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Clinical Policy: Critical Issues in the Sedation of Pediatric Patients in the Emergency Department

      Other members of the EMSC Panel included:
      Ramon W. Johnson, MD (ACEP Board Liaison)
      Rhonda R. Whitson, RHIA (Clinical Policies Manager, ACEP)
      Tuei Doong (Vice President, The Nakamoto Group, Inc)
      Jenni Nakamoto-Yingling (President, The Nakamoto Group, Inc)
      Karen Belli (Public Policy and Partnerships Specialist, EMSC)
      Tasmeen Singh, MPH, NREMT-P (Executive Director, National Resource Center, EMSC)
      Tina Turgel (Nurse Consultant, EMSC)
      [Ann Emerg Med. 2008;51:378-399.]

      Preface

      Emergency physicians routinely provide sedation and analgesia, monitor the respiratory and cardiovascular status, and manage critically ill patients of all ages.
      • Innes G.
      • Murphy M.
      • Nijssen-Jordan C.
      • et al.
      Procedural sedation and analgesia in the emergency department Canadian Consensus Guidelines.
      American College of Emergency Physicians
      Rapid sequence intubation.
      • Glauser J.
      • Mace S.E.
      Procedural sedation in the emergency department: regulations as promulgated by the Joint Commission on Accreditation of Healthcare Organizations and establishment of procedural sedation policy within the emergency department.
      The provision of safe and effective sedation and analgesia is an integral part of emergency medicine practice and a component of the core curriculum for emergency medicine residency programs.
      Core Content Task Force II
      The model of the clinical practice of emergency medicine.
      Task Force on the Core Content for Emergency Medicine Revision
      Core content for emergency medicine.
      • Hostetler M.A.
      • Auinger P.
      • Szilagyi P.G.
      Parenteral analgesic and sedative use among ED patients in the United States: combined results from the National Hospital Ambulatory Medical Care Survey (NHAMCS) 1992-1997.
      Failure to adequately treat a patient’s pain can have negative consequences, the event potentially affecting later physiologic responses and behaviors. Appropriately treating pain and anxiety decreases patient suffering, facilitates medical interventions, increases patient/family satisfaction, improves patient care, and may improve patient outcome.
      American Academy of Pediatrics and American Pain Society
      The assessment and management of acute pain in infants, children, and adolescents.
      • Mace S.E.
      • Murphy M.
      Pain management and procedural sedation: definitions and clinical emergency department management.
      American Academy of Pediatrics and Canadian Paediatric Society
      Prevention and management of pain and stress in the neonate.
      • Anand K.J.
      Clinical importance of pain and stress in preterm neonates.
      Providing effective and safe procedural sedation in the emergency department (ED) is a multifactorial process beginning with the preprocedural patient assessment and continuing through intraprocedural monitoring and postprocedure evaluation. Setting up the proper environment and selecting the most appropriate pharmacologic and nonpharmacologic agents are keys to successful procedural sedation.
      • Innes G.
      • Murphy M.
      • Nijssen-Jordan C.
      • et al.
      Procedural sedation and analgesia in the emergency department Canadian Consensus Guidelines.
      • Glauser J.
      Documentation and standard forms for use during procedural sedation in the emergency department.
      • Mace S.E.
      • Barata I.A.
      • Cravero J.P.
      • et al.
      EMSC Grant Panel Writing Committee on Pharmacologic Agents Used in Pediatric Sedation and Analgesia in the Emergency Department Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department.
      • Zempsky W.T.
      • Cravero J.P.
      American Academy of Pediatrics Committee on Pediatric Emergency Medicine and Section on Anesthesiology and Pain Medicine
      Relief of pain and anxiety in pediatric patients in emergency medical systems.
      • Brown L.
      • Minasyan L.
      Nonpharmacologic interventions.
      • Rogovik A.L.
      • Goldman R.D.
      Hypnosis as treatment for pain.
      There are many drugs that can be used for procedural sedation and analgesia. In addition, there are various nonpharmacologic modalities that can be used for procedural sedation and analgesia.
      • Zempsky W.T.
      • Cravero J.P.
      American Academy of Pediatrics Committee on Pediatric Emergency Medicine and Section on Anesthesiology and Pain Medicine
      Relief of pain and anxiety in pediatric patients in emergency medical systems.
      • Brown L.
      • Minasyan L.
      Nonpharmacologic interventions.
      • Rogovik A.L.
      • Goldman R.D.
      Hypnosis as treatment for pain.
      The choice of a particular agent or modality is influenced by many factors.
      • Mace S.E.
      • Barata I.A.
      • Cravero J.P.
      • et al.
      EMSC Grant Panel Writing Committee on Pharmacologic Agents Used in Pediatric Sedation and Analgesia in the Emergency Department Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department.
      These include patient characteristics (eg, age, comorbidity, special health care needs) and the procedure to be performed (painful or painless, duration, etc).
      • Mace S.E.
      • Barata I.A.
      • Cravero J.P.
      • et al.
      EMSC Grant Panel Writing Committee on Pharmacologic Agents Used in Pediatric Sedation and Analgesia in the Emergency Department Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department.
      Appropriate monitoring and assessment are critical for safe and effective procedural sedation and analgesia.
      • Glauser J.
      • Mace S.E.
      Procedural sedation in the emergency department: regulations as promulgated by the Joint Commission on Accreditation of Healthcare Organizations and establishment of procedural sedation policy within the emergency department.
      • Glauser J.
      Documentation and standard forms for use during procedural sedation in the emergency department.
      American College of Emergency Physicians
      Clinical policy for procedural sedation and analgesia in the emergency department.
      • Godwin S.A.
      • Caro D.A.
      • Wolf S.J.
      • et al.
      American College of Emergency Physicians Subcommittee (Writing Committee) on Procedural Sedation and Analgesia in the Emergency Department
      Clinical policy: procedural sedation and analgesia in the emergency department.
      A previous clinical policy focused on medications for achieving sedation and analgesia in pediatric patients undergoing procedures in the ED.
      • Mace S.E.
      • Barata I.A.
      • Cravero J.P.
      • et al.
      EMSC Grant Panel Writing Committee on Pharmacologic Agents Used in Pediatric Sedation and Analgesia in the Emergency Department Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department.
      This clinical policy deals with 2 additional sedation drugs, nitrous oxide and chloral hydrate; a nonpharmacologic agent for sedation, sucrose; as well as preprocedural fasting or nulla per os (NPO) status, and discharge criteria.
      Multiple documents about procedural sedation have been issued by various professional organizations, including The Joint Commission, the American Academy of Pediatrics (AAP), the American Society of Anesthesiologists (ASA), and the American College of Emergency Physicians (ACEP).
      • Mace S.E.
      • Barata I.A.
      • Cravero J.P.
      • et al.
      EMSC Grant Panel Writing Committee on Pharmacologic Agents Used in Pediatric Sedation and Analgesia in the Emergency Department Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department.
      American College of Emergency Physicians
      Clinical policy for procedural sedation and analgesia in the emergency department.
      • Godwin S.A.
      • Caro D.A.
      • Wolf S.J.
      • et al.
      American College of Emergency Physicians Subcommittee (Writing Committee) on Procedural Sedation and Analgesia in the Emergency Department
      Clinical policy: procedural sedation and analgesia in the emergency department.
      Joint Commission on Accreditation of Healthcare Organizations
      Hospital Accreditation Standards.
      American Academy of Pediatrics
      Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures.
      American Academy of Pediatrics
      Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: Addendum.
      American Society of Anesthesiology
      Practice guidelines for sedation and analgesia by non-anesthesiologists.
      American Society of Anesthesiology Task Force on Sedation and Analgesia by Non-Anesthesiologists
      Practice guidelines for sedation and analgesia by non-anesthesiologists.
      The goal of this panel is to eliminate the bias from the recommendations by creating a document that is, to the degree possible, evidence-based. With some aspects of procedural sedation, there is a relative deficiency of high-quality data.
      American College of Emergency Physicians
      Clinical policy for procedural sedation and analgesia in the emergency department.
      This policy is not intended to set standards for individual institutions or practitioners and cannot address every topic about pediatric procedural sedation but does give data for answering key management issues using an evidence-based approach.

      Introduction

      Procedural sedation is the technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardiorespiratory function.
      American College of Emergency Physicians
      Clinical policy for procedural sedation and analgesia in the emergency department.
      Analgesia is usually a component of procedural sedation particularly for painful procedures. Procedural sedation and analgesia yields a depressed level of consciousness while allowing the patient to maintain independent control of the airway and oxygenation by preserving the protective airway reflexes. Moderate sedation/analgesia, previously “conscious sedation,” is a drug-induced depression of consciousness during which patients respond purposefully to verbal or light tactile stimulation while maintaining protective airway reflexes.
      Joint Commission on Accreditation of Healthcare Organizations
      Hospital Accreditation Standards.
      American Academy of Pediatrics
      Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: Addendum.
      American Society of Anesthesiology Task Force on Sedation and Analgesia by Non-Anesthesiologists
      Practice guidelines for sedation and analgesia by non-anesthesiologists.
      Deep sedation/analgesia is a drug-induced depression of consciousness during which patients are not easily aroused, and may need airway and/or ventilatory assistance but may respond purposefully to repeated or painful stimulation.
      American Academy of Pediatrics
      Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures.
      American Academy of Pediatrics
      Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: Addendum.
      American Society of Anesthesiology Task Force on Sedation and Analgesia by Non-Anesthesiologists
      Practice guidelines for sedation and analgesia by non-anesthesiologists.
      General anesthesia, in contrast, is a state of drug-induced loss of consciousness in which patients are not arousable and often have impaired cardiorespiratory function needing support.
      American Academy of Pediatrics
      Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures.
      American Academy of Pediatrics
      Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: Addendum.
      American Society of Anesthesiology Task Force on Sedation and Analgesia by Non-Anesthesiologists
      Practice guidelines for sedation and analgesia by non-anesthesiologists.
      The terminology “moderate sedation,” “deep sedation,” and “general anesthesia” may not apply to dissociative sedation. In dissociative sedation, as with ketamine, a trancelike cataleptic state occurs with both profound analgesia and amnesia while maintaining protective airway reflexes, spontaneous respirations, and cardiopulmonary stability.
      • Green S.M.
      • Krauss B.
      The semantics of ketamine.
      In children, deep or dissociative sedation is usually required for painful procedures.
      • Cote C.J.
      • Wilson S.
      Work Group on Sedation
      Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update.
      Because individuals vary in their responses to a given dose of a specific sedative, practitioners providing procedural sedation and analgesia require the skills needed to provide airway/respiratory management and cardiovascular support. Health care providers administering procedural sedation/analgesia should be proficient in the skills needed to rescue a patient at a level greater than the desired level of sedation. Thus, if moderate sedation is desired, the practitioner should be able to provide the skills needed for deep sedation, and if deep sedation is intended, the practitioner should be competent in the airway management and cardiovascular support involved in general anesthesia.
      • Godwin S.A.
      • Caro D.A.
      • Wolf S.J.
      • et al.
      American College of Emergency Physicians Subcommittee (Writing Committee) on Procedural Sedation and Analgesia in the Emergency Department
      Clinical policy: procedural sedation and analgesia in the emergency department.
      Such skills are a requirement of emergency medicine training programs and an essential component of emergency medicine practice.
      • Glauser J.
      • Mace S.E.
      Procedural sedation in the emergency department: regulations as promulgated by the Joint Commission on Accreditation of Healthcare Organizations and establishment of procedural sedation policy within the emergency department.
      Core Content Task Force II
      The model of the clinical practice of emergency medicine.
      Task Force on the Core Content for Emergency Medicine Revision
      Core content for emergency medicine.

      Methodology

      This clinical policy was created after careful review and critical analysis of the medical literature. Multiple searches of MEDLINE and the Cochrane database were performed. Specific key words/phrases used in the searches are identified under each critical question. All searches were limited to English-language sources, human studies, and years 1976 to 2006. References obtained on the searches were reviewed by panel members (title and abstract) for relevance before inclusion in the pool of studies to be reviewed. Abstracts and articles were reviewed by panel members, and pertinent articles were selected. These articles were evaluated, and those addressing the questions considered in this document were chosen for grading. Additional articles were reviewed from the bibliographies of studies cited. Panel members also supplied articles from their own knowledge and files.
      The panel used the ACEP clinical policy development process; this policy is based on the existing literature; where literature was not available, consensus of panel members was used. The draft was sent to all of the participating organizations for comments during the expert review stage of development.
      All articles used in the formulation of this clinical policy were graded by at least 2 panel members for strength of evidence and classified by the panel members into 3 classes of evidence on the basis of the design of the study, with design 1 representing the strongest evidence and design 3 representing the weakest evidence for therapeutic, diagnostic, and prognostic clinical reports, respectively (Appendix A). Articles were then graded on 6 dimensions thought to be most relevant to the development of a clinical guideline: blinded versus nonblinded outcome assessment, blinded or randomized allocation, direct or indirect outcome measures (reliability and validity), biases (eg, selection, detection, transfer), external validity (ie, generalizability), and sufficient sample size. Articles received a final grade (Class I, II, III) on the basis of a predetermined formula taking into account design and quality of study (Appendix B). Articles with fatal flaws were given an “X” grade and not used in the creation of this policy. Evidence grading was done with respect to the specific data being extracted and the specific critical question being reviewed. Thus, the level of evidence for any one study may vary according to the question, and it is possible for a single article to receive different levels of grading as different critical questions are answered. Question-specific level of evidence 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.
      Clinical findings and strength of recommendations regarding patient management were then made according to the following criteria:

       Level A recommendations

      Generally accepted principles for patient management that reflect a high degree of clinical certainty (ie, based on strength of evidence Class I or overwhelming evidence from strength of evidence Class II studies that directly address all of the issues).

       Level B recommendations

      Recommendations for patient management that may identify a particular strategy or range of management strategies that reflect moderate clinical certainty (ie, based on strength of evidence Class II studies that directly address the issue, decision analysis that directly addresses the issue, or strong consensus of strength of evidence Class III studies).

       Level C recommendations

      Other strategies for patient management that are based on preliminary, inconclusive, or conflicting evidence, or in the absence of any published literature, based on panel consensus.
      There are certain circumstances in which the recommendations stemming from a body of evidence should not be rated as highly as the individual studies on which they are based. Factors such as heterogeneity of results, uncertainty about effect magnitude and consequences, strength of prior beliefs, and publication bias, among others, might lead to such a downgrading of recommendations.
      This policy is not intended to be a complete manual on pediatric sedation issues but rather a focused examination of critical issues that have particular relevance to the current practice of emergency medicine.
      It is the goal of the panel to provide an evidence-based recommendation when the medical literature provides enough quality information to answer a critical question. When the medical literature does not contain enough quality information to answer a critical question, panel members believe that it is equally important to alert emergency physicians to this fact.
      Recommendations offered in this policy are not intended to represent the only diagnostic and management options that the emergency physician should consider. The panel clearly recognizes the importance of the individual physician’s judgment. Rather, this guideline defines for the physician those strategies for which medical literature exists to provide support for answers to the crucial questions addressed in this policy.

       Scope of Application

      This guideline is intended for physicians administering procedural sedation and analgesia to pediatric patients in hospital-based EDs.

       Inclusion Criteria

      This guideline applies to pediatric patients less than or equal to 18 years of age who are in a hospital ED and have conditions necessitating the alleviation of anxiety, pain, or both.

       Exclusion Criteria

      This guideline excludes patients greater than 18 years of age.

      Critical Questions

      • 1
        Should pediatric patients undergo a period of preprocedural fasting to decrease the incidence of clinically important complications during procedural sedation in the ED?

       Patient Management Recommendations

       Level A recommendations

      None specified.

       Level B recommendations

      Procedural sedation may be safely administered to pediatric patients in the ED who have had recent oral intake.

       Level C recommendations

      None specified.
      Key words/phrases for literature searches: preprocedural fasting, NPO, gastric emptying agents, vomiting, aspiration, procedural sedation.
      Recommendations concerning preprocedural fasting in both pediatric and adult sedation are based on a rare but real risk of pulmonary aspiration. Definitive sedation guidelines based on sound evidence are lacking because of a paucity of ED studies about preprocedural fasting. The ASA fasting guidelines, adopted by the AAP, are consensus-based, extrapolated from patients undergoing general anesthesia.
      American Society of Anesthesiologists Task Force on Preoperative Fasting
      Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures.
      As noted in these guidelines, “Published evidence is silent on the relationship between fasting times, gastric volume, or gastric acidity and the risk of emesis/reflux or pulmonary aspiration in humans.” Although these recommendations may be appropriately cautious when considering patients who are undergoing elective general anesthesia, controversy exists as to whether these guidelines are applicable to the pediatric ED population.
      An important distinction between procedural sedation and analgesia in the ED and general anesthesia in the operating room involves the preservation of airway reflexes. In moderate sedation, airway reflexes are generally maintained. These reflexes, although normally present, are less reliably maintained in deep sedation. However, in general anesthesia, airway reflexes are significantly blunted or completely suppressed, thus increasing the potential risk of aspiration.
      • Agrawal D.
      • Manzi S.F.
      • Gupta R.
      • et al.
      Preprocedural fasting state and adverse events in children undergoing procedural sedation and analgesia in a pediatric emergency department.
      • Warner M.A.
      • Warner M.E.
      • Weber J.G.
      Clinical significance of pulmonary aspiration during the perioperative period.
      • Warner M.A.
      • Warner M.E.
      • Warner D.O.
      Perioperative pulmonary aspiration in infants and children.
      • Borland L.M.
      • Sereika S.M.
      • Woelfel S.K.
      • et al.
      Pulmonary aspiration in pediatric patients during general anesthesia: incidence and outcome.
      • Green S.M.
      • Krauss B.
      Pulmonary aspiration risk during emergency department procedural sedation—an examination of the role of fasting and sedation depth.
      Dissociative agents such as ketamine and inhalational agents such as nitrous oxide have a different mechanism of action and do not blunt the airway reflexes to the same degree as other sedatives. Therefore, the description for the continuum of sedation that ranges from anxiolysis to general anesthesia may not accurately reflect the minimal effect of these agents on protective airway mechanisms.
      Aspiration is a rare but well-documented associated risk in patients undergoing general anesthesia. The incidence of aspiration in pediatric patients has been reported to be 1:978 and 1:2,632 patients in 2 pediatric specific studies by Warner et al
      • Warner M.A.
      • Warner M.E.
      • Warner D.O.
      Perioperative pulmonary aspiration in infants and children.
      and Borland et al.
      • Borland L.M.
      • Sereika S.M.
      • Woelfel S.K.
      • et al.
      Pulmonary aspiration in pediatric patients during general anesthesia: incidence and outcome.
      When both emergent and elective patients of all ages are reviewed, the incidence decreases to less than 1:3,500.
      • Green S.M.
      • Krauss B.
      Pulmonary aspiration risk during emergency department procedural sedation—an examination of the role of fasting and sedation depth.
      • Mellin-Olsen J.
      • Fasting S.
      • Gisvold S.E.
      Routine preoperative gastric emptying is seldom indicated A study of 85,594 anaesthetics with special focus on aspiration pneumonia.
      • Engelhardt T.
      • Webster N.R.
      Pulmonary aspiration of gastric contents in anaesthesia.
      During emergency surgery, the incidence of reported aspiration increases to 1:895 in adults and general population patients
      • Warner M.A.
      • Warner M.E.
      • Weber J.G.
      Clinical significance of pulmonary aspiration during the perioperative period.
      and as frequent as 1:373 patients in the Warner et al pediatric study.
      • Warner M.A.
      • Warner M.E.
      • Warner D.O.
      Perioperative pulmonary aspiration in infants and children.
      The timing of reported aspiration events is most commonly seen during induction, laryngoscopy, and extubation (50% to 78%, 30% to 36%, and 4% to 33%, respectively), which does not apply to procedural sedation and analgesia.
      • Warner M.A.
      • Warner M.E.
      • Weber J.G.
      Clinical significance of pulmonary aspiration during the perioperative period.
      • Warner M.A.
      • Warner M.E.
      • Warner D.O.
      Perioperative pulmonary aspiration in infants and children.
      • Borland L.M.
      • Sereika S.M.
      • Woelfel S.K.
      • et al.
      Pulmonary aspiration in pediatric patients during general anesthesia: incidence and outcome.
      Further, inhalational anesthetics can be emetogenic, with documented postoperative nausea and vomiting described in up to one third of all surgical patients.
      • Kovac A.L.
      Prevention and treatment of postoperative nausea and vomiting.
      • Tramer M.R.
      • Reynolds D.J.
      • Moore R.A.
      • et al.
      Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled trials.
      In contrast, pediatric patients undergoing procedural sedation and analgesia are not intubated and have a much lower incidence of nausea and vomiting, varying from 0.3% to 10%.
      • Agrawal D.
      • Manzi S.F.
      • Gupta R.
      • et al.
      Preprocedural fasting state and adverse events in children undergoing procedural sedation and analgesia in a pediatric emergency department.
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      • Egelhoff J.C.
      • Ball Jr, W.S.
      • Koch B.L.
      • et al.
      Safety and efficacy of sedation in children using a structured sedation program.
      • Roback M.G.
      • Bajaj L.
      • Wathen J.E.
      • et al.
      Preprocedural fasting and adverse events in procedural sedation and analgesia in a pediatric emergency department: are they related?.
      • Kennedy R.M.
      • Porter F.L.
      • Miller J.P.
      • et al.
      Comparison of fentanyl/midazolam with ketamine/midazolam for pediatric orthopedic emergencies.
      • Green S.M.
      • Rothrock S.G.
      • Lynch E.L.
      • et al.
      Intramuscular ketamine for pediatric sedation in the emergency department: safety profile in 1,022 cases.
      • McDowall R.H.
      • Scher C.S.
      • Barst S.M.
      Total intravenous anesthesia for children undergoing brief diagnostic or therapeutic procedures.
      A significant relationship has been demonstrated to exist between aspiration during general anesthesia and the patient’s ASA physical status.
      • Borland L.M.
      • Sereika S.M.
      • Woelfel S.K.
      • et al.
      Pulmonary aspiration in pediatric patients during general anesthesia: incidence and outcome.
      Physical status classes of III and IV have been shown to have a significantly increased risk of aspiration compared to that of ASA I and II patients (1:418 versus 1:1,341).
      • Borland L.M.
      • Sereika S.M.
      • Woelfel S.K.
      • et al.
      Pulmonary aspiration in pediatric patients during general anesthesia: incidence and outcome.
      Warner et al
      • Warner M.A.
      • Warner M.E.
      • Warner D.O.
      Perioperative pulmonary aspiration in infants and children.
      found a greater safety range, with only a 1:7,945 risk of aspiration in pediatric patients with ASA I and II physical status classes. The majority of reported pediatric ED procedural sedation and analgesia occurs in a healthier patient population, classified as ASA physical status I or II.
      • Agrawal D.
      • Manzi S.F.
      • Gupta R.
      • et al.
      Preprocedural fasting state and adverse events in children undergoing procedural sedation and analgesia in a pediatric emergency department.
      • Green S.M.
      • Krauss B.
      Pulmonary aspiration risk during emergency department procedural sedation—an examination of the role of fasting and sedation depth.
      • Roback M.G.
      • Bajaj L.
      • Wathen J.E.
      • et al.
      Preprocedural fasting and adverse events in procedural sedation and analgesia in a pediatric emergency department: are they related?.
      • Kennedy R.M.
      • Porter F.L.
      • Miller J.P.
      • et al.
      Comparison of fentanyl/midazolam with ketamine/midazolam for pediatric orthopedic emergencies.
      • Green S.M.
      • Rothrock S.G.
      • Lynch E.L.
      • et al.
      Intramuscular ketamine for pediatric sedation in the emergency department: safety profile in 1,022 cases.
      • Godambe S.A.
      • Elliot V.
      • Matheny D.
      • et al.
      Comparison of propofol/fentanyl versus ketamine/midazolam for brief orthopedic procedural sedation in a pediatric emergency department.
      • Bassett K.E.
      • Anderson J.L.
      • Pribble C.G.
      • et al.
      Propofol for procedural sedation in children in the emergency department.
      Documentation of clinically significant or subclinical aspiration events during procedural sedation and analgesia is extremely limited. Only 1 study reports any incidents of aspiration.
      • Hoffman G.M.
      • Nowakowski R.
      • Troshynski T.J.
      • et al.
      Risk reduction in pediatric procedural sedation by application of an American Academy of Pediatrics/American Society of Anesthesiologists process model.
      The adverse event occurred in 2 pediatric patients, both of whom met NPO criteria for fasting. These patients were deeply sedated with opioid-barbiturate combinations, one for a radiologic procedure and the other for bronchoscopy. Both required only supplemental oxygen and observation. A review of the literature reveals no other reported cases of aspiration as a result of procedural sedation and analgesia in the ED. Given the rare occurrence of aspiration, to date no single study is adequately powered to determine the incidence of aspiration during ED procedural sedation.
      Multiple factors have been investigated in an attempt to identify risk factors for aspiration in the general anesthesia population. These questions include the relationship between aspiration and gastric contents, motility, and acidity. To date, no benefit from the routine addition of antacids and other pharmacologic motility regimens preoperatively has been demonstrated.
      American Society of Anesthesiologists Task Force on Preoperative Fasting
      Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures.
      • Engelhardt T.
      • Webster N.R.
      Pulmonary aspiration of gastric contents in anaesthesia.
      Concerning NPO status, 2 Class I
      • Maekawa N.
      • Mikawa K.
      • Yaku H.
      • et al.
      Effects of 2-, 4- and 12-hour fasting intervals on preoperative gastric fluid pH and volume, and plasma glucose and lipid homeostasis in children.
      • Splinter W.M.
      • Schaefer J.D.
      Unlimited clear fluid ingestion three hours before surgery in children does not affect volume or pH of stomach contents.
      and 2 Class II studies
      • Ingebo K.R.
      • Rayhorn N.J.
      • Hecht R.M.
      • et al.
      Sedation in children: adequacy of two-hour fasting.
      • Soreide E.
      • Hausken T.
      • Soreide J.A.
      • et al.
      Gastric emptying of a light hospital breakfast A study using real time ultrasonography.
      evaluated gastric fluid volume and pH after various fasting periods. In one of the Class I studies, Maekawa et al
      • Maekawa N.
      • Mikawa K.
      • Yaku H.
      • et al.
      Effects of 2-, 4- and 12-hour fasting intervals on preoperative gastric fluid pH and volume, and plasma glucose and lipid homeostasis in children.
      found no difference in gastric fluid volume, pH, lipid homeostasis, or glucose levels with NPO periods of 2, 4, and 12 hours after drinking apple juice. The other Class I study compared NPO after midnight with clear liquids up to 3 hours preoperatively and demonstrated no difference between groups’ gastric fluid volume or pH.
      • Splinter W.M.
      • Schaefer J.D.
      Unlimited clear fluid ingestion three hours before surgery in children does not affect volume or pH of stomach contents.
      These findings are supported by a Class II study by Ingebo et al
      • Ingebo K.R.
      • Rayhorn N.J.
      • Hecht R.M.
      • et al.
      Sedation in children: adequacy of two-hour fasting.
      that used endoscopic suction after intravenous sedation. The duration of fasting after clear fluid ingestion ranged from 0.5 to 24 hours, with a mean period of 6.7+/-5.3 hours. There was no significant difference in gastric fluid volumes or pH between the groups with the following fasting times: 30 minutes to 3 hours, more than 3 hours to 8 hours, and more than 8 hours.
      • Ingebo K.R.
      • Rayhorn N.J.
      • Hecht R.M.
      • et al.
      Sedation in children: adequacy of two-hour fasting.
      There are limited data about clearance of solids alone. A Class II adult study evaluated 8 healthy adult female volunteers who received a light meal and underwent gastric ultrasonography, followed by nasogastric placement for gastric volume monitoring.
      • Soreide E.
      • Hausken T.
      • Soreide J.A.
      • et al.
      Gastric emptying of a light hospital breakfast A study using real time ultrasonography.
      A gastric emptying study with paracetamol was then performed. Although 3 patients cleared 120 minutes after the meal, it took 240 minutes for all patients to be solid free.
      A total of 8 studies were found that evaluated the effect of fasting versus nonfasting on adverse events in pediatric patients undergoing procedural sedation.
      • Agrawal D.
      • Manzi S.F.
      • Gupta R.
      • et al.
      Preprocedural fasting state and adverse events in children undergoing procedural sedation and analgesia in a pediatric emergency department.
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      • Roback M.G.
      • Bajaj L.
      • Wathen J.E.
      • et al.
      Preprocedural fasting and adverse events in procedural sedation and analgesia in a pediatric emergency department: are they related?.
      • Kennedy R.M.
      • Porter F.L.
      • Miller J.P.
      • et al.
      Comparison of fentanyl/midazolam with ketamine/midazolam for pediatric orthopedic emergencies.
      • Bassett K.E.
      • Anderson J.L.
      • Pribble C.G.
      • et al.
      Propofol for procedural sedation in children in the emergency department.
      • Hoffman G.M.
      • Nowakowski R.
      • Troshynski T.J.
      • et al.
      Risk reduction in pediatric procedural sedation by application of an American Academy of Pediatrics/American Society of Anesthesiologists process model.
      • Ghaffer S.
      • Haverland C.
      • Ramaciotti C.
      • et al.
      Sedation for pediatric echocardiography: evaluation of preprocedure fasting guidelines.
      • Keidan I.
      • Gozal D.
      • Minuskin T.
      • et al.
      The effect of fasting practice on sedation with chloral hydrate.
      Five Class II
      • Agrawal D.
      • Manzi S.F.
      • Gupta R.
      • et al.
      Preprocedural fasting state and adverse events in children undergoing procedural sedation and analgesia in a pediatric emergency department.
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      • Roback M.G.
      • Bajaj L.
      • Wathen J.E.
      • et al.
      Preprocedural fasting and adverse events in procedural sedation and analgesia in a pediatric emergency department: are they related?.
      • Bassett K.E.
      • Anderson J.L.
      • Pribble C.G.
      • et al.
      Propofol for procedural sedation in children in the emergency department.
      • Hoffman G.M.
      • Nowakowski R.
      • Troshynski T.J.
      • et al.
      Risk reduction in pediatric procedural sedation by application of an American Academy of Pediatrics/American Society of Anesthesiologists process model.
      and 3 Class III
      • Kennedy R.M.
      • Porter F.L.
      • Miller J.P.
      • et al.
      Comparison of fentanyl/midazolam with ketamine/midazolam for pediatric orthopedic emergencies.
      • Ghaffer S.
      • Haverland C.
      • Ramaciotti C.
      • et al.
      Sedation for pediatric echocardiography: evaluation of preprocedure fasting guidelines.
      • Keidan I.
      • Gozal D.
      • Minuskin T.
      • et al.
      The effect of fasting practice on sedation with chloral hydrate.
      studies evaluating NPO status were reviewed. These studies recorded a total of 4,814 patient encounters, with 2 documented episodes of clinically apparent pulmonary aspiration. As noted above by Hoffman et al,
      • Hoffman G.M.
      • Nowakowski R.
      • Troshynski T.J.
      • et al.
      Risk reduction in pediatric procedural sedation by application of an American Academy of Pediatrics/American Society of Anesthesiologists process model.
      both of these patients were fasted. On pooling of these data, the incidence of clinically apparent pulmonary aspiration during sedation may reflect an incidence of less than 1:2,000 pediatric patient encounters.
      Two studies evaluated the NPO status for solids and liquids. In a Class II study by Agrawal et al,
      • Agrawal D.
      • Manzi S.F.
      • Gupta R.
      • et al.
      Preprocedural fasting state and adverse events in children undergoing procedural sedation and analgesia in a pediatric emergency department.
      only 44% (396/905 patients) met published ASA/AAP guidelines. There was no significant difference in adverse events, including emesis, between patients meeting or not meeting established guidelines. The median time for fasting duration in patients with emesis was 6.8 hours (interquartile range [IQR] 5.1 to 9.5 hours) for solids and 5.8 hours (IQR 3.6 to 8.1 hours) for clear liquids. Median fasting duration for solids increased with age and ranged from 4.2 hours (IQR 2.4 to 6.3 hours) in patients younger than 6 months (n=14) to 7.3 hours (IQR 5.5 to 9.7 hours) in patients older than 36 months (n=644). The median fasting duration for clear liquids also increased with age. The duration increased from 4.1 hours in patients younger than 6 months (IQR 2.4 to 6.3 hours) to 6.4 hours (IQR 4.4 to 8.6 hours) in patients older than 36 months. The authors suggested that given that 56% of patients did not meet criteria and no increase in adverse events was found, that noncompliance with ASA/AAP guidelines does not appear to be a contraindication for procedural sedation.
      • Agrawal D.
      • Manzi S.F.
      • Gupta R.
      • et al.
      Preprocedural fasting state and adverse events in children undergoing procedural sedation and analgesia in a pediatric emergency department.
      In another Class II study, Babl et al
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      identified 155 of 220 children (71.1%; 95% confidence interval [CI] 64.5% to 77.0%) who did not meet fasting guidelines for solids. Thirty-seven (20.6%; 95% CI 15.0% to 27.3%) children did not meet fasting guidelines for clear liquids. The median fasting duration was 4.4 hours (IQR 3 to 6.5 hours) for solids and 4 hours (IQR 2.2 to 6.3) for liquids. Again, there was no significant difference in emesis rate between patients meeting and not meeting fasting guidelines.
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      Few patient data sets are available with numbers involving fasting of less than 2 hours. In a Class II study involving a pediatric ED sedation databank, authors extracted data about fasting status, sedation, and adverse events.
      • Roback M.G.
      • Bajaj L.
      • Wathen J.E.
      • et al.
      Preprocedural fasting and adverse events in procedural sedation and analgesia in a pediatric emergency department: are they related?.
      The fasting time was documented in 1,555 of 2,085 (74.6%) patients. Median fasting time before sedation was 5.1 hours (range 5 minutes to 32.5 hours). No significant difference was found in adverse events when patients were compared with fasting times in 2-hour time blocks up to greater than 8 hours (0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, >8 hours, and undocumented). A total of 156 of 1,555 (7.5%) patients experienced emesis. One hundred fifty patients were fasted for less than 2 hours, with 10 (6.7%) of these patients experiencing emesis. A total of 391 patients were fasted for 2 to 4 hours, with 40 (10.2%) episodes of documented emesis.
      • Roback M.G.
      • Bajaj L.
      • Wathen J.E.
      • et al.
      Preprocedural fasting and adverse events in procedural sedation and analgesia in a pediatric emergency department: are they related?.
      In a Class III study of children undergoing echocardiography, 334 children were divided into 2 groups treated with chloral hydrate.48 The first group of 140 patients was fasted for less than 2 hours, with a mean of 80 minutes. A second group of 184 patients was fasted for greater than 2 hours, with a mean of 225 minutes. There were no major adverse outcomes in either group, as well as no differences in rates of emesis between groups (P=.74). Patients less than 6 months of age who were fasted for greater than 2 hours experienced a significantly higher incidence of inadequate sedation (P=.03) than patients fasted for less than 2 hours.
      • Ghaffer S.
      • Haverland C.
      • Ramaciotti C.
      • et al.
      Sedation for pediatric echocardiography: evaluation of preprocedure fasting guidelines.
      In a Class III study, Keiden et al
      • Keidan I.
      • Gozal D.
      • Minuskin T.
      • et al.
      The effect of fasting practice on sedation with chloral hydrate.
      evaluated children undergoing a hearing test who were sedated with chloral hydrate. This retrospective cohort study extracted data from 2 hospitals using different fasting guidelines. At one hospital (group 1), fasting guidelines were strictly enforced, whereas the second hospital (group 2) enforced no fasting guidelines prior to sedation. The average fasting period was significantly longer in patients with strictly enforced fasting guidelines than in the second group of patients who had no fasting guidelines (5.7 +/- 1.7 versus 2 +/- 0.2 hours; P<0.001). Patients who followed fasting guidelines demonstrated a significantly higher failure rate in achieving sedation with an equivalent first dose of chloral hydrate compared with the second group of unfasted patients (21% versus 11%; P=0.03). The higher failure rate resulted in patients requiring higher medication dosages (83 +/- 31 versus 61 +/- 21 mg/kg; P<0.01) for adequate sedation and remaining sedated for longer periods (103 +/- 42 versus 73 +/- 48 minutes; P<0.001), resulting in a later discharge.
      • Keidan I.
      • Gozal D.
      • Minuskin T.
      • et al.
      The effect of fasting practice on sedation with chloral hydrate.
      As previously noted, the only documented cases of aspiration were discussed in a Class II study by Hoffman et al.
      • Hoffman G.M.
      • Nowakowski R.
      • Troshynski T.J.
      • et al.
      Risk reduction in pediatric procedural sedation by application of an American Academy of Pediatrics/American Society of Anesthesiologists process model.
      In this study, however, adherence to NPO guidelines did not affect overall risk of complications (11 of 309 NPO guidelines followed [3.6%], 95% CI 1.8% to 6.2% versus 29 of 651 NPO guidelines not followed [4.5%], 95% CI 3.0% to 6.3%; odds ratio [OR] 0.79; P=.64) and did not decrease the risk of hemodynamic and respiratory complications (9 of 309 NPO guidelines followed [2.9%], 95% CI 1.3% to 5.5% versus 18 of 651 NPO guidelines not followed [2.8%], 95% CI 1.6% to 4.3%; OR 0.97; NS). The complication risk was insignificantly different in patients without documented NPO status (3 of 45 [6.7%], 95% CI 1.4% to 18.3% versus 37 of 915 [4.0%], 95% CI 2.9% to 5.5%; OR 1.68; P=.43). The occurrence of sedation failures was significantly higher in patients who met NPO criteria (20 of 921 [2.2%], 95% CI 1.3% to 3.3% versus 2 of 443 [0.5%], 95% CI 0.05% to 1.6%; OR 4.4; P=.016). The authors suggest that this loss of effective sedation may be a result of increased agitation as a result of hunger in these children.
      • Hoffman G.M.
      • Nowakowski R.
      • Troshynski T.J.
      • et al.
      Risk reduction in pediatric procedural sedation by application of an American Academy of Pediatrics/American Society of Anesthesiologists process model.
      In conclusion, there is no evidence suggesting a correlation between fasting, emesis, and pulmonary aspiration in healthy pediatric patients undergoing procedural sedation in the ED. Overall it is important to note that although many studies do include patients who were not fasted before their procedure, it is possible that clinicians may have been considering other undisclosed factors that selectively affect NPO times prior to procedural sedation. This selection bias is difficult to identify in the studies but may more closely represent current clinical practice.
      Given the many variables present even in the best-designed studies, clinical judgment should always weigh the risk and benefits for each patient.
      • Green S.M.
      • Roback M.G.
      • Miner J.R.
      • et al.
      Fasting and emergency department procedural sedation and analgesia: a consensus-based clinical practice advisory.
      • 2
        Is nitrous oxide effective and safe for providing pediatric procedural sedation in the ED?
      A previous clinical policy focused on the efficacy and safety of etomidate, fentanyl/midazolam, ketamine, methohexital, pentobarbital, and propofol for achieving sedation and analgesia in pediatric patients undergoing procedures in the ED.
      • Mace S.E.
      • Barata I.A.
      • Cravero J.P.
      • et al.
      EMSC Grant Panel Writing Committee on Pharmacologic Agents Used in Pediatric Sedation and Analgesia in the Emergency Department Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department.
      SeeAppendix Cfor the recommendations from the previous clinical policy.

       Patient Management Recommendations for Nitrous Oxide

       Level A recommendations

      Nitrous oxide at 50% concentration can be used with concurrent local anesthesia for safe and effective procedural sedation in healthy children undergoing painful procedures.

       Level B recommendations

      A gas scavenging system should be used for protection of health care providers when administering nitrous oxide.

       Level C recommendations

      • (1)
        Nitrous oxide at 60% to 70% concentration may be used with concurrent local anesthesia for safe and effective procedural sedation in healthy children undergoing painful procedures.
      • (2)
        Nitrous oxide may be combined with other sedative analgesic agents to augment sedation, but patients receiving these combinations should be carefully monitored for deepening sedation, respiratory depression, and other adverse events.
      • (3)
        Nitrous oxide may be less effective in reducing procedure-related distress in younger children compared with older children.
      • (4)
        Nurses trained in principles of nitrous oxide sedation, including the specific nitrous oxide administration device, may safely administer nitrous oxide to healthy children while under the supervision of an emergency physician or other appropriately trained and credentialed specialist in the ED.
      The evidentiary basis for the efficacy and safety of a given drug may differ. Considering that significant adverse events are generally rare, it is likely that there is stronger evidence for efficacy than for safety. When assigning one overall recommendation for a given drug based on combining these 2 distinct attributes (efficacy and safety) of the drug, the lowest most conservative level of evidence has been designated.
      Efficacy of Nitrous Oxide
      Key words/phrases for literature searches: nitrous oxide, procedural sedation; age 1-18 years.
      Nitrous oxide (N2O) is a relatively weak dissociative anesthetic gas that provides mild to moderate procedural anxiolysis, analgesia, and amnesia in a linear dose-response pattern.
      • Parbrook G.D.
      The levels of nitrous oxide analgesia.
      When used for sedation, N2O is blended with oxygen (N2O/O2) and generally denoted, as in this guideline, as N2O, without acknowledgment of the O2 blend. Use of local anesthesia and imagery to prepare patients for the gas’s clinical effects, eg, imagining flying, significantly enhances the drug’s efficacy.
      • Benedetti C.
      • Chapman C.R.
      • Colpitts Y.H.
      • et al.
      Effects of nitrous oxide concentration on event-related potentials during painful tooth stimulation.
      N2O has both opioid agonist and N-methyl-D-aspartate (NMDA) glutamate receptor antagonist effects.
      • Gillman M.A.
      Analgesic (sub anesthetic) nitrous oxide interacts with the endogenous opioid system: a review of the evidence.
      • Jevtovic-Todorovic V.
      • Todorovic S.M.
      • Mennerick S.
      • et al.
      Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin.
      In healthy patients, N2O has minimal cardiovascular or respiratory effects;
      • Litman R.S.
      • Berkowitz R.J.
      • Ward D.S.
      Levels of consciousness and ventilatory parameters in young children during sedation with oral midazolam and nitrous oxide.
      • Litman R.S.
      • Kottra J.A.
      • Berkowitz R.J.
      • et al.
      Breathing patterns and levels of consciousness in children during administration of nitrous oxide after oral midazolam premedication.
      • Litman R.S.
      • Kottra J.A.
      • Verga K.A.
      • et al.
      Chloral hydrate sedation: the additive sedative and respiratory depressant effects of nitrous oxide.
      however, it may enhance the depressed response to hypoxia and hypercarbia induced by other agents.
      • Litman R.S.
      • Berkowitz R.J.
      • Ward D.S.
      Levels of consciousness and ventilatory parameters in young children during sedation with oral midazolam and nitrous oxide.
      • Litman R.S.
      • Kottra J.A.
      • Berkowitz R.J.
      • et al.
      Breathing patterns and levels of consciousness in children during administration of nitrous oxide after oral midazolam premedication.
      • Litman R.S.
      • Kottra J.A.
      • Verga K.A.
      • et al.
      Chloral hydrate sedation: the additive sedative and respiratory depressant effects of nitrous oxide.
      • Everett G.B.
      • Allen G.D.
      Simultaneous evaluation of cardiorespiratory and analgesic effects of nitrous oxide-oxygen inhalation analgesia.
      • Stewart R.D.
      • Gorayeb M.J.
      • Pelton G.H.
      Arterial blood gases before, during, and after nitrous oxide: oxygen administration.
      Onset and offset of effects occur within 5 minutes, and N2O does not require vascular access or painful administration.
      For more than a century and with few adverse events, 30% to 70% N2O has been widely used to reduce distress in children during dental procedures.
      • Ruben H.
      Nitrous oxide analgesia in dentistry Its use during 15 years in Denmark.
      A 50% concentration of N2O has also been used for management of acute pain in adults in out-of-hospital and ED settings.
      • O’Sullivan I.
      • Benger J.
      Nitrous oxide in emergency medicine.
      • Stewart R.D.
      Nitrous oxide sedation/analgesia in emergency medicine.
      The demand valve-equipped fixed 50% N2O delivery apparatus commonly available in EDs is difficult for children to activate, but patients of all ages easily use the continuous-circuit devices, some of which deliver up to 70% N2O.
      • Luhmann J.D.
      • Kennedy R.M.
      • Jaffe D.M.
      • et al.
      Continuous-flow delivery of nitrous oxide and oxygen: a safe and cost-effective technique for inhalation analgesia and sedation of pediatric patients.
      Numerous studies in children undergoing dental procedures in dental offices detail the effectiveness of N2O in reducing anxiety and distress,
      • Averley P.A.
      • Girdler N.M.
      • Bond S.
      • et al.
      A randomized controlled trial of paediatric conscious sedation for dental treatment using intravenous midazolam combined with inhaled nitrous oxide or nitrous oxide/sevoflurane.
      • Berge T.I.
      Acceptance and side effects of nitrous oxide oxygen sedation for oral surgical procedures.
      • Houpt M.I.
      • Kupietzky A.
      • Tofsky N.S.
      • et al.
      Effects of nitrous oxide on diazepam sedation of young children.
      • Houpt M.I.
      • Limb R.
      • Livingston R.L.
      Clinical effects of nitrous oxide conscious sedation in children.
      • McCann W.
      • Wilson S.
      • Larsen P.
      • et al.
      The effects of nitrous oxide on behavior and physiological parameters during conscious sedation with a moderate dose of chloral hydrate and hydroxyzine.
      • Weinstein P.
      • Domoto P.K.
      • Holleman E.
      The use of nitrous oxide in the treatment of children: results of a controlled study.
      • Wilson K.
      • Welbury R.R.
      • Girdler N.M.
      A randomized, controlled, crossover trial of oral midazolam and nitrous oxide for paediatric dental sedation.
      • Wilson K.E.
      • Girdler N.M.
      • Welbury R.R.
      Randomized, controlled, cross-over clinical trial comparing intravenous midazolam sedation with nitrous oxide sedation in children undergoing dental extractions.
      but relatively few studies have been conducted in children undergoing painful procedures in the ED. Sixty-one articles concerning use of nitrous oxide for procedural sedation in children were identified. Local anesthesia was routinely used as an adjunct. After grading, 44 articles were included in this analysis.
      Suturing-related distress in children was reduced by N2O in 2 Class I,
      • Luhmann J.D.
      • Kennedy R.M.
      • Porter F.L.
      • et al.
      A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair.
      • Burton J.H.
      • Auble T.E.
      • Fuchs S.M.
      Effectiveness of 50% nitrous oxide/50% oxygen during laceration repair in children.
      2 Class II,
      • Gamis A.S.
      • Knapp J.F.
      • Glenski J.A.
      Nitrous oxide analgesia in a pediatric emergency department.
      • Keidan I.
      • Zaslansky R.
      • Yusim Y.
      • et al.
      Continuous flow 50:50 nitrous oxide: oxygen is effective for relief of procedural pain in the pediatric emergency department.
      and 1 Class III
      • Bar-Meir E.
      • Zaslansky R.
      • Regev E.
      • et al.
      Nitrous oxide administered by the plastic surgeon for repair of facial lacerations in children in the emergency room.
      ED-based studies. Luhmann et al
      • Luhmann J.D.
      • Kennedy R.M.
      • Porter F.L.
      • et al.
      A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair.
      found that children aged 2 to 6 years had lower distress scores during wound cleaning, supplemental lidocaine injection, and suturing when they received 50% N2O instead of oral midazolam in addition to standard topical anesthetic, video cartoon viewing, and bedside parent. Combining midazolam with N2O did not further reduce distress. Children who received N2O alone were less likely to experience minor adverse effects (ataxia, dizziness, crying), other than vomiting, in the ED and within 24 hours. Vomiting occurred more frequently with N2O (10% with N2O, 2% with N2O+midazolam). Burton et al
      • Burton J.H.
      • Auble T.E.
      • Fuchs S.M.
      Effectiveness of 50% nitrous oxide/50% oxygen during laceration repair in children.
      also found reduced distress with 50% N2O during suturing. Gamis et al,
      • Gamis A.S.
      • Knapp J.F.
      • Glenski J.A.
      Nitrous oxide analgesia in a pediatric emergency department.
      using 30% N2O, found less distress with N2O in children older than 8 years but only a trend in that direction in younger children.
      Distress during fracture reduction in children was also reduced with use of N2O in 1 Class I study,
      • Luhmann J.D.
      • Schootman M.
      • Luhmann S.J.
      • et al.
      A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children.
      4 Class II studies,
      • Evans J.K.
      • Buckley S.L.
      • Alexander A.H.
      • et al.
      Analgesia for the reduction of fractures in children: a comparison of nitrous oxide with intramuscular sedation.
      • Gregory P.R.
      • Sullivan J.A.
      Nitrous oxide compared with intravenous regional anesthesia in pediatric forearm fracture manipulation.
      • Hennrikus W.L.
      • Simpson R.B.
      • Klingelberger C.E.
      • et al.
      Self-administered nitrous oxide analgesia for pediatric fracture reductions.
      • Hennrikus W.L.
      • Shin A.Y.
      • Klingelberger C.E.
      Self-administered nitrous oxide and a hematoma block for analgesia in the outpatient reduction of fractures in children.
      and 1 Class III
      • Wattenmaker I.
      • Kasser J.R.
      • McGravey A.
      Self-administered nitrous oxide for fracture reduction in children in an emergency room setting.
      study conducted in the ED or orthopedic clinic. Luhmann et al
      • Luhmann J.D.
      • Schootman M.
      • Luhmann S.J.
      • et al.
      A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children.
      found that N2O+lidocaine hematoma block (HB) for fractures was as effective in reducing distress as intravenous ketamine during forearm fracture reductions in children aged 5 to 17 years. Recovery was much faster for N2O+HB (16 minutes versus 83 minutes). Comparable decreases in distress during fracture reduction with 50% N2O were also found versus intravenous regional anesthesia
      • Gregory P.R.
      • Sullivan J.A.
      Nitrous oxide compared with intravenous regional anesthesia in pediatric forearm fracture manipulation.
      or intramuscular meperidine and promethazine.
      • Evans J.K.
      • Buckley S.L.
      • Alexander A.H.
      • et al.
      Analgesia for the reduction of fractures in children: a comparison of nitrous oxide with intramuscular sedation.
      Hennrikus et al
      • Hennrikus W.L.
      • Simpson R.B.
      • Klingelberger C.E.
      • et al.
      Self-administered nitrous oxide analgesia for pediatric fracture reductions.
      and Wattenmaker et al
      • Wattenmaker I.
      • Kasser J.R.
      • McGravey A.
      Self-administered nitrous oxide for fracture reduction in children in an emergency room setting.
      noted decreased levels of distress with 50% N2O alone. Hennrikus et al
      • Hennrikus W.L.
      • Shin A.Y.
      • Klingelberger C.E.
      Self-administered nitrous oxide and a hematoma block for analgesia in the outpatient reduction of fractures in children.
      found that subsequent addition of a HB further reduced distress.
      Use of N2O also reduced children’s distress during other painful procedures such as lumbar puncture, abscess drainage, cyst/nevi excision, bone marrow aspiration, dressing change, and intravenous catheter placement in 6 Class II
      • Averley P.A.
      • Girdler N.M.
      • Bond S.
      • et al.
      A randomized controlled trial of paediatric conscious sedation for dental treatment using intravenous midazolam combined with inhaled nitrous oxide or nitrous oxide/sevoflurane.
      • Keidan I.
      • Zaslansky R.
      • Yusim Y.
      • et al.
      Continuous flow 50:50 nitrous oxide: oxygen is effective for relief of procedural pain in the pediatric emergency department.
      • Burnweit C.
      • Diana-Zerpa J.A.
      • Nahmad M.H.
      • et al.
      Nitrous oxide analgesia for minor pediatric surgical procedures: an effective alternative to conscious sedation?.
      • Ekbom K.
      • Jakobsson J.
      • Marcus C.
      Nitrous oxide inhalation is a safe and effective way to facilitate procedures in paediatric outpatient departments.
      • Henderson J.M.
      • Spence D.G.
      • Komocar L.M.
      • et al.
      Administration of nitrous oxide to pediatric patients provides analgesia for venous cannulation.
      • Kanagasundaram S.A.
      • Lane L.J.
      • Cavalletto B.P.
      • et al.
      Efficacy and safety of nitrous oxide in alleviating pain and anxiety during painful procedures.
      studies and 1 Class III
      • Annequin D.
      • Carbajal R.
      • Chauvin P.
      • et al.
      Fixed 50% nitrous oxide oxygen mixture for painful procedures: a French survey.
      study conducted in various outpatient settings. Recovery from N2O sedation, when noted, was reported to be very rapid.
      • Wilson K.E.
      • Girdler N.M.
      • Welbury R.R.
      Randomized, controlled, cross-over clinical trial comparing intravenous midazolam sedation with nitrous oxide sedation in children undergoing dental extractions.
      • Luhmann J.D.
      • Kennedy R.M.
      • Porter F.L.
      • et al.
      A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair.
      • Burton J.H.
      • Auble T.E.
      • Fuchs S.M.
      Effectiveness of 50% nitrous oxide/50% oxygen during laceration repair in children.
      • Keidan I.
      • Zaslansky R.
      • Yusim Y.
      • et al.
      Continuous flow 50:50 nitrous oxide: oxygen is effective for relief of procedural pain in the pediatric emergency department.
      • Luhmann J.D.
      • Schootman M.
      • Luhmann S.J.
      • et al.
      A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children.
      • Evans J.K.
      • Buckley S.L.
      • Alexander A.H.
      • et al.
      Analgesia for the reduction of fractures in children: a comparison of nitrous oxide with intramuscular sedation.
      • Gregory P.R.
      • Sullivan J.A.
      Nitrous oxide compared with intravenous regional anesthesia in pediatric forearm fracture manipulation.
      • Keidan I.
      • Zaslansky R.
      • Weinberg M.
      • et al.
      Sedation during voiding cystourethrography: comparison of the efficacy and safety of using oral midazolam and continuous flow nitrous oxide.
      Depth of sedation with a specific concentration of N2O may vary.
      • Sundin R.H.
      • Adriani J.
      • Alam S.
      • et al.
      Anxiolytic effects of low dosage nitrous oxide-oxygen mixtures administered continuously in apprehensive subjects.
      In a Class II study, Babl et al
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      found that with 50% to 70% N2O, 86% of children were moderately, 7% deeply, and 7% poorly sedated during ED procedures. A Class I study by Burton et al
      • Burton J.H.
      • Auble T.E.
      • Fuchs S.M.
      Effectiveness of 50% nitrous oxide/50% oxygen during laceration repair in children.
      found deep sedation in 12% of children during suturing, and a Class I study by Luhmann et al
      • Luhmann J.D.
      • Schootman M.
      • Luhmann S.J.
      • et al.
      A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children.
      and Class II studies by Hennrikus et al
      • Hennrikus W.L.
      • Simpson R.B.
      • Klingelberger C.E.
      • et al.
      Self-administered nitrous oxide analgesia for pediatric fracture reductions.
      • Hennrikus W.L.
      • Shin A.Y.
      • Klingelberger C.E.
      Self-administered nitrous oxide and a hematoma block for analgesia in the outpatient reduction of fractures in children.
      found 2% to 9% of children poorly sedated with 50% N2O during fracture reduction. Sedation also may significantly deepen when other sedative or analgesic agents are co-administered with N2O. Several studies noted as secondarily observed outcomes, that although N2O was still effective when compared with placebo, increasing distress was observed with decreasing age, especially in children less than 6 to 8 years of age.
      • Weinstein P.
      • Domoto P.K.
      • Holleman E.
      The use of nitrous oxide in the treatment of children: results of a controlled study.
      • Gamis A.S.
      • Knapp J.F.
      • Glenski J.A.
      Nitrous oxide analgesia in a pediatric emergency department.
      • Kanagasundaram S.A.
      • Lane L.J.
      • Cavalletto B.P.
      • et al.
      Efficacy and safety of nitrous oxide in alleviating pain and anxiety during painful procedures.
      • Annequin D.
      • Carbajal R.
      • Chauvin P.
      • et al.
      Fixed 50% nitrous oxide oxygen mixture for painful procedures: a French survey.
      The relationship between effectiveness of N2O and age needs further evaluation using continuous-circuit devices easily used by young children.
      Safety of Nitrous Oxide
      Key words/phrases for literature searches: nitrous oxide, procedural sedation; age 1-18 years.
      When N2O was used alone or in combination with local anesthesia in healthy (ASA Physical Status class I and class II) children, no major cardiopulmonary adverse events (apnea, significant hypoxia, hypotension, or bradycardia) were reported in the studies examined, including two
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      • Frampton A.
      • Browne G.J.
      • Lam L.T.
      • et al.
      Nurse administered relative analgesia using high concentration nitrous oxide to facilitate minor procedures in children in an emergency department.
      in which 50% to 70% N2O without additional systemic sedative or analgesic medication was administered by specially trained nurses to ASA I or II ED patients.
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      • Averley P.A.
      • Girdler N.M.
      • Bond S.
      • et al.
      A randomized controlled trial of paediatric conscious sedation for dental treatment using intravenous midazolam combined with inhaled nitrous oxide or nitrous oxide/sevoflurane.
      • Berge T.I.
      Acceptance and side effects of nitrous oxide oxygen sedation for oral surgical procedures.
      • Houpt M.I.
      • Kupietzky A.
      • Tofsky N.S.
      • et al.
      Effects of nitrous oxide on diazepam sedation of young children.
      • McCann W.
      • Wilson S.
      • Larsen P.
      • et al.
      The effects of nitrous oxide on behavior and physiological parameters during conscious sedation with a moderate dose of chloral hydrate and hydroxyzine.
      • Wilson K.
      • Welbury R.R.
      • Girdler N.M.
      A randomized, controlled, crossover trial of oral midazolam and nitrous oxide for paediatric dental sedation.
      • Wilson K.E.
      • Girdler N.M.
      • Welbury R.R.
      Randomized, controlled, cross-over clinical trial comparing intravenous midazolam sedation with nitrous oxide sedation in children undergoing dental extractions.
      • Luhmann J.D.
      • Kennedy R.M.
      • Porter F.L.
      • et al.
      A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair.
      • Burton J.H.
      • Auble T.E.
      • Fuchs S.M.
      Effectiveness of 50% nitrous oxide/50% oxygen during laceration repair in children.
      • Gamis A.S.
      • Knapp J.F.
      • Glenski J.A.
      Nitrous oxide analgesia in a pediatric emergency department.
      • Keidan I.
      • Zaslansky R.
      • Yusim Y.
      • et al.
      Continuous flow 50:50 nitrous oxide: oxygen is effective for relief of procedural pain in the pediatric emergency department.
      • Bar-Meir E.
      • Zaslansky R.
      • Regev E.
      • et al.
      Nitrous oxide administered by the plastic surgeon for repair of facial lacerations in children in the emergency room.
      • Luhmann J.D.
      • Schootman M.
      • Luhmann S.J.
      • et al.
      A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children.
      • Evans J.K.
      • Buckley S.L.
      • Alexander A.H.
      • et al.
      Analgesia for the reduction of fractures in children: a comparison of nitrous oxide with intramuscular sedation.
      • Gregory P.R.
      • Sullivan J.A.
      Nitrous oxide compared with intravenous regional anesthesia in pediatric forearm fracture manipulation.
      • Hennrikus W.L.
      • Simpson R.B.
      • Klingelberger C.E.
      • et al.
      Self-administered nitrous oxide analgesia for pediatric fracture reductions.
      • Hennrikus W.L.
      • Shin A.Y.
      • Klingelberger C.E.
      Self-administered nitrous oxide and a hematoma block for analgesia in the outpatient reduction of fractures in children.
      • Wattenmaker I.
      • Kasser J.R.
      • McGravey A.
      Self-administered nitrous oxide for fracture reduction in children in an emergency room setting.
      • Burnweit C.
      • Diana-Zerpa J.A.
      • Nahmad M.H.
      • et al.
      Nitrous oxide analgesia for minor pediatric surgical procedures: an effective alternative to conscious sedation?.
      • Ekbom K.
      • Jakobsson J.
      • Marcus C.
      Nitrous oxide inhalation is a safe and effective way to facilitate procedures in paediatric outpatient departments.
      • Henderson J.M.
      • Spence D.G.
      • Komocar L.M.
      • et al.
      Administration of nitrous oxide to pediatric patients provides analgesia for venous cannulation.
      • Kanagasundaram S.A.
      • Lane L.J.
      • Cavalletto B.P.
      • et al.
      Efficacy and safety of nitrous oxide in alleviating pain and anxiety during painful procedures.
      • Annequin D.
      • Carbajal R.
      • Chauvin P.
      • et al.
      Fixed 50% nitrous oxide oxygen mixture for painful procedures: a French survey.
      • Keidan I.
      • Zaslansky R.
      • Weinberg M.
      • et al.
      Sedation during voiding cystourethrography: comparison of the efficacy and safety of using oral midazolam and continuous flow nitrous oxide.
      • Sundin R.H.
      • Adriani J.
      • Alam S.
      • et al.
      Anxiolytic effects of low dosage nitrous oxide-oxygen mixtures administered continuously in apprehensive subjects.
      • Frampton A.
      • Browne G.J.
      • Lam L.T.
      • et al.
      Nurse administered relative analgesia using high concentration nitrous oxide to facilitate minor procedures in children in an emergency department.
      • Cleaton-Jones P.
      The laryngeal-closure reflex and nitrous oxide—oxygen analgesia.
      • Dollfus C.
      • Annequin M.
      • Adam M.
      • et al.
      Analgesia with nitrous oxide for painful procedures in pediatric hematology-oncology.
      • Dunn-Russell T.
      • Adair S.M.
      • Sams D.R.
      • et al.
      Oxygen saturation and diffusion hypoxia in children following nitrous oxide sedation.
      • Gerhardt R.T.
      • King K.M.
      • Wiegert R.S.
      Inhaled nitrous oxide versus placebo as an analgesic and anxiolytic adjunct to peripheral intravenous cannulation.
      • Roberts G.J.
      • Wignall B.K.
      Efficacy of the laryngeal reflex during oxygen—nitrous oxide sedation (relative analgesia).
      • Rubin J.
      • Brock-Utne J.G.
      • Greenberg M.
      • et al.
      Laryngeal incompetence during experimental “relative analgesia” using 50% nitrous oxide in oxygen A preliminary report.
      A Class III report summarizing patient data sheets on 35,828 administrations of N2O, 82% of which were given to children, found that 9 (0.03%) serious adverse events (somnolence, vomiting, bradycardia, vertigo, headache, nightmares, sweating) were possibly attributed to the 50% N2O.
      • Onody P.
      • Gil P.
      • Hennequin M.
      Safety of inhalation of a 50% nitrous oxide/oxygen premix A prospective survey of 35,828 administrations.
      However, no clinical information about these cases was presented, nor about 18 others with more serious events (apnea, desaturation, laryngospasm, convulsions, and a cardiac arrest) thought not to have been caused by the N2O. Deaths associated with N2O use have been due to inadvertent administration of 100% nitrous oxide, with subsequent hypoxia. As reviewed by Duncan and Moore,
      • Duncan G.H.
      • Moore P.
      Nitrous oxide and the dental patient: a review of adverse reactions.
      these tragedies point out the essential need for clinicians to understand all aspects, including mechanical, of the gas delivery device being used.
      No study was large enough to determine the risk of clinically significant pulmonary aspiration during inhalation of N2O, because of the rarity of this event. Focused attempts to answer this question found no radiopaque dye on chest radiograph after the dye was placed in the posterior pharynx of 50 children undergoing dental procedures with 20% to 65% N2O
      • Roberts G.J.
      • Wignall B.K.
      Efficacy of the laryngeal reflex during oxygen—nitrous oxide sedation (relative analgesia).
      or in 14 adult volunteers sedated with 50% N2O for 5 minutes.
      • Cleaton-Jones P.
      The laryngeal-closure reflex and nitrous oxide—oxygen analgesia.
      However, traces of dye were found on chest radiograph in 2 of 10 volunteers sedated with 50% N2O for more than 10 minutes. The clinical significance of this micro-aspiration is unclear.
      • Rubin J.
      • Brock-Utne J.G.
      • Greenberg M.
      • et al.
      Laryngeal incompetence during experimental “relative analgesia” using 50% nitrous oxide in oxygen A preliminary report.
      Whether the combination of N2O with other sedative or analgesic medications increases the risk for aspiration and other adverse events is unknown.
      Emesis was the most common adverse event reported. In 2 Class I,
      • Luhmann J.D.
      • Kennedy R.M.
      • Porter F.L.
      • et al.
      A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair.
      • Luhmann J.D.
      • Schootman M.
      • Luhmann S.J.
      • et al.
      A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children.
      6 Class II,
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      • Burton J.H.
      • Auble T.E.
      • Fuchs S.M.
      Effectiveness of 50% nitrous oxide/50% oxygen during laceration repair in children.
      • Gamis A.S.
      • Knapp J.F.
      • Glenski J.A.
      Nitrous oxide analgesia in a pediatric emergency department.
      • Gregory P.R.
      • Sullivan J.A.
      Nitrous oxide compared with intravenous regional anesthesia in pediatric forearm fracture manipulation.
      • Hennrikus W.L.
      • Simpson R.B.
      • Klingelberger C.E.
      • et al.
      Self-administered nitrous oxide analgesia for pediatric fracture reductions.
      • Hennrikus W.L.
      • Shin A.Y.
      • Klingelberger C.E.
      Self-administered nitrous oxide and a hematoma block for analgesia in the outpatient reduction of fractures in children.
      and 1 Class III
      • Evans J.K.
      • Buckley S.L.
      • Alexander A.H.
      • et al.
      Analgesia for the reduction of fractures in children: a comparison of nitrous oxide with intramuscular sedation.
      trials, the frequency of emesis with 50% N2O varied from a high of 26% (6% during the procedure) when co-administered with oral oxycodone
      • Luhmann J.D.
      • Schootman M.
      • Luhmann S.J.
      • et al.
      A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children.
      to 10%,
      • Luhmann J.D.
      • Kennedy R.M.
      • Porter F.L.
      • et al.
      A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair.
      6%,
      • Burton J.H.
      • Auble T.E.
      • Fuchs S.M.
      Effectiveness of 50% nitrous oxide/50% oxygen during laceration repair in children.
      or none when administered alone.
      • Gamis A.S.
      • Knapp J.F.
      • Glenski J.A.
      Nitrous oxide analgesia in a pediatric emergency department.
      • Evans J.K.
      • Buckley S.L.
      • Alexander A.H.
      • et al.
      Analgesia for the reduction of fractures in children: a comparison of nitrous oxide with intramuscular sedation.
      • Gregory P.R.
      • Sullivan J.A.
      Nitrous oxide compared with intravenous regional anesthesia in pediatric forearm fracture manipulation.
      • Hennrikus W.L.
      • Simpson R.B.
      • Klingelberger C.E.
      • et al.
      Self-administered nitrous oxide analgesia for pediatric fracture reductions.
      • Hennrikus W.L.
      • Shin A.Y.
      • Klingelberger C.E.
      Self-administered nitrous oxide and a hematoma block for analgesia in the outpatient reduction of fractures in children.
      No clinically apparent aspiration was noted in these studies. Babl et al
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      found that vomiting occurred in 7% of pediatric patients during N2O administration in the ED. Emesis did not appear to be associated with the length of fasting, type of procedure, depth of sedation, or length of administration. Other commonly reported minor adverse effects include nausea, dizziness, euphoria, and dysphoria.
      • Babl F.E.
      • Puspitadewi A.
      • Barnett P.
      • et al.
      Preprocedural fasting state and adverse events in children receiving nitrous oxide for procedural sedation and analgesia.
      • Luhmann J.D.
      • Kennedy R.M.
      • Porter F.L.
      • et al.
      A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair.
      • Burton J.H.
      • Auble T.E.
      • Fuchs S.M.
      Effectiveness of 50% nitrous oxide/50% oxygen during laceration repair in children.
      • Luhmann J.D.
      • Schootman M.
      • Luhmann S.J.
      • et al.
      A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children.
      • Annequin D.
      • Carbajal R.
      • Chauvin P.
      • et al.
      Fixed 50% nitrous oxide oxygen mixture for painful procedures: a French survey.
      • Gall O.
      • Annequin D.
      • Benoit G.
      • et al.
      Adverse events of premixed nitrous oxide and oxygen for procedural sedation in children.
      Most reported resolution of these effects within 5 minutes of cessation of N2O administration.
      Hypoxemia was found to occur rarely with N2O administration in healthy patients, in part because N2O was blended with oxygen. When end-tidal carbon dioxide (ETCO2) was measured, mild respiratory depression was found to occur when N2O was co-administered with other sedative or analgesic medications. Class II safety studies conducted in the operating room prior to general anesthesia noted increasing etco2 with increasing concentrations of N2O in children who had also received oral chloral hydrate
      • Litman R.S.
      • Kottra J.A.
      • Verga K.A.
      • et al.
      Chloral hydrate sedation: the additive sedative and respiratory depressant effects of nitrous oxide.
      or oral midazolam 0.7 mg/kg
      • Litman R.S.
      • Kottra J.A.
      • Berkowitz R.J.
      • et al.
      Breathing patterns and levels of consciousness in children during administration of nitrous oxide after oral midazolam premedication.
      but not 0.5 mg/kg.
      • Litman R.S.
      • Berkowitz R.J.
      • Ward D.S.
      Levels of consciousness and ventilatory parameters in young children during sedation with oral midazolam and nitrous oxide.
      These studies are consistent with the finding that young children sedated with oral midazolam 0.5 mg/kg+50% N2O for facial laceration repair had no significant respiratory effects.
      • Luhmann J.D.
      • Kennedy R.M.
      • Porter F.L.
      • et al.
      A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair.
      Although there have been concerns about diffusion hypoxia with cessation of N2O administration, in a Class II study, comparison of room air versus O2 for “wash out” after 30 minutes of 40% N2O found no clinically significant difference in oxygen saturations.
      • Dunn-Russell T.
      • Adair S.M.
      • Sams D.R.
      • et al.
      Oxygen saturation and diffusion hypoxia in children following nitrous oxide sedation.
      Finally, studies in healthy children undergoing elective dental procedures found no significant adverse events when N2O was combined with other low-dose sedative medications;
      • Averley P.A.
      • Girdler N.M.
      • Bond S.
      • et al.
      A randomized controlled trial of paediatric conscious sedation for dental treatment using intravenous midazolam combined with inhaled nitrous oxide or nitrous oxide/sevoflurane.
      • Houpt M.I.
      • Kupietzky A.
      • Tofsky N.S.
      • et al.
      Effects of nitrous oxide on diazepam sedation of young children.
      • McCann W.
      • Wilson S.
      • Larsen P.
      • et al.
      The effects of nitrous oxide on behavior and physiological parameters during conscious sedation with a moderate dose of chloral hydrate and hydroxyzine.
      it is not clear whether these medication combinations are safe for procedural sedation in children in the ED.
      Chronic exposure to environmental N2O may have adverse effects on health care providers, but infrequent brief contact with N2O is likely safe for individual patients, with the exception of rare patients deficient in enzymes associated with methionine synthesis or deficient in vitamin B12, in whom N2O may cause central nervous system injury.
      • Selzer R.R.
      • Rosenblatt D.S.
      • Laxova R.
      • et al.
      Adverse effect of nitrous oxide in a child with 5, 10-methylenetetrahydrofolate reductase deficiency.
      A Class III survey of female dental assistants found 60% reduction in fertility with greater than 5 hours per week of exposure to unscavenged N2O; no effect was found if the N2O was scavenged.
      • Rowland A.S.
      • Baird D.D.
      • Weinberg C.R.
      • et al.
      Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide.
      Subsequent analysis of that data also found a relative risk of 2.6 for spontaneous abortion if female dental assistants were working with unscavenged N2O.
      • Rowland A.S.
      • Baird D.D.
      • Shore D.L.
      • et al.
      Nitrous oxide and spontaneous abortion in female dental assistants.
      A Class III survey of midwives found no association between N2O use at delivery and fertility except in those assisting at greater than 30 deliveries a month.
      • Ahlborg Jr, G.
      • Axelsson G.
      • Bodin L.
      Shift work, nitrous oxide exposure and subfertility among Swedish midwives.
      No association was found with spontaneous abortions.
      • Axelsson G.
      • Ahlborg Jr, G.
      • Bodin L.
      Shift work, nitrous oxide exposure, and spontaneous abortion among Swedish midwives.
      Another Class III survey of dentists and their assistants found that users with “heavy exposure” to N2O were more likely to report numbness, tingling, or muscle weakness.
      • Brodsky J.B.
      • Cohen E.N.
      • Brown Jr, B.W.
      • et al.
      Exposure to nitrous oxide and neurologic disease among dental professionals.
      • 3
        Can oral sucrose be used to reduce infant distress due to minor, painful procedures in the ED?

       Patient Management Recommendations

       Level A recommendations

      Oral sucrose can be used to reduce signs of distress due to minor, painful procedures in preterm and term neonates (less than 28 days old).

       Level B recommendations

      • (1)
        Effective doses for neonates range from 0.1 mL of 24% to 2 mL of 50% sucrose (with the most commonly studied dose being 2 mL of 24% sucrose).
      • (2)
        Oral sucrose can be used in combination with sucking (ie, a pacifier) to improve its efficacy.
      • (3)
        Oral sucrose may be safely administered to full-term neonates and infants.

       Level C recommendations

      • (1)
        Sucrose appears to be less effective in infants between 1 month and 6 months of age.
      • (2)
        Effective doses for infants between 1 month and 6 months of age may range from 0.75 mL of 50% to 2 mL of 75% sucrose.
      • (3)
        Effective doses for very-low-birth-weight, preterm infants may be as low as 0.05 mL of 24% sucrose.
      • (4)
        Oral sucrose should be given approximately 2 minutes before an invasive procedure.
      • (5)
        Oral sucrose may be safely given to low-birth-weight, preterm neonates.
       Key words/phrases for literature searches: sucrose, behavioral distress, pain, infants, neonates, procedural sedation; age 0-1 year.
      Sucrose has been widely studied as a nonpharmacologic intervention to reduce pain in young infants undergoing minor, invasive procedures. The AAP, in their guideline “The Relief of Pain and Anxiety in Pediatric Patients in Emergency Medical Systems,” recommends that oral sucrose be used as an adjunct for limiting procedural pain in neonates and infants younger than 6 months of age, and suggests that it may be more effective when given in combination with a pacifier.
      • Zempsky W.T.
      • Cravero J.P.
      American Academy of Pediatrics Committee on Pediatric Emergency Medicine and Section on Anesthesiology and Pain Medicine
      Relief of pain and anxiety in pediatric patients in emergency medical systems.
      The Cochrane Collaboration performed a systematic review of the topic for neonates and concluded that sucrose is safe and effective for reducing pain caused by a single, painful event (eg, heel lance or venipuncture).
      • Stevens B.
      • Yamada J.
      • Ohlsson A.
      Sucrose for analgesia in newborn infants undergoing painful procedures.
      Despite a large body of literature published on the subject, there are still a number of unanswered questions about the use of sucrose for pain relief in infants. Biological and contextual factors affect sucrose’s effectiveness and contribute to difficulty in determining the optimal dose and effect magnitude. Patient factors include the infant’s gestational age and postnatal age, baseline level of alertness, overall health, and previous painful experiences. Contextual factors include comfort measures used along with sucrose during the procedure, such as holding by a nurse or parent or using pacifiers. The “pharmacologic” variables related to sucrose involve not only the concentration and volume given but also the method of administration (by syringe or pacifier and whether on the anterior or posterior tongue), frequency of administration, and time of administration before the painful procedure. Questions also remain about the efficacy of sucrose in older infants. Published trials have most commonly enrolled preterm and term neonates. Fewer studies have included older infants, limiting the conclusions that can be drawn about this group. It is also unclear how well findings from the commonly studied neonatal intensive care unit (NICU) or well-baby population extrapolate to the ED; only 1 trial actually took place in the ED.
      • Rogers A.J.
      • Greenwald M.H.
      • Deguzman M.A.
      • et al.
      A randomized, controlled trial of sucrose analgesia in infants younger than 90 days of age who require bladder catheterization in the pediatric emergency department.
      The ED generally sees an overall healthier population, with fewer preterm infants than the NICU, but, unlike the well-baby nursery, sees infants with acute illnesses. Additionally, the painful stimulus studied in some trials is not relevant to the ED (eg, circumcision), whereas other common ED procedures, such as bladder catheterization or lumbar puncture, were rarely or never evaluated.
      Some uncertainty is also inherent in the measurement of an infant’s perception of pain. Most studies measured various behavioral or physiologic markers of distress or a combination thereof. A commonly used outcome measure is infant crying, which has intuitive “face validity.” However, the best quantitative measure of crying (percentage of time crying, duration of the cry, total time crying, etc) has yet to be determined. Vital signs have also been used. For example, tachycardia and a decrease in oxygen saturation have been identified as indirect evidence that pain is occurring.
      • Porter F.L.
      • Wolf C.M.
      • Miller J.P.
      Procedural pain in newborn infants: the influence of intensity and development.
      Physiologic variables may be affected by many factors other than pain and are therefore nonspecific. In an attempt to improve the sensitivity, reliability, and validity of infant pain assessment, numerous composite measures incorporating behavioral, physiologic, and contextual markers have been developed and validated. Validated composite scales that were used in the trials reviewed in this section include the Neonatal Infant Pain Scale (NIPS),
      • Lawrence J.
      • Alcock D.
      • McGrath P.
      • et al.
      The development of a tool to assess neonatal pain.
      the Neonatal Facial Coding Scale (NFCS),
      • Grunau R.V.
      • Craig K.D.
      Pain expression in neonates: facial action and cry.
      the Douleur Aigue chez le Nouveau-ne (DAN),
      • Carbajal R.
      • Paupe A.
      • Hoenn E.
      • et al.
      APN: evaluation behavioral scale of acute pain in newborn infants.
      and the Premature Infant Pain Profile (PIPP),
      • Stevens B.
      • Johnston C.
      • Petryshen P.
      • et al.
      Premature Infant Pain Profile: development and initial validation.
      the latter of which takes gestational age into account. Overall, the heterogeneity of outcome measures used, variability regarding when the measurements are taken (during or after the procedure), and the variable reliability of the measures themselves have made direct comparisons among studies difficult.
      The following discussion reviews the published literature to determine the efficacy of oral sucrose in reducing signs of pain or distress in infants. Overall, studies were well-designed, randomized controlled trials that were blinded unless precluded by the intervention. Many had fairly small sample sizes (<100 infants), resulting in wide CIs, and limiting external validity. Studies were downgraded for various methodological weaknesses, as detailed in the Evidentiary Table (available online at http://www.annemergmed.com, and online at http://www.acep.org on the Clinical Policies page), or if their design did not directly answer the critical question. Although glucose, breast milk (which contains 7% lactose), and some nonsucrose sweeteners may also act through the same mechanism, this discussion is limited to sucrose.
      Efficacy of sucrose in neonates
      The Class I Cochrane meta-analysis calculated a weighted mean difference (WMD) and CI for several outcome measures.
      • Stevens B.
      • Yamada J.
      • Ohlsson A.
      Sucrose for analgesia in newborn infants undergoing painful procedures.
      PIPP scores were pooled for 3 studies that used doses ranging from 0.1 mL to 0.5 mL of 24% sucrose.
      • Stevens B.
      • Johnston C.
      • Franck L.
      • et al.
      The efficacy of developmentally sensitive interventions and sucrose for relieving procedural pain in very low birth weight neonates.
      • Johnston C.C.
      • Stremler R.
      • Horton L.
      • et al.
      Effect of repeated doses of sucrose during heel stick procedure in preterm neonates.
      • Gibbins S.
      • Stevens B.
      • Hodnett E.
      • et al.
      Efficacy and safety of sucrose for procedural pain relief in preterm and term neonates.
      PIPP scores can range from 0 (no pain) to 18 for term, or 21 for preterm, infants (maximal pain). The WMD was highly statistically significant for sucrose relative to control at 30 seconds (-1.64; 95% CI –2.47 to –0.81; P=0.0001) and 60 seconds after heel stick (-2.0; 95% CI –3.08 to –1.05; P=0.0001). The authors also pooled data for change in heart rate from 2 studies and found that there was no significant change with doses ranging from 2 mL of 25% to 30% sucrose at 1 minute (WMD 0.90; 95% CI –5.81 to 7.61) or 3 minutes (WMD -6.20; 95% CI –15.27 to 2.88) after heel stick.
      • Isik U.
      • Ozek E.
      • Bilgen H.
      • et al.
      Comparison of oral glucose and sucrose solutions on pain response in neonates.
      • Haouari N.
      • Wood C.
      • Griffiths G.
      • et al.
      The analgesic effect of sucrose in full term infants: a randomised controlled trial.
      Results for preterm and term infants were not considered separately in this systematic review.
      Ten Class II, randomized, controlled trials evaluated the effect of sucrose on behavioral and/or physiologic indicators of pain, or composite pain scores, in full term neonates. Results of both primary and secondary outcome measures are described here.
      • Isik U.
      • Ozek E.
      • Bilgen H.
      • et al.
      Comparison of oral glucose and sucrose solutions on pain response in neonates.
      • Haouari N.
      • Wood C.
      • Griffiths G.
      • et al.
      The analgesic effect of sucrose in full term infants: a randomised controlled trial.
      • Abad F.
      • Diaz-Gomez N.M.
      • Domenech E.
      • et al.
      Oral sucrose compares favourably with lidocaine-prilocaine cream for pain relief during venepuncture in neonates.
      • Gormally S.
      • Barr R.G.
      • Wertheim L.
      • et al.
      Contact and nutrient caregiving effects on newborn infant pain responses.
      • Greenberg C.S.
      A sugar-coated pacifier reduces procedural pain in newborns.
      • Ors R.
      • Ozek E.
      • Baysoy G.
      • et al.
      Comparison of sucrose and human milk on pain response in newborns.
      • Allen K.D.
      • White D.D.
      • Walburn J.N.
      Sucrose as an analgesic agent for infants during immunization injections.
      • Ogawa S.
      • Ogihara T.
      • Fujiwara E.
      • et al.
      Venepuncture is preferable to heel lance for blood sampling in term neonates.
      • Carbajal R.
      • Chauvet X.
      • Couderc S.
      • et al.
      Randomised trial of analgesic effects of sucrose, glucose, and pacifiers in term neonates.
      • Guala A.
      • Pastore G.
      • Liverani M.E.
      • et al.
      Glucose or sucrose as an analgesic for newborns: a randomized controlled blind trial.
      Although some of the trials below had multiple treatment arms in addition to sucrose, only comparisons of sucrose versus water or placebo are described. The majority of trials found a reduction in crying in the sucrose group during heelstick or venipuncture,
      • Isik U.
      • Ozek E.
      • Bilgen H.
      • et al.
      Comparison of oral glucose and sucrose solutions on pain response in neonates.
      • Abad F.
      • Diaz-Gomez N.M.
      • Domenech E.
      • et al.
      Oral sucrose compares favourably with lidocaine-prilocaine cream for pain relief during venepuncture in neonates.
      • Gormally S.
      • Barr R.G.
      • Wertheim L.
      • et al.
      Contact and nutrient caregiving effects on newborn infant pain responses.
      • Greenberg C.S.
      A sugar-coated pacifier reduces procedural pain in newborns.
      • Ors R.
      • Ozek E.
      • Baysoy G.
      • et al.
      Comparison of sucrose and human milk on pain response in newborns.
      whereas a minority found no effect.
      • Allen K.D.
      • White D.D.
      • Walburn J.N.
      Sucrose as an analgesic agent for infants during immunization injections.
      • Ogawa S.
      • Ogihara T.
      • Fujiwara E.
      • et al.
      Venepuncture is preferable to heel lance for blood sampling in term neonates.
      Pain scores (including DAN and facial expression scores) were lower in the sucrose group in some trials
      • Ogawa S.
      • Ogihara T.
      • Fujiwara E.
      • et al.
      Venepuncture is preferable to heel lance for blood sampling in term neonates.
      • Carbajal R.
      • Chauvet X.
      • Couderc S.
      • et al.
      Randomised trial of analgesic effects of sucrose, glucose, and pacifiers in term neonates.
      but not in others.
      • Haouari N.
      • Wood C.
      • Griffiths G.
      • et al.
      The analgesic effect of sucrose in full term infants: a randomised controlled trial.
      • Gormally S.
      • Barr R.G.
      • Wertheim L.
      • et al.
      Contact and nutrient caregiving effects on newborn infant pain responses.
      Response of vital signs to painful stimulus was variable; some trials found a decrease in heart rate in the sucrose group,
      • Abad F.
      • Diaz-Gomez N.M.
      • Domenech E.
      • et al.
      Oral sucrose compares favourably with lidocaine-prilocaine cream for pain relief during venepuncture in neonates.
      • Ors R.
      • Ozek E.
      • Baysoy G.
      • et al.
      Comparison of sucrose and human milk on pain response in newborns.
      but most trials found no consistent difference in heart rate,
      • Isik U.
      • Ozek E.
      • Bilgen H.
      • et al.
      Comparison of oral glucose and sucrose solutions on pain response in neonates.
      • Gormally S.
      • Barr R.G.
      • Wertheim L.
      • et al.
      Contact and nutrient caregiving effects on newborn infant pain responses.
      • Guala A.
      • Pastore G.
      • Liverani M.E.
      • et al.
      Glucose or sucrose as an analgesic for newborns: a randomized controlled blind trial.
      respiratory rate,
      • Abad F.
      • Diaz-Gomez N.M.
      • Domenech E.
      • et al.
      Oral sucrose compares favourably with lidocaine-prilocaine cream for pain relief during venepuncture in neonates.
      SaO2,
      • Haouari N.
      • Wood C.
      • Griffiths G.
      • et al.
      The analgesic effect of sucrose in full term infants: a randomised controlled trial.
      • Abad F.
      • Diaz-Gomez N.M.
      • Domenech E.
      • et al.
      Oral sucrose compares favourably with lidocaine-prilocaine cream for pain relief during venepuncture in neonates.
      or vagal tone
      • Gormally S.
      • Barr R.G.
      • Wertheim L.
      • et al.
      Contact and nutrient caregiving effects on newborn infant pain responses.
      • Greenberg C.S.
      A sugar-coated pacifier reduces procedural pain in newborns.
      among treatment groups.
      Five Class II trials looked at sucrose in preterm infants. Crying time was consistently reduced with sucrose in this age group.
      • Abad F.
      • Diaz N.M.
      • Domenech E.
      • et al.
      Oral sweet solution reduces pain-related behaviour in preterm infants.
      • Acharya A.B.
      • Annamali S.
      • Taub N.A.
      • et al.
      Oral sucrose analgesia for preterm infant venepuncture.
      • Bucher H.U.
      • Moser T.
      • von Siebenthal K.
      • et al.
      Sucrose reduces pain reaction to heel lancing in preterm infants: a placebo-controlled, randomized and masked study.
      • Ramenghi L.A.
      • Evans D.J.
      • Levene M.I.
      ”Sucrose analgesia”: absorptive mechanism or taste perception?.
      • Johnston C.C.
      • Stremler R.L.
      • Stevens B.J.
      • et al.
      Effectiveness of oral sucrose and simulated rocking on pain response in preterm neonates.
      Three trials that evaluated behavior using the NFCS or a “composite behavioral scale” found that scores were lower in the treatment group.
      • Acharya A.B.
      • Annamali S.
      • Taub N.A.
      • et al.
      Oral sucrose analgesia for preterm infant venepuncture.
      • Ramenghi L.A.
      • Evans D.J.
      • Levene M.I.
      ”Sucrose analgesia”: absorptive mechanism or taste perception?.
      • Johnston C.C.
      • Stremler R.L.
      • Stevens B.J.
      • et al.
      Effectiveness of oral sucrose and simulated rocking on pain response in preterm neonates.
      Physiologic effects again were mixed; several studies found a lower heart rate
      • Acharya A.B.
      • Annamali S.
      • Taub N.A.
      • et al.
      Oral sucrose analgesia for preterm infant venepuncture.
      • Bucher H.U.
      • Moser T.
      • von Siebenthal K.
      • et al.
      Sucrose reduces pain reaction to heel lancing in preterm infants: a placebo-controlled, randomized and masked study.
      and respiratory rate
      • Bucher H.U.
      • Moser T.
      • von Siebenthal K.
      • et al.
      Sucrose reduces pain reaction to heel lancing in preterm infants: a placebo-controlled, randomized and masked study.
      in the treatment group, whereas others found no effect on heart rate,
      • Abad F.
      • Diaz N.M.
      • Domenech E.
      • et al.
      Oral sweet solution reduces pain-related behaviour in preterm infants.
      • Johnston C.C.
      • Stremler R.L.
      • Stevens B.J.
      • et al.
      Effectiveness of oral sucrose and simulated rocking on pain response in preterm neonates.
      SaO2,
      • Acharya A.B.
      • Annamali S.
      • Taub N.A.
      • et al.
      Oral sucrose analgesia for preterm infant venepuncture.
      • Bucher H.U.
      • Moser T.
      • von Siebenthal K.
      • et al.
      Sucrose reduces pain reaction to heel lancing in preterm infants: a placebo-controlled, randomized and masked study.
      or cerebral blood flow.
      • Bucher H.U.
      • Moser T.
      • von Siebenthal K.
      • et al.
      Sucrose reduces pain reaction to heel lancing in preterm infants: a placebo-controlled, randomized and masked study.
      An additional 11 Class III studies investigating the analgesic efficacy with various invasive procedures in term and/or preterm infants were identified.
      • Stevens B.
      • Johnston C.
      • Franck L.
      • et al.
      The efficacy of developmentally sensitive interventions and sucrose for relieving procedural pain in very low birth weight neonates.
      • Ramenghi L.A.
      • Griffith G.C.
      • Wood C.M.
      • et al.
      Effect of non-sucrose sweet tasting solution on neonatal heel prick responses.
      • Blass E.M.
      Milk-induced hypoalgesia in human newborns.
      • Blass E.M.
      • Hoffmeyer L.B.
      Sucrose as an analgesic for newborn infants.
      • Harrison D.
      • Johnston L.
      • Loughnan P.
      Oral sucrose for procedural pain in sick hospitalized infants: a randomized-controlled trial.
      • Herschel M.
      • Khoshnood B.
      • Ellman C.
      • et al.
      Neonatal circumcision Randomized trial of a sucrose pacifier for pain control.
      • Mitchell A.
      • Stevens B.
      • Mungan N.
      • et al.
      Analgesic effects of oral sucrose and pacifier during eye examinations for retinopathy of prematurity.
      • Mohan C.G.
      • Risucci D.A.
      • Casimir M.
      • et al.
      Comparison of analgesics in ameliorating the pain of circumcision.
      • Ramenghi L.A.
      • Wood C.M.
      • Griffith G.C.
      • et al.
      Reduction of pain response in premature infants using intraoral sucrose.
      • Rushforth J.A.
      • Levene M.I.
      Effect of sucrose on crying in response to heel stab.
      • Stang H.J.
      • Snellman L.W.
      • Condon L.M.
      • et al.
      Beyond dorsal penile nerve block: a more humane circumcision.
      Most found some reduction in measures of distress caused by painful procedures.
      Efficacy in older infants
      Fewer studies have evaluated the analgesic effect of sucrose in older infants. Overall sucrose appears to be less effective than in neonates, but there may be a modest reduction in crying time with higher doses of sucrose in 2-, 4-, and 6-month-olds. Three Class II trials evaluated sucrose for intramuscular vaccinations in an outpatient setting.
      • Allen K.D.
      • White D.D.
      • Walburn J.N.
      Sucrose as an analgesic agent for infants during immunization injections.
      • Barr R.G.
      • Young S.N.
      • Wright J.H.
      • et al.
      “Sucrose analgesia” and diphtheria-tetanus-pertussis immunizations at 2 and 4 months.
      • Lewindon P.J.
      • Harkness L.
      • Lewindon N.
      Randomised controlled trial of sucrose by mouth for the relief of infant crying after immunisation.
      Barr et al
      • Barr R.G.
      • Young S.N.
      • Wright J.H.
      • et al.
      “Sucrose analgesia” and diphtheria-tetanus-pertussis immunizations at 2 and 4 months.
      compared 0.75 mL of 50% sucrose versus water in infants receiving intramuscular immunizations at 2 months of age and then again at 4 months. They found no difference in percentage of time spent crying during injection, but a smaller percentage of time crying during the 60 seconds after injection in the sucrose group (69% versus 83%; P<0.05). In another study, Lewindon et al
      • Lewindon P.J.
      • Harkness L.
      • Lewindon N.
      Randomised controlled trial of sucrose by mouth for the relief of infant crying after immunisation.
      compared an unusually high concentration of sucrose (2 mL of 75%) against water in 2-, 4-, and 6-month-olds. Mean total crying time was reduced from 59 to 36 seconds (P=0.00008) and mean first cry duration decreased from 42 to 29 seconds (P=0.0004) in the sucrose group. Of interest, although nurses perceived infant distress to be lower in the sucrose group, parents did not perceive a difference in the level of infant distress between the 2 groups. Allen et al,
      • Allen K.D.
      • White D.D.
      • Walburn J.N.
      Sucrose as an analgesic agent for infants during immunization injections.
      on the other hand, found no difference in crying time between the 12% sucrose group versus water in any age category (2 weeks to 18 months). Another study, which differed from the others in that it compared 25% sucrose plus nonnutritive sucking, plus holding against control, found that total crying time and first cry duration were reduced in the treatment group, but there was no effect on heart rate.
      • Reis E.C.
      • Roth E.K.
      • Syphan J.L.
      • et al.
      Effective pain reduction for multiple immunization injections in young infants.
      Parents preferred the intervention, and nurses found the intervention to be no more difficult than control.
      The only trial to take place in the ED enrolled infants less than 91 days of age who required bladder catheterization during their evaluation.
      • Rogers A.J.
      • Greenwald M.H.
      • Deguzman M.A.
      • et al.
      A randomized, controlled trial of sucrose analgesia in infants younger than 90 days of age who require bladder catheterization in the pediatric emergency department.
      In this Class II trial, there was no difference between the placebo and 24% sucrose for any of the 3 primary outcome measures: composite behavioral scale (DAN score), percentage of infants crying during catheter insertion, and time to return to behavioral baseline. A post hoc subgroup analysis found a difference in the neonates but no difference in the 31- to 60- and 61- to 90-day age groups. The duration of the painful procedure was considerably longer than the noxious stimuli evaluated in the other studies and may have affected the observed efficacy of sucrose.
      Dose of sucrose
      Several studies have directly compared the efficacy of various doses of sucrose. In a Class II trial, Abad et al
      • Abad F.
      • Diaz N.M.
      • Domenech E.
      • et al.
      Oral sweet solution reduces pain-related behaviour in preterm infants.
      found a reduction in crying from 63 seconds in the 12% group to 19 seconds in the 24% group (versus 73 seconds in controls; P=0.0256). In another Class II trial, Haouari et al
      • Haouari N.
      • Wood C.
      • Griffiths G.
      • et al.
      The analgesic effect of sucrose in full term infants: a randomised controlled trial.
      compared 2 mL of 12.5%, 25%, and 50% sucrose in full-term infants and found a significant reduction in the primary outcome measure, postprocedural crying time, only in the 50% group versus controls (P=0.02). Blass and Shah,
      • Blass E.M.
      • Shah A.
      Pain-reducing properties of sucrose in human newborns.
      in a Class III study, compared a range of sucrose doses, 2 mL of 6%, 12%, and 17%, given over 2 minutes before heel stick. Looking at crying per unit time, they found no dose-response curve. Guala et al,
      • Guala A.
      • Pastore G.
      • Liverani M.E.
      • et al.
      Glucose or sucrose as an analgesic for newborns: a randomized controlled blind trial.
      in a Class II trial, compared 33% and 50% sucrose in full-term infants and found no difference in heart rate. Ramenghi et al
      • Ramenghi L.A.
      • Wood C.M.
      • Griffith G.C.
      • et al.
      Reduction of pain response in premature infants using intraoral sucrose.
      compared 25% and 50% sucrose (among other interventions) in a Class III trial and found that although sucrose was superior to water in reducing crying time and behavior scores, there was no difference in efficacy between the 25% and 50% groups. Thus, these individual trials did not show consistent evidence of a dose-response curve, although the higher doses more consistently had a positive effect. Unfortunately, as the authors of the Cochrane review note, the inconsistency of dosing across trials (both in amount and concentration given) preclude pooling of data to determine the minimal effective or optimal dose of sucrose.
      • Stevens B.
      • Yamada J.
      • Ohlsson A.
      Sucrose for analgesia in newborn infants undergoing painful procedures.
      Doses investigated and found to be effective in older infants were generally higher than those in neonates.
      Timing of sucrose administration
      Only 1 trial was specifically designed to evaluate the optimal timing of sucrose administration before a procedure. In this Class III study, Blass and Shah145 compared 2 mL of 12% sucrose at 30, 60, 90, 120, and 240 seconds before heel stick. The study included healthy newborns, but the number of subjects enrolled in this subsection of this 2-part study was not clearly stated. The group given sucrose 120 seconds before the procedure cried significantly less than all other groups (P<0.03). Most subsequent studies have administered sucrose approximately 2 minutes before the invasive procedure.
      Efficacy in combination with other comfort measures
      In many of the studies evaluating the efficacy of sucrose, 1 or more of the arms included other non-pharmacologic comfort measures, such as a pacifier or holding. Three Class II
      • Gibbins S.
      • Stevens B.
      • Hodnett E.
      • et al.
      Efficacy and safety of sucrose for procedural pain relief in preterm and term neonates.
      • Greenberg C.S.
      A sugar-coated pacifier reduces procedural pain in newborns.
      • Carbajal R.
      • Chauvet X.
      • Couderc S.
      • et al.
      Randomised trial of analgesic effects of sucrose, glucose, and pacifiers in term neonates.
      and 2 Class III studies
      • Blass E.M.
      • Hoffmeyer L.B.
      Sucrose as an analgesic for newborn infants.
      • Mohan C.G.
      • Risucci D.A.
      • Casimir M.
      • et al.
      Comparison of analgesics in ameliorating the pain of circumcision.
      found that the combination of 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 more effective than sucrose and/or a pacifier alone. In 1 Class III study in very-low-birth-weight, preterm infants, Stevens et al
      • Stevens B.
      • Johnston C.
      • Franck L.
      • et al.
      The efficacy of developmentally sensitive interventions and sucrose for relieving procedural pain in very low birth weight neonates.
      did not find a difference between the sucrose plus pacifier group and the water plus pacifier group. Another Class III study found sucrose plus a pacifier to be more effective than water plus a pacifier in preterm infants during portions of the retinal examination of prematurity, considered a ”highly invasive” procedure.
      • Mitchell A.
      • Stevens B.
      • Mungan N.
      • et al.
      Analgesic effects of oral sucrose and pacifier during eye examinations for retinopathy of prematurity.
      Two Class II studies compared sucrose plus holding versus sucrose or holding alone during heel stick.
      • Gormally S.
      • Barr R.G.
      • Wertheim L.
      • et al.
      Contact and nutrient caregiving effects on newborn infant pain responses.
      • Johnston C.C.
      • Stremler R.L.
      • Stevens B.J.
      • et al.
      Effectiveness of oral sucrose and simulated rocking on pain response in preterm neonates.
      Both found that sucrose and sucrose plus holding reduced crying or facial expressions of pain compared with controls. Reis et al
      • Reis E.C.
      • Roth E.K.
      • Syphan J.L.
      • et al.
      Effective pain reduction for multiple immunization injections in young infants.
      compared the combination of sucrose, nonnutritive sucking, and holding versus water in older infants and found a reduction in crying in the treatment group.
      Safety of sucrose
      Overall, adverse events appear to be uncommon and minor. Eight trials including more than 800 infants commented that no adverse effects of sucrose administration had been noted.
      • Rogers A.J.
      • Greenwald M.H.
      • Deguzman M.A.
      • et al.
      A randomized, controlled trial of sucrose analgesia in infants younger than 90 days of age who require bladder catheterization in the pediatric emergency department.
      • Stevens B.
      • Johnston C.
      • Franck L.
      • et al.
      The efficacy of developmentally sensitive interventions and sucrose for relieving procedural pain in very low birth weight neonates.
      • Ogawa S.
      • Ogihara T.
      • Fujiwara E.
      • et al.
      Venepuncture is preferable to heel lance for blood sampling in term neonates.
      • Carbajal R.
      • Chauvet X.
      • Couderc S.
      • et al.
      Randomised trial of analgesic effects of sucrose, glucose, and pacifiers in term neonates.
      • Guala A.
      • Pastore G.
      • Liverani M.E.
      • et al.
      Glucose or sucrose as an analgesic for newborns: a randomized controlled blind trial.
      • Mohan C.G.
      • Risucci D.A.
      • Casimir M.
      • et al.
      Comparison of analgesics in ameliorating the pain of circumcision.
      • Ramenghi L.A.
      • Wood C.M.
      • Griffith G.C.
      • et al.
      Reduction of pain response in premature infants using intraoral sucrose.
      • Reis E.C.
      • Roth E.K.
      • Syphan J.L.
      • et al.
      Effective pain reduction for multiple immunization injections in young infants.
      Only Gibbins et al
      • Gibbins S.
      • Stevens B.
      • Hodnett E.
      • et al.
      Efficacy and safety of sucrose for procedural pain relief in preterm and term neonates.
      noted any adverse events: 3 episodes of desaturation in the treatment group receiving oral sucrose through a syringe, 2 episodes in the pacifier group, and none in the combined sucrose plus pacifier group. These events were too infrequent to perform statistical analysis. As reported in the Cochrane review, no intervention was required. One infant choked on the water and pacifier but recovered within 10 seconds.
      A single, older study that was investigating the use of nutritional supplementation in very-low-birth-weight infants (<1.3 kg) administered frequent doses of calcium lactate in a 20% sucrose vehicle (with an osmolality of >1,700 mOsm/kg H2O), and found an increased risk of necrotizing enterocolitis.
      • Willis D.M.
      • Chabot J.
      • Radde I.C.
      • et al.
      Unsuspected hyperosmolality of oral solutions contributing to necrotizing enterocolitis in very-low-birth-weight infants.
      This raised concerns about the use of sucrose in at-risk infants. Although most subsequent studies administrating sucrose for analgesia have been designed to evaluate efficacy rather than safety, Stevens et al,
      • Stevens B.
      • Johnston C.
      • Franck L.
      • et al.
      The efficacy of developmentally sensitive interventions and sucrose for relieving procedural pain in very low birth weight neonates.
      in a study of 122 very-low-birth-weight, preterm infants, did not report an increased risk of necrotizing enterocolitis with a pacifier containing 0.1 mL of 24% sucrose. Necrotizing enterocolitis is generally not a risk in the ED population.
      • 4
        Is chloral hydrate effective and safe for providing procedural sedation in children in the ED?
      This critical question about chloral hydrate was included for completeness because of its use in some practice settings. A previous clinical policy focused on the efficacy and safety of etomidate, fentanyl/midazolam, ketamine, methohexital, pentobarbital, and propofol for achieving sedation and analgesia in pediatric patients undergoing procedures in the ED.
      • Mace S.E.
      • Barata I.A.
      • Cravero J.P.
      • et al.
      EMSC Grant Panel Writing Committee on Pharmacologic Agents Used in Pediatric Sedation and Analgesia in the Emergency Department Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department.
      These recommendations about the safety and efficacy of chloral hydrate do not imply superiority to the above medications. SeeAppendix Cfor the recommendations from the previous clinical policy.

       Patient Management Recommendations for Chloral Hydrate

       Level A recommendations

      • (1)
        Chloral hydrate may be used to provide effective procedural sedation in pediatric patients undergoing painless diagnostic studies. However, children receiving chloral hydrate should be properly monitored and managed by appropriately trained personnel due to the risk of respiratory depression and hypoxia.
      • (2)
        Chloral hydrate should not be considered a first-line agent in children older than 48 months because of decreased efficacy as compared with younger children.

       Level B recommendations

      None specified.

       Level C recommendations

      • (1)
        Chloral hydrate has the potential for resedation and may produce residual effects up to 24 hours after administration.
      • (2)
        Chloral hydrate may be used safely and effectively in properly monitored children who have congenital cardiac anomalies and are undergoing painless diagnostic procedures.
      • (3)
        Chloral hydrate should not be used in children with neurodevelopmental disorders due to an increased incidence of adverse effects and decreased efficacy as compared with healthy children.
      • (4)
        Pediatric patients receiving chloral hydrate should not be intentionally fasted because of increased procedural sedation failure rates.
      The evidentiary basis for the efficacy and safety of a given drug may differ. Considering that significant adverse events are generally rare, it is likely that there is stronger evidence for efficacy than for safety. When assigning one overall recommendation for a given drug based on combining these 2 distinct attributes (efficacy and safety) of the drug, the lowest most conservative level of evidence has been designated.
      Efficacy of Chloral Hydrate
      Key words/phrases for literature searches: chloral hydrate, procedural sedation; age 1-18 years.
      Chloral hydrate is a sedative hypnotic agent first introduced into clinical practice in the middle 1800s. The drug may be administered orally or rectally and has been described as an anxiolytic adjunct for dental procedures and as a single or combined sedative agent for painless diagnostic studies.