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Part II. Pediatric Procedural Sedation: Selecting an Agent
Authors: Jonathan Vlahos, MD, Stanford-Kaiser Emergency Medicine, Stanford, CA; and N. Ewen Wang, MD, Assistant Professor of Surgery, Associate Director of Pediatric Emergency Medicine, Stanford University Hospital, Stanford, CA.
Peer Reviewer: Susan B. Promes, MD, FACEP, Associate Professor and Program Director, Duke University Emergency Medicine Residency Program, Durham, NC.
The agents available for use in pediatric procedural sedation and analgesia (PSA) have expanded considerably over the last 20 years. Older, long acting agents with higher complication rates have been replaced by a larger number of safer, short acting agents and agents producing unique sedation states such as ketamine. While making agent selection more complex, a wide range of drugs with varying mechanisms, properties, and pharmacokinetics enables the provider to tailor the medication regimen to match each particular patient, procedure, and provider experience level. This article reviews available agents, advantages and disadvantages, and methods for selecting the most appropriate agent for PSA.
— The Editor
Many agents are available for PSA (see Table 1 for an overview). Available drug classes include sedative/hypnotics, analgesics, dissociative anesthetics, and inhalational and reversal agents. Some agents like propofol, etomidate, and ketamine are in their own unique classes, and many agents have actions that span two or more classes. Many agents provide inadequate analgesia; thus, they frequently are used in combination with an opiate analgesic. Understanding the indications and use of reversal agents and drugs used for rescue and resuscitation are a critical component of successful PSA practice.
A simplified approach to choosing an agent based on procedure characteristics is shown in Table 2. Suggested agents for common procedures are shown in Table 3. In practice, patient factors, procedure type, personal experience, skill level, monitoring capability, hospital policy, and desired administration route all guide the provider to selecting the ideal agent(s). A decreased fasting time may suggest the use of an agent with anti-emetic rather than pro-emetic properties. The influence of co-morbid illness on the rate of particular complications can make one drug preferable to another. A patient with asthma may benefit from the use of an agent that also has bronchodilatory effects. The desired depth of sedation is heavily influenced by the child's anxiety level, pain tolerance, ability to cooperate, previous exposure to healthcare providers, and level of alertness (e.g., close to napping time versus active or agitated).1,2
In general, PSA is indicated to facilitate diagnostic and therapeutic procedures and diagnostic radiology. The procedure type should be categorized with respect to anticipated duration, level of discomfort, need for motion control, and location as these factors influence the degree of sedation, anxiolysis, analgesia, and monitoring that will be required. The goal is to produce the minimal level of sedation required to successfully accomplish the procedure. The provider skill level, monitoring capability, and hospital policy may preclude the use of certain agents, particularly those, such as propofol, that are more likely to produce deep sedation or general anesthesia. For children who do not otherwise require an IV, non-parenteral agents can be safe; effective; and eliminate the pain, anxiety, and difficulty associated with IV placement. Conversely, parenteral agents tend to have more reliable pharmacokinetics, are more easily titrated, have shorter recovery times, and previously established IV access may be beneficial should complications arise. Selecting an agent(s) for PSA is a multifactorial decision making process that should take into account a diverse group of patient-, provider- and procedure-related factors. All agents have advantages and disadvantages. Often multiple appropriate options exist, with provider discretion being the final factor used when deciding between a variety of suitable options.
Older agents such as the lytic cocktail DPT (demerol, phenergan, and thorazine) and chloral hydrate are discussed only briefly as they can no longer be recommended as first-line agents. Although both regimens are fairly effective and have enjoyed wide-spread use in the past, safety concerns have limited their continuing use. The American Academy of Pediatrics (AAP) has officially cautioned against the use of DPT for pediatric PSA.3 Both agents have been associated with a variety of unfavorable outcomes, including prolonged sedation, agitation, permanent disability, and sedation related deaths.3-13 Thankfully, providers have numerous alternatives available with superior safety and efficacy, obviating the need for these older agents.
Ketamine. Ketamine is a dissociative anesthetic with sedative, analgesic, amnestic, and immobilizing properties that has gained significant popularity for facilitation of a wide variety of procedures. Developed in the early 1960s as a replacement for the anesthetic phencyclidine (PCP), ketamine is still the most commonly used anesthetic in the developing world and is commonly used as a veterinary anesthetic. When given parenterally or intramuscularly, ketamine reliably produces a unique state of trancelike catalepsy. This makes it an ideal choice for painful procedures in which motion control is important. Because of its ease of use, wide safety margin, and overall efficacy, ketamine also is indicated for a wide range of short- to intermediate-length procedures of almost any type. Prominent investigators have argued that the state it produces warrants its own term: "dissociative sedation." This is because it is outside the traditional sedation continuum (minimal, moderate, deep, general) and increasing doses do not seem to significantly alter its clinical effect once the dissociative sedation state is reached.14 The onset of action is rapid (1 minute IV, 3-5 minutes IM), and suitable procedural conditions last 10-15/15-30 minutes for the IV/IM routes, respectively. A dose of 1.5 mg/kg IV or 4-5 mg/kg IM is currently recommended;15 a repeated bolus of half the initial dose may be given for inadequate sedation or to prolong sedation.
Ketamine has been widely used both in and outside of the operating room since the 1970s and there are now published guidelines regarding its use in pediatric PSA.15 Although it is not without risk, ketamine has an extensive safety record specific to its use in the emergency department.4,16-28 Unlike many agents used in PSA, ketamine does not commonly produce respiratory depression or impair protective airway reflexes such as cough and gag22,25,26,28 as long as it is pushed slowly over 1-2 minutes. Cardiovascular function also is preserved and hypotension and bradycardia are extremely rare.
Serious adverse events with ketamine are rare and include airway misalignment (0.7%), laryngospasm (0.5%), and respiratory depression/apnea (0.3%).25 This risk is increased in procedures that may simulate the larynx directly (e.g., bronchoscopy) or indirectly secondary to secretions (e.g., incision and drainage of a peritonsillar abscess). Intractable laryngospasm leading to endotracheal intubation has been reported.29 Relative to other common regimens, ketamine may be more likely to produce vomiting.15,19,30 Emesis occurs approximately 5-20% of the time, although usually late in the post-recovery phase. Thus, the clinical significance of this difference is unclear. Ketamine can produce hypersalivation, which may then increase the incidence of laryngospasm. Concurrently administered atropine reduces the incidence of hypersalivation as well as emesis.31 Glycopyrrolate is an acceptable though not superior alternative, though it is typically less familiar to ED staff.15 Nystagmus is commonly noted during the procedure. Although it is benign and self-limited, parents observing the procedure should be warned in advance that this is a normal response. Post-procedure ataxia and diplopia also are common, and children should not be allowed to walk unassisted until these effects resolve.
Emergence reactions, the most notorious side effect of ketamine, refer to unpleasant or pleasant hallucinations occurring during the recovery phase. Mild reactions are common (5-30%), while severe reactions in children are relatively rare (1-4%). The reported incidence of these is highly variable, perhaps due to the difficulty identifying and quantifying such reactions.25,32,33 Adjunctive midazolam often is given with ketamine to prevent emergence reactions; however, large, randomized studies have failed to show any benefit to this approach.30,32 Citing the potential for increased respiratory complications and decreased hepatic ketamine clearance, recently published guidelines recommend against using adjunctive benzodiazepines. Although not useful to prevent emergence reactions, benzodiazepines offer rapid, effective treatment when severe reactions occur.24-26,34 Although not evidence based, providing a quiet, calming environment pre- and post-procedure have been suggested as useful techniques to reduce recovery agitation.15
The contraindications to ketamine are numerous (see Table 1), and including them in a procedural sedation paperwork packet or protocol may assist providers with remembering them. Absolute contraindications include age younger than 3 months and known or suspected psychosis, even if the patient is currently stabilized. Of particular importance to the emergency physician, active asthma or current upper respiratory tract infection are relative contraindications as they increase the risk of laryngospasm. Because it may increase intracranial pressure, ketamine also is contraindicated in patients with potential head injuries. Although generally not used in adults because of higher rates of emergence reactions, ketamine has been used without increased complication rates in children up to age 15, and may be considered safe in this group.15,21,25,26,30,32,33 Ketamine has become the cornerstone of the modern pediatric PSA pharmacopeia due to its safety, efficacy and ease of use. As its use continues to grow, it is important that the emergency physician remains as cognizant of when not to use ketamine as he or she is of the growing number of its indications.
Sedative-hypnotics represent the largest class of agents used for procedural sedation. Many agents are useful when used alone for non-painful or minimally painful procedures, but must be combined with local or systemic analgesia when used for painful procedures. In general, any use of systemic opiates for adjunctive anesthesia will increase the incidence of respiratory depression and prolonged sedation; therefore, they should be avoided when local techniques will suffice.
Chloral Hydrate. Newer, safer, more effective agents have largely replaced choral hydrate in the emergency department and it cannot be recommended as first line in this setting. Chloral hydrate is an older sedative-hypnotic agent that has been used for more than 20 years to provide pediatric PSA. It continues to be used in some settings to facilitate diagnostic imaging. The primary limitations of chloral hydrate are unreliable onset, numerous unpleasant side effects, and extremely prolonged sedation that can be delayed in onset. In one series, 52% of patients were still not back to baseline behavior by 8 hours, and 11% had behavioral effects lasting longer than 24 hours. In the ED setting, where timely discharge home is anticipated, this side effect is particularly concerning. Other side effects include ataxia, recovery agitation, gastrointestinal toxicity, arrhythmia, and, rarely, coma.8,9,11-13,35 Chloral hydrate also accounts for a disproportionate number of deaths associated with PSA, primarily secondary to prolonged sedation and inadequate monitoring.4 Chloral hydrate is contraindicated in patients with significant hepatic, renal, or cardiac disease. Compared to chloral hydrate, intravenous pentobarbital provides more reliable sedation across age groups, with a lower incidence of complications.36,37
Benzodiazepines, used alone or in conjunction with opiates, are used to facilitate a large variety of short- to medium-length non-painful and painful procedures. Available by a large number of routes, benzodiazepines provide sedation, anxiolysis, and variable amnesia, but have no intrinsic analgesic properties. Although diazepam also has been used, midazolam is generally the preferred agent in this class due to its rapid onset (2-3 minutes) and short duration of effect (10-15 minutes for the IV route). Midazolam also is available in rectal, intranasal, sublingual, oral, and intramuscular preparations. Of these, the rectal route may be the most useful as it is reliably absorbed (unlike the oral and intranasal routes) and avoids the need for a needle stick.
As a single agent, midazolam is useful to provide light to moderate sedation and anxiolysis for short-duration diagnostic imaging, laceration repair (with adjunctive local anesthetic), lumbar puncture, arthrocentesis, foreign body removal and other similar procedures.38-43 The success of midazolam when used alone depends on the child's anxiety level and ability to cooperate, how painful the procedure is, and the unpredictable incidence of paradoxical excitement. Respiratory or cardiovascular depression is possible but unlikely when no adjunctive medications are used. Paradoxical excitement or agitation is relatively common (~1-15%),40,44-48 but often can be treated with a repeated dose of midazolam44,49-52 or ketamine52 when appropriate.
When combined with fentanyl, midazolam can be used for a large variety of short to medium length procedures where systemic analgesia or moderate to deep sedation is required, such as joint and fracture reductions. The combination of fentanyl and a benzodiazepine to provide PSA is safe, effective, widely used, and extensively studied.4,16-20,34,39,48,53 In some emergency departments, it may be the only choice for PSA.
Despite its widespread acceptance, the incidence of complications with an opiate and benzodiazepine combination is synergistic. Respiratory depression occurs approximately 25% of the time;44,48 this is significantly higher than that found with most alternative regimens. However, respiratory depression necessitating endotracheal intubation is uncommon. Prolonged sedation and increasing sedation after the completion of the painful portion of the procedure also are more common compared to other agents used in similar circumstances. Reversal with flumazenil should be reserved for only the most severe or intractable cases as supportive measures are usually adequate (see section on "reversal agents").
Pentobarbital is a longer acting barbiturate primarily used to facilitate diagnostic imaging. At recommended doses it tends to produce moderate to deep sedation, amnesia, and immobilization without analgesia and has a good safety record when used in a monitored setting.36,40,54 Compared to rectal administration, the IV form provides a more rapid onset of action (3-5 minutes), a shorter duration of action (30-40 minutes), and is titratable. When avoiding IV placement is desirable, rectal administration has similar safety and efficacy, although its extended duration of action of up to 240 minutes may significantly increase the time necessary for post-procedure monitoring. For infants younger than 12 months, oral pentobarbital has similar efficacy but lower complication rates relative to the IV form.55,56 Respiratory depression is the most common side effect; consideration should be given to the use of capnography during prolonged procedures to facilitate detection of hypoventilation when close observation of the patient's chest wall is not possible. Significant hypotension is uncommon but does occasionally occur. Due to the increased risk of deep, non-reversible sedation, pentobarbital should not be combined with other agents. Relative to other agents commonly used to facilitate diagnostic imaging (chloral hydrate, midazolam, etomidate), pentobarbital has a higher rate of successful sedations and similar complication rates;35,36,40,54,56 this secures its place in the modern PSA pharmacopeia.
Thiopental and methohexital are short and ultra-short acting barbiturates that are useful for diagnostic imaging and brief, painful procedures and have a good safety profile.57-59 Given PR (rectal administration), both agents have similar effects to pentobarbital, but have shorter durations of action. Intravenous thiopental is typically not used as it has not been adequately studied in the setting of pediatric PSA. Intravenous methohexital is useful for orthopedic reductions as it produces extremely brief (5-10 minutes) deep sedation and may be given with adjunctive fentanyl for analgesia without significantly impacting complication rates.57-59 Respiratory depression occurs approximately 15% of the time, and cardiovascular depression while not uncommon, is rarely clinically significant.59 Rectal methohexital can be used to facilitate shorter diagnostic imaging procedures and is significantly less likely than the parenteral form to cause respiratory depression.60 Compared to pentobarbital, it has a slightly shorter recovery time (20-30 minutes) but a higher incidence of respiratory depression. Other minor side effects associated with barbiturates include hiccups, cough, hypersalivation, and paradoxical agitation. All barbiturates are contraindicated in patients with porphyria or temporal lobe epilepsy.
Propofol is a unique, ultra-short acting sedative gaining increasing acceptance outside of the operating room for use in PSA for brief, painful procedures. Propofol generally produces deep sedation to general anesthesia, profound amnesia, and euphoria but has no intrinsic analgesic properties. As an agent for PSA, propofol is very attractive due to its extremely rapid onset and recovery times, titratability, anti-emetic properties, and high degree of patient and parent satisfaction. A bolus dose of 1 mg/kg initially is typically used, followed by 0.5 mg/kg as needed. Continuous infusion is an alternative. Relative to other agents used for similar indications (versed/fentanyl, ketamine), propofol's main advantage is a more rapid recovery time with little or no incidence of post-recovery agitation or emergence phenomenon.23,61,62
Propofol continues to be controversial for use outside of the operating room at many institutions, largely out of concern that the deep sedation it causes may lead to serious adverse events. However, this concern has not been substantiated in published reports which demonstrate safety and efficacy in the pediatric ED population similar to that of other commonly used agents.23,62-73 Propofol has not been well studied for emergency department procedures of longer duration and currently should not be used for this indication. Significant respiratory depression is common with propofol, occurring 5-30% of the time depending on whether supplemental oxygen is used.23,62-71 Decreased blood pressure, caused by a combination of negative inotropy and vasodilation, is very common but generally not clinically significant in otherwise healthy children. Significant hypotension, when it occurs, can be readily treated with fluids and by withholding further sedation. Because of its lack of analgesic properties, propofol often is combined with fentanyl, although this practice is not universal. The diluent in propofol contains egg lecithin; thus, it is contraindicated in patients with egg or soybean allergy.
Etomidate is a unique, ultra-short acting sedative that is useful for a wide variety of brief procedures. In addition to profound, titratable sedation, it has amnestic and anxiolytic but not analgesic properties. Initially studied in the adult population, a growing number of studies support its safe use in children.44,54,64,74 Deep sedation occurs within 1 minute of administration and lasts 5-15 minutes. Etomidate alone can be used to facilitate non-painful procedures such as diagnostic imaging.54,64 It may safely be combined with fentanyl for painful procedures such as fracture reduction, and may offer significant advantages over commonly used alternatives. Compared to midazolam/fentanyl, etomidate/fentanyl has a shorter onset, more rapid recovery time and higher efficacy for fracture reduction, with no significant difference in adverse events.44 It produces respiratory depression at rates similar to other sedatives used in PSA, but has minimal hemodynamic side effects. This is an important difference from propofol. Etomidate may cause nausea, vomiting, myoclonus, and pain at the injection site which may be mitigated by mixing lidocaine 0.5 mg/kg with the first bolus injection. Adrenal suppression, while documented to occur with a single dose of etomidate, lasts less than 12 hours and is not clinically significant in otherwise healthy patients.75
Nitrous oxide is the only inhaled anesthetic available for use in ED PSA and is primarily useful for short, minimally painful procedures. Its primary effect is anxiolysis, although it also produces sedation and analgesia in a dose dependent fashion. Effects are typically noted within 30-60 seconds and recovery within minutes of discontinuation. Nitrous oxide is generally delivered in a mixture containing 30-70% oxygen either through a mask strapped to the patient's face, or self-administered with the patient holding the mask and using a demand valve. When self-administered, only minimal sedation is possible as the patient will drop the mask when a deeper sedation state is reached. With a cooperative child, and appropriate use of adjunctive analgesia, nitrous oxide can be useful for IV placement, laceration repair, lumbar puncture, and other similar procedures. Self-administered nitrous oxide is very safe with minimal or no impairment of protective airway reflexes or cardiovascular function.49-51,76,77 Continuously administered nitrous oxide is capable of producing moderate to deep sedation and the associated increase in respiratory side effects necessitates closer monitoring, though the overall incidence is still low. Used in this fashion nitrous oxide has been favorably compared to ketamine and midazolam for more painful procedures such as fracture reduction.76-82 Compared to ketamine, one study found similar efficacy, a lower incidence of side effects and shorter recovery times.78
Additional analgesia often is required when using nitrous oxide for painful procedures and includes local anesthetics, hematoma blocks, and systemic analgesia. The primary limitation of nitrous oxide is the specialized equipment needed to safely use it is not available in most emergency departments. Improperly scavenged nitrous oxide can increase the rate of spontaneous abortions83 and there is a potential for abuse by medical staff. Common side effects are mild and include euphoria, laughter, crying, voice changes, and occasionally emesis at higher doses. Due to high diffusability, nitrous oxide is contraindicated in diseases where patients may have air inside of a closed hollow viscous (e.g., bowel obstruction, pneumothorax).
Fentanyl. Opiate analgesics remain the mainstay of managing pain during PSA. Because of its favorable pharmacokinetics and side effect profile, fentanyl has largely replaced longer acting agents such as morphine and meperidine. Compared to these agents, fentanyl has a shorter onset (1-3 minutes) and duration of action (20-40 minutes). It provides reliable, titratable analgesia, with some sedative properties at doses greater than 2 mcg/kg but has no anxiolytic or amnestic properties. Unlike most opiates, fentanyl does not provoke histamine release and thus is less likely to cause hypotension, hives, nausea, and vomiting. The most commonly encountered serious side effect of fentanyl when used for PSA is respiratory depression and apnea which can be readily reversed with naloxone. Chest wall rigidity, though well known, is rare, tends to occur in neonates and young infants, and has only been associated with bolus doses greater than 3-5 mcg/kg. That is higher than the doses used during PSA.16,18,84,85 Other less common side effects include centrally mediated pruritus (especially nasal), and hypotension (rare). Fentanyl also is available in an oral transmucosal formulation, although this route of administration is limited by a high incidence of emesis and unreliable effect on pain scores.39,86,87
Because fentanyl has primarily analgesic properties, it is commonly administered as an adjunct to sedative-hypnotics such as propofol and etomidate. Fentanyl should not be combined with barbiturates as the incidence of respiratory complications is unacceptably high and barbiturates are not indicated for painful procedures. When fentanyl is used, an opiate reversal agent should be readily available.
Opiate and benzodiazepine antagonists are available to reverse the effects of agents in these classes. Although they should be readily available when opiate or benzodiazepine agents are used, in practice they should be reserved for only the most severe cases of accidental overdose, respiratory depression, oversedation not responsive to repositioning or stimulation, supplemental oxygen, and a brief course of bag-valve mask ventilation. Any patient administered reversal agents requires prolonged monitoring to protect against resedation when the effect of the reversal agent wears off.
Naloxone is a short acting opiate antagonist available by a wide variety of routes, and is safe for use in children and infants.88,89 Compared to a large initial dose, small, frequent doses titrated to effect offer a smoother recovery with reduced side effects. Common adverse effects include modest increase in respiratory rate, heart rate, and blood pressure, as well as vomiting and pain.88 Because of its short half-life, prolonged monitoring is particularly important in patients who have received naloxone.
Nalmefene is an opiate antagonist similar to naloxone but with a significantly longer half-life (4-10 hours). Although shown to be safe and effective for opiate overdose in both adults and children,90-92 it should be used only in severe overdose or when post-procedure pain is not anticipated as its long half-life will make opiate analgesia impractical.
Flumazenil rapidly reverses benzodiazepine-associated sedation, though its side effects and numerous contraindications limit its use. Because of their superior tolerability, opiate reversal agents should be used and their effect assessed prior to giving flumazenil when an opiate/benzodiazepine combination has been used for PSA. Flumazenil lowers the seizure threshold and its use should be avoided in any patient taking chronic benzodiazepines or other medications associated with a lowered seizure threshold.
Management of Laryngospasm
Drugs to facilitate rapid sequence intubation should be readily available. Although the need for intubation is rare, succinylcholine also may be useful in the management of intractable laryngospasm, of particular concern when using ketamine. Laryngospasm occurs when the vocal cords spasm and completely obstruct the airway at the level of the glottis. Symptoms of laryngospasm include inspiratory stridor/airway obstruction, increased inspiratory efforts/tracheal tug, paradoxical chest/abdominal movements, desaturation, and bradycardia. Management consists of application of 100% oxygen, and continuous positive airway pressure achieved by applying steady pressure with a bag-valve-mask. If this is unsuccessful, a low dose of succinylcholine (0.5 mg/kg IV or IM) often is successful at relieving the obstruction. Endotracheal intubation, though generally easily accomplished, is a measure of last resort.
Pediatric procedural sedation and analgesia is a continually evolving, critical component of emergency department practice. High quality research performed in emergency departments all over the world have provided the justification needed to move a growing number of previously restricted drugs into the hands of practicing emergency physicians. Compared to drugs used for PSA outside of the operating room twenty years ago, these agents provide dramatically better safety and efficacy, and have improved patient and provider satisfaction. Studies of new agents and combinations such as remifentanil, diamorphine, "ketofol" (ketamine and propofol), dexmedetomidine continue to push the sedation frontier forward. At the same time, large registries such as the Pediatric Sedation Research Consortium93 are providing much needed data about practice safety, with large enough power to detect and document rare complications. Past experience has taught us that less is often more: combining more than two agents can be a recipe for disaster. As the safety of pediatric PSA continues to improve, providers must remember that improved monitoring and skill of practitioners underlie much of these gains. Similarly, as PSA becomes more effective, time tested non-pharmacologic alternatives such as support from calm, caring providers and parents should continue to be the foundation of compassionate pediatric emergency care.
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