Contemporary trends in pediatric sedation and analgesia

PEDIATRIC EMERGENCY MEDICINE: CURRENT CONCEPTS AND CONTROVERSIES

0733–8627/02 $15.00
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CONTEMPORARY TRENDS IN PEDIATRIC SEDATION AND ANALGESIA Elliot Rodriguez, MD, and Rachel Jordan, MD

Patients can present to the emergency department (ED) with pain from a wide range of causes. In their efforts to diagnose and treat patients, emergency physicians perform procedures that also can cause pain or significant anxiety. The duty of physicians to relieve pain and suffering should be considered one of the highest obligations. The Agency for Health Care Policy and Research (AHCPR) has noted the inadequate treatment of pain by physicians and advocates for physicians to relieve pain and suffering in their patients.98 The American College of Emergency Physicians (ACEP) has also advocated for the adequate use of sedation and analgesia in pediatric patients undergoing ED procedures.9 Another priority for physicians is ‘‘primum nonnocere,’’ first do no harm. With approximately 30% of all visits to US EDs being pediatric patients,14 emergency physicians must possess the skills necessary to provide safe and effective pediatric sedation and analgesia. This article covers the current standards for administering pediatric sedation and analgesia. The different pharmacologic options available, and some recommendations on selecting a sedation and analgesia regimen, are also covered. The authors’ intent is to focus on the use of sedation and analgesia for procedures performed in the acute setting. The goal of procedural sedation and analgesia is to match the patient and procedure with the most appropriate technique and agent that can provide the

From the Department of Emergency Medicine, State University of New York, Upstate Medical University, Syracuse, New York

EMERGENCY MEDICINE CLINICS OF NORTH AMERICA VOLUME 20 • NUMBER 1 • FEBRUARY 2002

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patient with the most humane and compassionate environment safely possible. DEFINITIONS Sedation can encompass a range of different levels of consciousness and awareness. ACEP, the American Academy of Pediatricians (AAP),

Definitions of Sedation Conscious sedation

Sedation/analgesia

Deep sedation

Procedural sedation

‘‘[A] medically controlled state of depressed consciousness that (1) allows protective reflexes to be maintained; (2) retains the patient’s ability to maintain a patent airway independently and continuously; and (3) permits appropriate response by the patient to physical stimulation or verbal command (e.g., ‘open your eyes’).’’3 ‘‘[D]escribes a state that allows a patient to tolerate unpleasant procedures while maintaining adequate cardiorespiratory function and the ability to respond purposefully to verbal command and/or tactile stimulation. Note that patients whose only response is reflex withdrawal from a painful stimulus are sedated to a greater degree than encompassed by sedation/analgesia.’’11 ‘‘[A] medically controlled state of depressed consciousness or unconsciousness from which the patient is not easily aroused. It may be accompanied by a partial or complete loss of protective reflexes, and includes the inability to maintain a patent airway independently and respond purposefully to physical stimulation or verbal command.’’3 ‘‘[R]efers to a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardiorespiratory function. Procedural sedation and analgesia is intended to result in a depressed level of consciousness but one that allows the patient to maintain airway control independently and continuously. Specifically, the drugs, doses and techniques used are not likely to produce a loss of protective airway reflexes.’’7

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and the American Society of Anesthesiologists (ASA) all have somewhat different variations of what sedation should be (see box). In defining conscious sedation in their 1985 guidelines, the AAP states that ‘‘the drugs and techniques used should carry a margin of safety wide enough to render unintended loss of consciousness unlikely.’’4 Deep sedation is a state that is often necessary when performing pediatric procedures.63 It is not identical to general anesthesia, which is essentially an apneic, completely unresponsive state.3 The ACEP definition of procedural sedation is most applicable to the sedation and analgesia that emergency physicians provide. Analgesia refers to a decrease in the patient’s ability to perceive pain as noxious and does not necessarily have to induce an altered level of consciousness. The term anxiety alleviation has been used to describe a state in which there is no change in the patient’s level of awareness, only a decrease of apprehension for the situation.79 This is an appropriate state to achieve when there is very minimal or no pain anticipated, but a significant level of anxiety is present. The similarities and differences in each specialties’ definitions are less important than understanding that the different levels of sedation are a continuum and not separate and distinct in themselves. The implication is that patients undergoing procedural sedation can fluctuate between various levels of sedation, or possibly even anesthesia, depending on which agent is used and the individual patient’s response to similar dosages. PRESEDATION EVALUATION Once it has been determined that a patient requires sedation or analgesia, it is paramount to perform a thorough evaluation to help to determine which sedation and analgesia regimen is most suitable. A presedation evaluation should focus on identifying those conditions that can increase the chance of adverse outcomes, as well as those factors that can make it more difficult to provide interventions directed at adverse events. Some of these factors are listed here: Age under 12 months (especially younger than 3 months) Airway abnormalities (e.g., obstructive sleep apnea, tracheomalacia, congenital anomalies) Respiratory disorders (e.g., asthma, bronchopulmonary dysplasia, active infection) Cardiovascular disorders (e.g., congenital cyanotic heart disease, heart failure, dysrhythmias) Neurologic or developmental disorders (e.g., seizures) Hepatic and renal disorders Prior adverse event due to sedation, analgesia, or anesthesia The presence of an upper respiratory tract infection (URI) has been associated with an increased risk of respiratory complications, including laryngospasm, in patients undergoing general anesthesia.24, 70, 81 Patients with active asthma also have been shown to have a higher risk of

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laryngospasm when undergoing general anesthesia.70 It is unknown whether the same increased risk applies to patients undergoing procedural sedation and analgesia, but the presence of an URI or active asthma should raise one’s concern that laryngospasm could occur. Preexisting physical or psychological conditions should not be considered contraindications to the use of procedural sedation, however, a more judiciously selected regimen is warranted in that type of patient.79 A history that includes age, allergies and adverse drug reactions, medications and illicit drug use, last oral intake, medical history, previous hospitalizations, history of sedation/anesthesia events, pregnancy status, family history, and a review of systems should be obtained. The physical examination should include weight, vital signs, an airway evaluation, assessment of mental status, and a cardiopulmonary examination.3, 7 The ASA Physical Status Classification categories were developed for patients undergoing general endotracheal anesthesia: I. II. III. IV.

Normal healthy patient Patient with mild systemic disease Patient with severe systemic disease Patient with severe systemic disease that is a constant threat to life V. Moribund patient not expected to survive without operation E. Emergent procedure

Patients in class I or II are considered the best candidates for general endotracheal anesthesia, but it is unknown how that can extrapolate to patients undergoing procedural sedation and analgesia in the ED setting. Laboratory studies usually add little to the presedation evaluation. There has been no relationship demonstrated between gastric emptying and incidence of adverse outcomes from procedural sedation.7 The following recommendations offered by the AAP should be considered guidelines and not necessarily preclude the use of procedural sedation and analgesia altogether: patients of any age should not have consumed clear liquids for at least 2 hours prior to sedation, infants under 6 months need 4 hours of gastric emptying time for any milk or solids consumed, patients 6 months to 3 years need 6 hours of gastric emptying time, and patients over 3 years require 8 hours to pass after consuming any milk or solids prior to sedation.3 In those patients who have increased risk of aspiration because of medical history or suboptimal gastric emptying times, modified sedation regimens that ensure preserved airway protective reflexes should be considered or possibly delaying or aborting the procedure altogether. Once a focused presedation evaluation has been completed, informed consent should obtained. A discussion involving the parent or guardian that delineates risks, benefits, and alternatives should be had. This should be documented clearly on the patient’s medical record whether or not written consent is also obtained. The issue of needing written consent is controversial and is not a requirement set forth by JCAHO49; however, recommendations on having written consent prior

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to procedural sedation are best guided by state, local, and institutional regulations, and knowing those regulations can determine one’s practice. PATIENT MONITORING AND EQUIPMENT A minimum of two people is needed to perform procedural sedation safely. The physician who is overseeing the sedation must be readily available in the department at all times throughout the sedation and immediate postsedation period.79 This physician must be well trained in pediatric basic life support, although training in advanced life support is strongly recommended.3 This should include being skilled at handling the compromised airway. This physician may or may not be the same person performing the procedure, but if it is, he or she must be able to immediately stop the procedure to handle any adverse event that could occur. There must also be a separate person responsible for monitoring the patient’s vital signs and cardiopulmonary status. This person can also record medications, dosages, and times administered. When deep sedation is being performed, this person should have no other responsibilities except the direct monitoring and observation of the patient.4 This person should be able to maintain direct visualization of the patient’s head, neck, and chest to assess respiratory effort and airway positioning at all times. A well-designed flow sheet is helpful when monitoring the sedated patient. At minimum, mental status, heart rate, respiratory rate, and oxygen saturation should be monitored before, during, and after procedural sedation and analgesia. A minimum of five sets of vital signs has been suggested, although measurements should be obtained more frequently depending on the clinical situation.55 ACEP recommends that blood pressure also be monitored.79 For patients undergoing deep sedation, vital signs should be recorded every 5 minutes, and the use of continuous electrocardiographic monitoring is recommended.3 At least one final patient assessment should be done prior to the patient’s being discharged. Patients are at highest risk for complications during the 5 to 10 minutes after the intravenous administration of medication and during the period immediately after the procedure, when the procedural stimulus is discontinued.54 Capnography has been used in the monitoring of pediatric patients during the perioperative period by special cannulae and masks that deliver supplemental oxygen and record endtidal CO2.96 Although it can detect episodes of hypoventilation before hypoxemia has occurred,10 no definite advantage over pulse oximetry in the setting of procedural sedation and analgesia in the ED has been demonstrated.102 There is no mandate for having intravenous access established prior to the use of sedative or analgesic agents by the intramuscular, oral, nasal, rectal, inhaled, or topical route;54 however, it is recommended that the equipment and personnel needed for establishing IV access must be readily available when one is performing deep sedation, especially when using reversible agents.3

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The equipment needed to care for the acutely ill pediatric patient in an ED setting properly is listed elsewhere.8, 60 The recommendations by the AAP Committee on Drugs should be considered the minimal equipment necessary to perform procedural sedation and analgesia adequately in any setting.3 The physician should have supplemental oxygen, oral suctioning equipment, bag valve mask, IV tray, and reversal agents (if applicable) at the bedside before starting the procedural sedation and analgesia. A pediatric emergency resuscitation cart should be immediately available. The application of supplemental oxygen prior to the procedure is not mandatory and can delay early recognition of respiratory depression by pulse oximetry.11, 55 ANALGESIC AGENTS This is a brief overview of the most commonly used agents for control of mild to severe acute pain in children, both with and without accompanying sedation. Both nonopioid and opioid analgesic medications, as well as options for local anesthesia, inhalational anesthesia, and nonpharmacologic methods of pain control are discussed. Nonopioid Analgesics The most commonly used nonopioid analgesic medications are aspirin, ibuprofen, ketorolac, and acetaminophen. All are effective for mild to moderate pain. Aspirin acts by irreversibly inhibiting cyclo-oxygenase and thus inhibiting prostaglandin production and decreasing inflammation. The oral or rectal dosage is 10 to 15 mg/kg given every 4 hours. Care must be taken, however, in children with febrile illnesses such as varicella or influenza owing to the risk of Reye’s syndrome, which consists of hepatic fatty degeneration and encephalopathy. Adverse effects of aspirin at therapeutic doses include peptic ulcer disease, prolongation of bleeding time, and hypersensitivity. Ibuprofen is a nonsteroidal anti-inflammatory agent that like all nonsteroidals, decreases inflammation by reversibly inhibiting cyclooxygenase and inhibiting prostaglandin production. The oral dose is 5 to 10 mg/kg PO and can be repeated every 6 hours. Like all nonsteroidals, it also can cause peptic ulcer disease. Ketorolac is a newer parenteral nonsteroidal anti-inflammatory medication that has proved effective for moderate to severe pain. Its onset of action is approximately 10 minutes after administration, and peak effect occurs after 40 to 60 minutes, with a duration of about 6 hours. The recommended dosage for children over the age of 3 years is 0.5 mg/kg IVq6h, with a maximal daily dose of 90 mg. The dosage for children over 12 years of age is 30 mg IV or IMq6h. Acetaminophen has analgesic properties by an unknown central

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mechanism but does not have anti-inflammatory properties. The usual dose is 15 mg/kg PO or rectally, and it can be repeated every 4 hours. Acetaminophen has synergistic properties when combined with oral narcotics such as codeine, oxycodone, and hydrocodone and is effective for moderate to severe pain in these formulations.79 Adverse effects of acetaminophen when used at therapeutic doses are minimal. Opioids Opioids are divided into three major groups. Opiates, which are natural derivatives of the opium poppy, include morphine and codeine. Semisynthetic compounds include hydrocodone and oxycodone, and synthetic compounds include meperidine, fentanyl, and sufentanil. Opioids are generally used for moderate to severe pain such as fractures, burns, severe soft tissue injuries, and significant visceral pain, as well as to provide analgesia and sedation (with or without an additional sedative) for painful procedures. Both the sedative and analgesic effects of opioids are dose dependent, varying with plasma concentration from subanalgesia, to analgesia and euphoria, to nausea, dysphoria, and somnolence, to respiratory depression, to apnea, and unconsciousness. The practitioner must always be prepared to administer supplemental oxygen or support the airway when using these medications, particularly in a conscious sedation setting, because these effects are potentiated by the use of benzodiazepines. Several other common adverse effects of opioid administration for acute pain are often encountered. Hypotension commonly occurs from peripheral venous and arterial dilation. Nausea and vomiting occur from activation of the chemoreceptor trigger zone, a change in vestibular function, and the inhibitory effect of opioids on gastrointestinal function. Both are more common with escalating doses, ambulation, and the intravenous route. Combination with an intravenous antiemetic successfully alleviates these symptoms. Other gastrointestinal effects include constipation secondary to diminished intestinal motility and increased transit time. The histamine release associated with morphine, meperidine, and codeine administration frequently results in venodilation, local urticaria along the injected vessel, or generalized pruritis. Opioids constrict smooth muscle and can result in urinary retention and increased biliary colic. Less frequently, CNS hyperexcitability, myoclonus, and seizures have been observed with high doses of fentanyl and meperidine.100 Morphine is the most commonly used opiate and can be given IV, IM, or SC at doses of 0.08 to 0.1 mg/kg increments. Peak effects occur 15 to 30 minutes after IV administration and in 30 to 60 minutes after IM administration. It can be administered in increments every 5 to 10 minutes to desired effect. Morphine is capable of causing profound hypotension, particularly in hypovolemic states, and can also precipitate bronchospasm secondary to histamine release.101

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Meperidine, a synthetic opioid agonist with one tenth the potency of morphine, can be given either IV or IM in a dose of 1 to 2 mg/kg. The onset of action is between 15 to 30 minutes, peaking in 30 to 60 minutes, with a duration of 4 to 5 hours. Because IM absorption is erratic, the IV route is preferred. It is metabolized in the liver to normeperidine, an active metabolite with a half-life of 15 to 40 hours, which can cause seizures with high doses. Meperidine administration results in a more pronounced euphoric state than morphine and has a higher risk for producing psychological dependence with repeated use.79 Its pharmacodynamic profile makes it a difficult drug to titrate, and it is not a preferred agent for procedural analgesia. Because nausea and vomiting occur fairly frequently, meperidine is commonly administered with an antiemetic.101 Fentanyl is another synthetic opioid and is approximately 100 times more potent than morphine. It has a rapid onset of action (less than 30 seconds when administered IV), and duration of action of only 30 to 40 minutes. Its rapid onset and short duration make it an ideal analgesic for short, painful procedures, either alone or combined with a sedative. The usual dose is between 1-5 ␮g/kg IV.101 Fentanyl is also available as an oral preparation that was thought to be useful as a premedication or adjunct to local or regional anesthesia, but the associated 50% incidence of emesis has severely limited its utility in the emergency setting.101 Careful monitoring is essential with this drug, because hypoxemia and apnea are relatively common, especially when combined with midazolam. Fentanyl administration is not associated with histamine release and rarely causes hypotension. It does, however, have the unique and adverse effect of chest wall rigidity and laryngospasm, which can make ventilation difficult or impossible and is relieved only partially with naloxone. Chest wall rigidity is more common with rapid administration and higher doses (greater than 15 ␮g/kg).79, 100 Fentanyl also causes significant nasal pruritis, and care must be taken to restrain the patient’s hands for facial or oral procedures.35 Sufentanil is also associated with high rates of apnea and chest wall rigidity. Sufentanil is a fentanyl analogue that is five to ten times more potent than fentanyl, with a longer duration of action and less respiratory depression. The advantage of this medication is its availability as an intranasal preparation. When given intranasally, it has been shown to reach plasma concentrations similar to IV administration. The recommended dose is between 0.7 to 1 ␮g/kg, with an onset of action of 5 to 15 minutes and a duration of 30 to 60 minutes. Lower doses should be used combined with midazolam.101 Oral narcotic analgesic preparations are frequently used for acute pain and outpatient use. Codeine is the most commonly prescribed oral narcotic for pediatric patients, often combined with acetaminophen or a nonsteroidal agent. Other oral combinations with hydrocodone or oxycodone instead of codeine, or either compound alone, are less frequently used. Oxycodone is slightly more potent than hydrocodone, and both are more potent than the parent compound, codeine. Dosing varies

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by formulation, age, and weight, and most are available in liquid preparations. Local Anesthetics Local anesthesia is the condition that results when sensory transmission from a local area of the body to the CNS is blocked. The most frequently used local anesthetics function by blocking the sodium channels of excitable membranes. They can be administered by subcutaneous injection, topically, or by iontophoresis. Local anesthetics are divided into two major subgroups; esters, which include tetracaine, cocaine, and proparacaine (used for ophthalmic procedures), and amides, including lidocaine and bupivacaine. To decrease absorption, effect hemostasis, and prolong their efficacy, local anesthetics, with the exception of cocaine, which has its own vasoconstrictive properties, are commonly combined with epinephrine (adrenaline). The addition of epinephrine or use of epinephrine-containing solutions is contraindicated, however, in end-arterial areas, including fingers, toes, the penis, the nose, or the pinna of the ear, because of the ischemia. All local anesthetics have a similar toxicity profile. CNS effects include lightheadedness, tongue numbness, and restlessness at low levels, progressing to perioral paresthesias, slurred speech, and excitability or drowsiness at higher levels, to seizures and coma with respiratory arrest and cardiovascular depression in severe toxicity. Cardiovascular effects include palpitations, cardiac dysrhythmias (particularly bupivacaine), hyper- or hypotension, and cardiovascular collapse. Treatment for seizures is symptomatic, with IV benzodiazepines as the treatment of choice. Cardiac dysrhythmias are more difficult to treat, and fatalities have been reported, particularly with bupivacaine.71 Allergic reactions to local anesthetics are rare but more common with esters than amides, owing to para-aminobenzoic acid (PABA), which is a metabolite of the ester anesthetics. Patients who are allergic to esters generally do not react to members of the amide group. For patients with a true allergy, alternative anesthetic agents include saline with benzyl alcohol, benzyl alcohol with epinephrine, and 1% diphenhydramine.16, 33 Initial results indicate that benzyl alcohol is more effective than diphenhydramine.16 The most frequently used local anesthetic on both intact and nonintact skin is lidocaine. It is available in 0.5%, 1%, and 2% concentrations in solution and also as a jelly and an ointment. The maximal dose of lidocaine is 4.5 mg/kg without epinephrine and 7 mg/kg with epinephrine. Onset of action is within 2 to 5 minutes, and the duration of effect is between 30 and 60 minutes. Lidocaine is safe and effective when administered locally at appropriate doses, but its infiltration itself is extremely painful, even with a small (27- to 30-) gauge needle. Studies have shown that buffering, warming (between 37–42C), and slowing the speed of injection of lidocaine lessens the pain of injection.53, 71

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Buffered lidocaine is prepared by mixing 1% lidocaine with sodium bicarbonate solution in a 1 : 10 ratio. Unlike plain lidocaine, this solution has a limited shelf life and must be used within 7 days, depending on storage temperature.71 Bupivacaine is a longer-acting variant of lidocaine. It is available in 0.25% concentration, has an onset of action within 3 to 7 minutes and lasts for 90 minutes to 6 hours. The recommended doses are 2 mg/kg without epinephrine and 3 mg/kg with epinephrine. Bupivacaine is preferred for longer procedures and when longer postprocedural anesthesia is desired. The most frequently used topical anesthetics are tetracaine, adrenaline, cocaine (TAC), lidocaine, epinephrine, tetracaine (LET), and eutectic mixture of local anesthetics (EMLA). The advantage of these medications, particularly for pediatric patients, is that no injection is required. TAC, which is composed of tetracaine 0.5%, adrenaline (epinephrine) 0.5%, and cocaine 11.8%, was the first widely used topical anesthetic. Significant levels of cocaine in the blood have been demonstrated and TAC can have adverse effects similar to cocaine toxicity.71 After a series of studies proving its efficacy to be equal to that of TAC, LET (lidocaine 4%, epinephrine 0.1%, and tetracaine 0.5%) has largely replaced TAC.32, 80 LET is safer, less expensive, and does not contain any controlled substances. LET may be applied to broken or intact skin and is available as a gel and a solution, which are equally effective.76 After application of 1 mL to 3 mL with a swab, cotton ball, or sterile gauze, it should be covered with tape or occlusive dressing for at least 20 minutes and the child may be allowed to play during this period. Both TAC and LET contain epinephrine and thus must be avoided in end-arterial regions and mucous membranes. Other topical alternatives to TAC and lidocaine have been investigated as well, including prilocaine-phenylephrine and bupivicaine-phenylephrine. In one study, prilocaine-phenylephrine was found to be as effective as lidocaine for laceration repair.87 Another study found it more effective than bupivicaine-phenylephrine,86 and it represents another reasonable alternative method of providing local anesthesia. EMLA, an eutectic mixture of local anesthetics, consists of lidocaine 2.5% and prilocaine 2.5% combined with thickening agents to form an emulsion. It is not sterile and should be used only on intact skin to provide anesthesia for nonemergent procedures, including IV placement, blood draws, and lumbar puncture. EMLA must be applied under an occlusive dressing and left for at least 1 hour.54 Peak effect occurs after 2 hours and analgesia lasts for 1 hour after removal. A theoretical risk of methemoglobinemia exists in infants younger than 3 months of age owing to the immaturity of the NADH reductase enzyme.21 Multiple studies have shown, however, that a 1-g application is safe for infants younger than 3 months of age without an increase in metHgb to clinically significant levels.21, 32, 93 Amethocaine gel, a newer alternative to EMLA, has been proved to be equally effective to EMLA and has a faster onset of analgesia (30–45 min), but this agent is not yet available in the United States.12, 19, 67

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Ethyl chloride and fluori-methane are commonly used vapocoolant sprays that are alternatives to the topical anesthetics for transient local anesthesia on intact skin. These sprays cause local hypothermia, which results in anesthesia lasting less than 1 minute. Ethyl chloride does have the disadvantage of being highly combustible, whereas Fluori-Methane is not. Iontophoresis, the transfer of charged molecules into biologic tissue under the influence of electric current, is an alternative method of delivering anesthetic that has been investigated.52, 103 Two electrodes are placed on the skin, and drug molecules are driven across the skin by repulsion. Initial studies indicate that lidocaine iontophoresis could be an alternative to EMLA for IV line placement, but more studies are needed to demonstrate its utility for more emergent procedures.54, 52 There is a risk of superficial skin burns with improper use, and specialized equipment and training are required.103 Nitrous Oxide Nitrous oxide is one of the oldest anesthetic agents still in use. It was discovered in 1772 and has been in clinical use as an anesthetic since 1844. When inhaled, it provides anxiolysis, amnesia, and mild to moderate analgesia. When used in combination with local anesthesia, it has proved effective in children for a variety of procedures including laceration repair, fracture reduction, and lumbar puncture.61 The analgesic properties of nitrous oxide vary, and it is often necessary to add another analgesic such as an opioid for adequate analgesia.44, 100 Nitrous oxide is generally provided in a 50 : 50 mixture with oxygen for inhalation by handheld mask or mouthpiece. The patient determines the amount of gas delivered by maintaining a tight seal and generating negative inspiratory pressure. Using flavored lip balm or scent to coat the interior of the mask can increase mask acceptance in younger children.61 Because gas delivery requires patient cooperation, particular care and judgment must be used in children younger than 8 years old. It is poorly soluble in plasma, and has a rapid onset of action in 30 to 60 seconds, with maximal effect occurring in about 5 minutes. Its advantage over other methods of sedation and analgesia is that although it rapidly affects cortical function, it has little effect on the cardiovascular or respiratory systems and has little effect on airway reflexes.44, 79, 101 Termination of effect occurs rapidly after administration ceases; most of the gas is exhaled in its original form. Vigilant monitoring is necessary with cessation of anesthesia owing to the risk of diffusion hypoxia, especially with concentrations of nitrous oxide greater than 50%.79, 100 This occurs because of the dilution of alveolar oxygen by nitrous oxide diffusing from the blood to the alveoli, even after it has been turned off. Because the time of greatest risk for diffusion hypoxia is in the first 3 to 5 minutes after the nitrous oxide is stopped, this situation can be prevented by the administration of 100% oxygen for 3

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to 5 minutes immediately after the nitrous oxide is turned off.61 Recovery from the effects of nitrous oxide generally occurs within 5 minutes. Nitrous oxide is contraindicated in conditions involving closed air spaces such as pneumocephaly, pneumothorax, and bowel obstruction because of its high diffusability, which can cause expansion of these closed spaces.61 Caution must be taken in pregnant patients as well, although it is considered safe for short procedures.100 The most significant adverse effects of therapeutic doses of nitrous oxide are drowsiness, nausea, vomiting, and dizziness.79 Because of its potential for abuse, nitrous oxide must be carefully monitored and must be used in a well-ventilated treatment room, with a scavenging system capable of removing trace amounts of the gas.44, 61 Distraction and Hypnosis Investigation of nonpharmacologic methods of procedural analgesia and sedation for pediatric patients is ongoing. Methods have included storytelling, videotapes, blowing at pinwheels or other toys, and having the parent or patient rub skin adjacent to the area of focus to decrease local pain sensation.23 These methods have shown some promise, and further investigation is merited into potential applications in the emergency department. SEDATIVE AGENTS Propofol Propofol is a pure sedative with no analgesic or amnestic properties. Propofol is not related to barbiturates or benzodiazepines, and usually is used as an induction agent in general anesthesia. It has been used in the ICU as a sedative for intubated pediatric patients and for sedation for pediatric CT scan and MR imaging by anesthesiologists.20, 46, 99 It has also been studied as a procedural sedation agent in combination with fentanyl in adult ED patients undergoing a variety of procedures.92 It is highly lipid soluble, which contributes to its extremely quick onset (⬍ 1 minute). It must be administered as a bolus and followed by a continuous infusion. Recommended dosages for sedation are 0.5 to 1.0 mg/kg bolus over 2 minutes, with an infusion rate of 50 to 150 ␮g/kg/min. Repeat bolus doses of 0.5 to 1.0 mg/kg can be administered as needed. Although its half-life is about 30 to 90 minutes, its effective duration of action is only about 8 minutes once the infusion is stopped. Adverse effects of propofol include pain at the injection site, hypotension, apnea, and in the long-term sedated pediatric patient, severe lactic acidosis and bradyarrhythmias have been reported.27, 46, 72 The use of a large antecubital vein or concomitant administration of a 0.5 mg/kg bolus of intravenous lidocaine can ameliorate the pain of the propofol infusion. The

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use of a syringe pump is highly recommended because overly fast administration can increase the risk of hypotension and apnea.36 Aseptic handling of the propofol is required because of bacterial contamination of the lipid emulsion, causing sepsis. Lastly, patients with allergies to soybean oil, egg yolk, glycerol, and disodium edetate should not receive propofol. The pharmacokinetic properties of propofol could make it ideal for use as a pediatric procedural sedation agent; however, there has been only one published study regarding the use of propofol as a procedural sedation agent in the pediatric ED, involving only 91 total patients.45 In combination with morphine, propofol was shown to have essentially equivalent efficacy and complication rates compared with midazolam/morphine when used for closed-fracture reductions. No patient had hypotension, aspiration, apnea, or required assisted ventilation or intubation. Of the propofol patients, 11.6% compared with 10.9% of the midazolam patients—had episodes of hypoxemia (defined as an oxygen saturation ⬍ 93%), all of which responded to supplemental oxygen by nasal cannula, verbal stimulation, or airway repositioning within 30 seconds. Despite this promising study, further research is needed before the routine use of propofol for pediatric procedural sedation can be recommended.36, 54 Etomidate Etomidate, an imidazole derivative similar to the antifungal, ketoconazole, has minimal effects on the cardiovascular system. It has an onset time of less than 1 minute and is ultrashort-acting, lasting 5 to 15 minutes. It has been shown to reduce intracranial pressure. Despite its potential for interfering with normal adrenocortical function,1 etomidate is considered one of the preferred agents in the rapid sequence intubation (RSI) of the hemodynamically unstable or head-injured adult patient.18 It has been used to induce anesthesia in the hemodynamically unstable pediatric patient, but there is only one study evaluating its use in the RSI of the pediatric ED patient.30, 88 Despite its use in adult procedural sedation and analgesia,31 there are no studies reporting the use of etomidate for pediatric procedural sedation and analgesia. DPT The so-called lytic cocktail has been used in pediatric procedural sedation for over 35 years.79 It is a combination of meperidine (Demerol), promethazine (Phenergan), and chlorpromazine (Thorazine). The dosage is controversial but is generally considered to be based on a 1-mg/kg dose of meperidine and a 2 : 1 : 1 to 4 : 1 : 1 ratio of the total mixture. It is administered as a single IM injection. Although it is probably one of the oldest and most used agents in the history of pediatric procedural sedation, it has been found to have a significant failure rate94, 95 and is

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associated with significant incidence of life-threatening adverse events.66, 69 In 1995, the AAP Committee on Drugs issued a policy statement recommending that alternative agents be considered, especially for patients with seizure disorders or congenital heart disease.5 With safer, shorter-acting, more reliable regimens available and in light of the AAP’s statement, DPT should no longer be considered a reasonable option for procedural pediatric sedation and analgesia. Chloral Hydrate Chloral hydrate, a sedative hypnotic that offers no analgesic properties, is one of the most frequently used agents for sedation prior to outpatient radiologic imaging.62 It is immediately converted to trichloroethanol (which is the active metabolite) and is not reversible. It is administered orally or rectally at an initial dose of 50 to 75 mg/kg with maximal total dose not to exceed 100 kg/mg or 2.0 g, whichever is less. If no clinical effect is noted, the dose can be repeated after 30 minutes, staying within the maximal dosing guidelines. In therapeutic doses, it has only mild respiratory and blood pressure depressant effects.75 Chloral hydrate has a long onset of action, averaging over 40 minutes.79 It also has a relatively long duration of action, lasting 60 to 120 minutes.54 It has a lower single dose success rate in patients over 2 years of age.57 It is not recommended for patients over 3 years or for mentally retarded patients.58 D’Agostino and Terndrup found it to have a significantly better success rate than oral midazolam when used for sedation prior to neuroimaging in the pediatric ED.29 Adverse effects associated with chloral hydrate include nausea, vomiting, and arrhythmias.6, 75 A case report of seizures after a single 70-mg/kg dose has been reported.68 Chloral hydrate has been implicated as a potential carcinogen, but a 1993 statement from the AAP Committee on Drugs recommended its continued use because there was insufficient data to warrant concern.6 Barbiturates Barbiturates are sedative-hypnotic agents that have no analgesic properties unless the patient is rendered completely unconscious.79 They are highly lipid soluble and can be given IV, IM, PO, or rectally. They function at the GABA complex but in a different manner than benzodiazepines. They are not reversible. For procedural sedation, the most frequently used barbiturates are pentobarbital (Nembutal), methohexital, and thiopental. Barbiturates are contraindicated in patients with porphyria. They are direct myocardial depressants and can cause apnea.101 They lower intracranial pressure. In low doses they have been shown to cause hyperesthesia.35 They must be used in combination with analgesics for painful procedures but are more frequently used alone for sedation for radiologic imaging studies.

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Pentobarbital is the most widely used of the barbiturates for pediatric procedural sedation.25 It is commonly given IV or IM. The IV route allows for drug titration to effect and has shorter time to onset and shorter duration of action. When given IV, pentobarbital produces sedative effects within 3 to 5 minutes and lasts from 15 to 45 minutes. The IM route provides sedation in 10 to 20 minutes and lasts from 1 to 2 hours.54 Pentobarbital can cause persistent drowsiness for up to 24 hours, regardless of route.85 Its metabolism is prolonged in patients with hepatic disease. When used as a single agent, it has relatively low incidence of adverse effects.74, 90 Usual intravenous dose is 2 to 5 mg/kg. A reported dosing technique recommends a 2.5 mg/kg bolus over 30 seconds with additional 1.25 mg/kg aliquots given if no response noted after every 30 seconds of observation to a maximal dose of 5 mg/kg.89 The IM dose is 2 to 6 mg/kg to a maximum of 100 mg. IV administration has been shown to provide better-quality sedation (ie, less motion) but a higher incidence of respiratory adverse events compared with IM (2.4% vs 0.2%).74 Other studies have noted desaturation rates as high as 7.5%, although most of them resolved with noninvasive measures, and no long-term sequelae were noted.89 The desaturations usually occur within the first 5 minutes of IV administration.47 Methohexital and thiopental are ultrashort-acting barbiturates, given rectally. Each is given at the same dosage of 25 mg/kg, and each has an onset of 10 to 15 minutes. Methohexital has a duration of 1 hour and thiopental lasts 1 to 2 hours. Methohexital should not be used in patients with temporal lobe epilepsy. Benzodiazepines The benzodiazepines are sedative-hypnotic agents with excellent anxiolytic, amnestic, and skeletal muscle relaxant properties but no analgesic effects. They exert their effect at the GABA receptor and potentiate the GABA neuroinhibitory actions. This class of agents includes diazepam, lorazepam, and midazolam. Flumazenil reverses their effects. For procedural sedation, midazolam has become the most frequent used benzodiazepine because it can be administered by any route owing to its water solubility and has a shorter duration of action than diazepam or lorazepam. Midazolam can be given by the intranasal, PO, rectal, IM, and IV route. For anxiolysis and mild sedation, the mucosal or enteral routes are adequate. For more reliable sedation or in combination with opioids or ketamine for painful procedures, the IV route is recommended. The IM route is best reserved for use with ketamine IM. When given IV to patients age 6 months to 5 years, the dose is 0.05 to 0.1 mg/kg and titrated to a maximal total dose of 0.6 mg/kg. In patients over the age of 5 years, 0.025 to 0.05 mg/kg and titrated to a maximal total dose of 0.4 mg/kg. The onset of sedation after IV administration is 2 to 3 minutes, lasting 45 to 60 minutes. The oral dose is 0.5 to 0.75 mg/kg.

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The intranasal dose is 0.2 to 0.5 mg/kg. Midazolam lasts 60 to 90 minutes by these routes. When one is using the oral or intranasal route, a minimum of 20 to 30 minutes should be allowed for onset of effective sedation.79 Intranasal midazolam can be unpleasant and difficult to administer.65 Oral midazolam also has a bitter taste but can be mixed with noncitrus juice to disguise its taste. Oral midazolam has been noted to have variable effectiveness, with some studies showing it to be less effective than chloral hydrate29, 78 but better than placebo.34, 56 When combined with an opioid analgesic, there is higher risk of respiratory depression.15, 50, 59 Adverse events in 391 patients sedated with midazolam and IV fentanyl included desaturation (2.8%), and paradoxic excitability (2.3%). All were transient and minor.73 Although vomiting has been noted in as many as 10% of patients,85 most studies show a much lower incidence.73, 84 Hypotension and degree of respiratory depression depend on dose and speed of administration as well as concomitant medications used.35 Erythromycin, diltiazem, ketoconazole, and cimetidine can enhance midazolam’s sedative effects by inhibiting cytochrome P450 activity.77 Ketamine Ketamine is a dissociative agent, which induces a state of catalepsy that provides sedation, analgesia, and amnesia. It is related to phencyclidine (ie, PCP). Ketamine has the attractive qualities of preserving protective airway reflexes and minimal effects on respiratory drive. This unique combination of effects makes it an agent that defies categorization as a general anesthetic or traditional sedative.39 Ketamine can be administered by PO, IM, or IV routes. It has shown excellent efficacy for ED pediatric procedural sedation and analgesia and has demonstrated an excellent safety profile even when multiple doses are used or in cases of inadvertent overdose.28, 37, 41, 42, 43 Ketamine is well suited to pediatric orthopedic procedures and has been shown to provide better sedation with fewer respiratory complications compared with midazolam/ fentanyl.51, 64 The dose of ketamine IV is 1.0 to 1.5 mg/kg bolus with additional aliquots of 0.5 mg/kg given based on response and length of procedure. The onset is within 1 minute, and duration of sedation is 10 to 15 minutes. The dose for IM ketamine is 4 mg/kg, with an additional 2 to 4 mg/kg given based on response and length of procedure. IM ketamine achieves sedation within 5 to 10 minutes and lasts 15 to 30 minutes. Because ketamine stimulates ororespiratory secretions, an anticholinergic, such as atropine or glycopyrrolate, should be administered concurrently.79 The dose of atropine is 0.01 mg/kg with a minimal dose of 0.1 mg and a maximum of 0.5 mg. This needs to be given only with the initial dose of ketamine and can be mixed in the same syringe as the IM ketamine to avoid a second injection. Dysphoria and agitation have been noted during recovery from ketamine sedation, and the incidence of these side effects increases with age. Concerns over emergence

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reactions have prompted use of concurrent midazolam, but no evidence exists to support this practice.83 The midazolam dose used for this indication is 0.05 mg/kg. It too can be mixed in the same syringe with ketamine and atropine for a single IM injection. Rarely, ketamine has been noted to cause apnea if given too rapidly or in excessive doses. It should be pushed over a minimum of 60 seconds.38 PO ketamine has not been as extensively studied as parenteral ketamine and appears to have a less reliable effect, with longer times to recovery than the IV or IM route.13, 48, 97 Ketamine not only preserves airway reflexes but also sensitizes laryngeal reflexes, causing laryngospasm. Laryngospasm is usually transient and rarely requires nothing more than airway repositioning or brief positive-pressure ventilations.38 Other side effects of ketamine are nystagmus, random extremity or head movements, ataxia (can last up to 24 hours), transient rash, and emesis.38 Older children have an increased incidence of emesis.40 Ketamine has bronchodilatory effects and can be useful as an adjunct in the intubation of the acute asthmatic patient. Contraindications specific to ketamine include procedures involving the posterior pharynx, conditions associated with increased intracranial or intraocular pressure, thyroid disorders, and porphyria.38 REVERSAL AGENTS Naloxone is the most commonly used opioid reversal agent. It is a pure receptor antagonist, reversing both the sedative and analgesic properties of narcotics but not the hypotensive effects. In the conscious sedation setting, it is useful for management of respiratory depression and apnea secondary to opioid overdose. The recommended dose is 0.1 mg/kg IV, IM, SC, ET q2 to 3min until response for children ages 0 to 5 years or weighing less than 20 kg, and 2 mg IV, IM, SC, ET q2 to 3 min until response for children aged 5 years or greater, or weighing more than 20 kg. Care must be taken, however, because the half-life of naloxone (1–2 h) is often shorter than the half-life of the administered opioid, and rebound sedation and apnea can occur.79 Nalmefene is a longer acting opioid antagonist. It has a 4- to 8-hour duration of action. There have been no studies documenting the safety and efficacy in the pediatric population.22 Flumazenil is the reversal agent for benzodiazepines. Its duration of action is less than that of midazolam and repeat dosing may be required. It is given IV 0.02 mg/kg and can be repeated every minute to a maximum of 1 mg. It can precipitate seizures in patients who have ingested tricyclic antidepressants or patients chronically on benzodiazepines.82 SELECTING A PROCEDURAL SEDATION REGIMEN The goal of procedural sedation and analgesia should be to match the patient and procedure with the technique and agent(s) that afford

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the safest, most humane, and most compassionate environment possible. The lightest degree of sedation and analgesia required to achieve this state should be sought. Because no two patient clinical scenarios are the same, the approach to each procedural sedation must be carefully analyzed individually. Adverse events usually are associated with inadequate monitoring and equipment preparedness, as well as not having personnel present who have the skills and knowledge necessary to address potential cardiorespiratory events.26 Depending on the procedure or patient situation, nonpharmacologic methods can be attempted first. This obviously removes the risk of using drugs altogether. If only sedation or analgesia is needed, choosing an agent with only that effect is preferable. IV administration of sedative and analgesic agents provides the most reliable onset and duration and allows the best titration to desired effect. If time and situation allow for less predictable, less time-critical, and lighter sedation/analgesia regimens, however, PO, rectal, nasal or IM routes are sometimes preferred to avoid the pain, anxiety, and time of placing an IV line. The exception to this is intramuscular ketamine, which provides a reliable dissociative state for high-anxiety or painful procedures.41, 43 For painless procedures that require motion control, PO chloral hydrate or midazolam are reasonable options. For imaging procedures that require more titratable sedation, pentobarbital IV can be considered. For quick, lowanxiety, minor pain procedures, local or topical agents combined with distraction can be a good first choice. Nitrous oxide would another good option. Another option for high-anxiety, low-pain procedures is to administer a sedative and use a topical or local anesthetic for analgesia. For example, PO midazolam or chloral hydrate with EMLA and 1% local lidocaine can be used for a lumbar puncture in a 3-year-old child. A sedative plus a regional nerve block can be an option for more extensive extremity laceration repairs. For procedures that require better motion control (e.g., complex facial laceration) or are painful and anxiety provoking, deeper sedation is more appropriate. The use of IM or IV ketamine or an IV combination of midazolam and an opioid are acceptable options. Because the combination of benzodiazepines with opioids can increase the risk of respiratory depression,7 it has been suggested that the opioid should be administered first and the benzodiazepine dose titrated.17 POSTPROCEDURE EVALUATION Postprocedure monitoring should continue until the patient is no longer at risk for cardiorespiratory complications, and vital signs have returned to baseline levels. If the patient is moved to a recovery area after the procedure, the same emergency equipment should be available. The immediate postprocedure period, when the noxious stimulus of the procedure has been removed, is a time when the respiratory depressant effects of the medications become more apparent. If reversal agents have

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been used, discharge should be delayed to ensure no risk of resedation after reversal agent effect abates. A well-performed preprocedure assessment allows one to judge when the patient has returned to their presedation baseline functioning. Discharge criteria include the following: Having intact protective airway reflexes Vital signs that are stable and within normal age-specific parameters The patient is conscious and communicative or at their presedation level of functioning (ie, age and disability dependent) Postprocedure pain is adequately controlled The parent or guardian is capable of following the discharge instructions.3, 7, 11 Having a standardized discharge instruction form is helpful, the form should be reviewed and understood prior to discharge.7 SUMMARY The ability to provide safe, effective procedural sedation and analgesia is a necessary skill for physicians caring for the acutely ill or injured pediatric patient. The physician should be familiar with the agent(s) chosen, including dosage, duration, adverse effects, and contraindications. The choice of agent and regimen should be individualized for the patient and situation. Successful outcomes depend on performing careful pre- and postsedation evaluations, following appropriate monitoring and equipment guidelines, and having the knowledge and skills to manage any adverse cardiorespiratory event. ACKNOWLEDGEMENTS The authors would like to thank Diane Hartzog for her assistance in preparing this article.

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102. Wright S: Procedural sedation and analgesia in the emergency department: The value of capnography and pulse oximetry. Ann Emerg Med 21:551–555, 1992 103. Zempsky WT, Anand KJ, Sullivan KM, et al: Lidocaine iontophoresis for topical anesthesia before intravenous line placement in children. J Pediatr 32:1061–1063, 1998 Address reprint requests to Elliot Rodriguez, MD Department of Emergency Medicine State University of New York, Upstate Medical University 750 East Adams Street Syracuse, NY 13210 e-mail: [email protected]