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

Article Outline

• Preface
• Introduction
• Methodology
  • Level A recommendations
  • Level B recommendations
  • Level C recommendations
  • Scope of Application
  • Inclusion Criteria
  • Exclusion Criteria
• Critical Questions
  • Patient Management Recommendations
    • Level A recommendations
    • Level B recommendations
    • Level C recommendations
  • Patient Management Recommendations for Nitrous Oxide
    • Level A recommendations
    • Level B recommendations
    • Level C recommendations
  • Patient Management Recommendations
    • Level A recommendations
    • Level B recommendations
    • Level C recommendations
  • Patient Management Recommendations for Chloral Hydrate
    • Level A recommendations
    • Level B recommendations
    • Level C recommendations
    • Patient Management Recommendations
      • Level A recommendations
      • Level B recommendations
      • Level C recommendations
• Appendix
• Appendix C. Recommendations from the 2004 clinical policy.12
• References
• Copyright

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.]

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Preface 

Emergency physicians routinely provide sedation and analgesia, monitor the respiratory and cardiovascular status, and manage critically ill patients of all ages.¹, ², ³ 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.⁴, ⁵, ⁶ 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.⁷, ⁸, ⁹, ¹⁰

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.¹, ¹¹, ¹², ¹³, ¹⁴, ¹⁵ 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.¹³, ¹⁴, ¹⁵ The choice of a particular agent or modality is influenced by many factors.¹² These include patient characteristics (eg, age, comorbidity, special health care needs) and the procedure to be performed (painful or painless, duration, etc).¹² Appropriate monitoring and assessment are critical for safe and effective procedural sedation and analgesia.³, ¹¹, ¹⁶, ¹⁷

A previous clinical policy focused on medications for achieving sedation and analgesia in pediatric patients undergoing procedures in the ED.¹² 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).¹², ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²²

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.¹⁶ 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.

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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.¹⁶ 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.¹⁸, ²⁰, ²² 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.¹⁹, ²⁰, ²² 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.¹⁹, ²⁰, ²² 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.²³ In children, deep or dissociative sedation is usually required for painful procedures.²⁴

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.¹⁷ Such skills are a requirement of emergency medicine training programs and an essential component of emergency medicine practice.³, ⁴, ⁵

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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.

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Critical Questions 

Patient Management Recommendations 

None specified.

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

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.²⁵ 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.²⁶, ²⁷, ²⁸, ²⁹, ³⁰ 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 al²⁸ and Borland et al.²⁹ When both emergent and elective patients of all ages are reviewed, the incidence decreases to less than 1:3,500.³⁰, ³¹, ³² During emergency surgery, the incidence of reported aspiration increases to 1:895 in adults and general population patients²⁷ and as frequent as 1:373 patients in the Warner et al pediatric study.²⁸ 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.²⁷, ²⁸, ²⁹ Further, inhalational anesthetics can be emetogenic, with documented postoperative nausea and vomiting described in up to one third of all surgical patients.³³, ³⁴ 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%.²⁶, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰

A significant relationship has been demonstrated to exist between aspiration during general anesthesia and the patient’s ASA physical status.²⁹ 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).²⁹ Warner et al²⁸ 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.²⁶, ³⁰, ³⁷, ³⁸, ³⁹, ⁴¹, ⁴²

Documentation of clinically significant or subclinical aspiration events during procedural sedation and analgesia is extremely limited. Only 1 study reports any incidents of aspiration.⁴³ 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.²⁵, ³²

Concerning NPO status, 2 Class I⁴⁴, ⁴⁵ and 2 Class II studies⁴⁶, ⁴⁷ evaluated gastric fluid volume and pH after various fasting periods. In one of the Class I studies, Maekawa et al⁴⁴ 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.⁴⁵ These findings are supported by a Class II study by Ingebo et al⁴⁶ 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.⁴⁶

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.⁴⁷ 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.²⁶, ³⁵, ³⁷, ³⁸, ⁴², ⁴³, ⁴⁸, ⁴⁹ Five Class II²⁶, ³⁵, ³⁷, ⁴², ⁴³ and 3 Class III³⁸, ⁴⁸, ⁴⁹ 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,⁴³ 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,²⁶ 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.²⁶ In another Class II study, Babl et al³⁵ 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.³⁵

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.³⁷ 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.³⁷ 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.⁴⁸ In a Class III study, Keiden et al⁴⁹ 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.⁴⁹

As previously noted, the only documented cases of aspiration were discussed in a Class II study by Hoffman et al.⁴³ 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.⁴³

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.⁵⁰

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.¹² See Appendix C for the recommendations from the previous clinical policy.

Patient Management Recommendations for Nitrous Oxide 

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

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

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.⁵¹ 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.⁵² N₂O has both opioid agonist and N-methyl-D-aspartate (NMDA) glutamate receptor antagonist effects.⁵³, ⁵⁴ In healthy patients, N₂O has minimal cardiovascular or respiratory effects;⁵⁵, ⁵⁶, ⁵⁷ however, it may enhance the depressed response to hypoxia and hypercarbia induced by other agents.⁵⁵, ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹ 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.⁶⁰ A 50% concentration of N₂O has also been used for management of acute pain in adults in out-of-hospital and ED settings.⁶¹, ⁶² 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.⁶³

Numerous studies in children undergoing dental procedures in dental offices detail the effectiveness of N₂O in reducing anxiety and distress,⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹ 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,⁷², ⁷³ 2 Class II,⁷⁴, ⁷⁵ and 1 Class III⁷⁶ ED-based studies. Luhmann et al⁷² 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 al⁷³ also found reduced distress with 50% N₂O during suturing. Gamis et al,⁷⁴ 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,⁷⁷ 4 Class II studies,⁷⁸, ⁷⁹, ⁸⁰, ⁸¹ and 1 Class III⁸² study conducted in the ED or orthopedic clinic. Luhmann et al⁷⁷ 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 anesthesia⁷⁹ or intramuscular meperidine and promethazine.⁷⁸ Hennrikus et al⁸⁰ and Wattenmaker et al⁸² noted decreased levels of distress with 50% N₂O alone. Hennrikus et al⁸¹ 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 II⁶⁴, ⁷⁵, ⁸³, ⁸⁴, ⁸⁵, ⁸⁶ studies and 1 Class III⁸⁷ study conducted in various outpatient settings. Recovery from N₂O sedation, when noted, was reported to be very rapid.⁷¹, ⁷², ⁷³, ⁷⁵, ⁷⁷, ⁷⁸, ⁷⁹, ⁸⁸

Depth of sedation with a specific concentration of N₂O may vary.⁸⁹ In a Class II study, Babl et al³⁵ 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 al⁷³ found deep sedation in 12% of children during suturing, and a Class I study by Luhmann et al⁷⁷ and Class II studies by Hennrikus et al⁸⁰, ⁸¹ 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.⁶⁹, ⁷⁴, ⁸⁶, ⁸⁷ 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 two³⁵, ⁹⁰ 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.³⁵, ⁶⁴, ⁶⁵, ⁶⁶, ⁶⁸, ⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴, ⁷⁵, ⁷⁶, ⁷⁷, ⁷⁸, ⁷⁹, ⁸⁰, ⁸¹, ⁸², ⁸³, ⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷, ⁸⁸, ⁸⁹, ⁹⁰, ⁹¹, ⁹², ⁹³, ⁹⁴, ⁹⁵, ⁹⁶ 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.⁹⁷ 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,⁹⁸ 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% N₂O⁹⁵ or in 14 adult volunteers sedated with 50% N₂O for 5 minutes.⁹¹ 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.⁹⁶ 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,⁷², ⁷⁷ 6 Class II,³⁵, ⁷³, ⁷⁴, ⁷⁹, ⁸⁰, ⁸¹ and 1 Class III⁷⁸ trials, the frequency of emesis with 50% N₂O varied from a high of 26% (6% during the procedure) when co-administered with oral oxycodone⁷⁷ to 10%,⁷² 6%,⁷³ or none when administered alone.⁷⁴, ⁷⁸, ⁷⁹, ⁸⁰, ⁸¹ No clinically apparent aspiration was noted in these studies. Babl et al³⁵ 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.³⁵, ⁷², ⁷³, ⁷⁷, ⁸⁷, ⁹⁹ 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 hydrate⁵⁷ or oral midazolam 0.7 mg/kg⁵⁶ but not 0.5 mg/kg.⁵⁵ 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.⁷² 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.⁹³ Finally, studies in healthy children undergoing elective dental procedures found no significant adverse events when N₂O was combined with other low-dose sedative medications;⁶⁴, ⁶⁶, ⁶⁸ 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.¹⁰⁰ 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.¹⁰¹ 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.¹⁰² 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.¹⁰³ No association was found with spontaneous abortions.¹⁰⁴ 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.¹⁰⁵

Patient Management 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).

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.¹⁰⁶ 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).¹⁰⁷

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.¹⁰⁸ 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.¹⁰⁹ 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),¹¹⁰ the Neonatal Facial Coding Scale (NFCS),¹¹¹ the Douleur Aigue chez le Nouveau-ne (DAN),¹¹² and the Premature Infant Pain Profile (PIPP),¹¹³ 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.¹⁰⁷ PIPP scores were pooled for 3 studies that used doses ranging from 0.1 mL to 0.5 mL of 24% sucrose.¹¹⁴, ¹¹⁵, ¹¹⁶ 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.¹¹⁷, ¹¹⁸ 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.¹¹⁷, ¹¹⁸, ¹¹⁹, ¹²⁰, ¹²¹, ¹²², ¹²³, ¹²⁴, ¹²⁵, ¹²⁶ 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,¹¹⁷, ¹¹⁹, ¹²⁰, ¹²¹, ¹²² whereas a minority found no effect.¹²³, ¹²⁴ Pain scores (including DAN and facial expression scores) were lower in the sucrose group in some trials¹²⁴, ¹²⁵ but not in others.¹¹⁸, ¹²⁰ Response of vital signs to painful stimulus was variable; some trials found a decrease in heart rate in the sucrose group,¹¹⁹, ¹²² but most trials found no consistent difference in heart rate,¹¹⁷, ¹²⁰, ¹²⁶ respiratory rate,¹¹⁹ SaO₂,¹¹⁸, ¹¹⁹ or vagal tone¹²⁰, ¹²¹ among treatment groups.

Five Class II trials looked at sucrose in preterm infants. Crying time was consistently reduced with sucrose in this age group.¹²⁷, ¹²⁸, ¹²⁹, ¹³⁰, ¹³¹ Three trials that evaluated behavior using the NFCS or a “composite behavioral scale” found that scores were lower in the treatment group.¹²⁸, ¹³⁰, ¹³¹ Physiologic effects again were mixed; several studies found a lower heart rate¹²⁸, ¹²⁹ and respiratory rate¹²⁹ in the treatment group, whereas others found no effect on heart rate,¹²⁷, ¹³¹ SaO₂,¹²⁸, ¹²⁹ or cerebral blood flow.¹²⁹ An additional 11 Class III studies investigating the analgesic efficacy with various invasive procedures in term and/or preterm infants were identified.¹¹⁴, ¹³², ¹³³, ¹³⁴, ¹³⁵, ¹³⁶, ¹³⁷, ¹³⁸, ¹³⁹, ¹⁴⁰, ¹⁴¹ 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.¹²³, ¹⁴², ¹⁴³ Barr et al¹⁴² 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 al¹⁴³ 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,¹²³ 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.¹⁴⁴ 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.¹⁰⁸ 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 al¹²⁷ 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 al¹¹⁸ 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,¹⁴⁵ 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,¹²⁶ in a Class II trial, compared 33% and 50% sucrose in full-term infants and found no difference in heart rate. Ramenghi et al¹³⁹ 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.¹⁰⁷ 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 II¹¹⁶, ¹²¹, ¹²⁵ and 2 Class III studies¹³⁴, ¹³⁸ 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 al¹¹⁴ 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.¹³⁷

Two Class II studies compared sucrose plus holding versus sucrose or holding alone during heel stick.¹²⁰, ¹³¹ Both found that sucrose and sucrose plus holding reduced crying or facial expressions of pain compared with controls. Reis et al¹⁴⁴ 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.¹⁰⁸, ¹¹⁴, ¹²⁴, ¹²⁵, ¹²⁶, ¹³⁸, ¹³⁹, ¹⁴⁴ Only Gibbins et al¹¹⁶ 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.¹⁴⁶ 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,¹¹⁴ 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.

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.¹² These recommendations about the safety and efficacy of chloral hydrate do not imply superiority to the above medications. See Appendix C for the recommendations from the previous clinical policy.

Patient Management Recommendations for Chloral Hydrate 

None specified.

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. The oral preparation is reported as having a bitter unpalatable taste that frequently requires administration in a flavored vehicle to disguise its taste. In 1 Class II study, 30% of children would not accept the chloral hydrate orally and required rectal administration, and 30% of the remaining 108 patients vomited immediately after oral administration of the drug, yet there were no complications or serious adverse effects and successful sedation occurred in 95% of the patients.¹⁴⁷

The efficacy of chloral hydrate as a sedative for diagnostic or therapeutic procedures was 92% to 100% in 4 Class I studies,¹⁴⁸, ¹⁴⁹, ¹⁵⁰, ¹⁵¹ 85% to 100% in 8 Class II studies,¹⁴⁷, ¹⁵², ¹⁵³, ¹⁵⁴, ¹⁵⁵, ¹⁵⁶, ¹⁵⁷, ¹⁵⁸ and 80% to 100% in 12 Class III studies.⁴⁹, ¹⁵⁹, ¹⁶⁰, ¹⁶¹, ¹⁶², ¹⁶³, ¹⁶⁴, ¹⁶⁵, ¹⁶⁶, ¹⁶⁷, ¹⁶⁸, ¹⁶⁹

Two studies were done in the ED: 1 Class I study with 100% effectiveness¹⁵¹ and 1 Class III study with 88% effectiveness.¹⁶⁷ In other studies, chloral hydrate sedation was used for the performance of a diagnostic imaging study (computed tomography [CT] or magnetic resonance imaging [MRI] scan),¹⁴⁹, ¹⁵⁰, ¹⁵¹, ¹⁵², ¹⁵³, ¹⁵⁴, ¹⁵⁵, ¹⁵⁶, ¹⁵⁸, ¹⁵⁹, ¹⁶⁰, ¹⁶², ¹⁶³, ¹⁶⁴, ¹⁶⁵, ¹⁶⁸, ¹⁶⁹, ¹⁷⁰, ¹⁷¹ echocardiogram,¹⁴⁷, ¹⁴⁸, ¹⁵⁷, ¹⁶⁶ electroencephalogram (EEG),¹⁷² hearing testing,⁴⁹ various procedures (CT, MRI, bone scan, EEG, other),¹⁶⁰, ¹⁶⁸, ¹⁷³ radiation therapy,¹⁶¹ and dental procedures.¹⁷⁴

The dose of chloral hydrate administered generally varied between 50 and 100 mg/kg, with most studies providing the option of administering additional doses if adequate clinical effects were delayed. Two of the 3 Class I studies with greater than 92% efficacy used 75 mg/kg as their initial dose, with a third study using 70 mg/kg or 100 mg/kg.¹⁴⁸, ¹⁵⁰, ¹⁵¹ In Class II studies with greater than 90% efficacy, dosages varied from 50 mg/kg to 100 mg/kg.¹⁴⁷, ¹⁵³, ¹⁵⁴, ¹⁵⁶

Sedation failure rates are decreased when a second dose of chloral hydrate (up to a maximum of 2 g or 100 mg/kg, whichever is lowest) is given. First dose/second dose success rates for chloral hydrate are Class I 60%/93%,¹⁴⁸ 64%/92%,¹⁴⁹ Class III 89%/98%,¹⁷⁰ 88%/90%,¹⁶⁰ and 84.5%/94.5%.⁴⁹ Reports of success rates that listed just second doses included Class III 98%,¹⁵⁹ 99.3%,¹⁶² 98.7%,¹⁶³ and 99.5%¹⁶⁵ (with hydroxyzine also given if age >1 year).¹⁶⁵

Multiple doses of chloral hydrate were required to achieve high levels of efficacy in some studies. In the only Class I study designed to identify the optimal dose of chloral hydrate, 28% of children initially sedated with 70 mg/kg required supplemental chloral hydrate compared with 13% of children initially receiving 100 mg/kg.¹⁴⁹

Adequate sedation occurred in 64% of patients receiving an initial dose of 70 mg/kg versus 87% for an initial 100 mg/kg dose. After subsequent dosing, 92% of children in the 70 mg/kg group and 100% of those in the 100 mg/kg group were successfully sedated. They developed the following formula to determine the optimal dose of chloral hydrate according to age and weight: Dose (mg/kg)=56+(0.8xage in months).¹⁴⁹ In a Class II study, a lower dose yielded higher sedation failure rates, whereas higher doses increased the incidence of adverse reactions.¹⁵³

In addition to the total dose of chloral hydrate administered, chloral hydrate’s efficacy is affected by age, the patient population (special health care needs or not), and other factors. Failed sedations were noted to increase with increasing age.¹⁴⁷, ¹⁵³, ¹⁵⁴, ¹⁵⁸, ¹⁶⁰, ¹⁶⁷, ¹⁶⁸, ¹⁷⁰, ¹⁷¹, ¹⁷³ In 2 Class II studies, failed sedations were most common in children older than 48 months.¹⁴⁷, ¹⁵⁴ The efficacy of chloral hydrate in a Class II study decreased with increasing age from 98% in children younger than 12 months to 74% in children 6 to 11 years of age.¹⁵⁴ Sedation failure rates were greater than 15% for age older than 7 years, less than 7.5% for age up to 7 years, and less than 5% for age younger than 3 years.¹⁵³ A Class III study found that chloral hydrate sedation was successful in 84% of children greater than or equal to 3 years of age versus 99% of children less than 3 years of age.¹⁶⁶ A Class III ED study found the following first dose/second dose success rates based on age: 0 to 0.9 years 98%/100%, age 1 to 1.9 years 84%/91%, 3 years 76%/85%.¹⁶⁷ In another Class III study, the sedation failure rate for children older than 4 years was higher (20% versus 12.5%) than for younger children.¹⁶⁰ A study of hospital-wide procedural sedation in children noted that those who had failed procedures with chloral hydrate were significantly older (3.6 years) than children who were successfully sedated (2.6 years).¹⁷³

It is unclear from the literature whether these failures with increasing age are related to deficiencies with chloral hydrate or whether older children who require sedation for diagnostic studies may be more likely to have neurodevelopmental problems that make their sedation more difficult.

Studies found a decreased efficacy of chloral hydrate sedation in certain patient populations. Chloral hydrate’s success rate was only 80% in children with central nervous system disorders in a Class II study¹⁵³ and 73% in children with neurologic disorders (versus 4% for “normal” children) in a Class III study.¹⁶⁰ Another article (Class III) found that “most failed” sedations with chloral hydrate occurred in “children with seizure disorders or retardation.”¹⁶⁸ Failure to achieve adequate sedation occurred in 71% of patients with a genetic disorder (Class II study).¹⁴⁷ Olson et al¹⁷² found that only 9% of sedations with chloral hydrate for EEGs were unsuccessful but that 65.9% of those who could not be adequately sedated had a history of developmental delay or autism. In contrast to patients with neurodevelopmental disorders or genetic syndromes, children with congenital heart disease, including those with cyanotic heart disease, do not have a higher sedation failure rate or increased adverse effects with chloral hydrate.¹⁴⁷, ¹⁴⁸, ¹⁵⁷, ¹⁶⁶

There are other factors that may affect chloral hydrate’s efficacy. One Class III study⁴⁹ and 1 Class II study¹⁵⁷ demonstrated that the fasting state of a child affected the dose of chloral hydrate, with fed children demonstrating a quicker onset and a lower dose than fasted children. The greater dose requirement in fasted children was thought to be related to the longer duration to onset, which also resulted in a longer duration of action.⁴⁹, ¹⁵⁷ In one Class II study, the efficacy of chloral hydrate was increased when timed to coincide with nap times.¹⁵⁷

In direct comparison studies, chloral hydrate demonstrated comparable or superior efficacy to oral midazolam and pentobarbital.¹⁴⁸, ¹⁵⁰, ¹⁵¹, ¹⁵⁵, ¹⁵⁶, ¹⁵⁸, ¹⁶², ¹⁶³, ¹⁶⁴, ¹⁷⁴

Safety of Chloral Hydrate

Key words/phrases for literature searches: chloral hydrate, procedural sedation; age 1-18 years.

Three Class I studies demonstrated the presence of side effects such as vomiting (9% to 18%) and paradoxical excitement (0% to 2%) in children sedated with chloral hydrate, but no cardiac or respiratory adverse effects were reported.¹⁴⁹, ¹⁵⁰, ¹⁵¹

In 5 Class II studies the following was reported: vomiting 2% to 30%, paradoxical excitement 1% to 6%, and desaturation 0% to 4%.¹⁴⁷, ¹⁵³, ¹⁵⁴, ¹⁵⁶, ¹⁵⁸ In 4 Class III studies, vomiting occurred in 0% to 2%, paradoxical excitement in 0% to 15%, prolonged sedation in 0% to 1%, and desaturation in 0% to 7.6%.¹⁶², ¹⁶³, ¹⁶⁵, ¹⁶⁹ In all instances the hypoxia was responsive to positional maneuvers or supplemental oxygen.

In a single study of 7 neonates with pulmonary hypertension or persistent fetal circulation, desaturation occurred in 57%; treatment with additional oxygen was used in some infants but none required BVM support or intubation.¹⁵⁵

In 3 studies of children undergoing echocardiograms, no adverse effects were noted in one study,¹⁴⁸ whereas another study did demonstrate a 5% decrease in saturation in 6% of patients, which was more prominent in children with genetic disorders.¹⁶⁶ A Class II study demonstrated no difference in cyanotic and acyanotic children sedated with chloral hydrate.¹⁴⁷

Three studies reported clinical effects the day after sedation.¹⁵⁷, ¹⁷⁰, ¹⁷⁵ One Class II study noted grogginess and irritability in children younger than 6 months of age, and grogginess, irritability, and motor instability in children 6 months to 2 years of age.¹⁵⁷ One Class III study reported unsteadiness in 68% and hyperactivity in 29% of sedated children the day after treatment.¹⁷⁰ A second Class III study comparing chloral hydrate and midazolam noted motor imbalance in 31% of children receiving chloral hydrate compared with 18% of the midazolam group (P<0.05).¹⁷⁵ In the same study, agitation was noted in 18% of the chloral hydrate group compared with 8% of the midazolam group (P=NS). For both the chloral hydrate and midazolam groups, only 48% returned to baseline activity within 8 hours, although 89% were at baseline at 24 hours.¹⁵⁷, ¹⁷⁰, ¹⁷⁵

A single Class I study demonstrated the occurrence of vomiting, excitation, and nausea in 21% of children sedated with 2 different doses of chloral hydrate, 70 mg/kg or 100 mg/kg.¹⁴⁹ There was no difference in incidence of these effects between the 2 dosage groups.

One Class III study did demonstrate that chloral hydrate patients were more likely to achieve an unintended deeper level of sedation than occurred with other sedation agents.⁴³ However, this study provided no data on the specific dosing, personnel, or circumstances of the chloral hydrate use and did not report any need for rescue intubation or permanent neurologic deficits in these children.⁴³ In another anecdotal study, 13 deaths or severe neurologic injuries were found after chloral hydrate administration.¹⁷⁶ None of these severe adverse events occurred in the ED setting. The cases were identified in a review of US Food and Drug Administration records or surveys of specialists, with no information reported on monitoring or qualifications of personnel performing the procedures. Five of these patients were dental patients; 5 were undergoing radiologic procedures; 2 were cardiology procedures; and 1, an audiology procedure. In the 7 cases in which chloral hydrate was the single agent administered, 4 patients received an overdose. Significant preexisting medical problems were noted in 8 of the 13 patients. No information on the total number of cases sedated was presented.¹⁷⁶ This one report¹⁷⁶ is in contrast to the many formal Class I, II, and III studies involving chloral hydrate that demonstrated no significant adverse events and in particular no deaths or severe neurologic injuries.

Two studies found significant decreases in the oxygen saturation occurring with chloral hydrate in half of patients with genetic disorders: 50% of patients with Down’s syndrome in the Class II Coskun et al¹⁴⁷ study and 54% in the Class III Napoli et al¹⁶⁶ study.

In contrast to patients with genetic syndromes or neurologic disorders, children with congenital heart disease, including those with cyanotic heart disease, are not at particular risk with chloral hydrate sedation.¹⁵⁷

One particular concern with chloral hydrate is its potential for resedation because of its long half-life. Cote et al¹⁷⁶ and Malviya et al¹⁷⁵ note the possibility of resedation, in which the infant or child appears to have recovered and meets discharge criteria but then is resedated because of circulating active metabolites and residual drug.

Furthermore, the response to chloral hydrate’s sedative effects in a given patient may be varied and unpredictable. In a telephone follow-up of 376 children who received sedation for diagnostic radiology studies, 89% received chloral hydrate and 11% received midazolam as the primary sedative. After discharge, medical advice was sought for 15 children (4%). Three children required a visit to the ED for prolonged or excessive sedation. All of these children had received a recommended dose of chloral hydrate (61 mg/kg to 77 mg/kg) as a sole sedative. In one child, the procedure had been aborted because of inadequate sedation in the hospital, yet the child became difficult to arouse at home.¹⁷⁵

A study of procedural sedation in a pediatric ED at a children’s hospital used chloral hydrate in 122 patients (10% of their procedural sedation regimens) and reported no adverse events with chloral hydrate and no serious complications in their 1,180 patients.¹⁷⁷ A hospital-wide study of 1,140 children undergoing procedural sedation also revealed no long-term sequelae.¹⁷³

The use of chloral hydrate has been controversial, with some critics of the opinion that it should be banned.¹⁷⁸, ¹⁷⁹ Serious complications¹⁸⁰, ¹⁸¹, ¹⁸², ¹⁸³, ¹⁸⁴, ¹⁸⁵ and deaths³², ¹⁷⁶, ¹⁸⁶, ¹⁸⁷, ¹⁸⁸, ¹⁸⁹ have been associated with chloral hydrate. Like other sedative hypnotic agents, chloral hydrate has the potential for central nervous system depression, suppression of respiratory activity, direct or hypoxia-induced arrhythmias, and airway obstruction secondary to skeletal muscle relaxation. However, many of the adverse patient outcomes reported with chloral hydrate occurred in reports in which proper patient monitoring or clinician competence was not documented. In all graded studies included in this analysis, chloral hydrate did not demonstrate any of the catastrophic patient outcomes found above. Proper patient monitoring and improved physician training may account for the improved results in the more recent studies of chloral hydrate use.

Level A recommendations 

None specified.

Level B recommendations 

None specified.

Level C recommendations 

No universally applicable, evidence-based set of clinical indicators has been established. Emergency physicians, in conjunction with their institutions, should develop criteria for safe discharge.

Key words/phrases for literature searches: discharge, procedural sedation; age 1-18 years.

Most children who have undergone procedural sedation in the ED are discharged home. Determining discharge readiness is a process that takes place in each of these discharged cases. The intent of this process is to ensure that a child will not experience serious or life-threatening adverse events at home, where immediate medical intervention is not available. The balance between safety and practicality results in a tension between prolonged observation and premature discharge. The ideal solution would be a universally applicable, evidence-based set of clinical criteria that, if met, would ensure safe discharge from the ED at the earliest possible time. Unfortunately, we have yet to identify such a set of criteria.

Recommended criteria have been published by a number of organizations, such as the ASA,²² the AAP,²⁴ the Canadian Association of Emergency Physicians,¹ and the Australasian College for Emergency Medicine.¹⁹⁰ None of these are evidence based. Comprehensive review of the literature evaluating clinical indicators/discharge criteria has failed to yield well-supported measures of discharge readiness after pediatric procedural sedation.¹⁷⁰, ¹⁷⁶, ¹⁸⁷, ¹⁹¹, ¹⁹², ¹⁹³, ¹⁹⁴, ¹⁹⁵, ¹⁹⁶, ¹⁹⁷, ¹⁹⁸, ¹⁹⁹, ²⁰⁰

We identified 2 studies directly addressing pediatric-specific criteria for postsedation discharge readiness from an outpatient setting. The first is a Class III study of 29 children who underwent echocardiography facilitated by chloral hydrate (n=27) or midazolam/diphenhydramine (n=2) sedation given orally.¹⁹⁷ All children were ASA physical status classification III due to congenital cardiac diseases. These authors used Bispectral Index monitoring and 2 clinical scoring systems: the University of Michigan Sedation Scale²⁰¹ and a modified Maintenance of Wakefulness Test.²⁰² The authors concluded that incorporating these 2 clinical scoring systems into discharge decisionmaking prolonged the observation time (from a mean of 16 minutes to a mean of 75 minutes) but resulted in discharged children having Bispectral Index scores closer to baseline measurements than when traditional criteria were used. There are several problems with the applicability of this study to the ED. The population studied was medically complicated and likely to be dissimilar to most children in most EDs. The children underwent a relatively painless procedure, whereas many procedures in the ED are painful and require higher doses of sedation agents, which can complicate discharge readiness. Bispectral Index scoring has not been adequately validated as a surrogate marker for discharge readiness, nor has it been shown to be more useful than clinical observation.²⁰³ Bispectral Index monitoring is not applicable in cases involving ketamine sedation.²⁰⁴ The modified Maintenance of Wakefulness Test proposed by the authors requires a 20-minute period in a “soporific environment (ie, dim, quiet room),” an environment unlikely to be present in many EDs.

In the other Class III study, Newman et al²⁰⁵ found there were no serious adverse events beyond 25 minutes after the final medication administration if a serious adverse event did not occur within the first 25 minutes. However, the heterogeneity of this study population, the different sedative agents used, and the various routes of administration make universal time-based recommendations difficult.

It is likely that discharge decisionmaking will remain a complex process. The factors likely to influence this decision include the pharmacologic properties of the sedation agent or agents chosen, the route of administration, the procedure performed, preexisting medical conditions or ASA physical status classification, the use of reversal agents, the occurrence of adverse events during the procedure, individual patient factors (eg, age, metabolism, polypharmacy, obesity), and the social circumstances of the child. Further study may yield generally applicable clinical discharge criteria. Professional organization consensus guidelines have been developed to assess discharge readiness and may be used to develop institutional protocols or guidelines.

This clinical policy may also be found at:

When this document is cited, the following citation format is suggested: Mace SE, Brown LA, Francis L, Godwin SA, Hahn SA, Howard PK, Kennedy RM, Mooney DP, Sacchetti AD, Wears RL, Clark RM. EMSC Panel on Critical Issues in the Sedation of Pediatric Patients in the Emergency Department. Clinical policy: critical issues in the sedation of pediatric patients in the emergency department. Ann Emerg Med. 2008;51:378-399, e1-e57.

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Appendix 

Evidentiary Table.

Appendix A. Literature classification schema.^⁎

Appendix B. Approach to downgrading strength of evidence

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Appendix C. Recommendations from the 2004 clinical policy.¹² 

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