04 Clinical Pediatric Emergency Medicine - December2010

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C L I N I C A L
Pediatric Emergency Medicine

Vol 11, No 4 Editor
Steven E. Krug,
FAAP MD,
December 2010
Feinberg School of Medicine, Northwestern University, Childrens Memorial Hospital, Chicago, IL
Procedural Sedation in Children

Daniel Isaacman, MD, FAAP Guest Editor
231 . . . . . . . . . Procedural Sedation in Children

Daniel Isaacman
GUEST EDITORS PREFACE
233 . . . . . . . . Procedural Sedation and Analgesia in the Pediatric Emergency Department:

A Review of Sedative Pharmacology
Susanne Kost and Anita Roy
244 . . . . . . . . Nonpharmacologic Techniques for Distress Reduction During Emergency Medical Care:
A Review
Charles Eldridge and Robert Kennedy
251 . . . . . . . . . Monitoring the Procedural Sedation Patient: Optimal Constructs for Patient Safety
Joshua Nagler and Baruch Krauss
265 . . . . . . . . Evaluation and Treatment of Sickle Cell Pain in the Emergency Department:
Paths to a Better Future
William T. Zempsky
274 . . . . . . . . Tailoring Pediatric Procedural Sedation and Analgesia in the Emergency Department:
Choosing a Regimen to Fit the Situation
Jonathan Bennett, Andrew DePiero, and Susanne Kost
282 . . . . . . . . Progress in Pediatric Sedation Research

Joseph P. Cravero
290 . . . . . . . . The Sedation Service Reimbursement Dilemma

Jeffrey F. Linzer Sr. W.B. Saunders
293 . . . . . . . . Adolescent with Abdominal Pain and Altered Mental Status: Are You Confused?
Lorraine Ng
EMERGI-QUIZ CLINICAL PUZZLER
301 . . . . . . . . A Surprising Etiology of Neonatal Seizures

www.clinpedemergencymed.org
Jennifer Jacob and Seema Shah
C L I N I C A L
Pediatric Emergency Medicine

Editor
Steven E. Krug, MD, FAAP
Northwestern University Feinberg School of Medicine Childrens Memorial Hospital Chicago, Illinois
Editorial Board
Jeffrey R. Avner, MD, FAAP Albert Einstein College of Medicine Childrens Hospital at Monteore Bronx, New York M. Douglas Baker, MD, FAAP University of Texas, Southwestern Medical Center at Dallas Childrens Medical Center of Dallas Dallas, Texas Susan M. Fuchs, MD, FAAP, FACEP Northwestern University Feinberg School of Medicine Childrens Memorial Hospital Chicago, Illinois Marianne Gausche-Hill, MD, FAAP, FACEP UCLA School of Medicine HarborUCLA Medical Center Los Angeles, California Michael J. Gerardi, MD, FAAP, FACEP UMDNJ-NJ Medical School Childrens Medical Center and Morristown Memorial Hospital Morristown, New Jersey Daniel J. Isaacman, MD, FAAP Director, Clinical Affairs Global Medical Affairs Wyeth Pharmaceuticals Madison, New Jersey Nathan Kuppermann, MD, MPH, FAAP University of California at Davis U.C. Davis Medical Center Davis, California Jeffrey F. Linzer, Sr., MD, MICP, FAAP Emory University School of Medicine Childrens Healthcare of Atlanta at Egleston Altanta, Georgia Ronald I. Paul, MD, FAAP, FACEP University of Louisville School of Medicine Kosair Childrens Hospital Louisville, Kentucky Emory Petrack, MD, MPH, FAAP, FACEP Petrack Consulting, Inc. Case Western Reserve University Cleveland, Ohio Richard M. Ruddy, MD, FAAP, FACEP University of Cincinnati College of Medicine Childrens Hospital Medical Center Cincinnati, Ohio Joan E. Shook, MD, MBA, FAAP, FACEP Baylor College of Medicine Texas Childrens Hospital Houston, Texas Milton Tenenbein, MD, FRCPC, FAAP, FAACT, FACMT University of Manitoba Childrens Hospital Winnipeg, Manitoba, Canada Robert A. Wiebe, MD, FAAP, FACEP University of Texas, Southwestern Medical Center at Dallas Childrens Medical Center of Dallas Dallas, Texas Joseph L. Wright, MD, MPH, FAAP George Washington University School of Medicine and Health Sciences Childrens National Medical Center Washington, District of Columbia Martha S. Wright, MD Director, Residency Training Program Department of Pediatrics Attending Physician, Division of Pediatric Emergency Medicine Rainbow Babies and Childrens Hospital Case Western Reserve University School of Medicine
GUEST EDITOR'S PREFACE
Procedural Sedation in Children

By Daniel Isaacman, MD, FAAP
hildren are often fearful of visits to the emergency department (ED) because it represents a potentially painful experience in a foreign environment. Over the past 2 decades, a greater appreciation of the need to maximize patient comfort and minimize anxiety for the entire pediatric age spectrum has led to an appreciation of the role played by anxiolytics, narcotics, and sedatives in reducing unnecessary discomfort during the performance of procedures and radiologic examinations in children. The spectrum of agents available for pediatric procedural sedation and analgesia in the ED has broadened considerably over the past 2 decades. The intramuscular narcotic-phenothiazine cocktail has been relegated to historical lore, and the present day practitioner can choose from over a dozen pharmacologic options, enabling some finesse in matching the sedative-analgesic agents and routes of delivery to fit the clinical need.1,2 Administration of effective procedural sedation can maximize patient comfort, thus leading to a higher frequency of procedural success. In addition, because medications such as midazolam offer amnesia for the procedure, patients can undergo invasive procedures without building a fear for future patient encounters. Administration of procedural sedation is also often linked with increased parental satisfaction with the ED experience, despite the fact that the administration of sedation can be associated with increased length of stay. For all these reasons, it is safe to say that the administration of procedural sedation has become the standard of care for painful or anxiety producing procedures and certain radiologic studies. This issue of Clinical Pediatric Emergency Medicine is thus dedicated toward broadening practitioner
knowledge regarding the administration of procedural sedation and analgesia to the pediatric patient. Susanne Kost and Anita Roy discuss the various sedative, hypnotic, and anxiolytic agents available to the emergency care practitioner with a summary of the clinical pharmacology of each agent. Charles Eldridge and Robert Kennedy then offer a discussion of the use of adjunctive nonpharmacologic means of reducing pain and anxiety. Joshua Nagler and Baruch Krause reviews the important topic of patient monitoring for potential adverse effects associated with procedural sedation. William Zempsky then offers a review of the modern management of sickle cell pain in the ED. Jonathan Bennett, Andrew DePiero, and Sue Kost provide a very practical article that reviews 6 common clinical scenarios and discusses the possible options for their management. Joseph Cravero then summarizes the major research that has been conducted in the area of procedural sedation while offering recommendations for future work in the field. Finally, Jeffrey Linzer provides the readers with insight on proper coding for the administration and monitoring of procedural sedation and strategies for successful reimbursement. This issue of Clinical Pediatric Emergency Medicine also offers 2 outstanding case reports from the 2009 Emergi-Quiz Competition held at the American Academy of Pediatrics National Conference and Exhibition. In the first, Lorraine Ng presents a challenging adolescent with abdominal pain and altered mental status. In the second, Jennifer Jacob and Seema Shah discuss a very unusual presentation of seizures in a neonate. I hope that the various topics we have included will be useful to you in sharpening your skills for the
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administration of procedural sedation. Although we have come a long way in this area of pediatric emergency care, the topic is still one with room for continued growth. When administered properly, the provision of procedural sedation offers a major advance in the delivery of quality emergency care to pediatric patients.
REFERENCES
1. EMSC Grant Panel Writing Committee. Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department. Ann Emerg Med 2004;44(4):342-77. 2. Krauss B, Green SM. Procedural sedation and analgesia in children. Lancet 2006;367(9512):766-80.
Abstract:
The spectrum of sedative and analgesic agents available to those who provide pediatric sedation and analgesia in the emergency department has broadened considerably over the past 2 decades. Pharmacologic agents that can be used alone or in combination in this context include nitrous oxide, midazolam, chloral hydrate, pentobarbital, etomidate, dexmedetomidine, propofol, and ketamine. The pharmacology, common clinical uses, advantages, and disadvantages of each of these agents are reviewed. Pharmacokinetics of the agents is addressed in tabular form, whereas pharmacodynamic aspects of each agent are discussed in more detail. Clinical uses addressed include noninvasive as well as invasive procedures. Relevant studies involving comparison of various sedative regimens for common emergency department procedures are reviewed.
Keywords:
procedural sedation; analgesia; pediatrics; chloral hydrate; dexmedetomidine; etomidate; ketamine; midazolam; nitrous oxide; pentobarbital; propofol
Procedural Sedation and Analgesia in the Pediatric Emergency Department: A Review of Sedative Pharmacology
Susanne Kost, MD, Anita Roy, MD
he spectrum of agents available for pediatric procedural sedation and analgesia (PSA) in the emergency department (ED) has broadened considerably over the past 2 decades. The intramuscular narcotic-phenothiazine cocktail has been relegated to historical lore, and the presentday practitioner can choose from over a dozen pharmacologic options, enabling some finesse in matching the sedative-analgesic agents and routes of delivery to fit the clinical need.1,2 The procedural sedation pharmacopeia can be divided into 4 main categories: pure analgesic, sedative-hypnotic, dissociative, and inhalational. The analgesics can be divided into opioid and nonopioid, and the sedative-hypnotic category can be further subdivided into benzodiazepines, barbiturates, and others (Figure 1). The agents can be used alone or in combination, further
Jefferson Medical College, Philadelphia, PA; Nemours/A.I.duPont Hospital for Children, Wilmington, DE. Reprint requests and correspondence: Susanne Kost, MD, Nemours/A.I.duPont Hospital for Children, 1600 Rockland Rd, Wilmington, DE 19899. skost@nemours.org
1522-8401/$ - see front matter 2010 Elsevier Inc. All rights reserved.
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Figure 1. Pharmacopeia for procedural sedation and analgesia. EMLA - eutectic mixture of local anesthetic; LET - lidocaine, epinephrine, tetracaine; NSAIDs - nonsteroidal anti-inflammatory agents.
broadening the options for alleviating procedural pain and distress. This article will review the pharmacology and clinical indications for commonly used sedative agents in present-day pediatric emergency medicine. Pharmacokinetics (how the body metabolizes the drug, including onset and duration) will be outlined in Table 1; the text will focus on sedative pharmacodynamics (how the drugs affect the patient), the common indications, and the advantages and disadvantages of each agent.
NITROUS OXIDE
Nitrous oxide (NO) is a gas that produces mild to moderate levels of analgesia, sedation, and dissociation when inhaled in concentrations of 30% to
70%.3 Nitrous is administered with oxygen via 1 of 2 types of delivery systems, either fixed concentration (usually a 50:50 mixture) or titratable. The delivery system must include a scavenging mechanism to collect excess gas. Newer continuous-flow delivery systems alleviate the problem of the demand-valve mask, common in early systems designed for adult patients, which made use in the younger population difficult due to the inability to generate sufficient negative inspiratory pressure to open the valve. Systems with full face mask capability as compared to nasal hood only also expand the options for use in younger and less cooperative patients. Nitrous oxide has been used in dental care settings for decades, and it has been recently undergoing a slow but steady increase in popularity for alleviating pain and distress for a variety of minor
invasive procedures in both ED and scheduled outpatient settings.4-7 In particular, it has been useful for intravenous (IV) access procedures (vasodilatory properties are a helpful side effect),8 bladder catheterization,9 laceration repair,10 and abscess drainage. 7 Local anesthesia is recommended as an adjunct for more painful procedures, as the analgesic properties of NO are modest in some patients.11 When used with adequate local anesthetic, NO has been successful in alleviating pain in very painful procedures, including bone marrow aspiration and fracture reduction.5,12 A recent evidence-based clinical policy deemed NO both safe and effective for pediatric PSA when used with concurrent local anesthesia, though the evidence quality is better for lower doses (50%) than for higher doses (up to 70%).13 The primary clinical advantage of NO is its very rapid onset and recovery, allowing its use at a moment's notice with return to baseline full function within 5 minutes. When used in lower concentrations (30%-50%), levels of sedation are unlikely to progress beyond mild sedation, and the typical regulatory requirements for moderate and deep sedation may be waived for lower concentration NO use. 4,7,14 However, nitrous is not completely free of risks. Adverse effects include nausea and vomiting in up to 10% of patients and dysphoria, restlessness, and headache in smaller percentages. Although delivery systems are improving, set up can still be cumbersome, and some patients do not cooperate well with inhaling from a mask. Nitrous oxide use is contraindicated in patients with risk of diffusion of gas into enclosed spaces, such as pneumothorax, pneumocephalus, or bowel obstruction. It has also been linked to increased risk of spontaneous abortion with chronic occupational exposure.
MIDAZOLAM
Midazolam (MDZ) is a benzodiazepine, a medication class (including diazepam and lorazepam, among others) with anxiolytic, amnestic, sedativehypnotic, muscle relaxant, and anticonvulsant properties. Since its release in 1985, MDZ has far surpassed the other benzodiazepines for use in the PSA context due to its faster onset and offset, and to its water-soluble properties allowing administration via almost any route (intranasal, IV, oral, rectal, and intramuscular). 2 Intranasal administration causes significant stinging of the nasal mucosa, but onset of action is slightly faster than administration via enteral routes.15 The IV formulation (5 mg/mL) can be used via any route; the commer-
cially prepared oral formulation is less concentrated (2 mg/mL) and slightly more palatable than the IV formulation given orally. Like the other benzodiazepines, MDZ has no analgesic properties, and it should be administered with an analgesic for painful procedures. On a per-kilogram basis, larger doses are required for toddlers and young schoolaged children compared to young infants and adolescents to achieve the same effect. Midazolam alone is useful for taking the edge off an anxious or uncooperative child; however, when used as a single agent, it is unlikely to result in immobility, thus limiting its use in longer or more complex imaging studies. Ten percent of 516 children undergoing computed tomographic (CT) scans failed to achieve adequate sedation after 0.2 mg/kg of MDZ IV, 16 and half of 22 children randomized to 0.5 mg/kg of oral MDZ failed sedation for neuroimaging studies.17 Midazolam has been used successfully, alone or in combination with topical or systemic analgesics, to provide adequate sedation for a wide variety of invasive procedures.1 However, several comparison studies found MDZ alone or in combination with narcotics less desirable than newer unique short-acting sedatives and dissociative agents. In a blinded, randomized controlled trial of MDZ/fentanyl vs MDZ/ketamine for pediatric fracture reduction, MDZ/fentanyl was found to be less effective and to have a greater incidence of hypoxia (25% vs 6%) than MDZ/ketamine.18 Another pediatric fracture reduction study found MDZ/morphine to be as effective as propofol/morphine; however, recovery times were an hour longer for the MDZ/morphine group.19 Midazolam is often used as an adjunct with ketamine, though randomized placebo-controlled trials fail to show a clear benefit.20 The clinical advantages of MDZ include its versatility, beneficial spectrum of effects (including amnesia), and safety profile. When administered via incremental IV dosing, MDZ and MDZ/fentanyl combinations can be titrated to achieve truly moderate sedation, with the patient responsive to voice, more so than sedative regimens using dissociative or more potent sedative/hypnotic agents. However, MDZ has a synergistic respiratory depressant effect with narcotics and alcohol, and the practitioner using MDZ in combination with other respiratory depressants must monitor the patient with increased vigilance. Midazolam is wellknown to produce dysphoria or agitation in a small percentage of patients, and the authors have found it helpful to warn parents ahead of time of the possibility of a paradoxical response. Both respiratory depression and paradoxical responses can be reversed with flumazenil.21,22
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TABLE 1. Pharmacokinetics and dosing range for procedural sedation and analgesia agents
Dose 10-30 30-120 No Onset (min) Duration (min) Reversible Comments Unreliable effects in N3 y, best if b10 kg, terrible taste, unpredictable onset and duration Use lower doses if in combination with opioids; irritating to vein if given IV
Drug
Effect
Chloral hydrate
Sedative-hypnotic
Diazepam
Sedative-hypnotic
IV: 4-5 PO: 15-30 PR: 5-15 IV: 5-10 IN: 10-30 IV: 30-70 IN: 30-60
IV: 60-120
Yes Flumazenil Yes, in theory Atipamezole (no published use in pediatric PSA) No No Yes Flumazenil
Dexmedetomidine Sedative-hypnotic Analgesic Anxiolysis IV: b 1 IV: 5-15
PO/PR: 25-100 mg/kg Can repeat 25-50 mg/kg Max dose 2 g or 100 mg/kg Single use in neonates IV: 0.05-0.1 mg/kg titrated to max 0.25 mg/kg PO: 0.2-0.5 mg/kg PR: 0.2-0.5 mg/kg IV load: 1-2 g/kg for 10 min; then 0.5-1 g/kg per hour IN: 1-2 g/kg
Etomidate
Sedative-hypnotic
IV: 0.1 mg/kg titrated to effect
Methohexital
Sedative-hypnotic
Cardiorespiratory suppression Initial hypertension Use caution when administered with antisialagogue; avoid in patients on digoxin or other medications acting on the sinus node Can cause respiratory depression, vomiting, myoclonus Avoid in temporal lobe epilepsy and porphyria PR: 30-60 IV: 15-30 PO: 60-90 PR: 60-90 IN: 15-60 IM: 60-120 IV: 45-60 Use lower dose if in combination with opioids May cause paradoxical excitement/irritability
Midazolam
PR: 20-25 mg/kg IV: 0.5-1 mg/kg Sedative-hypnotic, PO: 0.5-0.75 mg/kg Anxiolysis PR: 0.25-0.5 mg/kg IN: 0.2-0.5 mg/kg IM: 0.1-0.2 mg/kg IV b5 y old: 0.05-0.1 mg/kg titrated to max 0.6 mg/kg IV N5 y old: 0.025-0.05 mg/kg titrate to max 0.4-0.5 mg/kg
PR: 10-15 IV: 1-2 PO: 15-30 PR: 10-30 IN: 10-15 IM: 5-20 IV: 1-3
Pentobarbital IV: 3-5 IV: 15-90 PO/PR: 15-60 PO/PR: 60-240 IM: 10-15 IM: 60-120 No Younger children with paradoxical restlessness before sleep Avoid in porphyria
Sedative-hypnotic
Propofol PR: 10-15 IV: 1-5 PR: 60-120 IV: 30-60 No Yes Naloxone Yes Naloxone No
Sedative-hypnotic
IV: b 1
IV: 5-15
No
Thiopental Fentanyl
Sedative-hypnotic Analgesic
IV: 1-6 mg/kg titrated 1-2 mg/kg q2-5 min max 200 mg PO/PR b4 y old: 3-6 mg/kg titrated to max 200 mg PO/PR N4 y old: 1.5-3 mg/kg titrated to max 200 mg IM: 2-6 mg/kg max 200 mg IV: 1 mg/kg titrated 0.5 mg/kg to effect IV infusion: 50-200 g/kg per min PR: 25 mg/kg IV: 1-2 g/kg titrated 1 g/kg q3-5 min IV: 5-10 IM: 3-5 IV: 1-2 PO: 15-30 1-5 b5 No IM: 15-90 IV: 15-30 PO: 30-60 IV: 120-180
Morphine
Analgesic
Ketamine
IV: 0.05-0.15 mg/kg titrated to max 3 mg/kg IM: 4-5 mg/kg titrated to effect IV: 1-1.5 mg/kg titrated to effect PO: 5-10 mg/kg
Cardiorespiratory suppression Avoid with egg/soy allergies Avoid in porphyria Use lower dose if in combination with benzodiazepines Chest wall rigidity possible with IV push, especially in neonates Use lower dose if in combination with benzodiazepines Contraindicated in increased ocular pressure, psychosis, thyroid disease Emergence phenomenon
Nitrous Oxide
Dissociative sedative Analgesic Amnesic Inhalation sedative Inhaled 30%-50% mixed Amnesic with oxygen Mild analgesia
Naloxone
Narcotic reversal
Must have specialized gas scavenger apparatus; caution in patients with entrapped gas (recent craniotomy, pneumothorax, bowel obstruction); avoid with methyltetrahydrofolate reductase mutations Repeat doses needed if sedative is longer acting Repeat doses needed if sedative is longer acting
Flumazenil
Benzodiazepine reversal
IM/IV: 0.1 mg/kg titrated to max 2 mg IV: 0.02 mg/kg titrated q 1 min to max 1 mg
IM: 10-15 IV: 2-3 IV: 1-2
IM: 60-90 IV: 20-40 IV: 30-60
IM indicates intramuscular; IN indicates intranasal, IV indicates intravenous, PO indicates per oral, PR indicates per rectum.
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CHLORAL HYDRATE
Chloral hydrate (CH) is an alcohol-based sedative-hypnotic in use for pediatric procedural sedation for more than 100 years. Its use in this context has been reviewed extensively in a recently published clinical policy.13 From an evidence-based perspective, CH is safe and effective (level A recommendations) for sedation in young patients (b3 years old) undergoing painless diagnostic studies, provided that the children are properly monitored. However, it is not recommended for use in this context in children older than 4 years, or in children with neurodevelopmental disorders, due to lack of efficacy.13 Advantages of CH include its extensive clinical history and its ability to reliably provide effective moderate to deep sedation, resulting in sleep and immobility in young children within the context specified above. Enteral administration increases its appeal in the chubby infant with poor IV access. Disadvantages, especially in a busy ED, include its relatively long and unpredictable onset (15-30 minutes, with 10%-25% of children requiring re-dosing after the first 30 minutes to induce sleep) and its long half-life. From the patient perspective, the biggest disadvantage is the bitter taste. Rectal administration is possible, although also unpredictable.
DEXMEDETOMIDINE
The newest agent on the pediatric procedural sedation scene is dexmedetomidine (DEX), a highly selective -2 agonist with both sedative and analgesic effects, analogous to a faster-acting version of clonidine with fewer cardiovascular side effects. Dexmedetomidine can be delivered as an IV bolus/ infusion, orally, or transmucosally via intranasal or buccal routes. Published clinical uses for DEX to date include use as a preoperative premedication (before general anesthesia), as a long-term sedative in an intensive care unit setting, and as an adjunct sedative for invasive cardiology procedures. As an intranasal premedication, DEX was found to provide a slightly deeper sedation than oral MDZ, with a similar low rate of adverse side effects,23 suggesting that it could serve as a less irritating substitute for ED procedures in which intranasal MDZ is considered. Indications more relevant to the ED setting include sedation for medical imaging procedures, both short (CT) 24 and long duration (magnetic resonance imaging [MRI]).25 One recent publication suggests that DEX may be particularly useful in sedating autistic
patients, in whom it was found to be effective with minimal recovery agitation for imaging and electroencephalographic procedures.26 This population is not infrequently encountered in the ED and can be difficult to sedate with conventional means. Advantages to DEX include multiple routes of administration, like MDZ, with better patient tolerance of the nasal and oral routes. Those who administer it frequently liken it to natural sleep, a belief borne out by electroencephalographic findings during DEX very closely resembling normal sleep.27 Although ED experience is limited, DEX shows promise as a valuable addition to the sedation toolbox. An administrative advantage of DEX lies in its Food and Drug Administration labeling as a sedative as opposed to an anesthetic (unlike ketamine and propofol), thus potentially bypassing the need for approval by the anesthesia department in hospital systems where the ED sedation practice requires such approval. Dexmedetomidine is also potentially reversible with the -2 adrenoreceptor antagonist atipamezole, with one report of success in adults28 but no published use in children. Disadvantages of DEX include its pharmacokinetics and hemodynamic side effects. From a pharmacokinetic standpoint, the onset and recovery times for DEX sedation are somewhat longer than propofol and ketamine but shorter than pentobarbital and chloral hydrate. Hemodynamically, DEX is known to cause an initial phase of hypertension with reflex bradycardia, followed by stabilization of both heart rate (HR) and blood pressure (BP) below baseline. In the high-dose DEX for MRI study by Mason et al,30 16% of the patient population had HRs below age-specific norms, and in 4% of patients, HR fell more than 20% below norms, although all patients maintained acceptable mean arterial BPs and recovered uneventfully. Care has to be taken with other agents acting on the sinus node, as severe sinus bradycardia has been reported with the combination of DEX and digoxin,29 and Mason et al30 reported several cases of exaggerated hypertension when glycopyrrolate was used to treat bradycardia in the setting of DEX infusions.
ETOMIDATE
Etomidate, an imidazole derivative, is an ultrashort-acting hypnotic sedative without analgesic properties that first appeared in ED practice as a favorable agent for rapid-sequence induction before tracheal intubation.31 Deliverable only via IV, etomidate produces very potent sedation, anxiolysis, and amnesia, with minimal hemody-
namic effects, making it potentially desirable for procedural sedation.2 An evidence-based review found etomidate to be safe and effective for pediatric procedural sedation with level C recommendations, as initial publications of its use in this context were descriptive, retrospective studies.1 Since that review, several randomized prospective trials using etomidate for pediatric PSA have been published. Etomidate/ fentanyl was found to be more effective than MDZ/ fentanyl for PSA in extremity fracture reduction, with shorter induction and recovery times.32 A small randomized trial compared etomidate/fentanyl to ketamine/MDZ for fracture reduction and found higher pain scores but shorter recoveries with the former. Parents preferred the ketamine/ MDZ combination despite the longer recovery times.33 Etomidate was compared to pentobarbital for CT sedations in a large prospective, descriptive cohort study and was found to be both more effective and efficient than pentobarbital, with fewer complications.34 The advantages of etomidate include its rapid onset and recovery and the lack of effect on HR and BP. Rates of respiratory depression are similar to those of other sedative-hypnotics. The hemodynamic characteristics of etomidate increase its appeal for use in settings of potential cardiovascular instability, including sedation for electrical cardioversion of dysrhythmias, and for the trauma patient. However, etomidate is known to transiently suppress adrenal function via inhibition of 11 hydroxylase, which has been linked to adrenal insufficiency in a cohort of critically injured adults. 35 A definite causal link has not been established, and this transient adrenal suppression does not seem to cause problems in the routine sedation of healthier children. Other drawbacks of etomidate include pain on injection, nausea and vomiting, and potentially significant myoclonus. Myoclonus may be alleviated by the coadministration of low-dose midazolam.36
PENTOBARBITAL
Pentobarbital, along with its shorter-acting relatives methohexital and thiopental, is a barbiturate, a class of sedative known for profound sedation, hypnosis, amnesia, and anticonvulsant properties but no inherent analgesia. Barbiturates are in fact postulated to cause hyperesthesia and may increase pain sensation. Pentobarbital is typically delivered IV, whereas thiopental and methohexital have typically been delivered rectally, likely based on the very rapid effects achieved with transmu-
cosal administration and potent respiratory depression when the latter are delivered IV. Pentobarbital can also be given orally, with a much longer time to onset. Barbiturates have been used successfully for decades to provide procedural sedation in children, particularly for painless diagnostic imaging procedures. An evidence-based review found pentobarbital effective for producing cooperation for painless diagnostic procedures in children younger than 8 years, and safe, with the caveat that oxygen, positioning, and occasional positive pressure ventilation may be required (level B recommendations).1 When compared to newer agents, however, pentobarbital has been found to be less effective and less efficient, with a higher rate of adverse effects, in particular vomiting and recovery agitation. Pentobarbital compared unfavorably to etomidate as described above.34 Pentobarbital was also found to have much longer recovery times than propofol for MRI sedation in a small randomized controlled trial,37 and pentobarbital was associated with higher rates of prolonged recovery, vomiting, and unplanned admission when compared to propofol for the same indication in a large descriptive cohort study.38 The advantages of pentobarbital sedation include decades of cumulative experience, with a relatively good efficacy and safety profile. Pentobarbital reliably produces deep sedation, and once a child reaches that point, they are likely to remain in steady state without further drug dosing or infusions of drug, for 30 to 90 minutes. However, the disadvantage of pentobarbital is that it may take anywhere from 5 to 15 minutes of irritability and fighting sleep to reach that steady state. Induction is often not smooth, particularly in toddlers. This irritability has led to the practice of adjunct medications, such as midazolam and fentanyl, being delivered along with pentobarbital, a practice that may contribute to prolonged sedation and that may not be necessary.39 Other disadvantages of pentobarbital include respiratory depression, typically during induction of sleep, and nausea/vomiting and irritability, typically during recovery.
PROPOFOL
Propofol is a highly lipid-soluble, ultrashort-acting alkyl phenol agent with pure sedative properties. Although it provides no analgesia, it is capable of inducing a state of deep sedation allowing tolerance of painful procedures. It can only be administered IV and may be delivered as bolus doses for short procedures or via an infusion for longer ones.
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Propofol is manufactured as a lipid emulsion that contains soy and egg lecithin, with the potential for allergic reactions in patients sensitive to soy or egg.40 The lipid emulsion also promotes bacterial growth, and care must be taken to avoid contamination of the vial. It has a low pH and tends to burn when pushed. This injection pain can be ameliorated by coadministration with lidocaine, either IV lidocaine first to pretreat the vein or by mixing the two (1 part 1% lidocaine to 9 parts propofol). Propofol has been in use as a general anesthetic since the 1970s. The first published use in a pediatric ED setting was in 1999, where it was shown to be an effective agent for fracture reduction.19 Although controversy still exists in some institutions as to its appropriateness for use by nonanesthesiologists, the use of propofol in pediatric ED settings has expanded, and several published retrospective,41,42 prospective,43 and comparative studies have documented its safe and effective use in this setting. In addition, propofol has been shown to be more efficient and cost-effective than other procedural sedation regimens. 44 An evidencebased review found propofol effective for producing cooperation for painless diagnostic procedures (level C recommendations) and effective for painful procedures when combined with a narcotic (level B recommendations). Propofol was also deemed safe, with the caveat that oxygen, positioning, and occasional positive pressure ventilation may be required (level B recommendations).1 The advantages of propofol include its favorable pharmacokinetics, with very rapid onset and recovery, its effectiveness, and its low incidence of vomiting and other undesirable after effects. Disadvantages include its potential for respiratory depression, with transient hypoxia in 5% to 20% of patients, depending on the rate and amount of the initial bolus. Propofol also drops mean arterial BP by 10% to 25%, likely not significant in healthy children but potentially a problem in children with hemodynamic instability. Despite these disadvantages, its safe use by nonanesthesiologists has been documented in large cohorts of patients, with positive pressure ventilation required in 0.5% and tracheal intubation required in none of 1059,45 and cardiopulmonary resuscitation required in 2 of 49 836 patients (both successful) as reported by the Pediatric Sedation Research Consortium.46 The latter publication showed no difference in adverse events with propofol use between anesthesiologists and nonanesthesiologists in the centers reporting to the Pediatric Sedation Research Consortium, all of which have well-organized sedation systems.
Propofol also lacks analgesic properties. Although one can administer enough propofol to render a patient tolerant to painful procedures, this level of sedation may be considered general anesthesia. Other analgesics can be added to propofol for painful procedures. The addition of narcotics to propofol is common, although the combination may lead to increased respiratory and hemodynamic compromise. Propofol can be effectively combined with ketamine as these agents have complementary hemodynamic properties, and the ketofol combination may lead to less respiratory depression than propofol/fentanyl.47-49 Prolonged infusion of propofol has also been temporally linked to severe metabolic acidosis in intensive care unit settings, the so-called propofol infusion syndrome,50 although this complication has not been reported in the setting of procedural sedation.
KETAMINE
Ketamine is a dissociative agent that produces a trancelike catatonic state with profound sedation, analgesia, and amnesia. As a noncompetitive Nmethyl D-aspartate receptor antagonist, it works by blocking effects of excitatory amino acids on Nmethyl D-aspartate receptors responsible for sensory perception, nociception, cognition, and consciousness. Ketamine is water soluble and lipophilic, allowing delivery via multiple routes.51 Currently, the IV and intramuscular routes are most used given their effectiveness and reliability; however, ketamine can also be given orally, 52,53 rectally,54 and intranasally.55 At low doses, ketamine is primarily an analgesic with mild sedative properties. Higher doses produce the catatonic dissociative state; once this state is reached, additional doses will maintain but not deepen the level of sedation.2 First used in humans in the late 1960s, the use of ketamine for pediatric procedural sedation in the ED setting took off after a landmark series of articles published by Green et al56-58 in the 1990s. It has since become one of the most popular and widely studied sedatives used for children in ED settings, used in 41% of all sedated procedures in a community ED sedation database.59 Ketamine has been used successfully in a tremendous variety of procedures, including fracture reduction, laceration repair, arthrocentesis, incision and drainage, foreign body removal, central line or intraosseus needle placement, CT scan, hernia reduction, lumbar puncture, chest tube placement, eye examination, pelvic examination, paraphimosis
reduction, and rectal prolapse reduction.58 It has become the gold standard to which other sedative regimens are compared, and it was the only parenteral sedative in an extensive evidencebased review of pediatric sedation to receive level A recommendations for safety and efficacy.1 Ketamine is unique among the commonly used sedatives in that respiratory drive and airway reflexes are maintained although the patient has been rendered unresponsive. Another advantage is its mild bronchodilatory effect, making it a desirable choice for sedation in the asthmatic patient. A randomized controlled trial of subdissociative dosing of ketamine failed to show a difference in asthma recovery,60 but case series reports using higher doses did report an effect.61,62 Because of the potential for laryngospasm (0.4% of patients in one large series),58 ketamine use in intraoral procedures was initially discouraged, although it has been used successfully with dental procedures63 and peritonsillar abscess drainage.64 In addition to laryngospasm, potential side effects include airway malalignment, excessive salivation, transient respiratory depression (especially if it is pushed quickly via IV), tachycardia, and hypertension. A large meta-analysis failed to note a benefit of antisialagogue use with ketamine, and in fact linked antisialagogue use to a slight increase in adverse respiratory events, although confounding bias could not be eliminated.65 Another effect of ketamine is catecholaminemediated increase in HR and blood pressure, associated with increased intracranial and intraocular pressure. These effects are well tolerated in healthy children but have led to restrictions in the use of ketamine in patients with cardiac disease, brain injury, or elevated intracranial pressure. Recent literature raises questions about these restrictions, as ketamine has been used successfully for sedation for cardiac catheterization in patients with congenital heart disease66 and in patients with documented elevated intracranial pressure. In a cohort of intensive care unit patients with intracranial monitors in place, ketamine sedation actually lowered intracranial pressure.67 Ketamine is also notorious for emergence phenomena and vomiting during recovery, reported in 5% to 15% of patients in a large meta-analysis. Contrary to initial beliefs, emergence phenomena are not age related and are not affected by the coadministration of benzodiazepines. 68 Parents and patients should be notified in advance of the common visual side effects of nystagmus and double vision. Double vision and visual hallucinations are common during recovery and may contribute to emergence agitation. Vomiting after
ketamine administration peaks in the young adolescent age groups and is more common with intramuscular or high-dose (N2.5 mg/kg) IV administration. Administration of ondansetron may alleviate the vomiting.69 Ketamine use is contraindicated in children younger than 3 months due to increased apnea risk and in patients with suspected or known psychosis. Relative contraindications include children younger than 12 months and in patients with hyperthyroidism or porphyria.2
SUMMARY
Emergency medicine physicians caring for children can choose from multiple pharmacologic agents that are capable of creating safe and effective procedural conditions in the ED, either alone or in combination. Clinicians should become familiar with these agents, their pharmacokinetics, pharmacodynamics, and availability in their own practice environments, to alleviate procedural distress whenever possible. Future directions in sedation pharmacology will likely bring refinements in the drugs themselves, as well as an increased understanding of the patient's response to the drugs, in part through the burgeoning field of pharmacogenetics.70 Further understanding of the effect of sedative and anesthetic agents on the developing brain is also forthcoming, as current investigations are underway to evaluate the potential for neuroapoptosis in young infants with the use of commonly used sedatives such as ketamine and propofol.71 In addition to sedative effects in young infants, research is also progressing on the use of sedatives for other specific patient populations, such as cardiac patients.72 Emergency medicine physicians have been and will continue to be integrally involved in advancing pediatric procedural sedation.
REFERENCES
1. EMSC Grant Panel Writing Committee. Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department. Ann Emerg Med 2004;44:342-77. 2. Krauss B, Green SM. Procedural sedation and analgesia in children. Lancet 2006;367:766-80. 3. Clark MS, Brunick AL. Handbook of titrous oxide and oxygen sedation. 3rd ed. Philadelphia, (PA): Mosby; 2007. 4. Babl FE, Oakley E, Seaman C, et al. High-concentration nitrous oxide for procedural sedation in children: adverse events and depth of sedation. Pediatrics 2008;121:e528-32. 5. Ekbom K, Jakobsson J, Marcus C. Nitrous oxide inhalation is a safe and effective way to facilitate procedures in paediatric outpatient departments. Arch Dis Child 2005;90:1073-6.
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6. Kanagasundaram SA, Lane LJ, Cavalletto B, et al. Efficacy and safety of nitrous oxide in alleviating pain and anxiety during painful procedures. Arch Dis Child 2001;84:492-5. 7. Burnweit C, Diana-Zerpa JA, Nahmad MH, et al. Nitrous oxide analgesia for minor pediatric surgical procedures: an effective alternative to conscious sedation? J Pediatr Surg 2004;39: 495-9. 8. Paut O, Calmejane C, Delorme J, et al. EMLA versus nitrous oxide for venous cannulation in children. Anesth Analg 2001; 93:590-3. 9. Zier JL, Kvam KA, Kurachek SC, et al. Sedation with nitrous oxide compared with no sedation during catheterization for urologic imaging in children. Pediatr Radiol 2007;37:678-84. 10. Luhmann JD, Kennedy RM, Porter FL, et al. A randomized clinical trial or continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair. Ann Emerg Med 2001;37:61-2. 11. Babl FE, Oakley E, Pupitadewi A, et al. Limited analgesic efficacy of nitrous oxide for painful procedures in children. Emerg Med J 2008;25:717-21. 12. Luhmann JD, Schootman M, Luhmann S, et al. A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for ED forearm fracture reduction in children. Pediatr 2006;118:e1078-86. 13. EMSC Grant Panel Writing Committee. Clinical policy: critical issue in the sedation of pediatric patients in the emergency department. Ann Emerg Med 2008;51:378-97. 14. Zier JL, Tarrago R, Liu M. Level of sedation with nitrous oxide for pediatric medical procedures. Anesth Analg 2010;110: 1399-405. 15. Connors K, Terndrup TE. Nasal versus oral midazolam for sedation of anxious children undergoing laceration repair. Ann Emerg Med 1994;24:1074-9. 16. Singh R, Kumar N, Vajifdar H. Midazolam as a sole sedative for computed tomography imaging in pediatric patients. Pediatr Anesth 2009;19:899-904. 17. D'Agostino J, Terndrup T. Chloral hydrate versus midazolam for sedation of children for neuroimaging: a randomized clinical trial. Pediatr Emerg Care 2000;16:1-4. 18. Kennedy RM, Porter FL, Miller JP, et al. Comparison of fentanyl/midazolam with ketamine/midazolam for pediatric orthopedic emergencies. Pediatr 1998;102:956-63. 19. Havel CJ, Strait RT, Hennes H. A clinical trial of propofol vs midazolam for procedural sedation in a pediatric emergency department. Acad Emerg Med 1999;6:975-8. 20. Wathen JE, Roback MG, Mackenzie T, et al. Does midazolam alter the clinical effects of intravenous ketamine sedation in children? A double-blind, randomized, controlled, emergency department trial. Ann Emerg Med 2000;36:579-88. 21. Shannon M, Albers G, Burkhart K, et al. Safety and efficacy of flumazenil in the reversal of benzodiazepineinduced conscious sedation. The flumazenil pediatric study group. J Pediatr 1997;131:582-6. 22. Massanari M, Novitsky J, Reinstein LJ. Paradoxical reactions in children associated with midazolam use during endoscopy. Clin Pediatr 1997;36:681-4. 23. Yuen VM, Hui TW, Irwin MG, et al. A comparison of intranasal dexmedetomidine and oral midazolam for premedication in pediatric anesthesia: a double-blinded randomized controlled trial. Anesth Anal 2008;106:1715-21. 24. Mason KP, Zgleszewski SE, Dearden JL, et al. Dexmedetomidine for pediatric sedation for computed tomography imaging studies. Anesth Analg 2006;103:57-62.
25. Mason KP, Zurakowski D, Zleszewski SE, et al. High dose dexmedetomidine as the sole sedative for pediatric MRI. Pediatr Anesth 2008;18:403-11. 26. Lubisch N, Roskos R, Berkenbosch JW. Dexmedetomidine for procedural sedation in children with autism and other behavioral disorders. Pediatr Neurol 2009;41:88-94. 27. Mason KP, O'Mahoney E, Zurakowski D, et al. Effects of dexmedetomidine on the EEG in children. Pediatr Anesth 2009;19:1175-83. 28. Scheinin H, Aantaa R, Anttila M, et al. Reversal of the sedative and sympatholytic effects of dexmedetomidine with specific alpha2-adrenoreceptor antagonist atipamezole: a pharmacodynamic and kinetic study in healthy volunteers. Anesthesiology 1998;89:574-84. 29. Berkenbosch JW, Tobias JD. Development of bradycardia during sedation with dexmedetomidine in an infant concurrently receiving digoxin. Pediatr Crit Care Med 2003;4: 203-5. 30. Mason KP, Zgleszewski S, Forman RE, et al. An exaggerated hypertensive response to glycopyrrolate therapy for bradycardia associated with high-dose dexmedetomidine. Anesth Analg 2009;108:906-8. 31. Guldner G, Schultz J, Sexton P, et al. Etomidate for rapidsequence intubation in young children: hemodynamic effects and adverse events. Acad Emerg Med 2002;10:134-9. 32. DiLiddo L, D'Angelo A, Nguyen B, et al. Etomidate versus midazolam for procedural sedation in pediatric outpatients: a randomized controlled trial. Ann Emerg Med 2006;48: 433-40. 33. Lee-Jayaram JJ, Green A, Siembieda J, et al. Ketamine/ midazolam versus etomidate/fentanyl: procedural sedation for pediatric orthopedic reductions. Pediatr Emerg Care 2010;26:408-12. 34. Baxter AL, Mallory MD, Spandorfer PR, et al. Etomidate versus pentobarbital for computerized tomography sedations: report from the Pediatric Sedation Research Consortium. Pediatr Emerg Care 2007;23:690-5. 35. Cotton BA, Guillamondegui OD, Fleming SB, et al. Increased risk of adrenal insufficiency following etomidate exposure in critically injured patients. Arch Surg 2008;143:62-7. 36. Huter L, Schreiber T, Gugel M, et al. Low-dose intravenous midazolam reduces etomidate-induced myoclonus: a prospective, randomized study in patients undergoing elective cardioversion. Anesth Analg 2007;105:1298-302. 37. Pershad J, Wan J, Anghelescu DL. Comparison of propofol with pentobarbital/midazolam/fentanyl sedation for magnetic resonance imaging of the brain in children. Pediatr 2007;120: e629-36. 38. Mallory MD, Baxter AL, Kost SI. Propofol versus pentobarbital for sedation of children undergoing magnetic resonance imaging: results from the Pediatric Sedation Research Consortium. Pediatr Anesth 2009;19:601-11. 39. Mason KP, Zurakowski D, Karian VE, et al. Sedatives used in pediatric imaging: comparison of IV pentobarbital with IV pentobarbital with midazolam added. Am J Roentgenol 2001; 117:427-30. 40. Hofer KN, McCarthy MW, Buck ML, et al. Possible anaphylaxis after propofol in a child with food allergy. Ann Pharmacother 2003;37:398-401. 41. Bassett KE, Anderson JL, Pribble CG, et al. Propofol for procedural sedation in children in the emergency department. Ann Emerg Med 2003;42:773-82. 42. Pershad J, Godambe SA. Propofol for procedural sedation in the pediatric emergency department. J Emerg Med 2004;27: 11-4.
43. Skokan EG, Pribble C, Bassett KE, et al. Use of propofol sedation in a pediatric emergency department: a prospective study. Clin Pediatr 2001;40:663-71. 44. Pershad J, Todd K, Waters T. Cost-effectiveness analysis of sedation and analgesia regimens during fracture manipulation in the pediatric emergency department. Pediatr Emerg Care 2006;22:729-36. 45. Barbi E, Gerarduzzi T, Marchetti F, et al. Deep sedation with propofol by nonanesthesiologists: a prospective pediatric experience. Arch Pediatr Adolesc Med 2003;157:1097-103. 46. Cravero JP, Beach ML, Blike GT, et al. The incidence and nature of adverse events during pediatric sedation/anesthesia with propofol for procedures outside the operating room: a report from the Pediatric Sedation Research Consortium. Anesth Analg 2009;108:795-804. 47. Messenger DW, Murray HE, Dungey PE, et al. Subdissociative-dose ketamine versus fentanyl for analgesia during propofol procedural sedation: a randomized clinical trial. Acad Emerg Med 2008;15:877-86. 48. Erden IA, Pamuk AG, Akinci SB, et al. Comparison of propofol-fentanyl with propofol-fentanyl-ketamine combination in pediatric patients undergoing interventional radiology procedures. Pediatr Anesth 2009;19:500-6. 49. Andolfatto G, Willman E. A prospective case series of pediatric procedural sedation and analgesia in the emergency department using single-syringe ketamine-propofol combination (ketafol). Acad Emerg Med 2010;17:194-201. 50. Bray RJ. Propofol infusion syndrome in children. Pediatr Anesth 1998;8:491-6. 51. Jolly AS, Jain P, Sood J. Ketaminecurrent uses and future perspectives. J Anesth Clin Pharm 2007;23:169-81. 52. Gutstein HB, Johnson KL, Heard MB, et al. Oral ketamine preanesthetic medication in children. Anesthesiology 1992 Jan;76:28-33. 53. Tobias JD, Phipps S, Smith B, et al. Oral ketamine premedication to alleviate the distress of invasive procedures in pediatric oncology patients. Pediatrics 1992;90: 537-41. 54. Tanaka M, Sato M, Saito A, et al. Reevaluation of rectal ketamine premedication in children: comparison with rectal midazolam. Anesthesiology 2000;93:1217-24. 55. Weber F, Wulf H, Gruber M, et al. S-ketamine and Snorketamine plasma concentrations after nasal and intravenous administration in anesthetized children. Pediatr Anesth 2004;14:983-8. 56. Green SM. Ketamine sedation for pediatric procedures. Part 1: a prospective series. Ann Emerg Med 1990;19:1024-32. 57. Green SM. Ketamine sedation for pediatric procedures. Part 2: review and implications. Ann Emerg Med 1990;19: 1033-46.
58. Green SM, Rothrock SG, Lynch EL, et al. Intramuscular ketamine for pediatric sedation in the emergency department: safety profile with 1,022 cases. Ann Emerg Med 1998; 31:688-97. 59. Sacchetti A, Stander E, Ferguson N, et al. Pediatric procedural sedation in the community emergency department: results from the ProSCED registry. Pediatr Emerg Care 2007;23:218-22. 60. Allen JY, Macias CG. The efficacy of ketamine in pediatric emergency department patients who present with acute severe asthma. Ann Emerg Med 2005;46:43-50. 61. Petrillo TM, Fortenberry JD, Linzer JF, et al. Emergency department use of ketamine in pediatric status asthmaticus. J Asthma 2001;38:657-64. 62. Denmark TK, Crane HA, Brown L. Ketamine to avoid mechanical ventilation in severe pediatric asthma. J Emerg Med 2006;30:163-6. 63. Rai K, Hegde AM, Goel K. Sedation in uncooperative children undergoing dental procedures: a comparative evaluation of midazolam, propofol, and ketamine. J Clin Pediatr Dent 2007;32:1-4. 64. Luhmann JD, Kennedy RM. Sedation for peritonsillar abscess drainage in the pediatric emergency department. Pediatr Emerg Care 2002;18:1-3. 65. Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual patient data metaanalysis of 8,282 children. Ann Emerg Med 2009;54:158-68. 66. Oklu E, Bulutcu FS, Yalcin Y, et al. Which anesthetic agent alters the hemodynamic status during pediatric catheterization? Comparison of propofol versus ketamine. J Cardiothorac Vasc Anesth 2003;17:686-90. 67. Bar-Joseph G, Guilburd Y, Tamir A, et al. Effectiveness of ketamine in decreasing intracranial pressure in children with intracranial hypertension. J Neurosurg Pediatr 2009;4:40-6. 68. Green SM, Roback MG, Krauss B, et al. Predictors of emesis and recovery agitation with emergency department ketamine sedation: an individual patient data meta-analysis of 8,282 children. Ann Emerg Med 2009;54:171-80. 69. Langston WT, Wathen JE, Roback MG, et al. Effect of ondansetron on the incidence of vomiting associated with ketamine sedation in children: a double-blind, randomized, placebo-controlled trial. Ann Emerg Med 2008;52:30-4. 70. Husain A, Loehle JA, Hein DW. Clinical pharmacogenetics in pediatric patients. Pharmacogenomics 2007;8:1403-11. 71. Wang C, Slikker Jr W. Strategies and experimental models for evaluating anesthetics: effects on the developing nervous system. Anesth Analg 2008;106:1643-58. 72. Diaz LK, Jones L. Sedating the child with congenital heart disease. Anesth Clin 2009;27:301-19.
Abstract:
When pain is effectively managed, distress in children undergoing Emergency Department procedures is often due to anxiety and fear. This distress can be caused by many factors including being in an unfamiliar environment, exposed to strangers, not knowing what to expect or anticipation based upon previous painful experiences. This article reviews some of the many non-pharmacological developmentally-based strategies that can be implemented in the emergency department to reduce a childs distress. These techniques can help improve treatment and procedural success, and ultimately create a more satisfying experience for the patient, family and medical team.
Nonpharmacologic Techniques for Distress Reduction During Emergency Medical Care: A Review
Charles Eldridge, MD, Robert Kennedy, MD
Keywords:
anxiety; distress; pain; pediatric; cognitive-behavioral; family presence; guided-imagery; child life; distraction
Reprint requests and correspondence: Charles Eldridge, MD, Washington University in St Louis School of Medicine, Campus Box 8116, St Louis, MO 63110. eldridge_c@kids.wustl.edu (C. Eldridge), kennedy@kids.wustl.edu (R. Kennedy)
1522-8401/$ - see front matter Published by Elsevier Inc.
any aspects of medical care in the emergency department (ED) are frightening to young patients. Their fear frequently causes them to resist treatment, creating delays and increasing staff and other resources needed to achieve their care. Some medical care involves painful procedures, addressed in detail below; but frequently, children's distress is primarily due to anxiety. Examples include simple stranger anxiety in toddlers, frightening nebulization treatments for asthma exacerbations, positioning for radiographs, and performance of computed tomography and magnetic resonance imaging scans. Because crying due to pain is often difficult to distinguish from that due to anxiety, especially in preverbal infants, toddlers, and preschool children, the global term distress is often used for these reactions. Procedural sedation and analgesia (PSA) are core skills in pediatric emergency medicine and have become common methods for facilitation of painful and nonpainful procedures for children in the ED. However, administration of PSA significantly
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increases the use of often-scarce ED resources and cost of care. Furthermore, minor adverse effects, such as nausea and vomiting; rare major events, such as hypoxia or laryngospasm; and painful intravenous (IV) catheter placement or intramuscular administration are also associated with PSA. When procedural pain is effectively managed or the medical care is not painful, patient cooperation can frequently be obtained and care effectively and efficiently rendered by use of nonpharmacologic techniques. There are numerous variables to consider when dealing with children as patients. Along with underlying diagnoses and conditions, a child's past experiences, methods of family support, level of development, and cognition must be assessed when determining how best to proceed with evaluation and care. Even parents often have difficulty predicting how their child will react to procedures and the emergency care environment. Children of all ages have coping mechanisms that can be encouraged to help them control their anxiety and behavior. These range from the infant vigorously sucking on a pacifier to the teenager focusing on favorite imagery. Unlike scheduled visits to their familiar primary health care provider, the unanticipated and urgent nature of events leading to emergency care frequently interferes with a child's employment of these coping strategies.1 Age-specific preparation for pain and anxiety in acute medical situations may dramatically help decrease distress in parents and children. Once a child becomes frightened or anxious, these coping strategies may be overwhelmed and behavior may be uncontrolled. In addition, even after completion of a procedure, lingering memories of the distressful event and anticipation of pain may make the next health care visit or procedural experience all the more challenging.2 In addition to accomplishment of necessary procedures, the goal of emergency care providers should be to make the experience as painless and stress-free as possible. This increases child and parent satisfaction, can increase efficiency of care, and improves future health care interactions. Certified child life specialists, a relatively new type of health care provider, have developed expertise in techniques that help patients and families cope with medical carerelated stress and anxiety and have become an invaluable member of the emergency care team. They help build rapport with the patient and family, soothe tensions, and effectively distract the patient, thus helping accomplish necessary procedures efficiently and with greater patient and family satisfaction.3,4
DEVELOPMENTAL STAGES
As children grow from infancy into young adulthood, dramatic psychological as well as physical changes occur. The young infant communicates primarily by crying, has no capacity for understanding, and is completely dependent upon nurturing adults for protection, food, and other essential needs. Practitioners have long believed infants have no memory of painful experiences, but recent studies found painful circumcision5 or heel punctures for blood samples6 within the first days or months7 of life resulted in increased distress during subsequent procedures days to months later. Explicit memory of procedures is unlikely at this age, but poorly controlled pain during early infancy may impact central nervous system development in poorly understood ways that impact behavior later in infancy and childhood.2 Furthermore, during the first months to year of life, incomplete development of inhibitory central nervous system pain pathways likely results in increased intensity of pain when compared with that experienced by older children and adults from the same stimulus.8 Child psychologist Jean Piaget described 4 stages of cognitive development that explain how children understand and assimilate new information.9,10 In the sensorimotor stage from birth to about age 2 years, infants and children interpret their surroundings by what they see, taste, and touch. Familiar objects, faces, or soothing voices help to calm infants and toddlers, whereas seeing a needle or unfamiliar objects such as gloves or a stethoscope can be distressing during this stage. Rationalizing the procedure to the young child is of little benefit, but it may be helpful to ask the parents of the toddler to reinforce that your care is important to help you (the patient) get better. Separation anxiety becomes important during this period. Infants younger than 6 months typically adapt well to other caregivers, as long as their needs are being met. At 5 to 8 months of age, babies develop a sense of object permanence and begin to learn that things and people exist even when they are out of sight. They also begin to differentiate their parents from other adults. If they cannot see their parents, they now begin to know they have gone away and do not know if or when they are coming back. Separating the older infant from his parents frequently leads to crying as an attempt to bring the parent back. Performing the physical examination or procedures with the older infant or toddler sitting in a parent's lap can effectively reduce distress in this age group.11
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In the preoperational stage, from about the time the child starts to talk until about age 7 years, the child begins to use symbols (eg, language) to represent and personify objects. She has difficulty conceptualizing time, but she is better able to think about things and events that are not immediately present. Fantasies, the way she would like things to be, become prominent; and she assumes others see situations as she does. She adapts new information to fit her ideas. Interactions and preparation of the child should take into consideration these vivid fantasies and undeveloped sense of time. Understanding children's perceptions and feelings about anticipated procedures helps determine what information the child needs for preparation. Using neutral words, body outlines, and equipment a child can touch gives her an active role in learning; but explanations are still important. For example, allowing a child to play with suturing instruments and needleless suture can reduce her anxiety about the impending laceration repair by desensitization12 ; but she may fear the scissors will be used to cut her. General explanations of what the procedure will involve are helpful, but exposure of needles likely will exacerbate distress. As the child enters the concrete stage, from about first grade to early adolescence, the ability to think abstractly and make rational judgments about concrete observations develops. Giving the child the opportunity to ask questions and to explain his understandings allows him to mentally manipulate information and gives insight to his fears and expectations. During this stage, accommodation increases; but allowing the child to have control of specific aspects of the procedure may help to alleviate distress. For example, when injecting lidocaine, the child may be told, Let me know if this hurts and I'll slow down so it does not bother you so much. Be careful not to promise too much control such as If it hurts, I'll stop for a bit, as that may lead to repeated requests to stop. Finally, during the formal operations stage of adolescence, the child is capable of hypothetical and deductive reasoning. He will be able to consider many possibilities from several perspectives. Within each of these stages of development, there are wide variations in how children will react to medical care. Individual personalities, what they have already been told to expect by family members and friends, and previous experiences impact their responses. Working within the general understanding of the child's developmental stage, health care providers need to be flexible in their approach and guided by the child's responses to initial overtures and suggestions made by parents.
THE ENVIRONMENT
A quiet, controlled atmosphere in which the procedure is performed can be key to alleviating distress. Procedure-related instruments such as laceration trays are routine for the ED staff but are likely frightening for the young child. Instrument trays can be prepared out of view of the patient and covered with sterile towels when placed at the bedside. Closing the door to the examination room reduces potentially disturbing noises and distractions from elsewhere. Watching television or cartoons, reducing the volume on monitors, minimizing the number of staff, and in some cases family members can also help set the stage.
FAMILY PRESENCE
A large study of school-aged children found that having a parent present during the procedure was the most important way to help them cope during an emergency visit, despite knowing their parent could do little to help their pain.13,14 In toddlers and preschoolers, performing IV catheter placement as the child sat in the parent's lap with a gentle parental hug instead of being held down on an examination table reduced distress without compromising procedural success.11 Most parents/ guardians want to be present during procedures to help their children and do not interfere with care.15-19 It is helpful for many parents to be directed by staff with suggestions on how they might help their child cope (eg, sitting at the bedside where their child can easily see their face, singing their child's favorite song, storytelling, or simply touching their child's body). It is also helpful to clarify what the parents should be careful about (eg, sterile fields) so that they will not interfere with the procedure. Informed parents rarely interfere with the performance of a procedure, but preparation should be made for the possibility of parental distress or syncope by asking them to be seated as they help their child.19 Addressing parental questions and concerns also helps parents aid their children during the process. Many EDs now have policies that support parental presence during procedures, including resuscitation.20 Parental presence, however, may not consistently reduce children's distress.19,21 Some children may be more likely to exhibit disruptive behavior if they are accompanied by a parent during the procedure.22 Parental anxiety and children's distress have been found to be positively correlated during procedures.23 It is important to assess the parents' relationship with their child, the parents'
level of distress about the pending procedure, and their abilities to enhance or their potential to interfere with their children's ability to cope.
TEAM COORDINATION
The health care team may consist of physicians, nurses, paramedics, child life, social work, the patient, and family members. It is important for everyone to understand what will be required to accomplish the procedure and what are the likely painful/distressing steps. This allows everyone to prepare the patient and efficiently assist with the procedure. As noted above, parents need to understand how they can best help and benefit from specific suggestions.
parent should not promise that the child will feel no pain, even with procedural sedation. Rather, providers should assure that we will do everything we reasonably can to minimize pain or discomfort. Establishing acceptable behavior before the procedure begins and empowering parents to control the pain by using techniques such as relaxation, distraction, or self-hypnosis can also help minimize distress.
DISTRACTION
Distraction and imagery have long been used to reduce procedural distress in children.24,25 Recent studies using functional magnetic resonance imaging have shown that focusing on an object or idea reduces activity in the areas of the cerebral cortex associated with pain response and anxiety.26 Rocking, swaddling, or holding the infant in comfortable, well-supported positions while allowing sucking or providing something to grasp may reduce distress. With older children, slow deep breaths during a procedure to blow away the pain can be effective.27,28 Blowing soap bubbles can be powerfully distracting and evolve into a relaxation technique with slow rhythmic breathing. These techniques are best taught before the procedure and can be used to reduce distress both before and during the procedure. Distraction can be accomplished without special equipment by engaging children of all ages in a variety of tasks, such as focusing attention on objects in the room, singing, counting, and storytelling. Developmental considerations and individual interests are important in developing effective distraction techniques. Allowing children and parents to identify what is particularly interesting to them improves distraction and grants them some control in the procedure. Imagery uses the development of pleasant scenes, actions, hobbies, favorite television programs, movies, etc, into fantasies. This may be as simple as the child picturing him- or herself elsewhere or doing something fun. Storytelling can be developed into imagery by incorporating the sensory experience of the procedure. Developmental consideration and individual interests are essential in developing effective imagery techniques as well.
DEMEANOR
A warm smile and a slow respectful approach are particularly important to reduce the frightened child's perception of the provider as a threat. Playful interactions during explanations, smiling and maintaining patient eye contact, sitting during explanations, and allowing time for questions help establish trust and reduce anxiety. Speak directly to the patient and family and provide simple, clear explanations. Describe steps in positive terms, such as hugging your knees for a lumbar puncture. Avoid hospital jargon as it may cause confusion and the patient or family members may hesitate to ask for clarification. Similarly, avoid terms that may evoke fear or anxiety, such as needle, a stick and a burn, IV, or hurt. Use of less threatening descriptions, such as you may feel freezing (instead of burning) or if I push too hard, let me know and I'll slow down (during injection of buffered lidocaine), may reduce distress by changing the child's expectations and perceptions. With many patients, detailed discussion of the painful parts of the procedure may increase anticipatory anxiety. Explanations can be given to parents of young children using terms that the child is not likely to understand. The child should be assured that he will be warned before a step during which he might experience pain, comparing the potential pain to something less fearful with which the patient might be familiar, for example, a mosquito bite (instead of a bee sting). If a child is surprised by a painful step, he or she likely will lose confidence and may refuse to cooperate. When a step unexpectedly causes pain, the provider should immediately apologize to the patient and parent, indicate concern, and explain what will be done to reduce or prevent subsequent pain. A provider or
STRATEGIES BY AGE OR DEVELOPMENTAL STAGE

Children between 2 and 7 years of age (preoperational stage) will likely have difficulty understanding the reasons for medical procedures, and attempts to
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rationalize are usually not helpful. These children may benefit more from play therapy before the procedure and simple distraction techniques and reinforcement of positive behaviors during the procedure. Relatively passive interventions that involve concentration, such as music, movies, or television, may work well for some older children, whereas others respond better to activities that require more interaction.29,30 Younger children and those with developmental delay may do better with behavioral techniques that require less cognitive effort such as conversation, visual distractions, and counting. Structured strategies for toddlers include pop-up books and toys, blowing bubbles, looking through a kaleidoscope, and watching videos. Popup books and toys provide multiple novel stimuli that help capture and recapture children's attention whenever they start to focus on the painful procedure. Age-appropriate activities for preschool children include familiar videos, searching for objects in pictures, blowing away pain, and superhero imagery or other storytelling. Reading can be an effective means to distract a child because the book also can be used to create a visual barrier from the neck down to block the child from readily viewing needles, the procedure, etc. Mock demonstrations (modeling) of the procedure on a doll or the patient, or watching videos of other children undergoing the procedure can help desensitize the older preoperational child by helping them to better understand the upcoming procedure.31 Parents often will provide the best distraction for the patient. They know the child's interests and what may be most effective. They should be informed that it will be helpful if they are talking or interacting with their child during the procedure. It is important to help them feel comfortable interacting with their child in an uninhibited manner to better ease their child's distress. Getting the parents involved results in greater satisfaction by making them an important part of their child's health care team.11 Children 8 years and older (concrete stage) likely can understand reasons for procedures and respond well to distraction. Listening to music or a story through a headset or watching a familiar video or playing games can be highly effective. Singing a familiar song and keeping time to the music are some other simple distractions. Counting and imagery are also helpful in this age group. Adolescents may regress when they become acutely anxious and may require help to use effective coping mechanisms. Discussion of the procedure with plans for coping and practice of coping techniques can be quite useful.
Relaxation techniques, such as guided imagery, deep breathing, and massage therapy, can effectively reduce distress, especially in older children and adolescents (formal operations stage).32,33 These techniques are often used in tandem to enhance the effect. Patients are asked to close their eyes, take slow deep breaths, and imagine relaxing scenarios, such as drifting in the clouds or lying in the sun. Massage therapy can also help the patient relax and make the time in the ED more pleasant.34 These techniques can greatly enhance mild to moderate sedation with nitrous oxide or anxiolysis with midazolam.35
PAINLESS LOCAL ANESTHESIA

The effectiveness of nonpharmacologic techniques for reduction of distress is critically dependent upon pain relief. Effective local anesthesia greatly reduces anxiety and the need for procedural sedation,36 particularly when needleless and nearly painless placement of anesthetics can be achieved. Placing topical anesthetic solutions or gels containing 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine into lacerations is nearly painless and provides local anesthesia sufficient for suturing in most children.37-39 These solutions are more effective in scalp and facial wounds, as blood supply to these areas is high. This local anesthesia can be augmented, if necessary, by subcutaneous injection of buffered lidocaine. Injection pain can be markedly reduced by buffering of anesthetics, use of finer needles (30-gauge optimal) for injection, slowing the rate of injection, 40,41 subcutaneous instead of intradermal injection,42,43 and warming of the anesthetic to body temperature.44,45 Lidocaine hydrochloride, a weak amide base, is packaged in an acidic solution (pH 5.0-7.0) to maintain the anesthetic's stability.46 Buffering lidocaine to a neutral pH by mixing 1 part of 1 mEq/mL sodium bicarbonate with 9 to 10 parts of 1% lidocaine markedly decreases the pain of injection. 46,47 Buffering also decreases onset time for anesthesia without affecting efficacy or duration.47-49 Eutectic mixture of local anesthetic (EMLA) and 4% lidocaine are topical anesthetic preparations that penetrate intact skin, providing local anesthesia after 30 to 60 minutes.50 Depth of anesthesia is approximately 3 mm after 60 minutes of application of EMLA cream under an occlusive dressing and is maximum at 5 mm after 90 to 120 minutes. Similar studies have not been performed with the 4% lidocaine liposomal cream. Both preparations may be used for skin anesthesia through which buffered lidocaine can then be
injected for deeper anesthesia for procedures such as laceration repair, lumbar puncture, or abscess incision and drainage.
SUMMARY
The goal of health care providers is to provide safe and effective care. An important part of effective care of children is reduction of procedure- and other health carerelated pain and distress. This improves acceptance of recommendations (compliance) during current and future health care interactions. Use of age-appropriate and patient-guided nonpharmacologic techniques to reduce patient distress improves the efficiency of emergency care delivery as well as improves patient, family, and health care staff satisfaction.
REFERENCES
1. Siegel LJ. Preparation of children for hospitalization: a selected review of the research literature. J Pediatr Psychol 1976;1:26-30. 2. Kennedy RM, Luhmann J, Zempsky WT. Clinical implications of unmanaged needle-insertion pain and distress in children. Pediatrics 2008;122(Suppl 3):S130-3. 3. Stevenson MD, Bivins CM, O'Brien K, et al. Child life intervention during angiocatheter insertion in the pediatric emergency department. Pediatr Emerg Care 2005;21:712-8. 4. Christian B, Thomas DO. A child life program in one pediatric emergency department. J Emerg Nurs 1998;24:359-61. 5. Taddio A, Katz J, Ilersich AL, et al. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet 1997;349:599-603. 6. Taddio A, Shah V, Gilbert-MacLeod C, et al. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA 2002;288:857-61. 7. Peters JW, Koot HM, de Boer JB, et al. Major surgery within the first 3 months of life and subsequent biobehavioral pain responses to immunization at later age: a case comparison study. Pediatrics 2003;111:129-35. 8. Teng CJ, Abbott FV. The formalin test: a dose-response analysis at three developmental stages. Pain 1998;76:337-47. 9. Gesell A, Ilg FL, Ames LB. Infant and child in the culture of today: the guidance of development in home and nursery school. Rev. ed. Northvale (N.J.): J. Aronson; 1995. 10. Wood D. How children think and learn: the social contexts of cognitive development. 2nd ed. Malden (Ma): Blackwell; 1998. 11. Sparks LA, Setlik J, Luhman J. Parental holding and positioning to decrease IV distress in young children: a randomized controlled trial. J Pediatr Nurs 2007;22:440-7. 12. Zeltzer LK, Bush JP, Chen E, et al. Psychobiologic approach to pediatric pain: part II. Prevention and treatment. Curr Probl Pediatr 1997;27:264-84. 13. Ross DM, Ross SA. Childhood pain: the school-aged child's viewpoint. Pain 1984;20:179-91. 14. Ross DM, Ross SA. Assessment of pediatric pain: an overview. Issues Comprehen Pediatr Nurs 1988;11:73-91.
15. Bauchner H, Waring C, Vinci R. Parental presence during procedures in an emergency room: results from 50 observations. Pediatrics 1991;87:544-8. 16. Merritt KA, Sargent JR, Osborn LM. Attitudes regarding parental presence during medical procedures. Am J Dis Child 1990;144:270-1. 17. Sacchetti A, Lichenstein R, Carraccio CA, et al. Family member presence during pediatric emergency department procedures. Pediatr Emerg Care 1996;12:268-71. 18. Mangurten J, Scott SH, Guzzetta CE, et al. Effects of family presence during resuscitation and invasive procedures in a pediatric emergency department. J Emerg Nurs 2006;32: 225-33. 19. Bauchner H, Vinci R, Bak S, et al. Parents and procedures: a randomized controlled trial. Pediatrics 1996;98:861-7. 20. Henderson DP, Knapp JF. Report of the national consensus conference on family presence during pediatric cardiopulmonary resuscitation and procedures. Pediatr Emerg Care 2005;21:787-91. 21. Wright KD, Stewart SH, Finley GA. When are parents helpful? A randomized clinical trial of the efficacy of parental presence for pediatric anesthesia. Can J Anaesth 2010;57: 751-8. 22. Shaw EG, Routh DK. Effect of mother presence on children's reaction to aversive procedures. J Pediatr Psychol 1982;7: 33-42. 23. Caldwell-Andrews AA, Kain ZN, Mayes LC, et al. Motivation and maternal presence during induction of anesthesia. Anesthesiology 2005;103:478-83. 24. Alcock DS, Feldman W, Goodman JT, et al. Evaluation of child life intervention in emergency department suturing. Pediatr Emerg Care 1985;1:111-5. 25. Manne SL, Bakeman R, Jacobsen PB, et al. An analysis of a behavioral intervention for children undergoing venipuncture. Health Psychol 1994;13:556-66. 26. Valet M, Sprenger T, Boecker H, et al. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during painan fMRI analysis. Pain 2004;109:399-408. 27. French GM, Painter EC, Coury DL. Blowing away shot pain: a technique for pain management during immunization. Pediatrics 1994;93:384-8. 28. Peretz B, Gluck GM. Assessing an active distracting technique for local anesthetic injection in pediatric dental patients: repeated deep breathing and blowing out air. J Clin Pediatr Dent 1999;24:5-8. 29. MacLaren JE, Cohen LL. A comparison of distraction strategies for venipuncture distress in children. J Pediatr Psychol 2005;30:387-96. 30. Kleiber C, Craft-Rosenberg M, Harper DC. Parents as distraction coaches during IV insertion: a randomized study. J Pain Symptom Manage 2001;22:851-61. 31. Faust J, Olson R, Rodriguez H. Same-day surgery preparation: reduction of pediatric patient arousal and distress through participant modeling. J Consult Clin Psychol 1991;59:475-8. 32. Kline WH, Turnbull A, Labruna VE, et al. Enhancing pain management in the PICU by teaching guided mental imagery: a quality-improvement project. J Pediatr Psychol 2010;35: 25-31. 33. Youssef NN, Rosh JR, Loughran M, et al. Treatment of functional abdominal pain in childhood with cognitive behavioral strategies. J Pediatr Gastroenterol Nutr 2004;39: 192-6. 34. Hughes D, Ladas E, Rooney D, et al. Massage therapy as a supportive care intervention for children with cancer. Oncol Nurs Forum 2008;35:431-42.
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35. Benedetti C, Chapman CR, Colpitts YH, et al. Effect of nitrous oxide concentration on event-related potentials during painful tooth stimulation. Anesthesiology 1982;56:360-4. 36. Pierluisi GJ, Terndrup TE. Influence of topical anesthesia on the sedation of pediatric emergency department patients with lacerations. Pediatr Emerg Care 1989;5:211-5. 37. Bonadio WA. TAC: a review. Pediatr Emerg Care 1989;5: 128-30. 38. Ernst AA, Marvez E, Nick TG, et al. Lidocaine adrenaline tetracaine gel versus tetracaine adrenaline cocaine gel for topical anesthesia in linear scalp and facial lacerations in children aged 5 to 17 years. Pediatrics 1995;95:255-8. 39. Schilling CG, Bank DE, Borchert BA, et al. Tetracaine, epinephrine (adrenalin), and cocaine (TAC) versus lidocaine, epinephrine, and tetracaine (LET) for anesthesia of lacerations in children. Ann Emerg Med 1995;25:203-8. 40. Scarfone RJ, Jasani M, Gracely EJ. Pain of local anesthetics: rate of administration and buffering. Ann Emerg Med 1998; 31:36-40. 41. Krause RS, Moscati R, Filice M, et al. The effect of injection speed on the pain of lidocaine infiltration. Acad Emerg Med 1997;4:1032-5. 42. Arndt KA, Burton C, Noe JM. Minimizing the pain of local anesthesia. Plast Reconstr Surg 1983;72:676-9.
43. Morris R, McKay W, Mushlin P. Comparison of pain associated with intradermal and subcutaneous infiltration with various local anesthetic solutions. Anesth Analg 1987;66:1180-2. 44. Brogan GX, Giarrusso E, Hollander JE, et al. Comparison of plain, warmed, and buffered lidocaine for anesthesia of traumatic wounds. Ann Emerg Med 1995;26:121-5. 45. Colaric KB, Overton DT, Moore K. Pain reduction in lidocaine administration through buffering and warming. Am J Emerg Med 1998;16:353-6. 46. Christoph RA, Buchanan L, Begalla K, et al. Pain reduction in local anesthetic administration through pH buffering. Ann Emerg Med 1988;17:117-20. 47. McKay W, Morris R, Mushlin P. Sodium bicarbonate attenuates pain on skin infiltration with lidocaine, with or without epinephrine. Anesth Analg 1987;66:572-4. 48. Orlinsky M, Hudson C, Chan L, et al. Pain comparison of unbuffered versus buffered lidocaine in local wound infiltration. J Emerg Med 1992;10:411-5. 49. Bartfield JM, Gennis P, Barbera J, et al. Buffered versus plain lidocaine as a local anesthetic for simple laceration repair. Ann Emerg Med 1990;19:1387-9. 50. Bjerring P, Arendt-Nielsen L. Depth and duration of skin analgesia to needle insertion after topical application of EMLA cream. Br J Anaesth 1990;64:173-7.
Abstract:
Although emergency department procedural sedation in children is widely practiced, it is not without risk. Appropriate vital sign monitoring has been identified as an essential mechanism to reduce risk associated with procedural sedation. We describe the evolution of guidelines for procedural sedation monitoring in children and review monitoring principles, common adverse events, current monitoring modalities, future directions, and emerging monitoring technologies.
Keywords:
procedural sedation; monitoring; children; adverse events; capnography; oximetry; bispectral index
Monitoring the Procedural Sedation Patient: Optimal Constructs for Patient Safety
Joshua Nagler, MD, Baruch Krauss, MD, EdM
P
Division of Emergency Medicine, Childrens Hospital Boston and the Department of Pediatrics, Harvard Medical School, Boston, MA. Reprint requests and correspondence: Joshua Nagler, MD, Division of Emergency Medicine, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115. joshua.nagler@childrens.harvard.edu
rocedural sedation and analgesia (PSA) are essential parts of pediatric emergency medicine practice and the standard of care for relieving anxiety and pain associated with diagnostic and therapeutic procedures in children.1,2 Over the past 25 years, a robust body of literature supports the safety and efficacy of emergency department (ED) PSA in children. However, such pharmacologic interventions are not without risk. Monitoring modalities, both interactive and mechanical, are an integral part of procedural sedation and are the foundation for safe practice. In this article, we discuss the current state and future directions in PSA monitoring in children.
HISTORICAL BACKGROUND
In the mid-1980s, reports of adverse outcomes and even fatalities associated with the practice of pediatric PSA in the outpatient setting began to emerge. In response, the American Academy of Pediatrics (AAP) published in 1985 the first set of guidelines for procedural sedation in children, with the aim of minimizing risk associated with this practice.3 Continued reports of unfavorable outcomes led to revisions of the AAP recommendations, as well as the development of similar guidelines in multiple
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other specialties practicing PSA.4-7 In addition, investigations into risk factors and root causes of these incidents were performed.8,9 From these studies, inadequate and inconsistent physiologic monitoring was identified as a risk factor for adverse events, prompting standardization of practice. Recommendations regarding what constitutes appropriate monitoring during PSA have evolved. During the early years of pediatric PSA, the primary monitoring modality was direct clinical observation. The first AAP guidelines mandated continuous monitoring of heart rate, respiratory rate, and blood pressure, and visual monitoring of the patient's color.3 The AAP revision in 1992 added continuous quantitative monitoring of oxygen saturation (e.g., pulse oximetry) to the prior recommendations.10 The most recent iterations of published guidelines from pediatrics as well as anesthesia and emergency medicine have introduced ventilation monitoring with capnography in their recommendations.5,6,11 Table 1 summarizes the current guidelines from the American Society of Anesthesiologists (ASA), AAP, and American College of Emergency Physicians (ACEP). In each, varying levels of monitoring are recommended, depending on depth of sedation. For minimal/mild sedation (anxiolysis), monitoring is not routinely recommended. Because respiratory events are of greatest concern and can be appropriately detected, recommendations uniformly endorse continuous oximetry for moderate and deep sedation. Ventilation monitoring with capnography is suggested by all organizations, with an emphasis on its use during deep sedation and as an adjunct when direct visualization of respiratory
pattern is not feasible. Finally, hemodynamic monitoring with electrocardiography (ECG) and blood pressure is less strongly advocated, largely because there is a paucity of evidence supporting the benefit of this practice.
MONITORING PRINCIPLES
The implementation of guidelines has been demonstrated to reduce the risk of adverse events related to PSA. 12 Effective sedation protocols include the following elements: presedation assessment, trained personnel, appropriate equipment, continuous patient monitoring, documentation, and discharge criteria. Focusing specifically on monitoring, several general principles can be abstracted from the various procedural sedation guidelines and are discussed here.
Tailoring Monitoring to Pharmacopeia

The rational approach to patient monitoring is based on the adverse event profile of the PSA agents. The overwhelming majority of adverse events associated with sedation are respiratory-related, including respiratory depression and hypoventilation, central and obstructive apnea, and hypoxia.13 Hemodynamic compromise is rare in children with routine doses of agents, with the exception of propofol in which transient hypotension is well described.14,15 Therefore, monitoring should focus on ventilation and oxygenation, with hemodynamic monitoring having the greatest importance when using propofol.
TABLE 1. Current guidelines for hemodynamic and respiratory monitoring during different levels of procedural sedation.
Guidelines ASA AAP ACEP Level of Sedation Mild Moderate Deep Mild Moderate Deep Mild Moderate Deep Continuous ECG Should be used if comorbidity Should be used Should be used Should be used No evidence of benefit if no cardiopulmonary disease BP Q 5 min Q 5 min Intermittent Q 5 min Continuous Oximetry Should be used Should be used Should be used Should be used May not be necessary Should be used Should be used Capnography Consider, if separateda Consider Encouraged, especially if difficult to observe a Consider Consider
BP indicates blood pressure; AAP indicates American Academy of Pediatrics; ACEP indicates American College of Emergency Physicians; ASA indicates American Society of Anesthesiologists; ECG indicates electrocardiogram.
a
For example, in computed tomography/magnetic resonance imaging scanner, or in darkened room.
Depth of Sedation
Physiologic monitoring should vary, commensurate with the anticipated level of sedation. By definition, minimal sedation (anxiolysis) leaves ventilatory and cardiovascular functions unaffected, suggesting little need for cardiorespiratory monitoring. In contrast, during deep sedation where spontaneous ventilation may be inadequate and cardiovascular function is not always maintained, more extensive monitoring is required.6 The challenge, however, is that depth of sedation reflects a continuum, rather than discrete categories with clearly discernible boundaries. As a result, children may pass into deeper levels of sedation than originally targeted. 16,17 To accommodate this potential sedation drift, monitoring recommendations tend to be uniformly conservative to capture potential risks associated with deeper levels of sedation than planned.
as the rate and dose of administration, cardiorespiratory events can occur almost immediately. In addition, recognizing changes from baseline vitals can be valuable in alerting the provider to potential events. Standard cardiopulmonary leads are generally well tolerated by children. Challenges may occur in obtaining a blood pressure or placing a nasal cannula for oxygen delivery or end-tidal CO2 monitoring, or even placing an oximetry sensor on the finger or toe in some noncooperative children. Pediatric and anesthesia guidelines recognize that inability to obtain presedation vitals may be technically precluded in some cases. When necessary, these additional vitals can be obtained as soon as feasible after medication delivery.6,11
When to Remove Monitoring

Patient-specific variables, as well as pharmacokinetics and dosage of the agent(s) used, will determine when a patient is at low risk for cardiorespiratory events. In a large prospective study of pediatric sedation, the length of time between medication administration and serious adverse events varied widely, although the vast majority of events occurred within 25 minutes of administration of the final drug dose. 22 Given this variability, the duration of observation and monitoring should be based on clinical criteria rather than a predetermined fixed length of time. In addition, nearly 10% of adverse events occur after a procedure is completed, emphasizing the importance of continued vigilant monitoring. Several sedation and recovery scales have been validated for use in determining when a patient is safe for discharge and when monitoring can be discontinued. 23,24 In addition, institution-specific discharge criteria are commonly available. Most criteria encompass some combination of: stable vital signs, a level of consciousness that is near baseline, and the ability to adequately maintain a patent airway. Monitoring should continue until these criteria are met.
Preoxygenation
Although recommendations regarding preoxygenation with PSA vary, pediatric patients are likely to benefit from this practice. Children, particularly infants and toddlers, are more susceptible to rapid desaturation than their adult counterparts. Smaller functional residual capacity relative to total lung volume results in a decreased oxygen reservoir, whereas increased metabolic rate produces higher oxygen consumption. 18 The result is a more precipitous decline in oxygen saturation during hypoventilatory or apneic periods. Preoxygenation can maximize intrapulmonary oxygen stores and help offset this risk.19 However, recent studies in sedated adults did not demonstrate a clear reduction in episodes of desaturation.20,21 In addition, concern has been raised that supplemental oxygen delivery may delay the onset of hypoxemia in patients with respiratory compromise. As a result, based solely on oximetry, the detection of hypoventilation and subsequent response may be delayed. To accommodate this limitation, direct observation and the use of capnography can be used to concomitantly detect ventilatory changes when supplemental oxygen is being administered. With this qualification, ASA and ACEP guidelines currently support the use of supplemental oxygen administration for patients undergoing moderate and deep sedation.5,6
ADVERSE EVENTS
The frequency of adverse events related to PSA in children varies greatly, with reports ranging from 2% to 20% of cases.9,13,25 Differences in pharmacologic regimens, study design, and definition of adverse events contribute to this disparity.26 We will discuss those events for which monitoring may be beneficial, that is, respiratory and cardiac events. Other reported adverse outcomes including failure to achieve appropriate sedation, emergence and
When to Initiate Monitoring

Baseline determination of vital signs should be documented before the administration of medications. Depending on the agent(s) being used, as well
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TABLE 2. Capnographic airway assessment for PSA.
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paradoxical reactions, myoclonus/seizure activity, and emesis will not be discussed here. Respiratory-related abnormalities in oxygenation and ventilation comprise the overwhelming majority of adverse events associated with PSA in children. These events can be categorized as hypoxemia, hypoventilation, partial airway obstruction, and apnea.
Hypoxemia
Hypoxemia, manifest as oxygen desaturation, is the most common respiratory adverse event. The incidence across studies varies, depending on which medications were used and differing definitions of hypoxemia. Pena et al13 reported that 1% of patients desaturated to less than 90% (sea level) during PSA, Roback et al27 found that 7% to 8% of patients dropped to less than 90% (5280-ft elevation), and Pitetti et al25 noted that 15% of patients dropped to less than 93% (sea level). Drug regimens were also noted to influence the likelihood of hypoxemia, for example, fentanyl and midazolam being much more likely to result in hypoxemia than ketamine.25,27 Although there are no published supporting data, sound reasoning and expert consensus agree that early detection and response to hypoxemia during PSA should decrease the likelihood of a serious adverse outcome.6 Pulse oximetry has been demonstrated to be more effective than clinical observation in the detection of hypoxemia.28,29 In most circumstances, oxygen saturation will progressively decline, unless an acute airway event completely comprises oxygen delivery. Therefore, continuous oximetry provides a means to follow trends of declining oxygenation, allowing time for intervention before deleterious levels are reached. When detected or anticipated, the management of hypoxemia is to increase oxygen delivery and provide respiratory support as needed. In most circumstances, initiating or increasing supplemental oxygen delivery can be corrective. Reversal agents may also be useful when using opioids and/or benzodiazepines. When airway obstruction is a contributing factor, repositioning and, occasionally, an oral or nasal airway may be required. If these measures are ineffective, positive pressure ventilation with a bag and mask and, very rarely, via intubation can reverse profound hypoxemia (Table 2).
tion of any PSA drug regimen. Slowed (bradypneic hypoventilation) or shallow (hypopneic hypoventilation) breathing can be subtle and difficult to detect by clinical observation alone. Continuous capnography provides a noninvasive and effective means for early detection of hypoventilation and respiratory depression. In addition, recognition of the characteristic waveform morphology for each type of hypoventilation provides insight into the underlying pathophysiology, which can guide subsequent interventions (Table 2). Bradypneic hypoventilation, with decreased respiratory rate and waveforms with tall and wide plateaus, suggests that a patient is heavily sedated. Caution should be exercised before administering additional sedatives in this situation, particularly if oxygenation has also been compromised. Positive pressure ventilation is not required, but should be readied if the condition were to progress to apnea or profound hypoxemia. Reversal agents can be helpful, when appropriate.
Partial Airway Obstruction

Partial airway obstruction may also be seen during PSA. Many sedating medications lead to decreased upper airway muscle tone. As a result, the tongue or soft palate may fall into the posterior pharynx; or the epiglottis may drop forward in the supine child, leading to partial airway obstruction. Alternatively, partial laryngospasm may occur following the administration of some agents, particularly ketamine. Finally, secretions or gastric contents may occupy the hypopharynx or be aspirated, which can also partially occlude the upper airway or the vocal cords. Unlike hypoxemia and hypoventilation, partial airway obstruction is best detected clinically, with auditory cues from the patient indicating that the obstruction is partial and not complete. Changes in oxygenation or endtidal CO2 are unlikely to occur until there is nearcomplete obstruction. Treatment of partial upper airway obstruction will vary depending on the source of the obstruction. Supplemental oxygenation should be provided to increase intrapulmonary stores in case airway compromise progresses. Repositioning can help move soft tissue structures and maximize patency of the airway. If partial laryngospasm is suspected, pressure at the laryngospasm notch may also be helpful. The laryngospasm notch is posterior to the lobule of each ear, between the ascending ramus of the mandible, the mastoid process, and the base of the skull. Continuous pressure, using the thumbs at this point, over the styloid process may cause relaxation of the cords by a poorly defined mechanism,
Hypoventilation
Hypoventilation is a common adverse respiratory event that can occur during procedural sedation. Respiratory depression, with or without accompanying hypoxemia, can occur following administra-
speculated to be via afferent input, a modified jaw thrust, or an increase in pharyngeal airway muscle tone secondary to the painful stimulus. Positive pressure breaths with a bag and mask can actually trigger progression to complete laryngospasm and therefore are not routinely recommended unless oxygenation or ventilation is compromised.
Apnea
Apnea is a less frequent, though potentially more serious, respiratory event related to PSA. Central apnea most commonly results from oversedation, whereas obstructive apnea, including complete laryngospasm, may not correlate with a specific depth of sedation. Clinically, the 2 types of apnea can be distinguished by respiratory effort and airway patency. Patients with central apnea will have no respiratory effort (ie, no chest wall movement). Obstructive apnea is determined clinically by spontaneous respiratory effort with chest wall rise, but no effective air movement. Capnography has been shown to detect apnea more reliably than clinical observation or pulse oximetry, given that hypoxemia may lag behind corresponding ventilatory abnormalities, particularly when supplemental oxygen is being delivered. Either etiology of apnea will result in a flat capnogram. Importantly, with obstructive apnea, respiratory rate will still be registered if based on plethysmography (from impedance-sensitive ECG leads) because the chest wall continues to move, whereas airway-derived respiratory rate measured by capnography will be
zero given the absence of air movement (Table 2, Figure 1). When apnea is suspected, clinically correlate monitor findings by checking for a displaced or obstructed nasal-oral cannula or other equipment malfunction, which can result in a flat waveform in an otherwise spontaneously breathing patient. If equipment is properly functioning and central apnea is confirmed clinically, the patient should be stimulated. If there is no immediate response, reversal agents should be made available; and ventilation should be assisted with bag and mask using routine pressures. If obstructive apnea is determined, repositioning should be attempted. If there is no improvement with airway alignment maneuvers, positive pressure ventilation with bag and mask using constant high pressures should be initiated in an attempt to break the laryngospasm. Simultaneously, a neuromuscular blocking agent should be made immediately available in cases of complete laryngospasm.
MONITORING MODALITIES FOR PROCEDURAL SEDATION

Given that the majority of PSA adverse events in children are respiratory related, careful and continuous evaluation of respiratory status is paramount. In addition to those aspects of respiratory status that can be detected through clinical observation, continuous mechanical monitoring of oxygenation and ventilation enhances safety by providing real-
Figure 1. Using the capnogram to determine airway-related adverse events.
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time objective data on the clinical status of the patient during PSA.
Clinical Observation
Direct observation is the cornerstone of safe and effective PSA. Direct visualization of the patient allows for detection of changes in depth and rate of respirations, work of breathing, and skin color. In addition, patency of the airway and effectiveness of respiratory efforts can be quickly ascertained through auditory cues. However, to be effective, clinical observation needs to be continuous, which is not always feasible. Automated respiratory rate monitoring with adjustable limits and audible alarms can therefore help alert providers to concerning respiratory patterns.
Plethysmography
Transthoracic impedance plethysmography has been the conventional means of monitoring respiratory activity. Respiratory leads, often integrated within ECG leads, are commonly available, well tolerated, and convenient. Chest wall expansion during inspiration increases the distance between the leads, resulting in recording of individual respirations. The main limitation to plethysmography is that this modality may fail to detect partial or complete airway obstruction. With obstruction, chest wall motion continues; and therefore, the monitor will continue to register perceived respirations. However, air movement is compromised.
Oxygenation Monitoring
Pulse oximetry provides a noninvasive and reliable means for continuously monitoring oxygen saturation. Clinical detection of hypoxemia is unreliable until oxygen saturations have dropped to less than 80%.28 Oximetry, however, has been shown to allow more frequent and earlier detection of hypoxemic events than clinical assessment during general anethesia. 30 Similar data exist supporting the effective detection of oxygen desaturation during PSA as well.6 Oximeters use the relative absorption of specific wavelengths of light to determine oxygen saturation. Oximetry probes contain light-emitting diodes that produce 2 wavelengths of light that are differentially absorbed by oxygenated and deoxygenated hemoglobin. Measuring the amount of each wavelength that passes through a sample of blood can be used to calculate the concentration of the 2 forms of hemoglobin. Oxygen saturation is then derived by dividing the concentration of oxygenated hemoglo-
bin by the total amount of hemoglobin. To selectively determine the saturation of arterial samples, the amount of transmitted light is measured hundreds of times per second. Using these frequent measurements, the oximeter is able to detect the variable and pulsatile signal emanating from arterial flow. The static signal representing venous blood and other light-absorbing tissue can then be subtracted out, and arterial oxygen saturation can be derived (Figure 2).31 The finger is the most common probe site used for pulse oximetry. If the finger is inaccessible or unsuitable, other probe sites, such as the ear lobe or the bridge of the nose, may be used. In neonates and infants, the foot offers additional probe sites including the great toe, the heel, and the sole. There are several circumstances in which the accuracy of pulse oximetry is compromised. First, oximeters are not reliable at very low oxygen saturations. Microprocessors in oximeters use derived calibration curves that are based on measurements in healthy volunteers in whom hypoxemia was induced, but never less than 75% to 80%. Therefore, the shape of the calibration curves at lower saturations is extrapolated and not derived.31 Clinical studies have subsequently confirmed that pulse oximetry is less accurate at these lower saturations.10 Second, photodetectors can be affected by ambient light. Although devices are designed to subtract out such a static signal, oximeters can sometimes be affected by nontransmitted noise. Shielding the probe can be helpful in these circumstances. Third, oximeters can have difficulty distinguishing arterial signal if pulses in the measured tissue are weak, potentially secondary to hypovolemia, peripheral vasoconstriction, hypothermia, or hypotension. Warming the measured extremity and restoring effective circulating volume are required to correct this. Fourth, motion artifact can create an
Figure 2. Comparative light absorption of static and dynamic components by pulse oximetry. Reprinted with permission from The American Journal of Emergency Medicine, Sinex, J, Pulse oximetry: principles and limitations, 1999; 17.
alternating signal that is interpreted as a valid pulsatile arterial signal. Myoclonus, shivering, or spontaneous movement during lighter levels of sedation can also contribute to this. However, recent advances in motion control technology have made pulse oximetry more reliable during patient movement. Finally, the presence of other forms of hemoglobin (eg, carboxyhemoglobin or methemoglobin) will affect the relative absorption of the 2 specific wavelengths of light used by oximeters, affecting the calculated oxygen saturation, although this is unlikely to be an issue during most PSAs.
Ventilation Monitoring
Capnography provides an objective, noninvasive measure of ventilatory status. In addition to identifying the measured end-tidal CO2 value (ie, the maximum CO2 concentration for each breath), the capnograph adds a graphic display of a waveform (ie, capnogram) representing the concentration of expired CO2 as a function of time. Monitoring the waveform can provide important cues to actual or impending airway- or respiratory-related events during PSA. Capnography, like pulse oximetry, is based on the physics of infrared light absorption. A beam of filtered infrared radiation is sent through the sample of exhaled air to a photodetector. Based on the amount of radiation that is absorbed, a concentration of CO2 can be calculated. Capnographs are designed in a mainstream or sidestream configuration. Mainstream systems are configured for intubated patients, whereas sidestream systems can be used in either intubated or nonintubated patients. Mainstream devices measure CO2 directly from the airway, with the sensor located on the endotracheal tube. Sidestream devices measure CO2 by aspirating a small sample from the exhaled breath through tubing to a sensor located in the monitor. Nasal or nasal-oral cannula, which allow concomitant CO2 sampling and low-flow oxygen delivery, are used in spontaneously breathing patients. Controlled trials have demonstrated the superiority of capnography over clinical observation and pulse oximetry in detecting apnea and airway obstruction.20,32,33 As the majority of changes in oxygenation are preceded by changes in ventilation, capnography provides the earliest detection of respiratory compromise, allowing clinicians to recognize adverse airway and respiratory events and to intervene before they evolve into serious complications.34,35 Use of capnography, in conjunction with pulse oximetry, allows for preoxygenation before, and delivery of supplemental oxygen during,
the sedation. Furthermore, randomized controlled trials have shown that the use of capnography decreases the incidence of apnea and the number of hypoxic events during PSA. In one of these trials, the median time from detection of respiratory depression to hypoxia was 60 seconds, with a range of 5 to 240 seconds.21,36 There are several limitations to the use of capnography during PSA. First, partial obstruction of the cannula from nasal secretions, or displacement from the nares, can result in spuriously low end-tidal CO2 values. The cannula should be repositioned in the nares if partial obstruction or displacement is suspected. Complete obstruction of the cannula or the tubing will lead to the monitor displaying an obstruction warning. Second, some infants and young children will notice the sensation of the nasal cannula and may try to remove it.
Noninvasive Blood Pressure Monitoring

Noninvasive blood pressure monitoring (NIBP), an automated method of repetitively determining blood pressure, has been widely used in anesthesia practice for more than 20 years. Automated devices allow for intermittent measurements to be obtained at a programmable frequency, allowing single measurements as well as trends. Noninvasive blood pressure monitoring provides a display of the heart rate and the systolic, diastolic, and mean blood pressures by electronically determining the pulse amplitude. Multiple studies have evaluated the accuracy of NIBP compared with intraarterial blood pressure measurement in both adults and children. Most suggest that comparative measurements are within 5 mm Hg; however, there is wide variability across manufacturers and devices. Current devices use oscillometric technology. An occluding cuff impedes blood flow in the selected extremity, most commonly using the brachial artery. As pressure in the cuff slowly decreases, pulsatile blood flow through the vessel resumes, creating vibrations in the arterial wall. When the cuff pressure falls below diastolic pressure, blood flow is completely unimpeded and vibrations cease. The magnitude of these vibrations follows a predictable pattern, peaking at mean arterial pressure.37 The oscillations are transferred through the air in the cuff into a transducer that converts the measurements to electrical signals. Microprocessors within the devices use empirically derived algorithms to calculate systolic and diastolic blood pressures from the pattern of vibrations. There are many potential factors that may affect the accuracy of NIBP readings. First, choosing an
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appropriate-sized cuff is particularly important, especially in children and obese patients. An undersized cuff will give falsely elevated readings, whereas a cuff that is too large will lead to falsely low values. Many cuffs have reference lines on them to provide guidance in choosing cuff size, or standardized references from the American Heart Association are available to help choose cuff size based on extremity circumference. 38 Second, irregular or rapid cardiac rhythms can intrinsically cause vibrations in arterial walls and therefore affect cuff-induced oscillations. Similarly, excessive patient movement or muscle stiffness can interfere with the detection of oscillations, leading to unobtainable or erroneous blood pressure measurements. Finally, it is important to remember that an inflated cuff will transiently compromise distal arterial flow, which can affect pulse oximetry readings if they are being recorded in the ipsilateral extremity.
tion, inadequate contact between the electrodes and the patient can also lead to imprecise tracings that can be difficult to interpret. It is always important to interpret monitoring data in the clinical context to determine its reliability and usefulness.
FUTURE DIRECTIONS IN PROCEDURAL SEDATION MONITORING

Processed Electroencephalographic Monitoring
Processed electroencephalographic (EEG) monitoring has been proposed as an objective, quantitative means to measure the brain's response to anesthetic agents and to continuously monitor depth of sedation and awareness under anesthesia in the operating room. There are several versions of this technology that have been used in the operating room, with the bispectral index (BIS) being the most widely studied and the only one of these technologies to be used for ED PSA. Although these technologies have been used to monitor depth of sedation/anesthesia, in 2006, the ASA concluded that the clinical applicability in the operating room has not been established.39 The BIS technology uses a sensor placed across both sides of the forehead to record brain activity. The magnitude and distribution of EEG spikes are measured and processed to create a neurophysiologic variable with a unitless value from 0 to 100. Based on adult anesthesia data, an index was created to correlate depth of anesthesia with BIS values, with a BIS value of 100 considered to be complete alertness (ie, a fully awake patient), 40 to 60 consistent with general anesthesia, and zero depicting no cortical activity.40 Bispectral index monitoring has been studied in the ED in an attempt to objectify sedation end points by titrating to a target BIS score. Multiple pediatric and adult studies have evaluated the correlation between BIS values and depth of sedation as measured by validated sedation scales.41-45 However, these studies have found unacceptably wide ranges of BIS values at various depths of sedation that did not correlate with the Ramsey sedation scale. As a result, BIS monitoring may not be effective at discriminating between moderate and deep sedation, especially in children. 45,46 More importantly, the threshold above which ventilatory compromise will occur and the effectiveness of target BIS levels have not been determined, further limiting the usefulness of routine BIS monitoring for ED sedation.47,48 Miner et al48 found that the assignment of a preprocedural BIS target sedation
Electrocardiographic Monitoring
Continuous ECG monitoring can be used to detect alterations in cardiac rate or rhythm. Most commonly, 3 electrodes are used, allowing recognizable P waves and QRS complexes, with the option to change lead selection as needed to get the best tracing. In addition, the majority of current cardiac monitoring systems are interfaced with plethysmography to provide continuous impedance respiratory rate monitoring. Such devices are simple, inexpensive, and readily available in EDs. Characteristic pharmacodynamic changes occur following the administration of specific PSA agents, for example, increase in heart rate with ketamine or atropine, decreases in heart rate with propofol. In addition, heart rate can provide indirect information regarding a patient's level of comfort and whether he or she is experiencing pain. Bradycardia may develop as a direct result of some sedation medications or secondarily to physiologic alterations such as hypoxemia. Although extremely rare, reports of cardiac arrest have occurred in high-risk patients during PSA. Treatment of such events is determined by the underlying cardiac rhythm; and therefore, early recognition may be helpful. However, ECG monitoring is not mandatory nor standard of care for PSA in patients without underlying cardiovascular disease. There are few limitations to ECG monitoring. Perhaps the greatest is that tracings are easily affected by motion artifact. Calculated heart rate in particular can be spurious as a result of spikes in ECG tracings that are noncardiac-based. In addi-
level of moderate or deep sedation did not influence the level of sedation achieved, the rate of respiratory depression, the occurrence of complications, the time to return of baseline mental status, or the success of the procedure. Finally, BIS monitoring is less likely to correlate when using specific sedation agents, such as opioids, ketamine, and chloral hydrate.43,45,49 Ketamine leads to excitatory findings by EEG despite increasing level of dissociation. Conversely, sedation with opioids and chloral hydrate produces little change in the BIS despite increasing clinical effect of the medications. Newer depth of sedation technologies have recently been introduced into the operating room setting including entropy-based monitoring. Variability/irregularity in processed EEG signals and electromyography (EMG) signals from the forehead are used to gauge depth of sedation based on central nervous system response to anesthetic agents. At baseline in the normal nonsedated state (high levels of entropy activity), there is considerable variability in both EEG and EMG signals. With increasing depth of sedation, EEG cortical electrical activity becomes more regular with decreased variability; and EMG forehead muscle activity decreases and ultimately ceases (low levels of entropy activity). 50 This technology has not been studied outside of the operating room.
Initial investigation into the utility of cerebral oximetry during PSA in children shows promise.52 Cerebral oximetry was prospectively compared with traditional pulse oximetry and capnography during sedation in 100 children. The study demonstrated that cerebral oxygen saturation was well maintained throughout 98% of recordings. In only 23% of hypoxic events and 29% of hypercarbic events did cerebral oxygen saturation decrease. This suggests that transient cardiopulmonary events are probably of little clinical consequence. Conversely, other cerebral desaturation events were noted that did not correlate with changes in conventional monitoring. This initial study suggests that cerebral oximetry may provide additional insight into the significance and severity of conventionally detected events and may prove to be a more relevant measure of endorgan impact through direct measurement of oxygen delivery to brain tissue.
Noninvasive Hemodynamic Monitoring of Vascular Tone

During PSA, blood pressure is typically measured using an oscillometric technique with an inflatable cuff around the upper arm or leg. However, these measurements may be inaccurate in some children, particularly when an inappropriate cuff size is used. In addition, such measurements provide intermittent but not continuous data. Emerging technologies may offer an alternative means of noninvasive evaluation of blood pressure. A newly developed finger cuff offers the possibility of continuous arterial pressure monitoring. The finger device contains an infrared photoplethysmograph that recognizes changes in blood volume in the finger through corresponding differences in light absorption. These data are translated into changes in the volume of air in the cuff. Finger arterial pressure is then measured indirectly by recording the cuff pressure. Pediatric-sized finger cuffs were developed and initially pilot tested in children between 0 and 4 years of age.53 More recently, these prototypes were compared with intra-arterially measured blood pressure in intubated, sedated pediatric intensive care unit patients.54 Finger-cuff arterial pressures were consistently lower than intra-arterial pressures, as would be expected physiologically because of increased resistance to peripheral flow. Using software algorithms, the measured finger pressures were reconstructed to represent brachial pressures; and these were compared with intra-arterial pressures and direct cuff measurements. The new finger cuff was found to provide nearly continuous
Cerebral Oximetry
Respiratory, and less commonly cardiac, adverse events are not infrequent in PSA. With the exception of profound or prolonged compromise where clinical sequelae can be appreciated, the significance of transient changes in cardiorespiratory function is unclear. Cerebral oximetry (ie, regional as opposed to systemic oximetry) represents a new technology that provides a noninvasive measurement of oxygen delivery to the brain. As such, it may prove valuable in understanding which events detected by standard monitoring are most significant. Cerebral oximetry is based on the principles of near-infrared spectroscopy. Similar to pulse oximetry, sensors detect changes in light absorption. The use of 2 sensors allows measurements at different depths in nonpulsatile samples, thereby permitting tissue-level saturation recordings. Cerebral tissue oxygenation has been shown to correlate well with cerebral mixed venous oxygen saturation in pediatric cardiac surgery patients.51 Although determination of absolute values was judged to be unreliable, use of the device to follow trends was supported.
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readings that were more accurate than traditional, intermittent cuff measurements. The device was unsuccessful in obtaining measurements in less than 5% of cases, although more than one attempt was frequently needed to obtain a signal, particularly in the youngest children. It is not clear how well this device would be tolerated by noncritically ill children or how effective it is in recognizing abrupt changes in blood pressure.
Integrated Algorithms and Indices

In addition to the development of technologies to monitor novel physiologic parameters during sedation, efforts have also been extended to create computer-generated software programs (ie, adaptive algorithms) that help integrate and interpret multiparameter data. Such programs offer distinct advantages over current monitoring strategies by their ability to filter large amounts of data, recognize complex data patterns, and provide an enhanced interpretation of data significance and trends. Audible monitor alarms provide a means to alert a clinician when a patient has reached a predetermined physiologic threshold (eg, bradycardia, tachycardia, hypotension, hypertension). Because the goal of monitoring during procedural sedation is to create an early detection system, recognition of trends toward such a value would be useful, especially if the designated value correlates with a physiologic danger zone. Such systems provide an opportunity to detect subtle or gradual changes and to put them in a context not always discernible to, or appreciated by, the sedation providers, while placing them in the context of previous data, prioritizing recent changes. The methodology uses prior data to predict future observations and then compares real-time recorded values to those that had been previously predicted. Discrepancies between the predicted and the observed values suggest a change in trend that may be a more sensitive early warning system. Early work with integrated algorithms in the operating room has shown that such systems are more accurate at identifying physiologic changes than the anesthesiologist.55 In a pediatric study using a similar tool, clinicians rated more than 60% of the detected changes as clinically significant, with less than 7% being attributed to artifact.56 In contrast, traditional alarms have been reported to indicate actual risk to the patient only 3% of the time.57 Further work is needed to determine how to best integrate these intuitive algorithms into practice, and to establish the impact on clinical outcome.
The concept of using context-sensitive physiologic monitoring as a novel early warning system and as an adjunctive tool to guide clinical decision making holds promise. An example where such an algorithm would be valuable is in patient-controlled analgesia (PCA). In the ED, PCA is primarily used for pain management in vasoocclusive crisis. Recently, continuous pulse oximetry and capnography monitoring have been integrated into PCA pumps. A study of 178 postoperative patients using PCA with integrated continuous pulse oximetry and capnography monitoring found that 12% had desaturations to less than 90% for 3 minutes or greater and 41% had respiratory depression (respiratory rate b10) for 3 minutes or greater.58-60 The integration of continuous oxygenation and ventilation monitoring into PCA delivery systems may allow for the future development of intuitive safety algorithms based on physiologic parameters rather than theoretical lockout times and absolute drug doses.
SUMMARY
Patient monitoring during pediatric PSA has evolved over time. In addition to direct observation, cardiac and respiratory monitoring modalities can help rapidly identify physiologic changes and allow early intervention. In particular, data from oxygenation and ventilation monitoring provide important cues to the presence and etiology of airway or respiratory compromise. Novel application of available information and development of newer technologies continue to be investigated. Ongoing standardization of relevant definitions and collaborative research efforts offer the possibility of more precise outcome data to allow for continued improvement in the safety profile of ED procedural sedation in children.
ACKNOWLEDGMENTS
Financial disclosure: Baruch Krauss is a consultant for Oridion Medical, a capnography company, and holds 2 patents in the area of capnography.
REFERENCES
1. Krauss B, Green SM. Sedation and analgesia for procedures in children. N Engl J Med 2000;342:938-45. 2. Krauss B, Green SM. Procedural sedation and analgesia in children. Lancet 2006;367:766-80. 3. American Academy of Pediatrics Committee on Drugs, Section on Anesthesiology. Guidelines for the elective use of conscious sedation, deep sedation, and general anesthesia in pediatric patients. Pediatrics 1985;76:317-21. 4. American Academy of Pediatrics Committee on Drugs. Guidelines for monitoring and management of pediatric
patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89:1110-5. 5. Godwin SA, Caro DA, Wolf SJ, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med 2005;45:177-96. 6. American Society of Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002;96:1004-17. 7. Nelson MD. Guidelines for the monitoring and care of children during and after sedation for imaging studies. Am J Roentgenol 1993;160:581-2. 8. Cote CJ, Notterman DA, Karl HW, et al. Adverse sedation events in pediatrics: a critical incident analysis of contributing factors. Pediatrics 2000;105:805-14. 9. Malviya S, Voepel-Lewis T, Tait AR. Adverse events and risk factors associated with the sedation of children by nonanesthesiologists. Anesth Analg 1997;85:1207-13. 10. Severinghaus JW, Kelleher JF. Recent developments in pulse oximetry. Anesthesiology 1992;76:1018-38. 11. Cote CJ, Wilson S, American Academy of Pediatrics and American Academy of Pediatric Dentistry Work Group on Sedation. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update. Pediatrics 2006;118: 2587-602. 12. Pitetti R, Davis PJ, Redlinger R, et al. Effect on hospital-wide sedation practices after implementation of the 2001 JCAHO procedural sedation and analgesia guidelines. Arch Pediatr Adolesc Med 2006;160:211-6. 13. Pena BM, Krauss B. Adverse events of procedural sedation and analgesia in a pediatric emergency department. Ann Emerg Med 1999;34:483-91. 14. Vespasiano M, Finkelstein M, Kurachek S. Propofol sedation: intensivists' experience with 7304 cases in a children's hospital. Pediatrics 2007;120:e1411-7. 15. Bassett KE, Anderson JL, Pribble CG, et al. Propofol for procedural sedation in children in the emergency department. Ann Emerg Med 2003;42:773-82. 16. Dial S, Silver P, Bock K, et al. Pediatric sedation for procedures titrated to a desired degree of immobility results in unpredictable depth of sedation. Pediatr Emerg Care 2001; 17:414-20. 17. Motas D, McDermott NB, VanSickle T, et al. Depth of consciousness and deep sedation attained in children as administered by nonanaesthesiologists in a children's hospital. Paediatr Anaesth 2004;14:256-60. 18. Gerhardt T, Reifenberg L, Hehre D, et al. Functional residual capacity in normal neonates and children up to 5 years of age determined by a N2 washout method. Pediatr Res 1986;20: 668-71. 19. Carmichael FJ, Cruise CJ, Crago RR, et al. Preoxygenation: a study of denitrogenation. Anesth Analg 1989;68:406-9. 20. Deitch K, Chudnofsky CR, Dominici P. The utility of supplemental oxygen during emergency department procedural sedation and analgesia with midazolam and fentanyl: a randomized, controlled trial. Ann Emerg Med 2007;49: 1-8. 21. Deitch K, Chudnofsky CR, Dominici P. The utility of supplemental oxygen during emergency department procedural sedation with propofol: a randomized, controlled trial. Ann Emerg Med 2008;52:1-8. 22. Newman DH, Azer MM, Pitetti RD, et al. When is a patient safe for discharge after procedural sedation? The timing of adverse effect events in 1367 pediatric procedural sedations. Ann Emerg Med 2003;42:627-35.
23. Macnab AJ, Levine M, Glick N, et al. A research tool for measurement of recovery from sedation: the Vancouver Sedative Recovery Scale. J Pediatr Surg 1991;26:1263-7. 24. Malviya S, Voepel-Lewis T, Tait AR, et al. Depth of sedation in children undergoing computed tomography: validity and reliability of the University of Michigan Sedation Scale (UMSS). Br J Anaesth 2002;88:241-5. 25. Pitetti RD, Singh S, Pierce MC. Safe and efficacious use of procedural sedation and analgesia by nonanesthesiologists in a pediatric emergency department. Arch Pediatr Adolesc Med 2003;157:1090-6. 26. Bhatt M, Kennedy RM, Osmond MH, et al. Consensus-based recommendations for standardizing terminology and reporting adverse events for emergency department procedural sedation and analgesia in children. Ann Emerg Med 2009;53: 426-35. 27. Roback MG, Wathen JE, Bajaj L, et al. Adverse events associated with procedural sedation and analgesia in a pediatric emergency department: a comparison of common parenteral drugs. Acad Emerg Med 2005;12:508-13. 28. Comroe Jr JH, Botelho S. The unreliability of cyanosis in the recognition of arterial anoxemia. Am J Med Sci 1947;124: 1-6. 29. Cote CJ, Rolf N, Liu LMP, et al. A single-blind study of combined pulse oximetry and capnography in children. Anesthesiology 1991;74:980-7. 30. Cote CJ, Goldstein EA, Cote MA, et al. A single-blind study of pulse oximetry in children. Anesthesiology 1988;68:184-8. 31. Sinex JE. Pulse oximetry: principles and limitations. Am J Emerg Med 1999;17:59-67. 32. Soto RG, Fu ES, Vila H, et al. Capnography accurately detects apnea during monitored anesthesia care. Anesth Analg 2004; 99:379-82. 33. Lightdale JR, Goldmann DA, Feldman HA, et al. Microstream capnography improves patient monitoring during moderate sedation: a randomized, controlled trial. Pediatrics 2006;117: e1170-8. 34. Burton JH, Harrah JD, Germann CA, et al. Does end-tidal carbon dioxide monitoring detect respiratory events prior to current sedation monitoring practices? Acad Emerg Med 2006;13:500-4. 35. Krauss B, Hess DR. Capnography for procedural sedation and analgesia in the emergency department. Ann Emerg Med 2007;50:172-81. 36. Qadeer MA, Vargo JJ, Dumot JA, et al. Capnographic monitoring of respiratory activity improves safety of sedation for endoscopic cholangiopancreatography and ultrasonography. Gastroenterology 2009;136:1568-76. 37. Mauck GW, Smith CR, Geddes LA, et al. The meaning of the point of maximum oscillations in cuff pressure in the indirect measurement of blood pressurepart II. J Biomech Eng 1980;102:28-33. 38. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114:555-76. 39. Practice advisory for intraoperative awareness and brain function monitoring: a report by the American Society of Anesthesiologists task force on intraoperative awareness. Anesthesiology 2006;104:847-64. 40. Rosow C, Manberg PJ. Bispectral index monitoring. Anesthesiol Clin North Am 2001;19:947-66. 41. Agrawal D, Feldman HA, Krauss B, et al. Bispectral index monitoring quantifies depth of sedation during emergency department procedural sedation and analgesia in children. Ann Emerg Med 2004;43:247-55.
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42. Gill M, Green SM, Krauss B. A study of the Bispectral Index Monitor during procedural sedation and analgesia in the emergency department. Ann Emerg Med 2003;41:234-41. 43. Overly FL, Wright RO, Connor FA, et al. Bispectral analysis during pediatric procedural sedation. Pediatr Emerg Care 2005;21:6-11. 44. Shields CH, Styadi-Park G, McCown MY, et al. Clinical utility of the bispectral index score when compared to the University of Michigan Sedation Scale in assessing the depth of outpatient pediatric sedation. Clin Pediatr (Phila) 2005;44:229-36. 45. Malviya S, Voepel-Lewis T, Tait AR, et al. Effect of age and sedative agent on the accuracy of bispectral index in detecting depth of sedation in children. Pediatrics 2007; 120:e461-70. 46. Mason KP, Michna E, Zurakowski D, et al. Value of bispectral index monitor in differentiating between moderate and deep Ramsay Sedation Scores in children. Paediatr Anaesth 2006; 16:1226-31. 47. Fatovich DM, Gope M, Paech MJ. A pilot trial of BIS monitoring for procedural sedation in the emergency department. Emerg Med Australas 2004;16:103-7. 48. Miner JR, Huber D, Nichols S, et al. The effect of the assignment of a pre-sedation target level on procedural sedation using propofol. J Emerg Med 2007;32:249-55. 49. Dahaba AA. Different conditions that could result in the bispectral index indicating an incorrect hypnotic state. Anesth Analg 2005;101:765-73. 50. Davidson AJ, Kim MJ, Sangolt GK. Entropy and bispectral index during anaesthesia in children. Anaesth Inten Care 2004;32:485-93. 51. Tortoriello TA, Stayer SA, Mott AR, et al. A noninvasive estimation of mixed venous oxygen saturation using near-
52.
53.
54.
55. 56. 57. 58.
59. 60.
infrared spectroscopy by cerebral oximetry in pediatric cardiac surgery patients. Paediatr Anaesth 2005;15:495-503. Padmanabhan P, Berkenbosch JW, Lorenz D, et al. Evaluation of cerebral oxygenation during procedural sedation in children using near infrared spectroscopy. Ann Emerg Med 2009;54:205-13. Andriessen P, Schraa O, van den Bosch-Ruis W, et al. Feasibility of non-invasive continuous finger arterial blood pressure measurements in very young children, aged 04 years. Pediatr Res 2008;63:691-6. Lemson J, Hofhuizen CM, Schraa O, et al. The reliability of continuous noninvasive finger blood pressure measurement in critically ill children. Anesth Analg 2009;108: 814-21. Ansermino JM, Daniels JP, Hewgill RT, et al. An evaluation of a novel software tool for detecting changes in physiological monitoring. Anesth Analg 2009;108:873-80. Dosani M, Lim J, Yang P, Brouse C, et al. Clinical evaluation of algorithms for context-sensitive physiological monitoring in children. Br J Anaesth 2009;102:686-91. Edworthy J, Hellier E. Alarms and human behaviour: implications for medical alarms. Br J Anaesth 2006;97: 12-7. Overdyk FJ, Carter R, Maddox RR, et al. Continuous oximetry/capnometry monitoring reveals frequent desaturation and bradypnea during patient-controlled analgesia. Anesth Analg 2007;105:412-8. Hutchison R. Capnography monitoring during opioid PCA administration. J Opioid Manag 2006;2:207-8. Maddox RR, Williams CK, Oglesby H, et al. Clinical experience with patient-controlled analgesia using continuous respiratory monitoring and a smart infusion system. Am J Health Syst Pharm 2006;63:157-64.
Abstract:
Pain is the hallmark of sickle cell disease in children and adolescents. Many children seek relief from their pain in the emergency department. These visits have historically been characterized by undertreatment, bias, and distrust. Through compassionate care, aggressive pain management, and the development of clinical pathways or care guidelines, better analgesia, and a better care experience can be assured for the child with sickle cell disease in need of emergency services.
Keywords:
sickle cell disease; pain; vasoocclusive episode; opioids
Evaluation and Treatment of Sickle Cell Pain in the Emergency Department: Paths to a Better Future
William T. Zempsky, MD
S
Division of Pain Medicine, University of Connecticut School of Medicine, Connecticut Childrens Medical Center, Hartford, CT. Reprint requests and correspondence: William T. Zempsky, MD, Professor of Pediatrics, University of Connecticut School of Medicine, Division of Pain Medicine, Connecticut Children's Medical Center, 282 Washington Street, Hartford, CT 06106. wzempsk@ccmckids.org
ickle cell disease is the most common genetic disease of African Americans. In its most common form, it is an autosomal recessive disorder containing 2 abnormal copies of the gene coding for the hemoglobin -chain. In every 600 African Americans, 1 (0.2%) has sickle cell disease, whereas 8% of African Americans are heterozygotes for the abnormal gene and have sickle cell trait. Sickle cell disease (SCD) is also seen in the United States in those of Hispanic origin and those of Mediterranean extraction, albeit in much lower numbers. Although the most common form of the disease is found in those mentioned above with homozygous hemoglobin SS (sickle cell) disease, the disease also occurs if a patient has one sickle cell gene accompanied by either a hemoglobin C gene (hemoglobin sickle cell) or thalassemia gene (sickle -thal + or sickle -thal 0). These variants usually have milder disease than those with hemoglobin SS; however, they can present with similar manifestations of the disease. Children with SCD frequently present to the emergency department (ED) with pain. Pain is the hallmark of SCD and the dominant feature of children's medical lives;1,2 about 70% of
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hospitalizations in patients presenting to the ED with SCD are for uncontrolled pain.3 Despite the feeling that patients with SCD are often in the ED for pain, most painful episodes in children and adolescents with SCD do not reach medical attention. In fact, 90% of pain episodes are treated in the home.4 The intensity and complexity of pain in SCD are often underestimated and misunderstood by providers. Children with vasoocclusive episodes (VOEs) experience complex pain, which has features that are consistent with acute, recurrent, and chronic pain states.4,5 Sickle cell pain is worse than postoperative pain and is as intense as terminal cancer pain.6,7 Other pediatric pain states have considerably lower mean pain intensities than sickle cell disease.8-10 Increased frequency and severity of pain episodes are associated with shortened survival.2 Evidence of inadequate management of sickle cell pain abounds in the literature and is likely related to caregivers' preoccupation with the pathophysiologic causes of vasoocclusion and a profound fear of creating opioid dependence, as well as a negative attitude toward patients with SCD in urban hospitals and EDs.5,11,12 Schechter6 describes a cycle of undertreatment (Figure 1) in these patients which persists in many care settings.
of patients come from families that are below the poverty line.14 Almost 40% of ED visits in children with SCD result in hospitalization.3
PATHOGENESIS
The pathogenic process in SCD is more complicated than previously believed. Polymerization of the sickle cell hemoglobin causes the red blood cells to become rigid and sticky and formed into shapes that sometimes have the appearance of a sickle (thus the name). 15 These sickled cells subsequently will cause obstruction in both the microvasculature and macrovasculature. Although this is a key event in the vasoocclusive process, it does not completely explain the pathogenesis.16,17 It is probable that a multitude of factors contribute to VOEs including cell deformability, blood viscosity, red cell function, adherence of the sickled cells to vascular endothelium, endothelial, hemostatic, white cell and platelet activation, and vasoregulatory and environmental factors.16,17 This confluence of factors is called the multiple pathway model of vasoocclusion. In this model, the predominant mechanism leading to vasoocclusion may vary depending on the clinical circumstance. Patients may live in a homeostatic balance with circulating sickle cells, but a seemingly minor event such as a viral illness or exercise may tip this balance resulting in a full-blown VOE.
EPIDEMIOLOGY
There are somewhere between 80 000 and 100 000 individuals with SCD in the United States. In a retrospective cohort of more than 20 000 children and adults with SCD, a staggering 94% of the cohort had an ED visit in a single year.13 More than 70% of ED visits are for pain.3,13 Ninety percent of children with SCD who visit the ED are African American, and only 20% to 30% have private insurance.3 Almost 50%
COURSE OF VOES
Pain from a VOE can begin early in life when levels of fetal hemoglobin decrease. Dactylitis may be the first clinical manifestation of SCD. Infarctions in the metacarpals and metatarsals result in episodes of pain and swelling involving the hands and feet. Infants and toddlers with dactylitis may become irritable, refuse to walk, or cry when they are touched or held. Before neonatal testing, the diagnosis of SCD was often precipitated when a child presented to the ED with swollen, painful hands or feet. As children with SCD get older, sites of involvement shift to the arms, legs, back, and pelvis, whereas adolescents may also complain of involvement of the chest and abdomen. Vasoocclusive episodes typically last from 3 to 9 days. It is not atypical for those patients with longer episodes to continue to have patterns where their episodes remain prolonged. Beyer et al18 describe the chronology of VOE as an 8-phase phenomenon. In the first phase, at baseline, the child has no pain, but often children and
Figure 1. Cycle of pain undertreatment in sickle cell disease.
caregivers can point to a specific event occurring during phase 1 that precipitated the VOE. These can include change in weather, dehydration, or overexertion. In phase 2, no pain is present, but the child can exhibit some prodromal symptoms such as fatigue or scleral icterus. During phases 3 to 5, the child begins having mild pain of an achy quality, which is usually restricted to one area of the body. Pain intensity accelerates in phase 4 and may spread to other areas of the body. Pain peaks in phase 5 and often reaches a severe level. The child may describe it as pounding, banging, or throbbing. This is the phase where patients will often abandon home management and present to the ED or clinic. Often the pain will stay at this peak intensity for 2 to 3 days. Pain begins to decrease in phase 6 and steadily declines in phase 7. By phase 8, the pain intensity is much more tolerable and the child looks and acts more like himself or herself. A recent study documented significantly reduced health-related quality of life compared with historical controls at the time of presentation for VOE on both physical and psychosocial health scales.19 We have noted a correlation between mood and pain in our inpatient population.20
PAIN ASSESSMENT
Pain assessment in children is often complex and challenging. Developmental and cognitive changes that occur throughout childhood impact the ability of children to understand and describe pain.27 Difficulty in assessing pain in this population leads to problems with pain management as well.27,28 Guidelines for the management of acute pain, in general, and sickle cell pain, specifically, recommend the use of standard pain measures and advocate for regular documented pain assessment as an essential component of pain management.29-31 Although self-report scales are the norm for the assessment of acute pain intensity in older children and adults, they cannot be used in infants and toddlers and must be modified for use in children younger than 7 years.27,32 The visual analogue scale 0-10 or 0-100 is a valid tool for assessing acute pain in children older than 7 years,27 but the verbally administered numerical pain scale, commonly used in hospitalized patients, has been validated on a more limited basis.33,34 It is important to remember, however, that pain intensity is just one component of the pain experience for children with SCD. The acute but also recurrent and sometimes chronic nature of pain in SCD makes the assessment of pain in these children complex. Children with SCD often report high levels of pain without outward behavioral or physiologic signs of pain. This is likely due to a constant awareness of discomfort, which leads to an inability to identify improvement or deterioration. Recurrent bouts of severe pain may result in central sensitization, which in turn can permanently alter a child's perception of pain.4,35 In addition, previous experiences with inadequate pain relief may increase anxiety, which in itself can amplify pain.36-39 Given their previous experience with undertreatment, children with SCD may also alter the way in which they report pain to secure more opiates.5 Ratings of pain intensity, which are the primary measure used to assess acute pain, are often insensitive to clinical improvement or deterioration.40 Data from our center and others confirm that self-reported pain intensity scores remain at high levels throughout hospitalization, despite the use of potent opiates.41,42 Patients are routinely discharged despite the persistence of high pain scores. This underscores the need for assessment tools that are more sensitive to changes in clinical status than those currently used, and that coincide with the indicators used by caregivers when making clinical decisions.
PAIN MANAGEMENT CHALLENGES IN SICKLE CELL DISEASE

There is a long history of undertreatment of pain in patients presenting to the ED with a VOE. Perceived discrepancies between patient behavior and pain score have been documented in the care of patients with SCD and lead to mistrust between providers and their patients.21-23 Although verbal pain report is used to determine the severity of vasoocclusive pain, more than 85% of physician respondents felt that it was not a reliable indicator of the existence or intensity of pain.21 Almost 60% of nurses report that the greatest barrier to the management of sickle cell pain episodes is the lack of an adequate pain assessment tool.23 Health care providers may take the reports of pain in patients with SCD less seriously because of attitudes and beliefs about addiction and concerns regarding drug-seeking behavior.23 Patients are frustrated by the lack of consideration that they receive for their pain. Patients report insensitivity of hospital staff, inadequate analgesia administration, staff preoccupation with concerns of drug addiction, and an overall lack of sympathy and trust as contributors to their negative feelings toward medical care of SCD.24-26
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The Adolescent Pediatric Pain Tool has been demonstrated to detect change in patients hospitalized for vasoocclusive pain, although it has not been validated for this use.43 Although this tool is helpful, it paints only a narrow picture of the pain experience and does not address the functional change in patient status that is likely used by clinicians when making therapeutic decisions. The emergency clinician must be cognizant of difficulties associated with pain assessment in the sickle cell population. It is crucial to recognize the intensity of pain in SCD and to avoid allowing bias about patient report to alter treatment plans or the clinician patient relationship.
PAIN MANAGEMENT
Management of pain in SCD should take advantage of a multidisciplinary approach that would include pharmacologic, behavioral, and complementary interventions. Currently, the paradigm under which this pain has been treated focuses almost solely on acute pharmacologic management of recurrent episodes and does not treat SCD with the modalities that have typically been brought to bear on a chronic pain syndrome.
Pharmacologic Management
Although much has been written regarding the use of pharmacologic agents in SCD, there is a lack of data supporting the use of any of the agents that will be discussed in this section. Acetaminophen (APAP) and nonsteroid antiinflammatory agents (NSAIDs) are typically the first-line therapy for patients with SCD who have mild to moderate pain. These agents should be combined with opioids in patients whose pain is not reduced with these therapies alone. Acetaminophen, although a relatively weak analgesic, can be effective for some pain episodes in SCD. The effects of APAP are mostly central, and it does not have much anti-inflammatory action. Although the adverse effects of APAP are limited in SCD compared with NSAIDs, patients should be reminded to avoid exceeding recommended daily doses because this can result in hepatic toxicity. The use of combination products that contain APAP along with an opioid are especially problematic and can lead to inadvertent overdose in this population. Nonsteroid anti-inflammatory agents are commonly used for sickle cell patients with mild, moderate, or severe acute pain either in the outpatient or inpatient setting. These agents do
provide peripheral anti-inflammatory activity. They have a ceiling effect, meaning that there is a maximum dose beyond which no further benefit is derived. The present data on the efficacy of these agents in SCD are contradictory. A recent randomized controlled trial showed no benefit of ketoprofen in a group of hospitalized adults with sickle cell disease in regard to duration of pain episode or opiate consumption.44 One pediatric study showed no added benefit with the addition of ketorolac regarding opiate utilization or pain relief.45 Another pediatric trial demonstrated that more than 50% of VOEs resolved after ED treatment with ketorolac and intravenous fluids.46 It may be that ketorolac is effective in milder episodes of sickle cell pain but does not provide additional benefit for more severe or longer lasting pain. The answer to this question is an important one, given that NSAIDs are not without risks including gastritis, nephropathy, and antiplatelet activity. Opioids are the mainstay in the treatment of moderate to severe pain in SCD. Currently, available opioids traditionally provide their analgesic action through the -opioid receptor, although other agents such as agonist-antagonists are used in this population. The advantages of opioids include their potent centrally mediated analgesic action, the availability of many routes for delivery, a variety of available agents, as well as a lack of a ceiling effect, thus allowing for continued drug titration if there is a lack of analgesia at lower doses. Side effects and adverse events can limit the efficacy of opioids in children with SCD. These include nausea, vomiting, pruritus, constipation, and urinary retention. Other side effects can present more serious challenges such as respiratory depression, oversedation, or delirium. Children with SCD often exhibit tolerance to opioids due to repeated use of these agents. This results in the need for higher and higher doses of opioids to provide the same level of analgesia. A recent study demonstrated that the clearance of morphine is 3 times faster in adults with SCD than in normals.47 Patients with SCD can also develop opioid dependence and addiction. There are many misconceptions about these issues and their prevalence in this population. Opioid dependence is a physiologic phenomenon such that abrupt discontinuation of opioid treatment will lead to symptoms of withdrawal. Patients who are on chronic opioids are opioid dependent. In contrast, opioid addiction is a psychologic craving for these drugs. Clearly, concerns regarding overreporting of pain and addiction have major impact on the
administration of care to patients with SCD. Fear of drug abuse, reluctance to prescribe opioids, and disbelief in patients' report of pain severity are 3 of the top 5 barriers to optimal sickle cell pain management reported by clinicians. 21 Surveys have documented that 53% of emergency physicians and 23% of hematologists feel that more than 20% of patients with SCD are addicted to opiates, whereas 63% of nurses feel that drug addiction frequently develops in the treatment of sickle cell pain episodes.21,23 The truth regarding opiate addiction in patients with SCD is markedly less dramatic than popular opinion would suggest.48 Prevalence estimates for opiate addiction among patients with SCD range from 0.5% to 8%.48 Elander et al49 take a unique approach to this issue separating Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition substance abuse and dependence symptoms into pain-related symptoms and nonpain-related symptoms. When pain-related symptoms are included, 31% of sickle cell patients met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, but when only nonpain-related symptoms are included, the percentage of patients meeting these criteria drops to 2%.49 Elander et al49 also point out that concernraising behaviors inside the hospital, that is, asking for a certain dose or delivery mode for an opiate, are considerably less suspicious for potential abuse than behaviors such as illicit drug use, or using opiates for symptoms other than pain that typically occur outside the hospital setting. Because most care providers in the ED or other areas of the hospital are dealing with the former and not the latter behaviors, substance abuse should not be presumed. It may in fact be that pain-related behaviors are normative in patients within populations of medically ill patients. This pseudoaddiction is compounded in patients with SCD due to inadequate effect of current analgesic regimens even in the face of what is seemingly appropriate treatment. Opioids can be administered orally, transmucosally, transdermally, subcutaneously, intravenously, or intramuscularly. For acute, severe pain intravenously administered opioids are the drug and route of choice. At presentation, the patient should receive intermittent boluses of opioid with frequent (every 15 minutes) reassessment. The child who is going to stay in the hospital more than 2 or 3 hours should be transitioned to patient-controlled analgesia (PCA). Patient-controlled analgesia is a well-tolerated and effective mode of analgesia in children older
than 7 years. It allows for the child to control the titration of analgesia and reduces the delay inherent in nurse-delivered analgesia. Due to the severity of their pain at the time of presentation, children and adolescents with SCD hospitalized for pain should receive PCA with both continuous infusion and bolus dosing. Implementation of PCA in the ED especially for those patients who are going to be hospitalized should be encouraged. Initiation of PCA in the ED will facilitate aggressive management of pain and lessen the gap between bolus dosing and PCA initiation, which often occurs when the patient is transferred to the inpatient unit. For outpatient management of pain, either shortacting oral opioids or a combination of long-acting and short-acting opioids is appropriate depending on the severity and the duration of pain. As stressed earlier, avoid the use of combination products to avoid the risk of APAP toxicity.
Adjuvants and Other Analgesics

Patients with SCD demonstrate aspects of neuropathic as well as nociceptive pain. In addition, it is likely that recurrent episodes of severe pain experienced by this patient group lead to augmentation of pain processing and centrally mediated pain. These types of pain may respond to adjuvant analgesics such antidepressants (amitriptyline and duloxetine) or anticonvulsants (gabapentin and pregabalin). There is limited evidence for the efficacy of these drugs for chronic pain syndromes in children, nor is there any data for these drug classes in sickle cell pain. Although these drugs are used for the management of chronic pain in sickle cell disease, further study is warranted to define their utility in this patient group. Sickle cell patients with acute and chronic pain also develop a number of other issues that may need pharmacologic intervention. Sleep disorders are common in this population and can lead to increased pain complaints as well as decreased pain coping ability. We have used a variety of sleep medications in this population including zolpidem, trazodone, melatonin, and amitriptyline. None of these drugs have been well studied in this population. For patients with sedation secondary to opioids, a stimulant such as methylphenidate in low dose may be appropriate. It is important to place patients on opioids on a daily bowel regimen. Treatment of mood disorders such as anxiety and depression is also essential in the overall care of the patient with a recurrent or chronic pain disorder.
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Topical preparations may also be helpful in the treatment of pain in SCD. For those with chronic pain in areas such as the lower back, topical lidocaine patches can be used. Our patients report relief from capsaicin patches applied during VOE. Further evaluation of these modalities as well as topical NSAIDs is indicated.
Behavioral Treatment
There is ample evidence for behavioral treatments for pain associated with SCD.50-52 Many patients with pain experience comorbid mood disorders. Patients with SCD can also benefit from help with coping and relaxation.
Physical Treatments
For patients with recurrent and chronic pain, physical therapy to develop better functional ability and speed functional recovery from painful episodes is helpful. Modalities such as graded exercise, heat, and ultrasound can all be used to good effect. Many of our patients report relief using transcutaneous electrical nerve stimulation for both acute VOE and chronic pain. Transcutaneous electrical nerve stimulation allows the patient to have some control of their pain therapy and can be used in a variety of settings including the classroom or the workplace.
Complementary Therapies
There are limited data to support the use of complementary therapies in SCD, although they are clearly used by those who have sickle cell pain.53,54 Anecdotally, our patients have benefited from a range of treatments such as acupuncture and massage. The limited availability and expense of these modalities are problematic. Further research on the efficacy of these techniques is warranted.
APPROACH TO CARE IN THE ED

When a child with SCD presents to the ED with pain, they should be rapidly assessed (Figure 2). Those with a pain score of 7 or above are in severe pain and should be immediately triaged into the ED for further assessment and immediate analgesic administration. Although analgesia is being administered, a full history and physical examination as well as laboratory evaluation should proceed. History should focus on precipitating factors for pain, its location, intensity, and how it compares with usual episodes. Changes in the usual characteristics of pain should trigger the clinician to look for other causes of pain other than straightforward
VOE. The presence of fever, cough, chest pain, or shortness of breath should also be elicited because this may indicate the presence of an infection including pneumonia or acute chest syndrome. Physical examination should focus on the areas of pain, but a careful examination for signs of infection should occur. Attention should be paid to evaluate for signs of pneumonia, osteomyelitis, or sepsis. The examination should also evaluate for splenomegaly, which may indicate splenic sequestration. Males should be evaluated for signs of priapism, as they may be reluctant to report this symptom. Laboratory evaluation will typically include a complete blood count with a reticulocyte count. Other laboratory studies should be considered if fever or other findings are present, which would indicate the need for an expanded evaluation. Aggressive pain management is the key to the appropriate care of vasoocclusive pain. Ideally, information regarding the patient's acute pain plan would be available to the ED physician in the form of a pain passport held by the patient, or a hospital database, or direct communication with the hematology staff. The patient and their family should be considered as a partner in care. Their knowledge of appropriate dosing and medication should not be disregarded and is not evidence of drug seeking or addiction. Starting doses of opioids for many patients will be higher than that in a patient who is opioid nave. Starting doses of intravenous morphine in the 10 to 15 mg range are not unusual. Following the first intravenous opioid dose, reassessment should take place in 30 minutes. If the patient's pain remains severe, a second dose of opioid should be given. Therapy for vasoocclusive pain in the ED with our current understanding of the literature should also include either an intravenous or an oral dose of an NSAID. A bolus of isotonic fluid at 20 mL/kg (maximum 1 L) should also be given over an hour. Patients who fail to improve after 2 doses of opioids will likely need hospitalization. Ideally, PCA should be initiated at this point, but if this is unavailable or delayed, another dose of opioids should be given. For those patients who do show improvement, discharge preparations should be made. These patients should receive oral opioids. Where appropriate, a long-acting opioid should be given (with a short-acting opioid available for breakthrough pain). Again, the availability of an individualized pain plan would assist in these decisions. Early follow-up with the hematologist or primary care giver should be arranged, as this has been shown to reduce return visits to the ED.
Figure 2. Management of uncomplicated vasoocclusive pain.
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IMPROVING CARE AND REDUCING BARRIERS

Improvement in the ED care of patients with SCD should start with the development and implementation of a clinical practice guideline or pathway. These should be developed in conjunction with the institution's hematologists and should include: strategies for avoiding ED visitation and decreasing hospitalization, ensuring ED follow-up in a primary care or hematology office setting, as well as recommending appropriate pain assessment. Rapid triage, timely and adequate opioid dosing, and utilization of PCA should all be components of a pathway. These guidelines can impact a variety of benchmarks including time to analgesia, return visits, totals ED visits, and the use of PCA in the ED for patients with SCD.55,56 In some centers where the volume of patients permits, day hospital programs for those with vasoocclusive pain allow for patients to be treated by providers who know them well. As mentioned previously, individualized acute pain plans are helpful in improving patient care as well. A pain passport would allow the patient's pain plan to be given to the provider in the acute setting and would validate the patient's requests. Mandating the use of pain protocols and clinical guidelines may be needed to help reduce the bias that has typified the care of this patient group. Bidirectional communication between ED providers and the sickle cell community should be encouraged. This can be achieved by reaching out to local community-based organizations or to hospital-based family advisory boards. Specific champions within the ED with knowledge and interest in SCD can act as a resource for both providers and patients.
SUMMARY
The care of pain in sickle cell disease is challenging and historically has been underrecognized and undertreated. Rapid assessment and treatment of children and adolescents presenting to the ED with VOE using a carefully crafted pathway or guideline is essential for improving the care of this patient group and reducing the bias and distrust that has characterized their care.
REFERENCES
1. Ballas SK. Pain management of sickle cell disease. Hematol Oncol Clin North Am 2005;19:785-802.
2. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991;325: 11-6. 3. Yusuf HR, Atrah HK, Grosse SD, et al. Emergency department visits made by patients with sickle cell disease: a descriptive study, 1999-2007. Am J Prev Med 2010;38:S536-541. 4. Yang Y, Shah A, Watson M, et al. Comparison of costs to the health sector of comprehensive and episodic health care for sickle cell disease patients. Pub Health Rep 1997; 110:80-6. 5. Ballas SK. Sickle cell pain. Seattle (Wash): IASP Press; 1998. 6. Schechter NL. The management of pain in sickle cell disease. In: McGrath PJ, Finley GA, editors. Chronic and recurrent pain in children and adolescents. Seattle (Wash): IASP Press; 1999. p. 99-114. 7. Dampier CD, Shapiro BS. Management of pain in sickle cell disease. In: Schechter NL, Berde CB, Yaster M, editors. Pain in infants, children, and adolescents, 2nd ed. Philadelphia (Pa): Lippincott Williams & Wilkins2003. p. 489-516. 8. Conner-Warren RL. Pain intensity and home pain management of children with sickle cell disease. Issues Compr Pediatr Nurs 1996;19:183-95. 9. Walco GA, Dampier CD. Pain in children and adolescents with sickle cell disease: a descriptive study. J Pediatr Psychol 1990;15:643-58. 10. Varni JW, Walco CA. Chronic and recurrent pain associated with pediatric chronic diseases. Issues Compr Pediatr Nurs 1988;11:73-86. 11. Smith LA, Oyeku SO, Homer C, et al. Sickle cell disease: a question of equity and quality. Pediatrics 2006;117:1763-70. 12. Todd KH, Green C, Bonham VL, et al. Sickle cell disease related pain: crisis and conflict. J Pain 2006;7:453-8. 13. Brousseau DC, Owens PL, Mosso AL, et al. Acute care utilizations and rehospitalizations for sickle cell disease. JAMA 2010;303:1288-94. 14. Boulet SL, Yanni EA, Creary MS, et al. Health status and healthcare use in a national sample of children with sickle cell disease. Am J Prev Med 2010;38:S528-35. 15. Eton WA, Hofrichter J. Sickle cell hemoglobin polymerization. Adv Protein Chem 1990;40:63-279. 16. Embury SH. The not so simple process of sickle cell vasoocclusion. Microcirculation 2004;11:101-13. 17. Vekilov PG. Sickle-Cell haemoglobin polymerization: is it the primary pathogenic event of sickle cell anaemia? Br J Haemotol 2007;139:173-84. 18. Beyer JE, Simmons LE, Woods GM, et al. A chronology of pain and comfort in children with sickle cell disease. Arch Pediatr Adolesc Med 1999;153:913-20. 19. Brandow AM, Brousseau D, Pajewski NM, et al. Vasoocclusive events in sickle cell disease: impact on child wellbeing. Pediatr Blood Cancer 2009;54:92-7. 20. Zempsky WT, Corsi JM, Loiselle KA, et al. Functional assessment for children hospitalized for sickle cell pain: a new paradigm. Blood 2009;2561:114. 21. Pack-Mabien A, Labb E, Herbert D, et al. Nurses attitudes and practices in sickle cell pain management. Appl Nurs Res 2001;14:187-92. 22. Labb E. Physicians' attitude and practices in sickle cell disease pain management. J Palliat Care 2005;21:246-51. 23. Shapiro BS, Benjamin LJ, Payne R, et al. Sickle cell-related pain: perceptions of medical practitioners. J Pain Symptom Manage 1997;14:168-74. 24. Alleyne J, Thomas VJ. The management of sickle cell crisis pain as experienced by patients and their carers. J Adv Nurs 1993;19:725-32.
25. Harris A, Parker N, Barker C. Adults with sickle cell disease: psychological impact and experience of hospital services. Psychol Health Med 1998;3:171-9. 26. Maxwell K, Streetly A, Bevan D. Experiences of hospital care and treatment seeking for pain from sickle cell disease: qualitative study. BMJ 1999;318:1585-90. 27. McGrath PJ, Turk DC, Dworkin RH, et al. Core outcome domains and measures for pediatric acute and chronic/ recurrent pain clinical trials: PedIMMPACT recommendations. Pain 2008;9:771-83. 28. Finley GA, McGrath PJ, editors. Measurement of pain in infants and children. Seattle (Wash): IASP Press; 1998. p. 1-4. 29. Platt A, Eckman JR, Beasley J, et al. Treating sickle cell pain: an update from the Georgia Comprehensive Sickle Cell Center. J Emerg Nurs 2002;28:297-303. 30. Rees DC, Olujohungbe AD, Parker NE. Guidelines for the management of the acute painful crisis in sickle cell disease. Br J Haematol 2003;120:744-52. 31. Benjamin LJ, Dampier CD, Jacox AK, et al. Guideline for the management of acute and chronic pain in sickle cell disease. Glenview (Ill): American Pain Society; 1999. 32. Johnston CC. Psychometric issues in the measurement of pain. In: Finley GA, McGrath PJ, editors. Measurement of pain in infants and children. Seattle (Wash): IASP Press; 1998. p. 5-20. 33. Stinson JN, Kavanagh T, Yamada J, et al. Systematic review of the psychometric properties interpretability and feasibility of self-report pain intensity measures for use in clinical trials in children and adolescents. Pain 2006;125:143-57. 34. von Baeyer CL, Spagrud LJ, McCormick JC, et al. Three new datasets supporting use of the numerical rating scale NRS-11) for children's self-reports of pain intensity. Pain 2009;143: 223-7. 35. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartate acid receptor activation: implication for the treatment of post-injury pain hypersensitivity states. Pain 1991;44:293-9. 36. Gil KM, Thompson RJ, Keith BR, et al. Sickle cell disease pain in children and adolescents: change in pain frequency and coping strategies over time. J Pediatr Psychol 1993;18: 621-37. 37. McCrae JD, Lumley MA. Health status in sickle cell disease: examining the roles of pain coping strategies, somatic awareness, and negative affectivity. J Behav Med 1998;21: 35-55. 38. Varni JW, Rapoff MA, Waldron SA, et al. Chronic pain and emotional distress in children and adolescents. J Dev Behav Pediatr 1996;17:154-61. 39. Varni JW, Rapoff MA, Waldron SA, et al. Effects of perceived stress on pediatric chronic pain. J Behav Med 1996;19: 515-28. 40. Palermo TM. Impact of recurrent and chronic pain on child and family daily functioning: a critical review of the literature. J Dev Behav Pediatr 2000;21:58-69.
41. Jacob E, Miaskowski C, Savedra M, et al. Management of vasoocclusive pain in children with sickle cell disease. J Pediatr Hematol Oncol 2003;25:307-11. 42. Zempsky WT, Loiselle KA, McKay K, et al. Retrospective evaluation of pain assessment and treatment for vasoocclusive episodes in children with sickle cell disease. Pediatr Blood Cancer 2008;51:265-8. 43. Jacob E, Miaskowski C, Savedra M, et al. Changes in intensity, location, and quality of vaso-occlusive pain in children with sickle cell disease. Pain 2003;102:187-93. 44. Bartolucci P, El Murr E, Roudot-Thoroval F, et al. A randomized, controlled clinical trial of ketoprofen for sickle-cell disease vaso-occlusive crises in adults. Blood 2009;114:3742-7. 45. Hardwick WE, Givens TG, Monroe KW, et al. Effect of ketorolac in pediatric sickle cell vaso-oclusive pain crisis. Pediatr Emerg Care 1999;15:179-82. 46. Bieter JL, Simon HK. Intravenous ketorolac in the emergency department management of sickle cell pain and predictors of its effectiveness. Arch Pedatri Adol Med 2001;155:496-500. 47. Darbari DS, Neely M, VandenAnker J, et al. Morphine pharmacokinetics in sickle cell disease: implications for pain management. Blood 2009;114:2574. 48. Zempsky WT. Treatment of sickle cell pain: fostering trust and justice. JAMA 2009;302:2479-80. 49. Elander J, Lusher J, Bevan D, et al. Understanding the causes of problematic pain management in sickle cell disease: evidence that pseudo-addiction plays a more important role than genuine analgesic dependence. J Pain Symptom Manage 2004;27:156-69. 50. Thomas V. Cognitive behavioral therapy in pain management for sickle cell disease. Int J Palliat Nurs 2000;6:434-42. 51. Broome ME, Maikler V, Kelber S, et al. An intervention to increase coping and reduce health care utilization for schoolage children and adolescents with sickle cell disease. J Natl Black Nurses Assoc 2001;12:6-14. 52. Chen E, Cole SW, Kato PM. A review of empirically supported psychosocial interventions for pain and adherence outcomes in sickle cell disease. J Pediatr Psychol 2004; 29:197-209. 53. Lemanek KL, Ranalli M, Lukens C. A randomized controlled trial of massage therapy in children with sickle cell disease. J Pediatr Psychol 2009;34:1091-6. 54. Sebigna EM, Shindell DL, Casella JF, et al. Pediatric patients with sickle cell disease: use of complementary and alternative therapies. J Altern Complement Med 2006;12:291-8. 55. Morrisey LK, Shea JO, Kalish LA, et al. Clinical practice guidelines improve the treatment of sickle cell vasoocclusive pain. Pediatr Blood Cancer 2009;52:369-72. 56. Givens M, Rutherford C, Joshi G, et al. Impact of an emergency department pain management protocol on the pattern of visits by patients with sickle cell disease. J Emerg Med 2007;32:239-43.
Abstract:
Practitioners of procedural sedation and analgesia for children in an emergency department setting must balance the needs of individual patients, including safety and efficacy, with the needs of the department as a whole, including efficiency and appropriate use of resources. Individual patient needs will vary depending on the age and developmental stage of the patient, the anticipated level of pain and distress, the degree of immobility required, and the duration of the procedure. The ability to accurately predict the need for sedation, the level of sedation and degree of analgesia required for patient comfort, and the best sedative agent to accomplish these goals without undesirable consequences is a skill that requires knowledge and experience. This review presents 6 case scenarios illustrating various sedation options, from an evidence-based perspective whenever possible, for common pediatric presenting complaints.
Keywords:
procedural sedation analgesia; pediatrics; tailoring sedation
Tailoring Pediatric Procedural Sedation and Analgesia in the Emergency Department: Choosing a Regimen to Fit the Situation
Jonathan Bennett, MD, Andrew DePiero, MD, Susanne Kost, MD
Division of Emergency Medicine, Procedural Sedation Service, Nemours/ A.I. duPont Hospital for Children, Wilmington, DE. Reprint requests and correspondence: Susanne Kost, MD, Division of Emergency Medicine, Procedural Sedation Service, Nemours/A.I. duPont Hospital for Children, 1600 Rockland Rd. Wilmington, DE 19899. skost@nemours.org
rocedures performed on children in the emergency department (ED) can be anxiety-producing, painful, or both. Many procedures require relative or complete immobility to be performed safely, both for the practitioner and the patient. In addition to ensuring safety, relief of anxiety and pain, and control of motion, the practitioner providing sedation in the ED must keep in mind big picture issues. These bigger issues include using bed space and staff
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TAILORING PEDIATRIC PROCEDURAL SEDATION / ANALGESIA IN THE ED / BENNETT, DEPIERO, AND KOST VOL. 11, NO. 4 275
efficiently, as well as heeding institutional and national regulatory requirements. The ability to choose a sedation regimen that optimizes all of these factors is an invaluable skill in creating an ideal procedural environment for the patients and providers. The following case scenarios will illustrate approaches to sedation of pediatric patients in the ED and provide a practical, evidence-based approach to common ED problems.
CASE 1
An 18-month-old boy presents to the ED after falling from a shopping cart. He had a brief loss of consciousness but no vomiting. The episode occurred approximately 1 hour ago. He is previously healthy. The patient's vital signs are normal, but he is somewhat fussy during physical examination. He has a large, boggy parietal hematoma. You order a computerized tomography (CT) study of the head. What are your sedation options? This case provides an example of a brief, painless procedure that may require sedation to obtain highquality diagnostic images. In many situations, this study could be completed without sedation. The child may be able to be briefly calmed and distracted by a parent, child life practitioner, or design features in the scanning room, such as pictures on the ceiling. The increased speed of new CT scanners has decreased the number of patients needing sedation. The use of multisectional helical CT compared with single-section helical CT was shown to decrease the need for sedation 3-fold.1 Another study noted that sedation was only required in 8.6% of all pediatric patients but in 36.4% of patients between 12 and 30 months of age.2 If distraction and immobilizer devices fail, midazolam is commonly used as a first-line agent in this setting. Although it can be administered in a number of routes, most literature related to the above vignette has considered its intravenous use. More than 90% of children ages 6 months to 6 years were able to complete a CT scan with a single dose of intravenous midazolam (0.2 mg/kg). 3 Adverse effects were minimal and included mild desaturation (SpO2 90%-95%) in 7% of patients, and there were no airway complications among the 516 patients enrolled in the study. An alternative to midazolam is pentobarbital. It has long been used for pediatric CT, with success rates as high as 97% and with few failures or complications.4,5 In 2000, Moro-Sutherland et al6 compared the use of intravenous midazolam with pentobarbital for sedation for head CT imaging. In this prospective, randomized clinical trial, 55
patients were enrolled. In the pentobarbital group, 97% of patients were successfully sedated and scanned as opposed to 19% of patients who received midazolam. Oral pentobarbital has been shown to be as effective as chloral hydrate in sedating patients younger than 1 year for imaging studies, with fewer adverse events.7 A number of other agents have been compared with pentobarbital. In a prospective study of pediatric patients undergoing diagnostic CT, propofol was found to require more airway manipulations to relieve obstruction (23% vs 0%) and to have more adverse respiratory events (12% vs 0%).8 Etomidate has also been compared with pentobarbital in sedation for CT scans. 9 In a cohort from a prospectively gathered database, fewer unsuccessful sedations were noted in the etomidate group. Adverse events were more common in the pentobarbital group, whereas both groups had few apneic events. A prospective double-blinded study showed the rate of successful sedations in the etomidate group to be 76% as compared with 97% for pentobarbital.10 Use of etomidate does have a much shorter recovery time compared with pentobarbital.9,10 Dexmedetomidine is a newer sedative with more limited data pertaining to its use in pediatric patients. Its use was first reported prospectively in 2006.11 In a pilot program, 62 patients undergoing CT were sedated with dexmedetomidine. Some decreases in heart rate and blood pressure were noted initially, but no changes were noted in respiratory rate or end-tidal CO2. Further work demonstrated that the use of dexmedetomidine was associated with transient sinus arrhythmias in 12% of patients and modest but unpredictable hemodynamic fluctuations.12 For brief painless procedures such as head CT, there are a number of safe and efficacious sedative options. Intravenous access may be an important consideration. In this scenario, an agent with a short half-life may be most efficient and will provide the opportunity to more accurately monitor the patient's mental status.
CASE 2
A 4-year-old boy presents to the ED with abdominal pain. He was well until 2 days ago when he developed diffuse abdominal pain. The pain has now worsened. He has fever and anorexia. He vomited once approximately 6 hours ago. On examination, he is uncomfortable but not toxic-appearing. His vitals are stable. He has significant diffuse abdominal pain. You order a complete blood count, which shows a
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white blood cell count of 17 000 with left shift. You request surgical consultation. As there is concern for appendicitis, the surgeon requests a CT. What is the best sedative choice? Although seemingly similar, this scenario does vary importantly from that in case 1. Although new CT technology continues to decrease study time, this study is still much longer than a noncontrast head CT. The other consideration is the injection of contrast. Contrast will often result in a flushed or uncomfortable sensation that may cause a child to move. Given the concerns for radiation exposure and the issues with redosing contrast, a careful selection of sedative agent is indicated to maximize successful imaging on the initial attempt. In this scenario, the current literature is less helpful. Many studies have considered sedation of pediatric patients for CT, but none have addressed this more complex CT case scenario. Most sedation regimens that were considered in case 1 primarily addressed the issue of noncontrast head CT alone. In addition to contrast studies, other examples of more complex CT studies requiring more complete immobility include studies with fine cuts, such as CT of the temporal bones; studies with the anticipated need for 3-dimensional reconstruction, as in maxillofacial trauma; and studies that require crucial timing in the injection of contrast, such as with CT angiography. With these considerations, short-acting agents may not be the ideal choice. Whereas the patient may be sedated, they must also be still. An abdominal CT will require that the patient be still for a longer period than in the case of a noncontrast head CT. As always, the clinical scenario and the patient's level of cooperation will help guide the sedation choice. The use of oral contrast poses a challenge to sedation providers because, by definition, it is in conflict with the patient's NPO status. A retrospective study with pentobarbital noted complications in almost 15% of patients. 13 These complications included desaturation, vomiting, airway secretions, airway obstruction, coughing, and bronchospasm. A larger retrospective study considered a similar question in patients receiving pentobarbital or chloral hydrate.14 Most patients in the study were sedated with pentobarbital, and none of the 367 patients had any complications related to the administration of the oral contrast material. As in the previous case, a number of safe and efficacious sedative options exist. Very short-acting agents may not be appropriate for a number of patients. Use of a somewhat longer-acting agent, such as propofol via repeated mini-bolus or by
infusion, dexmedetomidine infusion, or ketamine, may be most efficient in the scenario given the higher radiation doses and the issues associated with the readministration of intravenous contrast.
CASE 3
A 6-year-old girl presents to the ED with leg weakness. She has had mild weakness for several days and is now having some difficulty with ambulation. She also reports some mild back pain. She has no upper extremity weakness or breathing difficulty. Part of the ED diagnostic evaluation includes lumbar spine radiographs that are concerning for a mass. A magnetic resonance imaging (MRI) study of the spine is indicated, and you are asked to provide the sedation. What are your alternatives? This is an example of a long painless procedure that will require sedation. The patient is having some back pain, the degree to which that may affect the sedation strategy. Ideally, the MRI could be performed without sedation; however, several obstacles exist. The noise generated by the machine and narrow space contribute to anxiety for many children (and adults). As in the case vignette, the patient may be experiencing pain. The family will have had little time to speak to their child to help prepare her for the procedure. Also of importance is the length of the study itself. An MRI of the spine is a much longer procedure than an MRI of the brain, with an average table time of 60 to 90 minutes. Alternatives to sedation have been investigated. A protocol that used a mock scanner with training sessions was successful in allowing functional MRI studies to be accomplished without sedation in 90% of cases overall and in more than 88% of patients younger than 7 years.15 In the acute setting, this approach may not be practical. Audiovisual systems may have more benefit in the acute setting. In the ambulatory setting, alternatives such as these have been shown to decrease the need for sedation.16 Intravenous pentobarbital has been used successfully for this purpose, with a success rate greater than 90% and few adverse events.17,18 However, pentobarbital's success rate in children older than 12 years or in those greater than 50 kg is decreased.18 Another frequently used sedative for MRI is propofol. In a larger multicenter study in children undergoing MRI, both pentobarbital and propofol were found to provide an equal number of successful sedations (96%). Patients receiving propofol had more apneic events, but the rate of apnea and airway complications combined was similar in
the 2 groups. Pentobarbital was associated with more failed sedation, unplanned admissions, and prolonged recovery and vomiting.19 In another study comparing propofol to a regimen of pentobarbital/fentanyl/midazolam, propofol had faster onset and recovery with a similar or superior success rate.20 The rate of adverse events was also similar. Propofol is typically administered as a constant infusion after an initial bolus, but some have reported success with intermittent small doses21 or a single dose for shorter studies.22 As in the case of CT, dexmedetomidine has been used for pediatric MRI. The largest study is a retrospective analysis of 747 patients.23 At higher doses, the success rate for completing the MRI was 97.6%. Bradycardia and hypotension were noted, but there were no adverse events. The sedation options in this setting may be more limited, but they are safe and efficacious. Agents such as propofol may require physician presence and may not represent efficient use of time for a busy ED physician.
CASE 4
A 23-month-old boy was chasing his 4-year-old brother around the living room. He tripped over a toy dump truck and fell, striking his forehead on the coffee table. He sustained a 3-cm laceration to his mid-forehead. It is sufficiently long and deep such that it will require sutures. The injury occurred 3 hours ago, and he has been acting normally since. The result of his examination is otherwise unremarkable. He last ate at breakfast time (6 hours ago) and drank some apple juice 2 hours ago. The mother describes him as wild, and she asks for something to knock him out for the repair. Simple facial lacerations are extremely common injuries that may require suturing in the ED. Although these typically can be repaired without significant discomfort because of topical anesthetic preparations such as LET (lidocaine, epinephrine, tetracaine) gel they frequently cause significant anxiety in toddlers and school-aged children. In addition, although complete immobility is not necessary, relative immobility is required. This can be achieved with restraint devices, such as soft papoose board, or additional personnel; but restraint itself can cause additional fear and anxiety. In children where routine comfort measures and distraction are not adequate, mild to moderate sedation is helpful to provide the necessary procedure environment. Given the goal of reducing fear and anxiety, midazolam, a short-acting benzodiazepine, is an excellent choice for mild-to-moderate sedation in
children undergoing simple laceration repair. It provides anxiolysis, sedation, and antegrade amnesia. It can be given by various nonparenteral routes including oral, intranasal, and rectal, and has been shown to decrease fear and anxiety significantly.24-26 Recommended dosing ranges for midazolam are 0.2 to 0.4 mg/kg intranasally and 0.5 to 0.7 mg/kg orally. Intranasal administration can be facilitated by use of an atomizer, although more than 5 mg in a single dose is difficult to administer. Onset of action is route dependent. Intranasal is the fastest, with an onset in less than 5 minutes; and oral is the slowest, with onset in 20 to 30 minutes. Typically, there are minimal adverse effects with nonparenteral administration. Pulse oximetry should be performed, but respiratory depression is extremely unusual with the use of nonparenteral midazolam alone. Duration of action is usually about an hour. Paradoxical agitation is the most disturbing adverse effect, and in one study, occurred in 12.5% of patients.25 It is our practice to warn parents of this adverse effect, as at times it may occur after discharge. An alternative to midazolam, if available, is nitrous oxide (NO). This inhalational agent can provide anxiolysis, sedation, and analgesia. It is available in commercial units that can provide continuous flow of up to 70% NO (30% 02) through either a nasal mask or a full face mask. These commercially available units have combined delivery/scavenger systems that are necessary to isolate exposure to the patient. Nitrous oxide use has been studied by Luhmann et al 27 for simple facial lacerations and was shown to decrease distress and improve provider satisfaction compared with midazolam or standard care. There were no respiratory complications in their study, although there was vomiting in about 10% of patients receiving NO. Nitrous oxide is advantageous because the desired effects resolve within minutes of its discontinuation, it has significantly less adverse effects in the following 24 hours, and it has significantly shorter recovery times compared with midazolam.27
CASE 5
A 10-year-old boy has suffered a distal radius and ulna fracture in a fall on his right arm. The fractures are angulated 45 dorsally and displaced. He has sustained no head or abdominal injuries. The orthopedist requests conscious sedation so that he can reduce the fracture. Extremely painful short procedures such as this one (others in this category include large joint dislocation, abscess drainage, and burn debridement)
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are generally best performed under procedural sedation with ketamine or deep sedation with propofol. The term conscious sedation is not applicable, as the goal is to not have the patient conscious for the procedure. Ketamine, a dissociative anesthetic, is in many ways the ideal agent for such procedures. It places the patient in a trance-like state of sedation, also providing significant analgesia, immobility, and amnesia. This state is accomplished while usually maintaining upper airway muscle tone, protective airway reflexes, and spontaneous respiration. Significant respiratory complications are extremely uncommon.28 Duration of peak action when given intravenously is 5 to 10 minutes, allowing for fracture reduction, casting, and molding to be accomplished with a small number of doses. Although it may be given intramuscularly, the potential need for repeat dosing and higher rates of adverse effects make the intramuscular route less desirable for this procedure. The most common adverse effect of ketamine is postprocedure vomiting, occurring in 8% of patients. Larger doses and intramuscular administration are associated with increased rates of emesis. 29 The most feared adverse effect, laryngospasm, is exceedingly rare and usually relieved with positive pressure ventilation.30 Midazolam has traditionally been used with ketamine to prevent emergence reactions, which, when severe, can be frightening for parents and disruptive to care. Two randomized trials have specifically looked at the emergence phenomena.31,32 Wathen et al31 showed no difference in either overall emergence or severe emergence between all patients receiving ketamine compared with patients receiving ketamine and midazolam for sedation. Similarly, Sherwin et al32 showed no difference in recovery agitation, severe hallucinations, or nightmares. However, in the Wathen et al study for patients older than 10 years, there was a nonsignificant trend toward a lower incidence of severe emergence and less vomiting in patients receiving ketamine and midazolam. The combination of ketamine/midazolam has been shown to be superior to fentanyl/midazolam in sedation for orthopedic procedures.33 In cases where ketamine may be contraindicated (increased intracranial pressure, increased ocular pressure, hypertension), fentanyl/midazolam is an alternative. Propofol is another option in this case. By providing deep sedation, propofol can allow for painful procedures to be performed. Propofol itself, unlike ketamine, does not provide analgesia and therefore may require an analgesic agent such as fentanyl or sufentanil. Combination of propofol with
a narcotic agent may increase respiratory depression and apnea. Propofol has been shown to be effective in one study of brief orthopedic procedures in a pediatric ED.34 Patients in that study showed slightly more distress with propofol/fentanyl compared with ketamine/midazolam. Parental scoring of perceived pain, orthopedist satisfaction, and patient recall of the procedure were not different for the 2 groups. Propofol/fentanyl allowed significantly faster recovery times (20.8 vs 54.2 minutes). However, propofol/fentanyl did cause more frequent oxygen desaturations and required more minor airway interventions (jaw thrust and supplemental oxygen). Given the increased risk of potential airway complications, propofol should only be used by practitioners skilled in pediatric airway management. When used for brief painful procedures, propofol is typically given in 0.5 to 1 mg/kg increments titrated to the desired effect. In the Godambe et al34 study, the mean propofol dose over the duration of the procedure was 4.5 mg/kg. Although not extensively studied in the pediatric emergency setting, the combination of ketamine and propofol may also provide adequate deep sedation. The addition of ketamine theoretically provides analgesia effects that propofol does not, without the increased respiratory depression of narcotic agents. The combined sedative effects may allow for smaller doses to be used than if either were used alone. In a large case series using this regimen of propofol and ketamine mixed 1:1 in a single syringe for primarily orthopedic procedures, sedation was effective and well tolerated with average doses of 0.8 mg/kg of each agent.35 Finally, in cases where there is a desire or necessity to avoid deep sedation, the use of NO combined with hematoma block is a sedation alternative for pediatric forearm fracture reductions. Luhmann et al36 compared 50% NO combined with lidocaine hematoma block (NO was given for both hematoma block and fracture reduction) to ketamine (1 mg/kg)/ midazolam for middle to distal forearm fractures in patients aged 5 to 17 years. They found that both groups had very little distress with the procedure; and in fact, those receiving NO/hematoma block had slightly less distress. In addition, recovery time was remarkably shorter with NO/hematoma block, 16 minutes compared with 83 minutes with ketamine/ midazolam. The groups had similar rates of vomiting in the ED, but the ketamine/midazolam group selfreported more adverse effects in the 24 hours following the procedure. It should be noted that, in this study, all patients received an oral narcotic as routine care for presumed fractures. Nitrous oxide's effectiveness in this setting implies that it may be
useful for other moderately to severely painful procedures where local anesthesia can be used, such as abscess drainage.
CASE 6
A 4-year-old boy was bitten on the lip by his grandmother's dog. He has sustained a complex laceration to the upper lip that causes significant disruption to the vermillion border and will require multiple layers to close. The plastic surgeon on call has agreed to perform the repair, but wants the child sedated so he will not be moving at all for the 25 minutes he estimates the repair will take. Prolonged procedures that require significant immobility such as this may require deeper sedation than is possible with midazolam or NO. In this case, either procedural sedation, with ketamine (with or without midazolam), or deep sedation with propofol may be used. Ketamine would need to be given in a number of intermittent doses (0.5-1 mg/kg) over the duration of the procedure. As discussed earlier, larger doses may increase the incidence of postprocedure emesis. Propofol may be the ideal sedation agent for procedures such as this. Pain of the procedure can be managed with either topical anesthetics before sedation or local injection or nerve block during sedation. However, topicals may not be practical on a mucosal surface or advisable near the vermillion border because of systemic absorption of the agent. A propofol bolus of 1 to 3 mg/kg followed by an infusion of 100 to 300 g/kg/ min can then be used to achieve deep sedation for the duration of the procedure. Propofol may be used similarly in procedures where ketamine may be contraindicated such as ophthalmologic examina-
tions (because of concern of elevated intraocular pressure) or lumbar puncture (because of concern of elevated intracranial pressure).37 Sedation is an invaluable tool in the ED for performing procedures on children. As discussed, there are various agents that can be used depending on the length of the study and the degree of sedation required. For anxiety-producing, but relatively painless procedures, both midazolam and NO have been shown to be extremely safe and effective. For intensely painful procedures or prolonged procedures, ketamine (with or without midazolam) and propofol are effective. Ketamine may provide a very small, perhaps clinically irrelevant, benefit in sedation level, whereas propofol provides more rapid recovery and less postprocedure vomiting. Propofol has a narrower therapeutic range and is likely to require more minor airway positioning maneuvers and supplemental oxygen. Nitrous oxide, when available and when combined with oral narcotic and local anesthesia, is an alternative that does not require intravenous access for even moderately to severely painful procedures.
SUMMARY
The pharmacologic and nonpharmacologic options for the provision of pediatric procedural sedation and analgesia have expanded dramatically over the past 2 decades. With experience, emergency care providers can begin to use finesse in the decision of when to provide pharmacologic sedation, which agent(s) to use, and how best to deliver the medications. Figure 1 provides a 3-dimensional illustration of this concept, with an approximation of where various sedative agents fall when
Figure 1. A 3-dimensional approach to tailoring sedation. CH chloral hydrate; DEX dexmedetomidine; ETOM etomidate; FENT fentanyl; INF infusion; KET ketamine; MDZ midazolam; N2O nitrous oxide; PENT pentobarbital; PROP propofol.
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considering control of pain, need for immobility, and the duration of the procedure. Sufficiently powered studies involving large numbers of patients attest to the safety of current practice given modern monitoring standards.28,29,38,39 As we mature as a specialty, we should continue to broaden procedural sedation and analgesia research and clinical policy to include other aspects of quality besides safety, such as efficacy, efficiency, and patient- and family-centered sedation care. We are starting to recognize additional opportunities to alleviate suffering, exemplified by a recent study looking at the cumulative stress of multiple minor procedures over the course of an ED visit.40 In another recent study, preliminary research into intraprocedure agitation as a sedation complication suggests that even in procedures that are considered successful, 8% of the patients experienced some period of agitation.41 Much progress has been made, but we continue to strive for ideal methods for relieving procedural pain and stress.
REFERENCES
1. Pappas JN, Donnelly LF, Frush DP. Reduced frequency of sedation of young children with multisection helical CT. Radiology 2000;215:897-9. 2. Sacchetti A, Carraccio C, Giardino A, et al. Sedation for pediatric CT scanning: is radiology becoming a drug-free zone? Pediatr Emerg Care 2005;21:295-7. 3. Singh R, Kumar N, Vajifdar H. Midazolam as a sole sedative for computed tomography imaging in pediatric patients. Paediatr Anaesth 2009;19:899-904. 4. Strain JD, Harvey LA, Foley LC, et al. Intravenously administered pentobarbital sodium for sedation in pediatric CT. Radiology 1986;161:105-8. 5. Pereira JK, Burrows PE, Richards HM, et al. Comparison of sedation regimens for pediatric outpatient CT. Pediatr Radiol 1993;23:341-4. 6. Moro-Sutherland DM, Algren JT, Louis PT, et al. Comparison of intravenous midazolam with pentobarbital for sedation for head computed tomography imaging. Acad Emerg Med 2000; 7:1370-5. 7. Mason KP, Sanborn P, Zurakowski D, et al. Superiority of pentobarbital versus chloral hydrate for sedation in infants during imaging. Radiology 2004;230:537-42. 8. Zgleszewski SE, Zurakowski D, Fontaine PJ, et al. Is propofol a safe alternative to pentobarbital for sedation during pediatric diagnostic CT? Radiology 2008;247:528-34. 9. Baxter AL, Mallory MD, Spandorfer PR, and the Pediatric Sedation Research Consortium. Etomidate versus pentobarbital for computed tomography sedations: report from the Pediatric Sedation Research Consortium. Pediatr Emerg Care 2007;23:690-5. 10. Kienstra AJ, Ward MA, Sasan F, et al. Etomidate versus pentobarbital for sedation of children for head and neck CT imaging. Pediatr Emerg Care 2004;20:499-506. 11. Mason KP, Zgleszewski SE, Dearden JL, et al. Dexmedetomidine for pediatric sedation for computed tomography imaging studies. Anesth Analg 2006;103:57-62.
12. Mason KP, Zgleszewski SE, Prescilla R, et al. Hemodynamic effects of dexmedetomidine sedation for CT imaging studies. Paediatr Anaesth 2008;18:393-402. 13. Sanderson PM. A survey of pentobarbital sedation for children undergoing abdominal CT scans after oral contrast medium. Paediatr Anaesth 1997;7:309-15. 14. Ziegler MA, Fricke BL, Donnelly LF. Is administration of enteric contrast material safe before abdominal CT in children who require sedation? Experience with chloral hydrate and pentobarbital. Am J Roentgenol 2003;180:13-5. 15. de Bie HM, Boersma M, Wattjes MP, et al. Preparing children with a mock scanner training protocol results in high quality structural and functional MRI scans. Eur J Pediatr 2010;169: 1079-85. 16. Lemaire C, Moran GR, Swan H. Impact of audio/visual systems on pediatric sedation in magnetic resonance imaging. J Magn Reson Imaging 2009;30:649-55. 17. Bloomfield EL, Masaryk TJ, Caplin A, et al. Intravenous sedation for MR imaging of the brain and spine in children: pentobarbital versus propofol. Radiology 1993;186:93-7. 18. Greenberg SB, Adams RC, Aspinall CL. Initial experience with intravenous pentobarbital sedation for children undergoing MRI at a tertiary care pediatric hospital: the learning curve. Pediatr Radiol 2000;30:689-91. 19. Mallory MD, Baxter AL, Kost SI, and the Pediatric Sedation Research Consortium. Propofol vs pentobarbital for sedation of children undergoing magnetic resonance imaging: results from the Pediatric Sedation Research Consortium. Paediatr Anaesth 2009;19:601-11. 20. Pershad J, Wan J, Anghelescu DL. Comparison of propofol with pentobarbital/midazolam/fentanyl sedation for magnetic resonance imaging of the brain in children. Pediatrics 2007; 120:e629-36. 21. Chen YL, Chen CC. Intermittent small doses of propofol for sedation of pediatric patients undergoing magnetic resonance imaging. Acta Paediatr Taiwan 2007;48:305-8. 22. Cho JE, Kim WO, Chang DJ, et al. Titrated propofol induction vs. continuous infusion in children undergoing magnetic resonance imaging. Acta Anaesthesiol Scand 2010; 54:453-7. 23. Mason KP, Zurakowski D, Zgleszewski SE, et al. High dose dexmedetomidine as the sole sedative for pediatric MRI. Paediatr Anaesth 2008;18:403-11. 24. Hennes HM, Wagner V, Bonadio WA, et al. The effect of oral midazolam on anxiety of preschool children during laceration repair. Ann Emerg Med 1991;20:713-6. 25. Shane SA, Fuchs SM, Khine H. Efficacy of rectal midazolam for the sedation of preschool children undergoing laceration repair. Ann Emerg Med 1994;24:1170-2. 26. Theroux MC, West DW, Corddry DH, et al. Efficacy of intranasal midazolam in facilitating suturing of lacerations in preschool children in the emergency department. Pediatrics 1993;91:624-7. 27. Luhmann JD, Kennedy RM, Porter FL, et al. A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair. Ann Emerg Med 2001;37:20-7. 28. Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data metaanalysis of 8,282 children. Ann Emerg Med 2009;54:158-70. 29. Green SM, Roback MG, Krauss B, et al. Predictors of emesis and recovery agitation with emergency department ketamine sedation: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med 2009;54:171-80.
30. Green SM, Kupperman N, Rothrock SG, et al. Predictors of adverse events with intramuscular ketamine sedation in children. Ann Emerg Med 2000;35:35-42. 31. Wathen JE, Roback MG, Mackenzie T, et al. Does midazolam alter the clinical effects of intravenous ketamine sedation in children? A double-blind, randomized, controlled, emergency department trial. Ann Emerg Med 2000;36:579-88. 32. Sherwin TS, Green SM, Khan A, et al. Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized, double-blind, placebo-controlled trial. Ann Emerg Med 2000; 35:229-38. 33. Kennedy RM, Porter FL, Miller JP, et al. Comparison of fentanyl/midazolam with ketamine/midazolam for pediatric orthopedic procedures. Pediatrics 1998;102:956-63. 34. Godambe SA, Elliot V, Matheny D, et al. Comparison of propofol/fentanyl versus ketamine/midazolam for brief orthopedic procedural sedation in a pediatric emergency department. Pediatrics 2003;112:116-23. 35. Andolfatto G, William M. A prospective case series of pediatric procedural sedation and analgesia in the emergency department using single-syringe ketamine-propofol combination (ketofol). Acad Emerg Med 2010;17:194-201.
36. Luhmann JD, Shootman M, Luhmann SJ, et al. A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children. Pediatrics 2006;118:e1078-86. 37. Ben Yehuda Y, Watemborg N. Ketamine increases opening cerebrospinal pressure in children undergoing lumbar puncture. J Child Neurol 2006;21:441-3. 38. Cravero JP, Beach ML, Blike GT, et al. The incidence and nature of adverse events during pediatric sedation/anesthesia with propofol for procedures outside the operating room: a report from the Pediatric Sedation Research Consortium. Anesth Analg 2009;108:795-804. 39. Cravero JP, Blike GT, Beach M, et al. Incidence and nature of adverse events during pediatric sedation/anesthesia for procedures outside the operating room: report from the Pediatric Sedation Research Consortium. Pediatrics 2006; 118:1087-96. 40. Sacchetti A, Baren J, Carraccio C. Total procedural requirements as indication for emergency department sedation. Pediatr Emerg Care 2010;26:209-11. 41. Lightdale J, Valim C, Mahoney LB, et al. Agitation during procedural sedation and analgesia in children. Clin Pediatr 2010;49:35-42.
Abstract:
The practice of pediatric sedation continues to evolve, largely based on data that are produced by researchers in this field. This article reviews notable recent trends in research as reported in peer-reviewed journals, including large prospective database studies that have improved our understanding of the incidence and nature of adverse events in pediatric sedation. Along with this effort has come an attempt to better develop a new lexicon to describe adverse events or complications. In addition to these descriptive demographic articles, investigators continue to add to the cumulative experience with new drugs such as dexmedetomidine and older sedatives/analgesics such as ketamine and nitrous oxide in children. Finally, evaluation of the workload and trends in sedation utilization in children have been reported and will be reviewed; and future needs for pediatric sedation research are suggested.
Progress in Pediatric Sedation Research

Joseph P. Cravero, MD
Keywords:
procedural sedation; analgesia; pediatrics; adverse events; dexmedetomidine; ketamine; nitrous oxide; sedation services
ediatric sedation research has undergone significant evolution in the last several years. This article will focus not simply on the best articles, but on the trends in sedation research that will shape what we read and how policy concerning sedation may be formulated in the future. We will review some articles that are changing the process of pediatric research, and follow with examples of articles that are more traditional in nature but provide insight into new drugs or techniques for sedation.
CHANGING THE LANDSCAPE

Traditionally, the pediatric sedation literature has been dominated by studies that evaluate a specific sedation technique for a given procedure. In addition, most of these studies are carried out at one institution. Outcome measures generally include such things as desaturation events, requirements for airway intervention or resuscitation, and (rarely) some measure of how effective the sedation was for the given procedure. Numbers of patients involved generally range between 40 to several hundred. These studies are rarely controlled or blinded, but rather are most often retrospective reviews of practice or are prospective and observational in nature. Several problems exist in attempting to use these studies to refine the art of pediatric sedation. First, few of these studies have the power to detect rare but significant events that may occur only once or twice in thousands of patients. Attempting to describe the safety of a technique is simply not possible when only tens or hundreds of patients are included. Second, there is a lack of uniformity in terms of what is reported as an adverse outcome in these studies. For instance, what degree of hypoxia, and for
Department of Anesthesiology, Dartmouth Hitchcock Medical Center, Lebanon, NH. Reprint requests and correspondence: Joseph P. Cravero, MD, Department of Anesthesiology, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756. Joseph.cravero@hitchcock.org
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what duration, do we term a hypoxic incident? Finally, most studies are undertaken in one institution. Although this may serve to eliminate some of the variability in technique that can occur in multicenter studies, single-institution studies suffer from questionable generalizabilityin that the unique aspects of a study site may be difficult to recreate.
DEFINITIONS OF ADVERSE EVENTS

In an effort to address issues related to a lack of standardization among the various studies that evaluate pediatric sedation practice, Baat et al1 developed consensus-based terminology to describe adverse events during emergency department sedation. This effort included a large number of experts representing the Consensus Panel on Sedation Research of Pediatric Emergency Research Canada and the Pediatric Emergency Care Applied Research Network (United States). Experts involved were drawn from both emergency medicine and anesthesiology. Using literature review and expert opinion, the group reviewed much of the terminology that is commonly used when reporting pediatric sedation outcomes. They begin with describing such terms as Procedural Sedation and Analgesia and continue through operational definitions for oxygen desaturation, apnea, laryngospasm, etc. This article should be read in its entirety because it is complex and in many ways ground breaking. Although the specific definitions chosen may or may not be widely applied, or stand the test of time, the method of description will surely be maintained. In particular, these researchers chose to include actions taken during a given event to help define an event. For instance, rather than define a specific pulse oximeter reading as oxygen desaturation, the authors chose to include any degree of desaturation that was associated with a specific action designed to reverse that desaturation. In this way, the authors suggest that researchers would be less likely to miss a dangerous event that required intervention, but never led to a very low oxygen saturation reading. Likewise, if studies used this definition, minor oxygen desaturation events that resolve in a short period without intervention would not be included as an adverse event and, indeed, probably do not belong in that category. In short, by combining the observation of the patient state (such as hypoxia or apnea) with actions taken by the sedation provider, the authors seek to include some dangerous events that would not be noted by some authors. Similarly, they attempt to exclude minor adverse events that require no intervention and therefore are of dubious importance.
This new framework has limitations. Retrospective studies are essentially eliminated from consideration using these definitions because they lack sufficient detail on actions taken etc. In addition, the difference between routine maneuvers that are done as a standard operating procedure vs those done for a specific patient condition needs to be defined. Further work is required to refine the methodology used and obtain buy in from a wider representation of the pediatric sedation community. Despite these issues, the effort to standardize terminology and incorporate action along with simple state descriptions in defining adverse events deserves close attention from all who study and report work in this area.
LARGE DATABASE RESEARCH

The Internet has provided a tool for collecting data simultaneously from any geographical distribution imaginable. Data-sharing collaboratives have the power to collect huge numbers of cases that can begin to describe the incidence of relatively rare events. The future of this type of data gathering is likely to be bright, as electronic records will allow simultaneous clinical and research data collection as well as the opportunity to seamlessly link a huge number of care systems. Readers need to carefully follow and understand the advantages and limitations of this type of data to put the reported results in proper perspective. In 2004, a group of pediatric sedation researchers formed the Pediatric Sedation Research Consortium (PSRC). This group was specifically created to share data and create a database that would reach the kind of critical numbers that would allow the more accurate description of the incidence of relatively rare events. The methodology used involves prospective data collection on a Web-based tool that allows central storage of deidentified data that is compliant with Health Insurance Portability and Accountability Act rules. The 37 member institutions use the data as part of their quality improvement process, and the aggregate data are used to evaluate adverse events and effectiveness related to sedation regimens. The first article from this group was published in 2006 and involved an evaluation of the data from the first 30 000 sedation encounters in the database.2 These encounters were collected from more than 30 institutions and included a variety of sedation providers using a number of sedation regimens. Predictably, adverse events were rare, with no deaths and only one cardiac arrest in this data set (Table 1).
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TABLE 1. Complications reported for PSRC sedation study.

Incidence per 10 000 Adverse Events Death Cardiac arrest Aspiration Hypothermia Seizure (unanticipated) during sedation Stridor Laryngospasm Wheeze (new onset during sedation) Allergic reaction (rash) Intravenous related problems/complication Prolonged sedation Prolonged recovery Apnea (unexpected) Secretions (requiring suction) Vomiting during procedure (non-gastrointestinal) Desaturation, b90% Total adverse events Unplanned Treatments Reversal agent required, unanticipated Emergency anesthesia consult for airway Admission to hospital, unanticipated (sedation related) Intubation required, unanticipated Airway (oral), unexpected requirement Bag-mask ventilation, unanticipated Total unplanned treatments Conditions Present During Procedure Inadequate sedation, could not complete 0.0 0.3 0.3 1.3 2.7 4.3 4.3 4.7 5.7 11.0 13.6 22.3 24.3 41.6 47.2 156.5 339.6 (1 per 29) 1.7 2.0 7.0 9.7 27.6 63.9 111.9 (1 per 89) 88.9 (1 per 338) n 0 1 1 4 8 11 13 14 17 33 41 67 73 125 142 470 1020 5 6 21 29 83 192 336 267 95% CI (0.0-0.0) (0.0-1.9) (0.0-1.9) (0.4-3.4) (1.1-5.2) (1.8-6.6) (2.3-7.4) (2.5-7.8) (3.3-9.1) (7.6-15.4) (9.8-18.5) (17.3-28.3) (19.1-30.5) (34.7-49.6) (39.8-55.7) (142.7-171.2) (308.1-371.5) (0.6-3.9) (0.7-4.3) (4.3-10.7) (6.5-13.9) (22.0-34.2) (55.2-73.6) (85.3-130.2) (78.6-100.2)
Rates are expressed as number of events per 10 000 sedations.2 CI indicates confidence interval.
On the other hand, there were 310 major unplanned airway interventions or approximately 1 per 100 sedations. The authors consider these data in 2 lights. On the one hand, it is clear that serious adverse events are rare in this cohort. Sedation provided by the multispecialty teams involved in this study is relatively safe. On the other hand, this group of institutions represents a highly motivated group of sedation services that likely outperforms the average or standard sedation provision system. They also point out that the relatively frequent need to intervene and manage airway issues reinforces the importance of appropriate training and preparation required to keep sedated patients safe. Another study from the PSRC evaluating the adverse events and efficacy of sedation with propofol as delivered by the multispecialty group of providers
participating in the consortium was published in 2009.3 In this case, nearly 50 000 sedation encounters using propofol were evaluated. The results were remarkable for a low rate of serious adverse events (no deaths, 2 arrests, and 6 aspiration events). An extremely high level of efficacy, with more than 99% successful sedation accomplishment, was documented. As with the prior study, the authors gathered information on airway interventions and found that 1 in 65 of the sedation encounters required an airway intervention such as a chin lift, jaw thrust, airway insertion, or positive pressure ventilation. Once again, the authors suggest that their data do not prove that propofol sedation is generally safe. Rather, they propose that, as practiced by the members of this consortium (with good protocols and appropriate oversight), excellent efficacy and a good safety record are possible.
The limitations of this kind of data analysis are clear. There is nonuniformity of technique, providers, patient selection, etc. This makes direct comparison of sedation performance impossible. In addition, the reliability of the reporting in any large group such as this is never as tight as that from one institution with a limited number of investigators. The authors point out, however, that this kind of data collection may help in giving readers a general description of the events that are associated with this practice. They further suggest that the interventions required during these sedation encounters could serve as a basis for evidence-driven training of sedation providers.
DEXMEDETOMIDINE
The last several years have seen an explosion in the number of studies that evaluate the utility of dexmedetomidine for procedural sedation, particularly in the radiology setting.4-6 A number of these studies have come from Dr Keira Mason and coworkers7-10 at Boston Children's Hospital. These investigators have used a large prospective database from their institution to evaluate the safety and efficacy data of dexmedetomidine sedation at their institution. These studies have been helpful in describing the effectiveness and safety issues involved in the utilization of dexmedetomidine, and they represent the largest collected experience with the drug reported so far. Notably, these authors have outlined the strategies required to make dexmedetomidine more effective as a sedative. These strategies require the use of much larger doses in children than in adultsbolus doses of 2 to 3 g/kg and maintenance doses of 1.5 to 2 g/kg/hr.7 Using these increased dosing protocols, this group was able to achieve a 97% success rate for sedation with dexmedetomidine alone. In terms of safety, the higher dose regimens were associated with a significant incidence of bradycardia (16%). These subjects included several occurrences of heart rates less than 60 beats per minute in patients younger than 1 year. Notably, this bradycardia was not accompanied by profound hypoxia or hypotension. The authors conclude that high-dose dexmedetomidine is useful in producing reliable sedation with minimal airway-related adverse events. They go on to suggest that bradycardia should be anticipated (and physician help should be available for any possible hemodynamic deterioration), but the importance of this finding is uncertain. In a more recent study, the same authors used their database to review the incidence and predictors of hypertension when dexmedetomidine was used for magnetic
resonance imaging (MRI) sedation. 11 Of 3522 sedation events with the drug, the incidence of hypertension was 4.9%. Statistically significant predictors of hypertensive response were young age and more than one bolus of the medication provided. Few direct comparison studies between dexmedetomidine and other sedatives have been published to date. In one of the few articles to attempt this, Heard et al12 compared a combination of midazolam (0.1 mg/kg bolus)/dexmedetomidine (1 g/kg bolus plus 0.5 g/kg/hr infusion) to propofol (250-300 g/ kg/min) for MRI scans. The midazolam/dexmedetomidine combination was chosen based on pilot work that indicated this combination resulted in the highest rate of effective sedation with minimal adverse effects. The results of this study found no significant respiratory adverse effects in either group. There were slower heart rates and higher mean blood pressures in the dexmedetomidine cohort. Recovery times were significantly faster for the propofol group compared with the dexmedetomidine/midazolam combination. The authors concluded that the combination regimen provided adequate sedation for MRI scans. To date, almost all published studies on accomplishing procedural sedation with dexmedetomidine have been by the intravenous route. At least one report of a case series administering dexmedetomidine by the transmucosal route has been reported.13 For this series, 2 to 3 g/kg was administered for computed tomography (CT) scans. Thirteen of the patients were successfully sedated (some requiring added doses). The authors reported no adverse events in this small group. The data on dexmedetomidine are still evolving. There is no doubt that this drug provides adequate sedation for diagnostic procedures. The most effective dosing regimen (or drug combination) is still being worked out. Look for more database reports and (hopefully) prospective randomized trials to further delineate the most effective and safe way to use this drug.
KETAMINE META-ANALYSIS
The methodology of meta-analysis is not new. This type of investigation combines the data from many similar articles investigating similar variables. The combined data can afford the authors statistical power that is simply not present in smaller individual studies on a given topic. A relatively recent article, Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individualpatient data meta-analysis of 8,282 children,14 is
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the first to apply this type of analysis to a topic involving pediatric sedation. The authors hypothesized that the larger number of sedation encounters that can be evaluated in a meta-analysis would allow them to evaluate factors related to airway emergencies that can occur when ketamine is used. Because these incidents are rare, previous studies have simply been too small to allow a meaningful analysis of contributing factors. To perform this study, the investigators pooled data from 32 emergency department studies and used multiple logistical regression to determine which clinical variables would predict airway and respiratory adverse events. Their findings confirmed previous data on ketamine and introduced some new, unanticipated factors. The overall incidence of airway/respiratory adverse events was 3.9%, with higher rates in children younger than 2 years old (odds ratio [OR], 2.0) and in those older than 13 years (OR, 2.72). High intravenous doses (initial dose N2.5 mg/kg or total dose N5 mg/kg) (OR, 2.18) were also associated with a higher incidence of adverse events. Coadministration of an anticholinergic agent or a benzodiazepine was also noted to have a slightly higher incidence of adverse events. Other, unexpected findings included the fact that several common variables (often thought to add to the risk of ketamine sedation) appeared to have no bearing on risk for airway/respiratory adverse events; these included oropharyngeal procedures, American Society of Anesthesiologists status of 3 or greater, or the choice of intravenous vs intramuscular route of administration. Two particularly unexpected findings included the observation that patients older than 13 years had added risk with ketamine sedation as did patients who were coadministered an anticholinergic drug. In considering these outcomes, it should be noted that this complex study suffers from all the difficulties that meta-analyses have simply by their nature. Most importantly, there is the heterogeneity of the studies and outcome variables. This refers to the subtle differences between the studies that were included in the analysis. The more differences that exist between the original studies that were used to create the pool of data, the more difficult it is to consider (based on that pooled data) the conclusions valid. Perhaps, most important for this analysis is the definition of what constituted an adverse event. In this case, desaturation events were lumped with laryngospasm or airway obstruction even though many would argue that these events have widely different clinical importance and implications for the patients. The authors note that future efforts in
this area would benefit from a more focused analysis of fewer variables. Despite these limitations, this study offers interesting insights into the use of ketamine and the risk of airway adverse effects. Further use of metaanalysis methodology could help in many areas of pediatric sedation where the existing literature consists of many small, but similar, studies.
NITROUS OXIDE
Nitrous oxide has been a useful anesthetic/ sedative for more than 100 years. Although the drug has been widely used and described in the dental profession,15,16 careful examination of its use in the area of procedural sedation outside of dentistry has not been common. A group of investigators in Minnesota led by Dr Judy Zier has recently produced a number of articles to reverse this state of affairs. In one study, Zier et al17 took the unusual step of comparing sedation with nitrous oxide (their standard) to no sedation for catheterization for urologic procedures (the standard practice at many institutions across the country). The study evaluated the state of the patient during the procedure and, not surprisingly, found that pain and stress scores were higher in the nonsedated patient group (P = .001). The authors also evaluated the time spent in the sedation unit and the radiology department. They found that time in the radiology department was longer for the sedated group (90 vs 30 minutes). Although the sedated group did spend more time in the nonimaging area, time in the imaging area of the radiology department was not different between the groups. This study is particularly valuable because it evaluated sedation impact on a procedure that does not always receive sedation. These data actually beg the question of why so many of these procedures are performed without any sedation. In addition, studies such as this bring forward data on time spent in the hospital and radiology unit that need to be part of the analysis of sedation techniques and are rarely present in sedation studies that are published today. Compelling arguments for sedation techniques need this kind of data as we look forward to a financially challenging era that will put a premium on the economic impact of sedation. Another study by the same group compared the effectiveness of nitrous oxide sedation to that of midazolam for botulinum toxin A injections in children.18 As one would expect, the patient population predominantly included children with cerebral palsy. In this case, the data showed similar effectiveness of sedation between the 2
agents, but with better pain control with nitrous oxide. Nitrous oxide patients were significantly less sedated at the time of discharge (P b .001). Once again, the study is helpful in that it is not simply an observational trial of nitrous oxide, but rather a comparison study that evaluated many important factors involved in the sedation process. The results clearly raise the question as to why providers do not work harder to overcome the technical difficulties of working with nitrous oxide, as its effectiveness for minor painful procedures is truly impressive. Most recently, Zier et al have investigated the depth of sedation and adverse event rate associated with the use of nitrous oxide for procedures. More than 1800 sedation encounters were evaluated retrospectively using a validated modified Ramsey score of sedation depth and a standard adverse event recording methodology. Unlike previous evaluations of nitrous oxide, the investigators compared 2 groups: one that received a high concentration of the drug (N50%) and one that received 50% or less inhaled concentration. Overall, the complication rate was less than 3%; there were no major complications that led to hospitalization or permanent injury, and all complications resolved quickly. There was no difference in complication rate between the low- and high-concentration groups. Surprisingly, there was also no difference in the number of patients who became moderately/ deeply sedated between the 2 groups. Only 0.9% of the procedures could not be completed because of inadequate sedation or problems related to the sedation, although the authors do comment that 5% of the procedures were completed while the patients were requiring restraint. This study has many limitations, including its retrospective nature, a predominance of patients in the high-concentration group, and coadministration of sedative medications in a small (but not negligible) number of the patients in the study. Still, there is some valuable information in this relatively large cohort of patients, including the relatively low complication rate and the attempt to further describe the level of sedation attained when using nitrous oxide at various concentrations.
anesthesia services can be estimated for the future based on various parameters.19-21 Unfortunately, there has been little work done to evaluate the care delivery systems that provide sedation or the nature of the caseload that surrounds this work. In the last year, Wachtel and colleagues 22 evaluated the growth rate in requirements for anesthesiabased pediatric sedation services for MRI and CT scans at the University of Iowa to determine if the growth rate paralleled or exceeded the growth in the number of studies performed. Although this study measured the use of anesthesia services, the results are clearly applicable to any expert sedation service regardless of subspecialty affiliation. The authors tracked the growth in requirements for sedation services and compared this to the overall rate of growth of CT and MRI scans for children. Confounding this analysis was the fact that the institution started a registered nurserun sedation service during the time of this analysis. Results showed that there was an increase in the number of children serviced by the anesthesiabased sedation service that was equal to the rate of growth of radiological studies. On the other hand, when the nurse sedation service was considered, there was an overall increase in the number and percentage of patients receiving sedation for these studies. This particular investigation is important for many reasons. It represents a form of analysis that is taking hold in other areas of medicine but is sorely needed in the complex world of pediatric sedation. Specifically, there needs to be an understanding of how changing demographics and practice patterns will change the need for sedation services. Without such data, we will have no way to plan our staffing and personnel requirements for the future. Because pediatric sedation services involve such a variety of specialty providers, this kind of analysis is incredibly hard to accomplish but will be critical going forward.
SUMMARY
We are witnessing a continuing evolution of pediatric sedation research. The first efforts at producing a standard lexicon for discussing sedation adverse events have started to appear. In addition, a number of articles have appeared that use large database analysis to gain power to describe relatively uncommon yet clinically significant events that occur during sedation. These studies can come from collaborative groups, single institutions, or meta-analysis methodologies. Regardless of methodology, they have provided information about
WORKLOAD AND SEDATION SERVICES

Over the last 20 years, a large number of articles have been produced that look specifically at the use of specific drugs to produce sedation for various procedures performed in hospitals or offices. There have also been a number of articles that analyze the manner in which caseload for
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sedation practice that has taken us to new levels of accuracy in making conclusions about effectiveness and safety of sedation techniques. Finally, data are also being reported on relatively new drugs such as dexmedetomidine and older agents like nitrous oxide. Further reports on these and other new drugs will help determine their ultimate role in the provision of sedation for children. Future research in pediatric sedation is needed in many areas. To begin, more detailed information is needed on how to define and measure quality in pediatric sedation. Specifically, what patient states are acceptable during painful procedures? Is movement during a procedure acceptable? Is some degree of distress acceptable as long as memory is impaired? What duration of recovery is appropriate? What rate of failure to achieve sedation is acceptable? Only with this type of analysis will sedation researchers be able to make meaningful comparisons between different sedation drugs or techniques. In addition, studies that evaluate the relationship between the adverse events that are routinely reported in sedation studies and important patient safety outcomes are sorely needed. For instance, sedation providers need to understand whether or not minor oxygen desaturation episodes are indicative of truly unsafe practice. Along with these data, there is a need to further develop broad agreement on common definitions for adverse events so that the literature concerning pediatric sedation will be more uniform and applicable across disciplines. Further research is also needed to define the critical competencies required for sedation providers who wish to deliver potent sedative and analgesic agents. Large, controlled, multi-institutional/multispecialty studies that help delineate reliable training for providers and appropriate scope of practice for sedation providers of all types are needed. Only this type of research will allow this field of practice to be free of strictly consensus guidelines that vary from one specialty to another and add confusion and uncertainty to this practice. Ultimately, we look to continuing research developments in all of these areas along with new research into the demographics of sedation care and the expected changes in caseload to help plan and improve the access, safety, and effectiveness of sedation care for children.
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REFERENCES
1. Bhatt M, Kennedy RM, Osmond MH, et al. Consensus-based recommendations for standardizing terminology and reporting adverse events for emergency department procedural
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sedation and analgesia in children. Ann Emerg Med 2009;53: 426-35 [e4]. Cravero JP, Blike GT, Beach M, et al. Incidence and nature of adverse events during pediatric sedation/anesthesia for procedures outside the operating room: report from the Pediatric Sedation Research Consortium. Pediatrics 2006; 118:1087-96. Cravero JP, Beach ML, Blike GT, et al. The incidence and nature of adverse events during pediatric sedation/anesthesia with propofol for procedures outside the operating room: a report from the Pediatric Sedation Research Consortium. Anesth Analg 2009;108:795-804. Ray T, Tobias JD. Dexmedetomidine for sedation during electroencephalographic analysis in children with autism, pervasive developmental disorders, and seizure disorders. J Clin Anesth 2008;20:364-8. Munro HM, Tirotta CF, Felix DE, et al. Initial experience with dexmedetomidine for diagnostic and interventional cardiac catheterization in children. Paediatr Anaesth 2007;17: 109-12. Hammer GB, Philip BM, Schroeder AR, et al. Prolonged infusion of dexmedetomidine for sedation following tracheal resection. Paediatr Anaesth 2005;15:616-20. Mason KP, Zurakowski D, Zgleszewski SE, et al. High dose dexmedetomidine as the sole sedative for pediatric MRI. Paediatr Anaesth 2008;18:403-11. Mason KP, Zgleszewski SE, Prescilla R, et al. Hemodynamic effects of dexmedetomidine sedation for CT imaging studies. Paediatr Anaesth 2008;18:393-402. Mason KP, Zgleszewski SE, Dearden JL, et al. Dexmedetomidine for pediatric sedation for computed tomography imaging studies. Anesth Analg 2006;103:57-62. Mason KP, O'Mahony E, Zurakowski D, et al. Effects of dexmedetomidine sedation on the EEG in children. Paediatr Anaesth 2009;19:1175-83. Mason KP, Zurakowski D, Zgleszewski S, et al. Incidence and predictors of hypertension during high-dose dexmedetomidine sedation for pediatric MRI. Pediatr Anesth 2010;20: 516-23. Heard C, Burrows F, Johnson K, et al. A comparison of dexmedetomidine-midazolam with propofol for maintenance of anesthesia in children undergoing magnetic resonance imaging. Anesth Analg 2008;107:1832-9. Lami RO, Pereira AC. Transmucosal dexmedetomidine for computed tomography sedation. Paediatr Anaesth 2008;18: 349-78. Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med 2009;54: 158-68. Houpt MI, Limb R, Livingston RL. Clinical effects of nitrous oxide conscious sedation in children. Pediatr Dent 2004;26: 29-36. Wilson S. A survey of the American Academy of Pediatric Dentistry membership: nitrous oxide and sedation. Pediatr Dent 1996;18:287-93. Zier JL, Kvam KA, Kurachek SC, et al. Sedation with nitrous oxide compared with no sedation during catheterization for urologic imaging in children. Pediatr Radiol 2007;37: 678-84. Zier JL, Rivard PF, Krach LE, et al. Effectiveness of sedation using nitrous oxide compared with enteral midazolam for botulinum toxin A injections in children. Dev Med Child Neurol 2008;50:854-8.
19. Masursky D, Dexter F, O'Leary CE, et al. Long-term forecasting of anesthesia workload in operating rooms from changes in a hospital's local population can be inaccurate. Anesth Analg 2008;106:1223-31. 20. O'Neill L, Dexter F. Tactical increases in operating room block time based on financial data and market growth estimates from data envelopment analysis. Anesth Analg 2007;104:355-68.
21. Wachtel RE, Dexter EU, Dexter F. Application of a similarity index to state discharge abstract data to identify opportunities for growth of surgical and anesthesia practices. Anesth Analg 2007;104:1157-70. 22. Wachtel RE, Dexter F, Dow AJ. Growth rates in pediatric diagnostic imaging and sedation. Anesth Analg 2009;108: 1616-21.
Abstract:
There are many misconceptions with billing for sedation services. It is not the setting or the type of provider or medication used, but the depth of sedation provided, that determines the type of sedation service that should be reported. Any qualified physician or nonphysician provider may report anesthesia services for deep sedation. Advanced negotiation with the hospital and third-party payers is the key to successful reimbursement for a sedation service.
The Sedation Service Reimbursement Dilemma

Jeffrey F. Linzer Sr., MD
Keywords:
coding; reimbursement; sedation services; professional services; third-party payer; anesthesia value units
Reprint requests and correspondence: Jeffrey F. Linzer Sr., MD, Children's Sedation Service, Children's Healthcare of Atlanta, 1405 Clifton Road, NE, Atlanta, Georgia 30322. jlinzer@emory.edu
ou have put together a team of physician and nurses to provide sedation services at your hospital. What do you need to do to ensure that third-party payers will reimburse for these services? What are your alternatives in billing for these services? And what are your options when the payers will not pay? Physicians and nonphysician providers (advanced practice nurses, certified registered nurse anesthetists, physician assistants, and physician anesthesia assistants) bill for their professional services using Current Procedural Terminology (CPT).1 CPT provides common definitions for physician work and may be used by nonphysician providers within their state-licensed scope of practice. It is important to note that these codes are service neutral and that any CPT code may be used by any physician or other appropriate health care provider. Hospitals bill facility charges for the physical use of the facility, staff (including nurses and respiratory care professional services), and supplies. The hospital may separately bill a room charge, nursing time, and supplies or may have a single fee for sedation (bundled charges). When receiving payment for inpatient services under diagnosis-related group billing, the hospital may not be able to receive any additional reimbursement for sedation services.
BILLING FOR PROFESSIONAL SERVICES

The type of professional service for sedation one should report depends on the level of sedation provided to the patient. It is not determined by the provider or location of the service, nor the specific medication used. There are 4 levels of sedation: minimal (anxiolysis), moderate, deep, and general anesthesia
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Figure 1. Sedation billing based on depth of sedation.
(Figure 1). Although there are many published definitions for these levels of sedation, the CPT guidelines should be used for billing purposes. For example, the provision of minimal sedation or anxiolysis is included in an evaluation and management service, for example, a clinic or inpatient service. According to CPT, moderate sedation is a druginduced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation.2 In moderate sedation, the patients are able to maintain their own airway. Services that are included with moderate sedation billing include a patient assessment, obtaining vascular access, administration of medication and maintenance of sedation, and patient monitoring and recovery. Billing for moderate sedation is based on face-toface time (first 30 minutes, then each additional 15 minutes) and age of the patient (is the patient younger than 5 years or not?). The period begins with the administration of the medication and ends when there is no longer any direct physician-patient contact. If the physician is both performing the procedure and providing the sedation, there must be an independent trained observer present to help monitor the patient. Minimal and deep levels of sedation are specifically excluded from the moderate sedation code set. There are 2 sets of moderate sedation codes, one for when the provider is also performing the procedure that the sedation supports (CPT codes 99148 & 99149), and one where the sedation is being provided in support for another physician performing the procedure (CPT codes 99143 & 99144). Procedures where sedation is considered inherent (a routine accompaniment of the procedure and, therefore, included in the physician work for that procedure) are listed in CPT Appendix G. These restrictions do not apply if a second phy-
sician is providing the sedation in a facility setting. Nonincluded (bundled) services may be separately billed. Because the moderate sedation codes are part of the medical procedures chapter, they are supposed to have relative value units. However, the Centers for Medicare and Medicaid Services (CMS) elected not to publish these values in the Federal Register, but instead have left them subject to Medicare carrier-based pricing since 2005.3
ANESTHESIA SERVICES
The anesthesia codes are used to report not only general anesthesia, but also regional anesthesia, monitored anesthesia care, and deep sedation. A common misconception is that the anesthesia codes cannot be used unless the patient is intubated or the providing physician is an anesthesiologist. In fact, the conditions of hospital Medicare and Medicaid participation state that anesthesia care may be provided by any nonanesthesiologist physician.4 Anesthesia services include a pre- and postprocedure evaluation, administration of medication during the procedure, administration of fluids, and necessary patient monitoring (eg, vital signs, pulse oximetry, and endtidal CO2). Nonbundled services such as emergent endotracheal intubation and critical care may be billed separately if provided to the patient. The choice of anesthesia code is based on the type of procedure being performed. Modifiers may be attached to reflect the patient's American Society of Anesthesiologists level, and there are additional codes to account for extremes of age (younger than 1 or older than 70 years) and emergency conditions where delay of the procedure could lead to a significant increase in threat to life or limb. Anesthesia code reimbursement is based on anesthesia value units (AVUs). As opposed to relative value units, AVUs do not differ as to place
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Figure 2. Anesthesia vale unit conversion.
of the service. Each code is assigned a set number of base units. Reimbursement is determined by the number of base units, plus the total anesthesia time (in fraction of 15-minute increments), multiplied by a conversion factor (Figure 2). Anesthesia time is a continuous period from when the patient is prepared for anesthesia or deep sedation until the time the patient can be safely placed in postprocedure recovery care. Current procedure AVUs and Medicare conversion factors are published annually by CMS and are posted in on the CMS Anesthesiologist's Center webpage.5
payer. Negotiations with payers in advance can help avoid these problems. It is generally useful to help the payer understand the cost-effective benefit of the service being provided. In those cases where the payer may be under the incorrect assumption that only an anesthesiologist may use the anesthesia codes, one should then review with them the CPT principals of service neutrality and the Medicare/ Medicaid conditions of hospital participation for anesthesia services. Most state and national professional organizations offer services to assist with these issues.
GETTING PAID FOR WHAT YOU DO

The old adage that just because there's a code does not mean that you will get paid clearly applies to sedation. There are 3 important steps that should be taken before starting a sedation service: (1) determine the support services that will be provided by the hospital; (2) negotiate with third-party payers for reimbursement; and (3) ensure that there is hospital credentialing policy for the provision of moderate and deep sedation. A sedation service can be reimbursed in 1 of 2 ways. It may receive a portion of a bundled hospital charge that is used to cover both the sedation and facility services (with or without a charge for the procedure for which the patient was sedated), or be a distinct charge for professional services. When billing for professional services, it is important that the appropriate CPT code be used. In the same way that one would not bill for a laceration repair when performing open-heart surgery, one should not bill for moderate sedation when providing deep sedation. It is important to appeal any denial for services that were appropriately reported to a third-party
SUMMARY
In today's economic environment, one cannot provide a service that is not financially viable. Advance preparation with the hospital and thirdparty payers is the key in establishing billing practices for sedation services. Correct coding for a provided service is important whether for sedation, procedures, or evaluation and management services. Do not underreport your services to avoid payment denials. Helping third-party payers understand the cost benefits of your services and the appropriateness of your reported codes can help to ensure appropriate reimbursement.
REFERENCES
1. Copyright 2009 American Medical Association. 2. American Medical Association. Current procedural terminology, 2010 professional edition. Chicago (IL): American Medical Association; 2010. p. 498. 3. Centers for Medicare and Medicaid Services. Federal register. 2005:70(223):70282. 4. Code of federal regulations 42 CFR 482.52 (a) (2). 5. Centers for Medicare and Medicaid Services. Anesthesiologists center. http://www.cms.gov/center/anesth.asp. Accessed 9/12/10.
Abstract:
The presenting manifestations of systemic lupus erythematosus (SLE) are diverse and can present insidiously over years with nonspecific complaints or acutely with lifethreatening symptoms. We report a case of a previously healthy 18-yearold female who presented to the pediatric emergency department with altered mental status, multi-system organ failure, and fulminant sepsis from pneumococcal meningitis. Further work-up of this patient confirmed a new diagnosis of SLE. This case highlights the potential degree of immune dysfunction in patients with SLE by opportunistic agents and common pathogens. A high index of suspicion for SLE in childhood is important as delays in diagnosis can lead to life-threatening complications and long-term sequelae.
Adolescent with Abdominal Pain and Altered Mental Status: Are You Confused?
Lorraine Ng, MD
Keywords:
altered mental status; sepsis; meningitis; pneumococcal infection; renal failure; multi system organ failure; systemic lupus erythematosus
Children's Hospital at Montefiore, Pediatric Emergency Department, Bronx, NY. This case report was originally presented at the American Academy of Pediatrics National Conference and Exhibition, Section on Emergency Medicine Emergi-Quiz Competition, Washington, DC, October 2009. Reprint requests and correspondence: Lorraine Ng, MD, Children's Hospital at Montefiore, Pediatric Emergency Department, 3315 Rochambeau Ave, 2nd Floor, Bronx, NY 10467. lng@montefiore.org
previously healthy 18-year-old female was brought to the emergency department (ED) by EMS with a chief complaint of abdominal pain for 2 days. She was in her usual state of health until two days prior when she had onset of abdominal pain with one episode of non-bloody, nonbilious vomiting that coincided with the onset of menstruation. These symptoms were similar to her prior symptoms of dysmenorrhea. However, over the next 2 days, her abdominal symptoms worsened and she also reported a one day history of progressive periorbital swelling, tactile fever, and 3 episodes of non-bloody, loose stools. On the day of presentation, she became confused with slurred speech and was unable to ambulate. En route to the ED, she had an episode of stool and urine incontinence. On review of systems, there was no recent history of upper respiratory infection, headaches, neck pain or stiffness, joint pain, trauma, or sick contacts. There was no history of recent travel, new foods or medications. She had no known drug allergies. There was no history of sexual activity or tampon use. Her past medical history was notable only for dysmenorrhea. The patient lived with her mother, 4 siblings and grandmother. The family medical history was significant for a maternal history of asthma and a father who died in his 30's from end-stage renal disease.
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On physical examination, the patient was alert, oriented to time, place and person but had intermittent episodes of confusion. Her initial vital signs included: temperature 102.9 F orally, heart rate 34 beats/min, respiratory rate 24/min, blood pressure 119/80 mm Hg, and her oxygen saturation was 100% on room air. Her weight was 64.5 kg. Her HEENT exam was significant for non-tender, bilateral mild periorbital swelling without any signs of trauma or erythema. Her pupils were symmetric, round and equally reactive to light. Extraocular movements were intact. Her neck was supple, without pain or stiffness with range of motion. Her breath sounds were symmetric and clear bilaterally. Cardiac exam revealed tachycardia with normal S1 and S2 without murmur. Her abdomen was soft, non-distended but tender to palpation of the lower quadrants bilaterally, with no rebound tenderness or guarding. She had no abdominal masses and her liver edge was palpable just below the right costal margin. Her lower legs had 1+ pitting edema bilaterally. Her skin was dry, warm and well perfused with scattered hyperpigmented macules on her arms and legs bilaterally. There was no bruising, petechiae or purpura. Her confusion made it difficult to assess her ability to follow commands, however, she was able to move all her extremities and had 2+ deep tendon reflexes. Initial laboratory results showed a white blood cell count of 10,600/mm3 (normal 4,500 12,000 mm3) with a differential of 85% neutrophils, 9% lymphocytes, 4% monocytes and 0% eosinophils. The hemoglobin was low at 5.2 g/dL (12.3-15.3 g/dL), the platelet count was 154,000/mm 3 (150,000400,000/mm 3 ) and the reticulocyte count was 2.6% (0.8-2.2%). Serum electrolytes were significant for a bicarbonate of 17 mEq/L (22-26 mEq/L), blood urea nitrogen of 42 mg/dL (6-20 mg/dL) and creatinine of 1.8 mg/dL (0.5-1mg/dL), with normal values for serum sodium, potassium, chloride, glucose, calcium, magnesium and phosphorus. Liver function tests revealed an albumin of 1.5 g/ dL (3.1-5.4 g/dL), a total protein 6.3 g/dL (6-8 g/dL), and with remaining values all normal. The erythrocyte sedimentation rate was 140 mm/h (b 21 mm/h). Her urinalysis results included a specific gravity of N1.030, 300 mg/dL protein, and large blood on dipstick. Blood, stool, and urine cultures were sent. Serum toxicology and urine drug screens were negative. Chest radiograph demonstrated diffuse interstitial infiltrates, bibasilar consolidations, with a left pleural effusion. Computed tomography of the head was negative for mass lesions, intracranial bleed, or enhancing lesions, but showed pansinusitis. Cerebrospinal fluid analysis showed 3 WBC/
mm3 (0-7/mm3), 8 RBC/mm3, glucose of 62 mg/dL (40-80 mg/dL) and protein of 13 mg/dL (5-40 mg/ dL). Gram stain of the cerebrospinal fluid showed gram positive cocci from the first tube but was negative on the fourth tube. While in the ED, she continued to have multiple episodes of loose stool and became increasingly confused and agitated. She was also oliguric despite attempts at fluid resuscitation with normal saline, 5% albumin and a packed red blood cell transfusion. She was given one dose of ceftriaxone intravenously. Pediatric nephrology, hematology/oncology and infectious disease services were consulted. The patient was admitted to the intensive care unit for further management. On hospital day 2, a diagnosis was made. In summary, this is a complicated picture of a previously healthy 18-year-old female who presents to the ED with altered mental status associated with fever, peripheral edema, and a hyperpigmented macular rash. Her initial evaluation showed severe anemia, hypoalbuminemia, elevated inflammatory markers, pleural effusion and renal failure. This constellation of findings suggests a multi-organ system disease process.
DIFFERENTIAL DIAGNOSIS
The patient who presents to the ED with altered mental status is always a cause for alarm, and requires careful scrutiny. The differential diagnosis of altered mental status is extensive and lends itself to a wide range of effective, life-saving management options if there is prompt recognition of the etiology. A complete list of conditions that present as altered mental status would not be practical. Therefore, only the most common etiologies relevant to our case discussion will be presented here for review. One approach to altered mental status is to divide the etiologies into 2 groups: structural and medical (Table 1). In general, structural causes often have focal neurologic findings with pupillary abnormality (asymmetric and/or non-reactive), while medical causes usually result in non-focal, generalized neurologic dysfunction, often with normal pupillary findings, except for toxicologic etiologies. A focused history and physical examination to rapidly assess the level of consciousness, pupillary response, extraocular movements, and motor response to pain is an essential component of the initial evaluation and may direct appropriate treatment.1 Structural causes of altered mental status include traumatic injuries, tumors, and vascular lesions. Traumatic injuries can lead to shearing injuries, which can cause brain contusions and rupture of blood vessels leading to intracranial bleeding. These
TABLE 1. Differential diagnosis of altered mental status. 1,2

Structural Trauma Intracranial bleed Cerebral edema Tumor Medical Toxin Oncologic Acute lymphoblastic leukemia (ALL) Acute myelocytic leukemia (AML)
Vascular lesions Hematologic Cerebral infarct Hemolytic uremic syndrome (HUS) Central venous thrombosis Thrombotic thrombocytopenic purpura (TTP) Intracranial hemorrhage Disseminated intravascular coagulation (DIC) Infectious Sepsis Meningitis Encephalitis Rocky mountain spotted fever (RMSF) Toxic shock syndrome (TSS) Immundodeficiency HIV/AIDS Seizures Renal Uremia Autoimmune Systemic lupus erythematosus (SLE) Goodpasture syndrome Wegener's granulomatosis
patients will typically have a history suggestive of trauma and present with a more acute deterioration in their mental status following injury. One exception is epidural hemorrhage which classically present with a lucid interval followed by a delayed alteration of mental status. Intracranial tumors can cause a mass effect on intracranial structures depending on their rate of growth, location and size. Symptoms can present insidiously with vomiting and headache as initial chief complaints then progress to more concerning symptoms such as focal neurologic deficits, altered mental status, and seizures. Vascular lesions can lead to interruptions in cerebral blood flow with resultant cerebral edema. These lesions can be due to ischemic, thrombotic or
hemorrhagic strokes. Ischemic/thrombotic strokes are more commonly seen in patients who are predisposed to thrombotic episodes, such as sickle cell disease, congenital heart disease, hypercoagulable disorders and vasculitides. Arteriovenous malformations (AVMs) are the most common cause of hemorrhagic stroke in children.1 Medical causes of altered mental status can result from an interruption of the delivery of substrates to the brain (hypoxia, hypoglycemia, hypotension, other electrolyte abnormalities) or may be due to changes in the rate of intracellular chemical reactions (hypothermia, hyperthermia).2 Some of the more common medical causes of altered mental status include toxicologic, oncologic, hematologic, infectious, immunodeficiency, seizure, renal, and autoimmune etiologies. Diagnosis and management of toxic ingestions requires a high index of suspicion, as many drugs and toxins are not detectable on serum and urine drug screens. Toxic ingestions frequently present with changes in blood pressure, as well as pupillary and skin findings, depending on the toxin exposure. Oncologic processes, such as acute lymphoblastic leukemia (ALL) and acute myelocytic leukemia (AML), can present with an insidious onset of fevers and generalized organ dysfunction. They are usually associated with signs of bone marrow failure such as neutropenia and thrombocytopenia, as well as organomegaly due to infiltration with leukemic cells. A peripheral smear may aid in this diagnosis as it might show circulating blast cells. Hemolytic uremic syndrome (HUS) causes multiorgan dysfunction as a result of endothelial damage, platelet activation and thrombi formation. Patients can present with neurologic depression due to central nervous system involvement. A blood smear, as well as stool cultures, would be indicated to further evaluate this patient for HUS. Thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation (DIC) can also present with acute mental status changes and evidence of hemolysis; these diagnoses are usually associated with a pronounced thrombocytopenia and/or coagulopathy. Altered mental status can be a presenting symptom of an overwhelming infection, especially when associated with fevers and multiorgan involvement. The clinical spectrum of sepsis can range from early signs of circulatory compromise to circulatory collapse with multi system organ failure. Meningitis and encephalitis can also present with altered mental status, as infection of the meninges and brain parenchyma, respectively, and a resultant inflammatory response can lead to brain edema and
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increased intracranial pressure. Patients will present with signs and symptoms of meningeal inflammation, such as nuchal rigidity, headache, photophobia, vomiting and an altered sensorium. Rocky mountain spotted fever (RMSF) can also present with fever, rash and altered mental status: the typical rash of RMSF starts as blanching erythematous maculopapular lesions beginning on the extremities spreading centripetally, typically with involvement of the palms and soles. Eventually, the rash of RMSF progresses to petechial lesions. RMSF has also been associated with interstitial nephritis, anemia and pulmonary infiltrates. Toxic shock syndrome (TSS) is caused by toxin-producing strains of staphylococci or streptococci and may be seen in women during menstruation. The typical rash of TSS is described as a diffuse macular erythroderma with desquamation and associated mucous membrane hyperemia. In previously healthy patients who present with signs and symptoms of severe sepsis, an underlying immunodeficiency should be considered. A history of frequent infections and/or high-risk activities, such as sexual activity, blood transfusions, or intravenous drug use, would be enough of an indication to test for an acquired immunodeficiency. While seizures can be a presenting symptom of an intracranial mass, bleed or infection, it can also be a primary cause of altered mental status itself. A history of tonic-clonic activity would suggest this as the etiology. However, patients with unwitnessed seizures can present in a post-ictal state or transient paralysis. An electroencephalogram would be indicated to further evaluate this patient if a seizure was suspected. Acute renal failure, or more specifically uremia, can present with altered mental status as the kidney fails to clear metabolites and toxins from the bloodstream. Metabolic abnormalities, such as anemia, acidemia, hyperkalemia, and hypertension, can occur. Uremia may be heralded by the clinical onset of nonspecific symptoms such as nausea, vomiting, fatigue, weight loss, and mental status changes. Autoimmune disorders are difficult to diagnose, as they are characterized by autoantibodies that cause damage to various organ systems depending on the disease process. Considering the organ systems affected in our patient, the most likely causes of autoimmune etiologies are Goodpasture syndrome, Wegener's granulomatosis and systemic lupus erythematosus (SLE). The classic presentation of Goodpasture syndrome includes glomerulonephritis and pulmonary alveolar hemorrhage, but it is rarely seen in children. Wegener's granuloma-
tosis also presents with renal and pulmonary symptoms, with necrotizing granulomatous inflammation of the upper and lower respiratory tracts, disseminated vasculitis and glomerulonephritis being the hallmarks of disease. SLE has protean manifestations, as the immune complexes can essentially cause damage to any organ system in the body; the mucocutaneous, musculoskeletal, renal, hematologic and pulmonary systems are most commonly affected. To diagnose SLE, a patient must meet 4 of the 11 diagnostic criteria as outlined by the American College of Rheumatology, and all patients must have a positive antinuclear antibody (ANA) to make the diagnosis. In our patient who presented with non-focal, generalized neurologic dysfunction in the setting of fever and multi-organ involvement, it seems unlikely that structural causes, such as trauma, intracranial masses or vascular lesions, would fully explain her clinical presentation in the setting of a normal head CT without further history to suggest otherwise. However, normal blood pressure, pupillary and skin findings together with laboratory findings of anemia, renal insufficiency, elevated sedimentation rate, and normal electrolytes make it unlikely that a toxic ingestion, seizures or metabolic disturbance could explain all of our patient's symptoms. Similarly, an isolated anemia without other signs of bone marrow suppression, thrombocytopenia or coagulopathy would not support an oncologic process, ITP or DIC as her primary diagnosis. Our patient's severe anemia in conjunction with her profuse diarrhea and acute renal failure does support the diagnosis of HUS as a potential etiology for her symptoms, although thrombocytopenia and higher reticulocyte count would have been more consistent with HUS. Uremia could also be explained by her acute renal failure, but the normal electrolytes and lack of acidemia suggest otherwise. Given the clinical presentation of fever and multi-organ failure, sepsis is still high on the differential diagnosis, as hypoperfusion of endorgans can lead to altered mental status and renal failure. It would be prudent to treat empirically with broad spectrum antibiotics while waiting for culture results, as sepsis, meningitis, or encephalitis cannot be entirely ruled out. If left untreated, these infections can progress rapidly. In addition, an evaluation for HIV is indicated, as overwhelming sepsis from an opportunistic infection in an immunocompromised host could account for her acute decompensation. While our patient does have a left pleural effusion, her lack of respiratory symptoms and hemoptysis make Goodpasture's diagnosis less likely.
Furthermore, our patient's normal blood pressure, peripheral edema and hypoalbuminemia are suggestive of nephrosis rather than nephritis. Findings in our patient's chest radiograph of diffuse interstitial infiltrates with bibasilar consolidations could be suggestive of granulomatous involvement as seen in Wegener's. In addition, pansinusitis is seen in up to 80% of Wegener's cases. With the protean manifestations of SLE, our patient's multi-system organ failure suggest that a further work-up is needed to fully rule out an autoimmune process. Based on the discussion above, the differential diagnosis for our patient's altered mental status can be narrowed down to hematologic, infectious, immunodeficiency, and autoimmune etiologies. With these working differential diagnoses, the initial evaluation of this patient should include a chest CT, peripheral blood smear and possible bone marrow biopsy pending blood smear results, markers of hemolytic anemia, coagulation panel, complement levels, HIV serology, anti-GBM titers, C-ANCA, PANCA, and rheumatologic panel.
CASE PROGRESSION
Upon admission to the intensive care unit, the patient's condition worsened with respiratory failure and hypotension as she became progressively septic and required endotracheal intubation, assisted ventilation and pressor support. Blood cultures and CSF cultures grew S. pneumoniae on day 1 of hospitalization and intravenous vancomycin was started. Urine and stool cultures showed no growth. Despite transfusion with 2 units of packed red blood cells, the patient's severe anemia was slow to respond, with a repeat hemoglobin of 5.6 g/dL. It appeared that the patient was having a hemolytic crisis, but the low reticulocyte count and normal indirect bilirubin was inconsistent with this suggested diagnosis. A direct Coombs IgG was negative. The blood smear was consistent with a microangiopathic hemolytic process. As a result, the diagnoses of hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP) as well as disseminated intravascular coagulation (DIC) were considered, although the low-normal levels of platelets, normal prothrombin and prolonged prothrombin times, made the latter two diagnoses less likely. The patient's renal function steadily declined as well, despite aggressive fluid resuscitation and a trial of hemodialysis. A renal ultrasound showed ascites and echogenic kidneys, without evidence of hydronephrosis.
By hospital day 2, the following lab results became available: Anti-nuclear antibody (ANA) 1:640 speckled (b 1:40), Anti-dsDNA 315.3 IU/ml (b 70.1), Anti-Smith N 8 EU/ml (b0.91), C3 55 mg/ dL (70-245), Anti-RNP N 8 EU/ml (b 0.91), and Anti-SSA (Ro) N 8 EU/ml (b 1). C4 and ASO were within normal limits. On the basis of these laboratory results, in conjunction with her hemolytic anemia and renal failure, our patient met 4 of the 11 criteria needed to make a final diagnosis of SLE. (See Table 2) The patient was started on a 3 day course of highdose pulse steroids. Despite this, the patient continued to have a prolonged, complicated hospital course marked by progressive sepsis and renal failure. Her initial hemolytic anemia was attributed to impaired splenic function, which can be seen in patients with SLE, making her susceptible to infections from encapsulated bacteria. This combination of functional asplenia with a hypocomplementemia increased her susceptibility to pneumococcal sepsis and meningitis, which likely originated from her initial sinus infection as found on her head CT. As her sepsis progressed, she also required a period of continuous veno-venous hemodialysis (CVVHD) during the admission. A renal biopsy showed acute tubulonephritis and class V membranous lupus nephritis, and she was subsequently started on immunosuppressive therapy with mycophenolate. After a number of weeks on steroids and mycophenolate, the patient's clinical status slowly improved. Her respiratory failure, renal failure, anemia and sepsis resolved, and the steroid therapy was slowly weaned during the remainder of her hospitalization. Her mental status returned to baseline, and a follow-up MRI/MRA of the brain prior to discharge was normal. After almost 2 months of hospitalization, the patient was discharged to an acute rehabilitation center with close follow-up with rheumatology, nephrology and pulmonology. Her discharge medications were prednisone and mycophenolate mofetil.
CASE DISCUSSION
Systemic lupus erythematosus affects between 5,000 and 10,000 children in the United States, with a female predominance. There is also a greater prevalence among Native American, Asian American, Latin American and African American populations, with African American children representing up to 60% of patients younger than 20 years old.3
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TABLE 2. American College of Rheumatology criteria for diagnosing SLE. 11

Criterion Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder Definition Fixed erythema (flat or raised) over the malar eminences, tending to spare the nasolabial folds Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions Skin rash as a result of unusual reaction to sunlight Oral or nasopharyngeal ulceration, usually painless, observed by physician Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling or effusion Pleuritis history of pleuritic pain or rub heard by physician or evidence of pleural effusion OR Pericarditis documented by electrocardiogram, rub or evidence of pericardial effusion Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if quantitation not performed OR Cellular casts may be red cell, hemoglobin, granular, tubular or mixed Seizures OR psychosis in the absence of offending drugs or known metabolic derangements Hemolytic anemia with reticulocytosis OR Leukopenia less than 4,000/mm3 on two or more occasions OR Lymphopenia less than 1,500/mm3 on two or more occasions OR Thrombocytopenia less than 100,000/mm3 in the absence of offending drugs Positive antiphospholipid antibody OR Anti-DNA OR Anti-Sm OR false positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome
Immunologic disorder
Antinuclear antibody
SLE is characterized by autoantibodies directed at self-antigens, resulting in inflammatory damage to various organs throughout the body. As a result, the presenting manifestations of SLE are diverse, and can range from nonspecific symptoms such as fever, malaise and multisystem dysfunction over several months, to acute life-threatening symptoms. It should therefore be considered in the differential diagnosis of many problems including fever of unknown origin, arthralgia, anemia, and nephritis, as well as patients who present with multi-organ symptoms.4
Clinical Presentation
The most common presentations of SLE in children are fever, fatigue, arthralgia, and rash. While any organ system can be affected by SLE, the most common systems affected are mucucutaneous, musculoskeletal, hematologic, renal and pulmonary, with the neurologic, cardiac and gastrointestinal systems affected less commonly.5 Cutane-
ous manifestations are frequently present, but the classic malar rash is only present in approximately one-third of individuals and should not be relied upon to make the diagnosis.6 Mucous membrane changes, discoid lesions, photosensitivity lesions, oral ulcers, vasculitic-appearing macular lesions, purpura and Raynaud phenomenon are among some of the common cutaneous findings in a patient with SLE. The most common musculoskeletal symptoms are arthralgias or arthritis affecting the small joints of the hands and wrists, followed by arthritis of the knees. Prolonged arthritis can lead to ligament damage and joint laxity. Hematologic manifestations include thrombocytopenia, hemolytic anemia, and persistent leukopenia. These hematologic findings are commonly present in patients with SLE, and should prompt further testing for antinuclear antibodies. SLE patients may also have positive antiphospholipid antibodies (aPL) or positive tests for lupus anticoagulant
(LA) activity, which can contribute to abnormal bleeding and thromboses. The kidneys are affected in approximately twothirds of patients with SLE.2 The deposition of immune complexes in the kidneys leads to an inflammatory response by activating the complement cascade and recruiting inflammatory cells. Glomerular thrombosis may also play a role in the pathogenesis of lupus nephritis in patients who are aPL positive. Patients with SLE can have a wide range of renal manifestations ranging from incidental hematuria, proteinuria or hypertension on routine exam to classic nephrotic syndrome, nephritis or acute renal failure.6 Approximately 30 to 50 percent of children with SLE have abnormal respiratory findings.7 While pulmonary involvement is common, children rarely present with predominantly pulmonary manifestions. The most common respiratory manifestation is pleuritis: subclinical lung disease (eg, restrictive lung disease, reduced diffusion capacity) is identified through pulmonary function testing in as many as 60 to 70 percent of patients who are evaluated. 8 Acute pulmonary hemorrhage and pulmonary hypertension are the most severe forms of lupus associated pulmonary involvement, although they occur infrequently in children with SLE. Neurologic manifestations may include either seizures or psychosis in the absence of offending drugs or known metabolic derangements, according to the criteria. However, patients may also present with other central nervous system findings such as stroke, pseudotumor cerebri, cerebral venous thrombosis, aseptic meningitis, chorea, global cognitive deficits, mood disorders, transverse myelitis and peripheral neuropathy.9 Lupus patients are also particularly susceptible to infections, and this can often be a presenting symptom. The immunosusceptibility of lupus patients is characterized by immunoglobulin deficiency (in cases of nephritic syndrome), chronic hypocomplementemia, functional asplenia, and impaired cellular immune responses.10 As a result, infections from common organisms, particularly Streptococcus pneumoniae, are common and severe in SLE patients due to their impaired ability to clear encapsulated organisms.
criteria, either serially or simultaneously, during any interval of observation. (Table 2) In addition to the physical criteria for SLE, patients who are being evaluated for SLE also need an extensive immunologic work-up to fulfill the ACR criteria, namely, levels of anti-dsDNA, anti-Smith and/or false positive serologic testing for syphilis in addition to an abnormal ANA titer.
Treatment
Treatment of SLE is guided by the patient's disease manifestations, with the goal of therapy to control these manifestations while maintaining a good quality of life and preventing serious organ damage that could limit life expectancy. Current survival rates for SLE are 95% in 5 years and 85% in 10 years.12 Poor adherence with medical care, neurologic complications, intercurrent infections and renal disease are poor prognostic indicators. Fever, rash, musculoskeletal manifestations and serositis generally respond well to symptomatic treatment with hydrochloroquine, nonsteroidal antiinflammatory drugs and low-to-moderate dose steroids, as needed for acute flare ups. Central nervous system and renal involvement constitute more serious disease and require high-dose steroids and other immunosuppressive agents, such as cyclophosphamide, azathioprine or mycophenolate. New investigations are in process to examine the role of rituximab and other biological therapies in SLE.
SUMMARY
Altered mental status is an alarming presenting complaint. When confronted with such patients, emergency physicians must first stabilize vital functions, and then do a focused history and physical that can help to direct timely and life-saving management. When evaluating a patient with multisystem involvement, it is important to remember that SLE is not an uncommon disorder and that the presenting manifestations of SLE are diverse. Patients can present insidiously over years with nonspecific complaints of fever, weight loss, joint pain and rash or acutely with life-threatening symptoms. Some patients may not fulfill diagnostic criteria immediately, presenting with only a couple of symptoms. Patients who present with new onset glomerular disease, hemolytic anemia, or overwhelming sepsis should stimulate an evaluation for lupus. These children should be monitored closely for the development of the other manifestations of SLE, with an elevated ANA titer being an early indicator that there may be an underlying autoimmune process. Therefore, a high index of suspicion for SLE in childhood is
Diagnostic Tests
The diagnosis of SLE in childhood is based upon the same American College of Rheumatology (ACR) criteria used for adults.11 This diagnosis of SLE requires that a patient meet four or more of the 11
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important in appropriately diagnosing SLE, as delays in diagnosis can lead to life-threatening complications and long-term sequelae.
REFERENCES
1. King D, Avner JA. Altered mental status. Clin Pediatr Emerg Med 2003;4:171-8. 2. Fleisher GR, Ludwig S, Henretig FM, editors. Textbook of pediatric emergency medicine. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. 3. Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus 2006;15:308-18. 4. Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics. 17th ed. Philadelphia, PA: Saunders; 2004. 5. Bader-Meunier B, Armengaud JB, Haddad E, et al. Initial presentation of childhood-onset systemic lupus erythematosus: a French multicenter study. J Pediatr 2005;146:648-53.
6. Lehman TJ. Systemic lupus erythematosus in children and adolescents. In: Wallace DA, Hahn B, editors. Dubois' Systemic Lupus Erythematosus. 5th ed. Philadelphia, PA: WB Saunders; 1996. 7. Beresford MW, Cleary AG, Sills JA, et al. Cardio-pulmonary involvement in juvenile systemic lupus erythematosus. Lupus 2005;14:152-8. 8. Delgado EA, Malleson PN, Pirie GE, et al. The pulmonary manifestations of childhood onset systemic lupus erythematosus. Semin Arthritis Rheum 1990;19:285-93. 9. Muscal E, Brey RL. Neurologic manifestations of systemic lupus erythematosus in children and adults. Neurol Clin 2010;28:61-73. 10. Faveau C, Houssiau FA. Pneumococcal sepsis in patients with systemic lupus erythematosus. Lupus 2005;14:903-6. 11. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725. 12. MacDermott EJ, Lehman TJ. Prospective, open-label trial of rituximab in childhood systemic lupus erythematosus. Curr Rheumatol Rep 2006;8:439.
Abstract:
Neonatal seizures are the most common neurologic emergency in the newborn period. Given that there is a broad differential diagnosis, emergency evaluation should first focus on identifying treatable causes. The following case describes a neonate who presented to the emergency department with seizures. The seizures were provoked by electrolyte abnormalities secondary to dehydration and renal failure from intestinal obstruction secondary to congenital duodenal atresia. This case illustrates a unique and potentially treatable etiology of neonatal seizures.
A Surprising Etiology of Neonatal Seizures

Jennifer Jacob, MD, Seema Shah, MD
6-day-old term female neonate was brought by her parents to the emergency department for shaking. The parents noted bilateral arm flexion and upward eye deviation lasting several seconds without associated color change. They witnessed 5 episodes over the prior 2 days, and the parents felt the episodes were increasing in frequency. Between the episodes, she was awake and alert. Two days before presentation, the patient's primary care physician evaluated her for spitting up feeds since birth. She had varying amounts of nonbilious emesis resembling curdled milk with each feeding. No hematemesis was noted. The pediatrician changed her formula with no effect on her symptoms. On the day before presentation, her feeds decreased to approximately 1 oz every few hours with persistent emesis shortly after each feed. She had reportedly passed meconium within 24 hours after birth and continued to have several small, greenish-yellow stools daily. The patient's parents were unable to quantify her urine output. There was no fever, respiratory symptoms, diarrhea, rash, bruising, or bleeding. The patient had an unremarkable medical history. The birth history was notable for a term pregnancy with full prenatal care. The infant was delivered via uncomplicated cesarean birth for failure to progress. There was no history of sexually transmitted diseases, and the infant's mother was group B streptococcus negative. Her birth weight was 3.5 kg. The infant went home with her mother on the second day of life. The patient's mother reportedly had a fever at the time of discharge, but did not require antibiotics. The infant was not taking any medications. Family history was negative for seizures, developmental delay, and other childhood illnesses.
Keywords:
neonatal seizure; hypomagnesemia; duodenal atresia
Division of Emergency Medicine, Rady Children's Hospital, University of California, San Diego, CA This case report was originally presented at the American Academy of Pediatrics National Conference and Exhibition, Section on Emergency Medicine Emergi-Quiz Competition, Washington, DC, October 2009. Reprint requests and correspondence: Seema Shah, MD, Division of Emergency Medicine, Rady Children's Hospital, University of California, 3020 Children's Way, MC 5075, San Diego, CA 92123. sshah@rchsd.org
1522-8401/$ - see front matter 2010 Published by Elsevier Inc.
A SURPRISING ETIOLOGY OF NEONATAL SEIZURES / JACOB AND SHAH VOL. 11, NO. 4 301
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VOL. 11, NO. 4 A SURPRISING ETIOLOGY OF NEONATAL SEIZURES / JACOB AND SHAH
On initial physical examination, her rectal temperature was 36.7C with a heart rate of 173 beats per minute, respiratory rate of 24 breaths per minute, and oxygen saturation of 96% on room air. The patient's weight was 3 kg, which was 14% less than her birth weight. The infant was initially alert and vigorous. Her head was atraumatic; and anterior fontanelle was soft, but sunken. Her pupils were equally round and reactive. The oropharynx was clear, but the mucus membranes were dry. The neck was supple. There were strong femoral pulses, and distal capillary refill was less than 3 seconds. Heart sounds were normal with no murmur. The lungs were clear to auscultation bilaterally. The abdomen was soft, nontender, and somewhat distended with decreased bowel sounds. The patient had normal female Tanner I genitalia. The extremities were cool. She was alert with normal tone and strength. She had normal suck, root, and Moro reflexes. Several minutes after arrival to the emergency department, she experienced recurrent periods of apnea. She was then noted to have bilateral tonicclonic movements of her upper and lower extremities with sluggish pupils and upward eye deviation. A heel-stick glucose was 84 mg/dL. Bag-valve-mask ventilation was initiated for recurrent apnea. A peripheral intravenous (IV) line was placed, but blood was unobtainable for further analysis. The patient received 0.1 mg/kg IV lorazepam, and the seizure-like activity initially ceased. She also received a 20 mL/kg isotonic sodium chloride solution bolus and 15 mg/kg of IV phenobarbital. Her airway was secured with endotracheal intubation. A portable chest radiograph demonstrated adequate placement of the endotracheal tube and gastric distension. After intubation and fluid resuscitation, blood work and additional radiographs were obtained, which were suggestive of the diagnosis. The patient was admitted to the pediatric intensive care unit, and a definitive diagnosis was made the next day.
TABLE 1. Differential diagnosis of neonatal seizure.

Trauma and hypoxia & Subdural/subarachnoid hemorrhage & Intraventricular hemorrhage & Hypoxic ischemic encephalopathy & Cerebral vasoocclusive lesions Congenital anomalies & Cortical dysplasia Metabolism & Hypoglycemia & Hypocalcemia & Other electrolyte imbalance (including hypomagnesemia) & Inborn errors of metabolism & Pyridoxine dependency & Kernicterus Infection & Meningitis/encephalitis (bacterial, herpes simplex virus) & TORCH infections (rubella, cytomegalovirus, toxoplasmosis) & Sepsis Drug related & Cocaine & Neonatal withdrawal (methadone, heroin, barbiturates) Familial syndromes & Benign familial epilepsy & Genetic syndromes (eg, Zellweger and Smith-Lemli-Opitz)
DIFFERENTIAL DIAGNOSIS
Seizures are the most commonly encountered neurologic emergency in newborns. The neonatal nervous system is more susceptible to seizures, yet is rarely able to produce and sustain generalized tonic-clonic activity because of its immaturity. Therefore, neonatal seizures are often difficult to recognize.1 Clinical manifestations usually consist of focal movements or subtle behaviors such as repetitive buccolingual movements, pedaling, or autonomic changes.2 In addition, subtle seizures
may be confused with the normal motor or autonomic behavior of healthy infants. Neonatal seizures have historically been subdivided into 5 clinical categories: focal clonic, multifocal clonic, tonic, myoclonic, and subtle.3,4 At least 50% of neonatal seizures manifest by the first day of life.2,5 In term infants, the most common etiologies of seizure occurring during the first 48 hours of life include perinatal asphyxia, intracranial hemorrhage from birth trauma, and hypoglycemia. The most common causes of seizures after 48 hours of life include metabolic, infectious, and genetic causes (Table 1). Cerebral hypoxia-ischemia is the most common cause of neonatal seizures.2,5 Postasphyxial seizures tend to occur within the first 2 days of life. They are often associated with hypotonia, hypothermia, hypoglycemia, hypocalcemia, and renal parenchymal injury. Congenital anomalies such as cerebral dysgenesis are also potential etiologies of neonatal seizures. These conditions are more likely to be associated with poor long-term neurologic outcome.5 Injury from birth or nonaccidental trauma may cause subarachnoid; subdural; and, rarely, intraparenchymal brain hemorrhage. These infants may present with seizures, irritability, increased tone,
high-pitched cry, or bulging fontanelle. It is important to maintain an index of suspicion for nonaccidental trauma in infants presenting with suspected seizure. The often subtle nature of seizure activity in newborns may be perceived by observers as an apparent life-threatening event. One study found a 2.5% prevalence of abusive head injury in infants admitted to the hospital for apparent lifethreatening event episodes that included breathing abnormality, color change, or alteration of muscle tone. 6 Therefore, nonaccidental trauma should always be considered in the evaluation of infants presenting with possible seizures. Various metabolic derangements may cause neonatal seizures. Neonatal hypoglycemia results from a myriad of causes. Infants of diabetic mothers and asphyxiated infants are susceptible to hypoglycemia, but manifestations typically occur early in the first days of life. Underlying metabolic abnormalities, including disorders of protein intolerance, carbohydrate metabolism, and fatty acid oxidation, may predispose newborns to profound hypoglycemia and seizure. Other electrolyte abnormalities that may cause seizures include hypocalcemia, hypomagnesemia, and sodium derangements. Hypocalcemia occurring in the first 3 days of life is associated with infants of diabetic mothers and DiGeorge syndrome. Lateronset causes include immature infant renal and parathyroid function, maternal vitamin D deficiency, and dietary imbalance from cow's milk or highphosphate feeds. Hypomagnesemia frequently complicates hypocalcemia, so serum magnesium levels should always be obtained because hypomagnesemic hypocalcemia will not respond to calcium alone. Isolated hypomagnesemia causes neuromuscular hyperexcitability and is recognized as an uncommon cause of both generalized and focal neonatal seizures.79 Decreased gastrointestinal absorption and renal wasting are potential causes of magnesium depletion. Seizures caused by transient metabolic disturbances have demonstrated favorable long-term neurologic outcome.5 Numerous inborn errors of metabolism may underlie neonatal seizures. The toxic effects of accumulating metabolites account for central nervous system symptoms. In utero, these metabolites cross the placenta and are cleared by the mother; so infants typically are not symptomatic at birth.10 Clinical symptoms may become evident in hours to months following delivery depending on the relative degree of enzyme deficiency. Urea cycle defects and some organic acidemias cause significant hyperammonemia and may present as a neonatal seizure. Other typical signs of these defects include vomit-
ing, lethargy, decreased tone, and coma. Newborns with organic acidemias such as maple syrup urine disease are unable to decarboxylate the branchedchain amino acids. These infants are well appearing until protein feeds are introduced or they become catabolic from another illness. Vomiting, shrill cry, and altered tone often accompany seizures. Metabolic acidosis is usually exhibited in organic acidemias, but not typically seen in urea cycle defects. Urine organic acids and plasma amino acids are helpful in further differentiating these disorders. A high index of suspicion for inborn errors of metabolism should be maintained, as initiating aggressive treatment before establishing a definitive diagnosis may reduce neurologic sequelae. Pyridoxine-dependent seizures typically manifest in the newborn period, but may present in children up to 3 years of age. Seizures result from decreased levels of the inhibitory neurotransmitter -aminobutyric acid. This is caused by abnormal binding of the enzymatic cofactor pyridoxine during the synthesis of -aminobutyric acid. Clinical seizure types vary widely. Affected infants may have a history consistent with fetal seizures including maternal report of unusual rhythmic movements in utero and meconium present at delivery. 11 Administration of pyridoxine (50-100 mg IV) should be considered in intractable neonatal seizures that are resistant to conventional anticonvulsant therapy. Pyridoxine typically stops clinical seizures within minutes, but may also result in respiratory depression. Seizures may be the initial manifestation of central nervous system infection. Primary maternal infection with rubella, cytomegalovirus, syphilis, or toxoplasmosis may cause neonatal infection and seizure. Congenital syphilis generally does not exhibit neurologic manifestations until after the neonatal period. During delivery, group B streptococci, Escherichia coli, Listeria monocytogenes, and herpes simplex virus may be transmitted to the newborn; and central nervous system infection or sepsis may cause seizures. Maternal drug use may also cause neonatal seizures. The neuropharmacologic properties of cocaine and/or secondary cerebral infarction from cocaine-induced vasospasm may result in newborn seizures. Withdrawal from narcotics or hypnotic sedatives used by the mother during pregnancy may cause neonatal seizures. Seizures resulting from narcotic withdrawal typically occur at about 10 days of life, but onset of symptoms can range from 3 to 34 days.2 Withdrawal from maternal methadone use more commonly causes seizures than withdrawal from maternal heroin.
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Many rare genetic syndromes including Zellweger and Smith-Lemli-Opitz syndrome are associated with neonatal seizures and neurologic impairment. The autosomal dominant benign familial epilepsy may cause severe, generalized seizures in the first week of life. This is a diagnosis of exclusion, and prognosis is usually good. Neonates presenting to the emergency department with suspected seizure activity should be closely monitored, and intravenous access should immediately be obtained. Because neonatal seizures tend to be localized, respiratory arrest is unusual. 2 However, respiratory depression can be caused by anticonvulsant administration; and resuscitation equipment should be readily available. The initial laboratory evaluation of a neonate with seizure should include blood measurements of glucose and a complete metabolic panel including bilirubin and ammonia. A complete blood count, blood culture, and urine culture should be sent. A lumbar puncture to evaluate for infection or hemorrhage should be performed if the patient is stable. Further studies include plasma amino acids and urine organic acids. Neuroimaging should be also performed to identify underlying injury or parenchymal abnormality. Cranial ultrasound can detect large space-occupying lesions, but may not be acutely available and is less sensitive for smaller lesions and hypoxic-ischemic injury. Computed tomography (CT) scans have higher resolution than ultrasound but deliver a significant dose of radiation. The criterion standard in evaluating for brain injury or abnormal development is magnetic resonance imaging.12 The emergency department practitioner must determine the most appropriate method of intracranial imaging based on their facility's resources and patient acuity.
Figure 1. Portable abdominal radiograph.
CASE PROGRESSION
After the patient was intubated and resuscitated, blood work was obtained for laboratory analysis. A venous blood gas revealed the following: pH 7.41, pCO2 53, pO2 29, base excess 6.8. Serum electrolytes included the following: sodium 142 mmol/L (reference range, 132-143), potassium 3.6 mmol/L (3.5-5), chloride 86 mmol/L (98-108), bicarbonate 31 mmol/L (18-27), blood urea nitrogen 89 mg/dL (5-17), creatinine 4 mg/dL (0.1-0.6), glucose 171 mg/dL (60-115), ionized calcium 1.01 mmol/L (1.00-1.35), magnesium 1.3 mg/dL (1.8-2.3). Ammonia level obtained several hours after initial presentation was 15 mol/L (20-55). An abdominal radiograph obtained in the emergency department demonstrated gaseous distension
of the stomach despite enteric tube placement. There was also a paucity of gas noted distally (Figure 1). Result of a noncontrast head CT was normal with no intracranial hemorrhage, hydrocephalus, mass, midline shift, or other anomaly. A CT of the abdomen and pelvis with IV contrast showed very little bowel gas. The kidneys and other solid organs were normal. The day after admission to the pediatric intensive care unit, an upper gastrointestinal series was performed, which was consistent with duodenal atresia (Figure 2). It demonstrated a dilated stomach and duodenum that abruptly ended in the postbulbar area with no barium passing through the second portion of the duodenum. The unifying diagnosis was seizure secondary to hypomagnesemia and azotemia from acute renal failure that was precipitated by severe dehydration from duodenal atresia. The patient was admitted to the pediatric intensive care unit and had an uncomplicated laparotomy and duodenoduodenostomy for definitive repair of duodenal atresia. Enteral feeds were then started, and she was on full oral feeds by the time of discharge. The patient's severe dehydration caused acute kidney injury and mild acute tubular necrosis. Although she was initially oliguric, her urine output improved with fluid resuscitation. Her blood urea nitrogen/creatinine normalized to 8/0.6 within 3 days of hospitalization. The sepsis evaluation revealed negative blood, urine, cerebrospinal
Figure 2. Upper gastrointestinal series.
fluid, and respiratory viral cultures. Urine organic acids, serum amino acids, and thyroid studies were all normal. The patient was loaded on phenobarbital in the emergency department and continued on antiepileptics while she was hospitalized. She had no further seizure activity. An electroencephalogram showed some multifocal independent sharp waves, but neurology consultants felt her seizure episodes had been provoked from hypomagnesemia in the setting of azotemia. She was discharged home on phenobarbital. In outpatient neurology follow-up 2 months later, the patient had no further seizures. Her repeat electroencephalogram was normal, and she was weaned off phenobarbital. She was tolerating full oral feedings and was gaining weight well.
DISCUSSION
Duodenal Atresia and PreRenal Failure Causing Hypomagnesemia
The patient's low magnesium in the setting of uremia and intestinal malabsorption was felt to be the provoking cause of seizure. Her renal failure was caused by severe dehydration from duodenal atresia. The renal wasting of magnesium was compounded by decreased gastrointestinal absorption, which ultimately led to her electrolyte abnormality.
Hypomagnesemia leads to increased central nervous system excitability and neuromuscular transmission. Serum magnesium levels linked to seizures are typically less than 1.0 mg/dL. However, levels as high as 1.4 mg/dL have been reported in association with seizure.13 Symptomatic hypomagnesemia is rare in childhood. It is often associated with hypocalcemia, which also leads to neurologic manifestations. However, there are reports of neurologic manifestations associated with isolated hypomagnesemia in children with normal serum calcium levels.7 Hypomagnesemia in young children may occur in a myriad of clinical scenarios including increased renal losses and malabsorption. Renal magnesium wasting may be genetic (eg, Bartter and Gitelman syndromes) or secondary to acute kidney injury. Prerenal injury from hypoperfusion or ischemia is the most common form of acute kidney injury in newborns.14 Neonatal kidneys are physiologically more susceptible to hypoperfusion injury, as this patient demonstrated. Hypomagnesemia has been described in association with uremia in infants. This contrasts with adults who typically develop hypermagnesemia with acute kidney injury.15 Intestinal absorption of magnesium occurs primarily in the distal small intestines and colon, so proximal small bowel obstruction or protracted vomiting may precipitate malabsorption. Familial hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disease with selective defects in the absorption of magnesium in the small intestine.16 This condition also manifests with recurrent convulsions that are refractory to treatment with calcium and only respond to magnesium therapy. Our patient presents an interesting case in which hypomagnesemia was the result of undiagnosed congenital bowel obstruction. Bowel obstruction in the neonate is commonly the result of congenital defects in intestinal continuity. Pyloric, duodenal, jejunoileal, and colonic atresias have been reported. Duodenal atresia is the most common, with an incidence of about 1:10,000.17,18 During the fifth week of embryonic development, the duodenal lumen undergoes obliteration by proliferating epithelial cells. This cord of cells then degenerates, and the duodenum recannulates. Failure of this process causes duodenal lumen abnormalities including partial or complete obstruction.18,19 Duodenal stenosis is an incomplete obstruction that is caused by a diaphragm or web with a small opening. Duodenal obstruction may also result from external compression as with an annular pancreas. Diagnosis of incompletely obstructing lesions may
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be delayed beyond the neonatal period. In fact, many reports describe delayed diagnosis of duodenal diaphragms or webs until adulthood.20 Duodenal atresia represents complete obstruction of the lumen and typically presents within the first few hours of life. Symptoms include vomiting of clear or bile-stained fluid. Emesis is typically bilious, as the site of obstruction is distal to the ampulla of Vater in more than two thirds of cases.19 However, emesis may also be nonbilious if the obstruction is more proximal, or blood-tinged if there is associated gastritis. Abdominal distension may or may not be present. Stooling patterns may be abnormal; but meconium is typically passed in the first 24 hours of life, and infants may continue to have stools that appear normal. This patient presented with a significant delay in the diagnosis of duodenal atresia, which is usually diagnosed before discharge from the newborn nursery. Prenatal ultrasound is reported to detect more than half of infants with duodenal atresia antenatally. However, it may go undetected until after birth especially if there are no other associated congenital anomalies. 21,22 One case series reported that 33% of infants were diagnosed with complete duodenal obstructions after discharge from the birth hospital. The average age at readmission was 5 days. These infants were more likely to be breastfed and have younger mothers than those infants diagnosed before birth hospital discharge. They were also more likely to have metabolic derangements and prerenal azotemia at the time of diagnosis.22
ruled out because they are reversible and often have a positive prognosis. In particular, clinicians should also obtain magnesium levels in newborns evaluated for new onset seizure.
REFERENCES
1. Rennie J, Boylan G. Neonatal seizures and their treatment. Curr Opin Neurol 2003;16:171-81. 2. Painter M. Neonatal seizure disorders. In: Levene IM, editor. Fetal and neonatal neurology and neurosurgery, 2nd ed. Churchill Livingstone: Edinburgh, 1995. p. 547-61. 3. Volpe J. Neurology of the newborn, 4th ed. Philadelphia (PA): WB Saunders Co; 2001. p. 178-214. 4. Scher M. Controversies regarding neonatal seizure recognition. Epileptic Disord 2002;4:139-58. 5. Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatr 2006;117:1270-80. 6. Altman R, Brand D, Forman S. Abusive head injury as a cause of apparent life-threatening events in infancy. Arch Pediatr Adolesc Med 2003;157:1011-5. 7. Weisleder P, Tobin J, Kerrigan JF, et al. Hypomagnesemic seizures: case report and presumed pathophysiology. J Child Neurol 2002;17:59-60. 8. Dharnidharka V, Carney P. Isolated idiopathic hypomagnesemia presenting as aphasia and seizures. Pediatr Neurol 2005;33:61-5. 9. Tsang R. Neonatal magnesium disturbances. Am J Dis Child 1972;124:282-93. 10. Burton B. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatr 1998;e69:102. 11. Gospe S. Pyridoxine-dependent seizures: findings from recent studies post new questions. Pediatr Neurol 2002;26: 181-5. 12. Glass H, Sullivan J. Neonatal seizures. Curr Treat Options Neurol 2009;11:405-13. 13. Fishman R. Neurological aspects of magnesium metabolism. Arch Neurol 1965;12:562-9. 14. Friedlich P, Evans S, Tulassay T, et al. Acute and chronic renal failure. In: Taeusch H, Ballard R, Gleason C, editors. Avery's diseases of the newborn, 8th ed. Philadelphia, (PA): Elsevier Saunders; 2005. p. 298-305. 15. Ghazali S, Hallett R, Barratt T. Hypomagnesemia in uremic infants. J Pediatr 1972;81:747-50. 16. Visudhiphan P, Visudtibhan A, Chiemchanya S, et al. Neonatal seizures and familial hypomagnesemia with secondary hypocalcemia. Pediatr Neurol 2005;33:202-5. 17. Nixon HH. Duodenal atresia. Br J Hosp Med 1989;41:134-40. 18. Dalla Vecchia L, Grosfeld J, West K, et al. Intestinal atresia and stenosis: a 25 year experience with 277 cases. Arch Surg 1998;133:490-7. 19. Millar A, Rode H, Cywes S. Intestinal atresia and stenosis. In: Ashcraft K, editor. Pediatric surgery, 4th ed. Philadelphia (PA): WB Saunders; 2005. p. 416-9. 20. Ladd A, Madura J. Congenital duodenal anomalies in the adult. Arch Surg 2001;136:576-84. 21. Choudhry M, Rahman N, Boyd P. Duodenal atresia: associated anomalies, prenatal diagnosis and outcome. Pediatr Surg Int 2009;25:727-30. 22. Kilbride H, Castor C, Andrews W. Congenital duodenal obstruction: timing of diagnosis during the newborn period. J Perinatol 2010;30:197-200.
SUMMARY
This patient had an unusual etiology of seizures, as an underlying congenital gastrointestinal obstruction led to electrolyte abnormalities. This illustrates how congenital gastrointestinal abnormalities may present after the immediate perinatal period. Therefore, it is important to consider obtaining abdominal radiographs on newborn infants with persistent vomiting, even if emesis is nonbilious or low volume. The differential diagnosis of seizure in the newborn period is broad and varied. Seizures are frequently subtle, so it is important to maintain a high index of suspicion when presented with an unusual history or clinical appearance. A prompt and thorough diagnostic evaluation is imperative as seizures often indicate significant underlying pathology. Although seizures in the newborn period often reflect serious underlying brain injury or pathology, electrolyte abnormalities should be

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Pediatric Emergency Medicine

Feinberg School of Medicine, Northwestern University, Childrens Memorial Hospital, Chicago, IL

Procedural Sedation in Children

231 . . . . . . . . . Procedural Sedation in Children

GUEST EDITORS PREFACE

233 . . . . . . . . Procedural Sedation and Analgesia in the Pediatric Emergency Department:

282 . . . . . . . . Progress in Pediatric Sedation Research

290 . . . . . . . . The Sedation Service Reimbursement Dilemma

EMERGI-QUIZ CLINICAL PUZZLER

301 . . . . . . . . A Surprising Etiology of Neonatal Seizures

Jennifer Jacob and Seema Shah

Pediatric Emergency Medicine

GUEST EDITOR'S PREFACE

Procedural Sedation in Children

PROCEDURAL SEDATION IN CHILDREN / ISAACMAN VOL. 11, NO. 4 231

VOL. 11, NO. 4 PROCEDURAL SEDATION IN CHILDREN / ISAACMAN

Dexmedetomidine Sedative-hypnotic Analgesic Anxiolysis IV: b 1 IV: 5-15

IV: 0.1 mg/kg titrated to effect

IM: 10-15 IV: 2-3 IV: 1-2

IM: 60-90 IV: 20-40 IV: 30-60

STRATEGIES BY AGE OR DEVELOPMENTAL STAGE

PAINLESS LOCAL ANESTHESIA

Tailoring Monitoring to Pharmacopeia

For example, in computed tomography/magnetic resonance imaging scanner, or in darkened room.

When to Remove Monitoring

When to Initiate Monitoring

TABLE 2. Capnographic airway assessment for PSA.

Partial Airway Obstruction

MONITORING MODALITIES FOR PROCEDURAL SEDATION

Figure 1. Using the capnogram to determine airway-related adverse events.

Noninvasive Blood Pressure Monitoring

FUTURE DIRECTIONS IN PROCEDURAL SEDATION MONITORING

Noninvasive Hemodynamic Monitoring of Vascular Tone

Integrated Algorithms and Indices

55. 56. 57. 58.

Figure 1. Cycle of pain undertreatment in sickle cell disease.

PAIN MANAGEMENT CHALLENGES IN SICKLE CELL DISEASE

Adjuvants and Other Analgesics

APPROACH TO CARE IN THE ED

Figure 2. Management of uncomplicated vasoocclusive pain.

IMPROVING CARE AND REDUCING BARRIERS

Progress in Pediatric Sedation Research

CHANGING THE LANDSCAPE

VOL. 11, NO. 4 PROGRESS IN PEDIATRIC SEDATION RESEARCH / CRAVERO

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DEFINITIONS OF ADVERSE EVENTS

LARGE DATABASE RESEARCH

VOL. 11, NO. 4 PROGRESS IN PEDIATRIC SEDATION RESEARCH / CRAVERO

TABLE 1. Complications reported for PSRC sedation study.

PROGRESS IN PEDIATRIC SEDATION RESEARCH / CRAVERO VOL. 11, NO. 4 285

VOL. 11, NO. 4 PROGRESS IN PEDIATRIC SEDATION RESEARCH / CRAVERO

PROGRESS IN PEDIATRIC SEDATION RESEARCH / CRAVERO VOL. 11, NO. 4 287

WORKLOAD AND SEDATION SERVICES

VOL. 11, NO. 4 PROGRESS IN PEDIATRIC SEDATION RESEARCH / CRAVERO

15. 16. 17.

PROGRESS IN PEDIATRIC SEDATION RESEARCH / CRAVERO VOL. 11, NO. 4 289

The Sedation Service Reimbursement Dilemma

BILLING FOR PROFESSIONAL SERVICES

VOL. 11, NO. 4 THE SEDATION SERVICE REIMBURSEMENT DILEMMA / LINZER

Figure 1. Sedation billing based on depth of sedation.

VOL. 11, NO. 4 THE SEDATION SERVICE REIMBURSEMENT DILEMMA / LINZER