studies received ability to complete for chloral hydrate and agent III study either chloral hydrate (50-100 test 90% for the pentobarbital mg/kg) or pentobarbital (4-6 mg/kg) group; infants were Safety orally; fasted 4.8 h; mean time to more likely to accept III onset 19 min (+/- 13); time to pentobarbital than discharge 102 (+/- 33) chloral hydrate (P<0.001); no desaturation reported Vade et al165 1995 Prospective 410 children undergoing imaging Efficacy defined as Successful sedation in Efficacy observational study received chloral hydrate in age- successful 99.5% of patients; III study based dosing regimen; age <1 y completion of study prolonged sedation 3% received 50 mg/kg, age 1-4 y with 95% of images of chloral hydrate only Safety received 75 mg/kg plus hydroxyzine free of motion group but17% of chloral III (0.8 mg/kg) artifact hydrate plus hydroxyzine group; mild hypoxia in 9% of chloral hydrate only group and 5% of combined group; moderate-to-severe

Annals hypoxia with oxygen desaturation, <90% occurred in 0.5% of of groups mrec Medicine Emergency lnclPolicy Clinical 399.e50 399.e51 Policy Clinical Annals of

mrec eiieVolume Medicine Emergency Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Napoli et al166 1996 Prospective 405 children ages 3 weeks to 14 y Efficacy by Successful sedation “Children ≤3 y 99% Efficacy observational received chloral hydrate (50-100 completion of study 98%; time to sedation successful sedation, >3 y III study mg/kg) for echocardiography 30 min or less in 82%, 84% successful sedation 30-60 min in 12%, and (P=0.003)”; decreases in Safety >60 min in 4%; oxygen saturation occurred III oxygen saturation more commonly in decreased by >5% in children with trisomy 21 6% of patients and was (7/13=53.8%) than in treated with head children without genetic repositioning in 83% syndromes (17/384=4.4%); and supplemental “chloral hydrate is a safe oxygen in the and effective agent for remainder; oxygen sedation of children with desaturation more likely congenital heart disease in children with genetic including cyanotic heart syndromes disease” Lichenstein et 1993 Retrospective 424 patients in a pediatric ED Successful sedation Overall 82% first dose, Retrospective chart review; Efficacy al167 chart review undergoing procedural sedation using not defined; sedation 88% total dose success no standardized scoring for III chloral hydrate; mean initial dose 51 was for diagnostic or rate; no adverse effects efficacy or safety; specific mg/kg; age range0.4 to 209 mo, 55% minor surgical other than vomiting and procedures not defined Safety male, 61% African American procedures hyperexcitability; III success rate (first dose, second dose, total) by age was: 0-0.9 y 98%, 100%, 100%; 1.0-1.9 y 84%, 91%, 97%; 2.0-2.9 y 76%, 87%, 97%; 3 y 76%, 85%, 89%; chloral hydrate as a single agent safe

  :  . , without life-threatening reactions April  Volume   :  . , April  Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class Measure/Criterion Standard Weir et al168 1986 Prospective, 252 children undergoing sedation for Success was defined Success rates: chloral Limitations: dosages of all Efficacy randomized trial CT (107), EEG (67), other (78); as procedure hydrate 80%, DPT 86%, drugs not given; some III randomized to one of 3 sedation performed; DN 86% (P=NS); patients not randomized if regimens: chloral hydrate (N=82) by complications were failure rates for chloral surgeon had a preference Safety mouth, DPT (N=113) intramuscular, or those that required hydrate were greater in for a sedative regimen III DN (N=57) intramuscular; initial hospitalization the older patients (>3 y); doses: chloral hydrate 30 mg/kg; most failures tended to DPT=demerol 2 mg/kg up to 50 mg occur in children with maximum, phenergan, thorazine; seizure disorders or DN=demerol 50 mg/M2 up to 50 mg retardation and required maximum, nembutal 90 mg/M2 up to augmentation more 90 mg maximum; repeat doses as frequently than patients needed were: chloral hydrate 15 mg/kg without these for failure of chloral hydrate or DPT, conditions; the highest and nembutal titrated slowly failure rates occurred intravenously for failure of DN with CT scans and EEGs; other is surgical examinations or procedures (urologic, otolaryngolic, orthopedic, ophthalmologic, dental),

Annals nuclear scans and radiologic procedures; no patient experienced of an adverse reaction that mrec Medicine Emergency resulted in hospitalization lnclPolicy Clinical 399.e52 399.e53 Policy Clinical

Annals Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class of Measure/Criterion mrec eiieVolume Medicine Emergency Standard Sanborn et 2005 Observational 16,647 sedations in 13,408 pediatric Adverse events rates: Patient characteristics for Efficacy al169 study patients (mean age 4.8 y); 645 chloral 1.8% intravenous pento- each sedative regimen III hydrate (per mouth or per rectal); 9,052 barbital+fentanyl, 1.2% were not given intravenous pentobarbital, 2,183 chloral hydrate by mouth, Safety pentobarbitol per mouth, 772 1.2% intravenous pento- III intravenous pentobarbital+fentanyl, 606 barbital+fentanyl+mida- intravenous zolam, 1% intravenous pentobarbital+fentanyl+midazolam, pentobarbital+midazolam, 1,260 intravenous midazolam+fentanyl, 0.2% intravenous pento- 229 other chloral hydrate; dose 20-50 barbital, 0.1% pento- mg/kg, repeat every 30 min up to barbital by mouth; maximum 100 mg/kg or 2 q; patients adverse respiratory event 95%ASA status I or II; radiology rate was higher for imaging chloral hydrate than pentobarbital by mouthor intravenous (P<.001); of 70 patients (0.4%) with adverse respiratory events 20 (29%) had a history of serious respiratory disease (asthma, bronchiolitis, pneumonia, congenital cystic adenomatoid malfor- mation) (N=12); there were no aspirations with chloral hydrate (1 with IV pentobarbital+fentanyl+ midazolam, 1 with IV pentobarbital); only 1.1% (7/645) desaturations, 0.1% (1/645) needed airway resuscitation; all airway resuscitations were brief, with the   :  . , patient receiving oxygen positive pressure ventilation with a face mask

April  Volume   :  . ,

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/Modality Outcome Results Limitations/Comments Class April Measure/Criterion

 Standard Kao et al170 1999 Prospective 80 children ages 2 mo to 11 y sedated Telephone survey on Normal activities were Survey the next day may Chloral telephone with chloral hydrate (80 mg/kg) for day after procedure resumed at 2 h in 24%, limit accuracy of time hydrate interview; radiology imaging study (CT or MRI); 2-4 h in 22%, 4-8 h in estimates; no description Efficacy consecutive supplemental dosing permitted 24%, and >8 h or of the decision N/A cohort of overnight in 30% of process/procedure for Safety children patients; unsteadiness in discharge; most ASA class III 68%, hyperactivity in I or II, but 7 ASA class III, ______29% and 2 ASA class IV; 67% (80of 119) response rate Discharge III Reeves et al174 1996 Randomized 40 children sedated for dental Sedation defined by Chloral hydrate group No safety data; efficacy Efficacy controlled trial; procedures with either chloral hydrate objective scale by demonstrated better data determined by II blinded (50 mg/kg)plus hydroxyzine (25 mg) trained observers somnolence at time of sedation scale; no efficacy or midazolam (0.5 mg/kg)plus with excellent procedure (P=0.002) data related to performance Safety acetaminophen (10 mg/kg); given interrater reliability of procedure N/A orally Malviya et 2000 Prospective 376 children had telephone interviews Formalized patient Motor imbalance was Clinical significance of Efficacy al175 observational 1 day after sedation for imaging study; family survey used to noted in 31% of chloral survey questions not N/A study medication selected by radiologists collect information hydrate group compared indicated to 18% of midazolam Safety group (P<0.05); III agitation in 18% of the pure chloral hydrate group compared to 8% of midazolam group (P=NS); 3 children in

Annals chloral hydrate group returned to ED for prolonged sedation; of only 48% of both the mrec Medicine Emergency chloral hydrate and midazolam groups returned to baseline activity within 8 h, although 89% were at

baseline at 24 h Policy Clinical 399.e54 399.e55 Policy Clinical Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Malviya et al197 2004 Clinical trial Interobserver agreement Comparison of the Based on a criterion Small sample size with III between clinical scores and University of Michigan standard of a BIS only 29 children; all ASA the Bispectral Index Sedation Scale score, value ≥90 as indicative class III undergoing echo- the Modified of discharge readiness, cardiogram; 27 received Maintenance of a University of chloral hydrate, 2 received Wakefulness Test, and Michigan Sedation midazolam; the same the Bispectral Index Scale score of 0 or 1 individual recording the (criterion standard) had a sensitivity of University of Michigan 89%, a specificity of Sedation Scale also scored 87%, and a positive the Modified Maintenance predictive value of of Wakefulness Test 70%; a Modified (potential for bias); Maintenance of institutional discharge Wakefulness Test guidelines were used using 20 min as the relying on the University standard had a of Michigan Sedation sensitivity of 77%, a Scale; criterion standard specificity of 89%, and for discharge readiness a positive predictive defined as BIS value ≥90 value of 89% (? validated); no follow-up after discharge Mason et al1982004Retrospective Reviewed records from a Description of time to Mean time to All infants younger than 12 III medical record sedation database at a discharge, duration of discharge was similar mo; all received review with an single institution sedation, sedation in the oral and pentobarbital; comparison uncontrolled failure rate intravenous groups is uncontrolled (potential comparison (108 min vs 109 min) for bias); large sample size (observational) (2,164 infants); used predefined discharge criteria (not validated)   :  . , April  Volume   :  . , April 

Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Malviya et al201 2002 Prospective study Real time assessment and a Interobserver reliability There was good Small sample size with III (selection process not review of videotaped for the University of agreement at lighter only 32 children in the clear) segments of sedations on Michigan Sedation sedation levels study; selection criteria children undergoing Scale for videotaped (University of for inclusion in the sedation for CT scanning segments; criterion Michigan Sedation study are not clearly standard was the Scale scores of 0 and presented; all children Observer's Assessment 1) but less agreement were ASA class I or II; of Alertness/Sedation at higher sedation children were 4 mo to Scale; comparison was scores (University of 5 y of age; all children also made with a nurse Michigan Sedation received chloral recording a visual Scale scores of 2 and hydrate analogue scale 3); there was poor agreement at the time of discharge Annals of mrec Medicine Emergency lnclPolicy Clinical 399.e56 399.e57 Policy Clinical Annals of

mrec eiieVolume Medicine Emergency Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/ Outcome Results Limitations/ Class Modality Measure/Criterion Comments Standard Newman et al205 2003 Database review Description of adverse Description of the Most (92%) adverse Multiple drugs were III (retrospective review of events and their timing in timing of "serious" and effects occurred during administered alone and a prospectively relation to the timing of a "other" adverse effects the procedure (only in a variety of generated database) sedation; database included 8% after); of 1,341 combinations; several information from 24-h sedations, 159 serious different routes for follow-up telephone calls adverse effects were drug administration identified; serious were used; telephone adverse effects that follow-up to evaluate occurred more than 25 for late complications min after the final was available for only sedation medication 64%; interobserver administration reliability was assessed occurred in children for 10% of records who had also with a simple experienced adverse concordance rate (85% effects earlier; authors agreement for the concluded it is safe to nature of adverse discharge events and 85% for approximately 30 min times recorded) after final sedation administration if no adverse effects have occurred

AAP, American Academy of Pediatrics; AMPS, atropine, meperidine, promethazine, and secobarbital; ANCOVA, analysis of covariance; ASA, American Society of Anesthesiologists; BIS, bispectral index; CHEOPS, Children’s Hospital of Eastern Ontario Pain Scale; CI, confidence interval; CNS, central nervous system; CT, computed tomography; CO2, carbon dioxide; DAN, Douleur Aigue chez le Nouveau-ne; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; ED, emergency department; EEG, electroencephalogram; ETCO2, end-tidal carbon dioxide; FiO2, fractional inspiratory oxygen; FLACC, Face, Leg, Activity, Crying, Consolability; g, gram; GERD, gastroesophageal reflux disease; h, hour; IQR, interquartile range; M, moles per liter of solution; min, minute; mo, month; MRI, magnetic resonance imaging; N2, nitrogen; N2O, nitrous oxide; N/A, not applicable; NEFA, nonesterified fatty acid; NFCS, Neonatal Facial Coding System; NICU, neonatal intensive care unit; NPO, nothing by mouth; NS, not significant; NTISS, Neonatal Therapeutic Intervention Scoring System; OR, odds ratio; OSBD-R, Observational Scale of Behavioral Distress–Revised; PCA, postconceptual age;

  :  . , PIPP, Premature Infant Pain Profile; PNA, postnatal age; RN, registered nurse; SaO2, arterial blood oxygen saturation; SNAP-PE, Scale for Neonatal Acute Physiology–Perinatal Extension; SpO2, pulse oximetry; VAS, visual analog scale; vs, versus; wk, week; WMD, weighted mean difference; y, year. April 