47 Sedation for Diagnostic and Therapeutic Procedures Outside the Operating Room
THE USE OF SEDATION and analgesia for diagnostic and therapeutic procedures performed by anesthesiologists and nonanesthesiologists outside the operating room (OR) continues to dramatically increase. Millions of such procedures are performed each year throughout the world. Great progress has been made in understanding the need for and the risks associated with sedation and analgesia outside the OR; the mere restraint of a child for a frightening and/or painful procedure is difficult to justify.1–4 Indeed, the time-honored techniques of immobilization by physical restraint or sedation with archaic medications, such as the “lytic cocktail” (meperidine, promethazine, and chlorpromazine), are unacceptable and were made possible only because children were easily overpowered, not routinely asked if they were in pain, and were unable to withdraw consent. Furthermore, many of these techniques were inefficient and failed to provide the conditions necessary to complete required procedures. Sedation/analgesia for painful procedures performed outside the OR (e.g., bone marrow aspiration, lumbar puncture, repair of minor surgical wounds, insertion of arterial or venous catheters, burn dressing changes, fracture reduction, bronchoscopy, and endoscopy) requires the same attention to detail as for procedures performed in the OR, because sedation levels needed often achieve the state of deep sedation or general anesthesia, particularly in children 6 years of age and younger. Nonpainful procedures often require sedation, immobility, and sometimes breath-holding. Children undergoing diagnostic studies (e.g., computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography, electroencephalography [EEG], electromyography), or who require high doses of ionizing radiation, also require deep levels of sedation or general anesthesia because they must remain absolutely motionless.5 Given these requirements, a team approach is required to provide appropriate care for the child and to provide optimal conditions for the procedure.
Young and developmentally delayed children, are often unable to remain motionless for even short periods of time. Even some older children and adults may be unable to enter the confined space and often frightening environment of a diagnostic imaging scanner. The fear and anxiety associated with procedures are difficult to control and may be exacerbated by parental anxiety, separation from parents, and the pain (or anticipation of pain) from the procedure. Although distraction, guided imagery, and the use of videos and music have clear and documented benefit, they are often not enough to efficiently and successfully complete procedures.6–10
The pharmacologic armamentarium for sedation for diagnostic and therapeutic procedures has greatly expanded to include drugs classified as sedatives, as well as those classified as general anesthetics. Who uses these drugs and what qualifications are needed by those who provide such sedation is controversial.11 The demand for safe efficient sedation and analgesia outside the OR comes from many sources, including hospital administrators, insurance companies, and medical specialists. Failed sedations for diagnostic or therapeutic procedures are no longer acceptable, as this increases costs and frustrates parents12; however, this manpower need has far outstripped the available supply of anesthesiologists. This led to the demand to create sedation services for diagnostic or therapeutic procedures by nonanesthesiologists (i.e., nurse practitioners, pediatricians, emergency medicine physicians, intensivists, and dentists) who often use sedative agents, including general anesthetics. The development of pediatric sedation services has taken many directions. In a 2005 survey of pediatric sedation practice in 116 children’s hospitals in the United States and Canada,13 only 50% of the hospitals had a formal pediatric sedation service. Anesthesiologists were the sole sedation providers in only 26% of institutions. A consortium of pediatric hospitals heavily involved in sedation noted that anesthesiologists were involved in 19% of sedation procedures.14 Even when looking at the use of drugs such as propofol, which is considered a “general anesthetic,” this group noted anesthesiologists involvement only 10% of the time.15 This chapter will focus on the current definitions of sedation for diagnostic and therapeutic procedures and the goals, risks, and guidelines for creation of safe conditions for children who require sedation for procedures outside the OR.
As anesthesiologists we need to ask—why should we care? We believe that we provide the best, most efficient, and safest conditions for procedures, whether they are painful or not and whether they are in the OR or not. However, there simply aren’t enough anesthesia care providers to meet the ever-increasing demand. Further, after years of training and the ability to provide anesthesia for “big” cases (e.g., liver transplants, craniofacial reconstruction, trauma, etc.), we need to ask ourselves whether we are “overtrained” to care for children who require sedation or anesthesia for procedures outside of the OR, or whether it can be safely done by others with less training. Federal regulatory agencies, hospital administrations, and professional societies have recognized the expertise of anesthesiologists to provide sedation and have required us to lead, teach, and be responsible for oversight and credentialing of all sedation providers. We must “grab this tiger by its tail.”12,16
Definition of Levels of Sedation
Several organizations have created guidelines and definitions of sedation for diagnostic and therapeutic procedures in children.17–20 The definitions of the American Academy of Pediatrics (AAP), the American Society of Anesthesiologists (ASA), The Joint Commission (previously called the Joint Commission on Accreditation of Healthcare Organizations), and the American Academy of Pediatric Dentistry (AAPD) are the most frequently cited and agreed-upon position statements.18,19,21–23 These organizations defined sedation and analgesia for procedures as a continuum of consciousness to unconsciousness, ranging from minimal sedation (anxiolysis) to moderate sedation (previously, “conscious sedation”) to deep sedation and general anesthesia (Fig. 47-1). Note that a child’s depth of sedation may easily pass from a light level all the way to general anesthesia.24
A clear understanding of the definition of sedation is mandatory to recognize when the child has progressed to a deeper level of sedation than anticipated (i.e., from moderate sedation to deep sedation or from deep sedation to general anesthesia). Recognition of this transition allows escalation of monitoring and care to avoid complications. The AAP, ASA, and The Joint Commission formalized and defined the concepts of minimal sedation, moderate sedation, deep sedation, and general anesthesia. The definitions that follow are taken from The Joint Commission (2010)25,26 and are in agreement with AAP, AAPD, and ASA definitions18,19,21:
Minimal sedation (anxiolysis): A drug-induced state during which patients respond normally to verbal commands. Although cognitive function and coordination may be impaired, ventilatory and cardiovascular functions are unaffected (Video 47-1)
.
.
.
.Painful procedures or nonpainful procedures requiring complete immobility (e.g., diagnostic imaging or radiation therapy) cannot be performed in a child who is moderately (“consciously”) sedated. Most pediatric procedures require deep sedation. The myth that a state of moderate sedation in which children are conscious and simultaneously responsive to voice command while immobile in the face of pain is just that, a myth.27
Assessing the depth of sedation based on the child’s responses to stimulation is illustrated in Figure 47-2. This is a difficult challenge in children and depends on their verbal abilities, age, level of maturity, and underlying condition. A common problem with classifying a child as either moderately or deeply sedated is to misinterpret any movement in response to touch as “purposeful” and therefore a sign of “moderate sedation.” A child who is moderately sedated should respond to touch or firm rubbing by an appropriate response, such as saying “ouch,” pushing your hand away, and pulling up the covers. An inappropriate response, such as nonpurposeful movement, is a sign that the child has progressed to a deeper sedation level, which should lead to an escalation of care because respiratory depression may occur.28–31 Similarly, children who are deeply sedated should respond purposefully to painful stimuli. Reflex withdrawal, a nonpurposeful response or no response to painful stimuli, is a sign that the child has progressed to a level of anesthesia and should be cared for using guidelines and personnel for general anesthesia. Children may quickly move from one level of sedation to another. A study in a large pediatric hospital showed that the goal of either moderate or deep sedation was only attained in 50% to 75% of patients. An awake state was noted in 12% to 28% of children, and a level consistent with general anesthesia was observed in up to 35% of children.32 The need for accurate assessment of the sedated child has brought about several scoring systems.
*Purposeful: opens eyes, talks back, pushes you out of the way.
†Nonpurposeful: winces, shrugs shoulders, nonspecific withdrawal to pain.
The Ramsay scale was described by Ramsay and colleagues33 in 1974 for the purpose of monitoring sedation with alphaxalone-alphadolone (Table 47-1). It continues to be the most widely used scale for assessing and monitoring sedation in daily practice, as well as in clinical research. It spans the continuum of sedation but does not clearly separate purposeful from nonpurposeful responses. The Ramsey scale has been modified to more clearly coincide with the AAP and Joint Commission guidelines (Table 47-2).34 A score of 2 to 3 is anxiolysis, 4 to 5 is moderate sedation, 6 is deep sedation, and 7 to 8 is general anesthesia.
| Level | Characteristics |
|---|---|
| 1 | Patient awake, anxious, agitated, or restless |
| 2 | Patient awake, cooperative, orientated, and tranquil |
| 3 | Patient drowsy, with response to commands |
| 4 | Patient asleep, brisk response to glabella tap or loud auditory stimulus |
| 5 | Patient asleep, sluggish response to stimulus |
| 6 | Patient has no response to firm nail-bed pressure or other noxious stimuli |
TABLE 47-2 Modified Ramsay Sedation Scale
| Score | Characteristics |
|---|---|
| 1 | Awake and alert, minimal or no cognitive impairment |
| 2* | Awake but tranquil, purposeful responses to verbal commands at conversation level |
| 3* | Appears asleep, purposeful responses to verbal commands at conversation level |
| 4† | Appears asleep, purposeful responses to verbal commands but at louder than usual conversation level or requiring light glabellar tap |
| 5† | Asleep, sluggish purposeful responses only to loud verbal commands or strong glabellar tap |
| 6‡ | Asleep, sluggish purposeful responses only to painful stimuli |
| 7§ | Asleep, reflex withdrawal to painful stimuli only (no purposeful responses) |
| 8§ | Unresponsive to external stimuli, including pain |
The Observer’s Assessment of Alertness/Sedation (OAA/S) scale35 is often cited as a scale for sedation. It is scored as follows: 1, no response to shaking; 2, responds to mild prodding; 3, responds to name called loudly; 4, lethargic response to name; and 5, readily responds to name. However, its inability to clearly categorize deep levels of sedation and lack of a clear differentiation between purposeful and nonpurposeful responses limit its usefulness. The University of Michigan Sedation Scale (UMSS)36 is an assessment tool that has been shown to be valid when compared with the OAA/S scale and other scales of sedation (Table 47-3). It readily separates patients into the sedation categories defined by the AAP, ASA, and Joint Commission.
TABLE 47-3 University of Michigan Sedation Scale (UMSS)
| Score | Characteristics |
|---|---|
| 0 | Awake and alert |
| 1 | Minimally sedated: tired/sleepy, appropriate response to verbal conversation and/or sound |
| 2 | Moderately sedated: somnolent/sleeping, easily aroused with light tactile stimulation or a simple verbal command |
| 3 | Deeply sedated: deep sleep, arousable only with significant physical stimulation |
| 4 | Unarousable |
These subjective, responsiveness-based assessment tools all have the disadvantage of intermittently stimulating the child during the procedure and thereby undoing the very reason that sedation was given in the first place! Poking or prodding the child to determine their depth of sedation defeats the purpose of sedation in many situations, e.g., infants, developmentally delayed, or procedures requiring immobility. None of the guidelines require this type of assessment. These responsiveness-based definitions are meant to provide a roadmap for safety, with the understanding that a nonresponding child requires an increased level of vigilance and the provider must have the skills to rescue should an adverse respiratory or cardiac event occur.12 Concerns regarding these types of assessment tools have led to a drive by some to revise the sedation continuum and to use other monitoring to assess level of sedation.37
To address the problem of defining the depth of sedation or anesthesia, a nonstimulating continuous-assessment tool using a processed EEG, as in the bispectral index (BIS) monitor, has been extensively explored. The BIS was derived from empirically estimating processed EEG parameters that best predicted OAA/S scale levels in adult volunteers receiving a wide variety of anesthetics, analgesics, and sedatives.38 BIS values in adults range from 100 to 95, awake; 95 to 70, light to moderate sedation; 70 to 60, deep sedation with low probability of explicit recall; and 60 to 40, general anesthesia.39 Unfortunately, the EEG in children varies markedly with age and drug, precluding accurate measures by the processed EEG.40,41 Attempts to correlate BIS values with the depth of sedation in children have had varying success. In healthy children between 1 and 12 years of age who were sedated with chloral hydrate, meperidine and promethazine, midazolam, fentanyl, or pentobarbital, the BIS reading correlated well with the UMSS scores.42 In a similar study with children between birth and 18 years of age who received inhalational anesthetics, chloral hydrate, midazolam, and fentanyl,43 the BIS readings validated the sedation scores, although the data identified several important limitations when distinguishing moderate from deep sedation. For example, the researchers concluded that a BIS of 80 is the optimal cutoff for a diagnosis of deep sedation although this value is inconsistent with that found in the adult literature. In children recovering from propofol and remifentanil anesthesia, there was a marked overlap between moderate and deep sedation using both the BIS and the composite A-line autoregressive index (auditory EEG).44,45 From a safety perspective, it is worrisome that the BIS underestimates the depth of sedation with certain medications, such as chloral hydrate.45,46 During pentobarbital sedation, the BIS had “limited ability to distinguish between moderate and deep sedation levels in children.”47
Furthermore BIS values are not age specific,48,49 may differ from one side of the head to the other, are diminished in developmentally delayed children,50 may increase with larger doses of ketamine because of ketamine-induced central excitation,51,52 and are unaffected even by high-dose dexmedetomidine.53 Therefore the overlap between levels of sedation, the few large well-controlled studies in children, the overall low quality of BIS data in some studies, as well as a lack of information for different age-groups and specific drugs, precludes validation of the BIS for use in sedated children.40 In addition, the use of BIS-type monitoring is not feasible for many procedures, such as MRI, CT scans, or those involving the mouth and airway (endoscopy, dental, bronchoscopy), because the monitor is either not compatible, creates artifacts, is easily dislodged, or is in the way of the proceduralist.
The definitions and tools discussed previously attempt to assess sedation and decrease risk by quantitating the response to stimulation or EEG activity. These tools, however, do not directly measure the risk of loss of control of the airway, which is the primary cause of morbidity and mortality during sedation.54,55 The implication is that there is a direct quantifiable correlation between response to touch or painful stimulation and the ability to control the airway. Thus a moderately sedated child who can respond to light touch can protect his or her airway and a deeply sedated child who can respond appropriately only to pain may not be able to protect his or her airway. The important assessment of the child is not the response to stimulation, but the ability to protect the airway. Furthermore, different sedative drugs have different effects on analgesia separate from obtundation of the airway. Propofol is not a profound analgesic but has profound effects on the airway.56 Conversely, the sedative dexmedetomidine may provide profound sedation with little depression of respiratory function. Ketamine produces intense analgesia and most children maintain a patent airway and adequate respiratory effort (Table 47-4).57
TABLE 47-4 Examples of Sedative Drugs That Have Varying Effects on Response to Pain and Airway Protection
| Response to Pain Does Not Predict Airway Maintenance All Drugs Are Different |
||
| Response to Pain | Airway Maintenance | |
| Fentanyl | ↓↓ | ↓ |
| Propofol | ± | ↓↓ |
| Ketamine | ↓↓ | ± |
| Dexmedetomidine | ↓ | + |
↓↓↓, Large decrease in response to pain or large effect on airway patency; ↓, some decrease in response to pain or some effect on airway patency; ±, minimal to no effect on response to pain or effect on airway patency; +, no effect on airway patency.
Until recently, a quantifiable metric to assess control of the airway in sedated children was not available.58 Studies on the changes of airway dimensions under different anesthetic and sedative agents, the effect of different positions on the upper airway,59–61 and upper airway collapsibility with different concentrations of sedative drugs provide a more meaningful assessment of airway risk and protection. The profound effect of propofol-induced collapse of the upper airway can be partially mitigated by reducing the dose and including supplemental drugs, such as midazolam and nalbuphine.62,63
Assessing sedation must also focus on appropriate discharge readiness. Adverse effects, including death, have occurred after premature discharge following sedation for a procedure.55 These events have occurred most often when a long-lasting (long half-life) sedative, such as chloral hydrate, has been given (Fig. 47-3). This can result in the child being unable to spontaneously clear his or her airway.54 A simple modified “maintenance of wakefulness” score (infants had to stay awake for at least 20 minutes in a quiet environment before discharge) ensured that more than 90% of children had returned to baseline, compared with only 55% of children assessed as “street ready” according to usual hospital discharge criteria.44
Goals of Sedation
The goals of pediatric sedation have not changed over the years and can be summarized as follows18,31:
Guard the child’s safety and welfare. The individual who performs the procedure cannot safely monitor the child as well. A second individual must monitor the child, administer drugs, and record vital signs.
Minimize physical discomfort and pain.
Control anxiety, minimize psychological trauma, and maximize the potential for amnesia.
Control behavior and/or movement, to allow the safe completion of the procedure.
Create an optimal and efficient system that is not a burden to the health care providers
Risks and Complications Associated with Sedation
A recent area of concern that was not previously recognized in providing safe sedation or anesthesia to small children is whether drugs used for sedation or anesthesia are neurotoxic to children64–71; this topic is covered in detail in Chapter 23. More important than the theoretical concern regarding potential neurotoxicity of sedating medications is the more practical risk assessment regarding both inadequate and excessive sedation. Sedation centers in the United States are less likely to offer sedation for painful procedures than similar centers in Europe. Thirty percent of U.S. respondents to a mail survey reported performing bone marrow biopsies in children without significant sedation more than 50% of the time, as compared with 0% of European centers!72 When 1140 children (mean age 2.96 ± 3.7 years) were sedated by nonanesthesiologists who followed AAP guidelines for procedures,73 approximately 13% received inadequate sedation.
The psychological consequences of inadequate sedation have not been specifically studied but can be inferred from children’s responses to other stressful situations. Inadequate preoperative sedation is clearly linked to increased anxiety in children and their families. Of children undergoing a stressful anesthesia induction, 54% have postoperative maladaptive behaviors for up to 2 weeks after the experience.74 The incidence of these behaviors decreases with the use of appropriate preoperative sedation. Similar sequelae have been reported after repeated invasive procedures in pediatric intensive care units (ICUs).75 Although the number of children who developed posttraumatic stress syndrome because of no sedation or less than optimal sedation during diagnostic and therapeutic procedures is unknown, one can assume that it would be similar to that found in the study situations.
There have been many approaches to assess the risk involved in oversedation of children. One approach is to review sedation-related deaths and critical incidents to find common causes. In 2000, a now classic retrospective review was undertaken of 95 cases of sedation-related deaths and critical incidents derived from the U.S. Food and Drug Administration’s (FDA) adverse drug event reporting system, the U.S. Pharmacopeia, and a survey of pediatric specialists.54 Although a number of the incidents cited in this study occurred over 20 years ago, the findings remain applicable today. The analysis revealed that, rather than being related to a specific medication, the overwhelming majority of critical events were preventable and caused by operator error or lack of robust rescue systems. Drug interactions were the most common factor, followed by drug overdose, inadequate monitoring, inadequate cardiopulmonary resuscitation skills, inadequate evaluation before sedation, and premature discharge from medical supervision. The report emphasizes that most sedation complications are related to adverse respiratory events (80%); a majority progressed to cardiac arrest, indicating a lack of rescue skills of the practitioners. A disproportionately large number of severe complications and deaths occurred when sedation was performed in offices outside of hospitals, pointing to a lack of trained personnel available for rescue. There was no relationship with class of drug or route of administration, although there was a positive correlation when three or more sedating medications were administered.55 Indeed, the combination of a sedative, hypnotic, and an opioid is well recognized as a precursor to significant respiratory depression.
There are many underpowered reports with relatively few patients (n <200) receiving a variety of sedative medications in a variety of settings declaring successful completion of the procedures and no fatalities.76–86 Most studies describe adequate conditions and successful completion with no severe outcomes, but with varying frequencies of transient airway obstruction or desaturation. Conclusions often state that the particular technique and sedation providers are safe and effective. An example is a study that prospectively followed 1140 children (mean age 2.96 ± 3.7 years) sedated for procedures by nonanesthesiologists following AAP guidelines and using a quality-assurance tool.73 Neither death nor sedation-induced crises occurred, although they reported a 5.3% incidence of respiratory events, including one in which a child developed apnea. Given that the expected incidence of a sedation-induced crisis should be on the order of one in tens of thousands, it is not surprising that the majority of similar studies are underpowered to report a critical event.87
Another approach to assessing safety is to carefully observe relatively small groups of children and track minute-to-minute changes in their level of sedation. This has been accomplished by the creation of the Dartmouth Operative Conditions Scale (DOCS) (Table 47-5).88 This scale was derived from observing 110 videos of pediatric sedation outside the OR. The DOCS quantifies the child’s “state” based on observable behavior. Continuously applying this scale allows for careful tracking of level of sedation, effectiveness of sedation, uncontrolled adverse effects, and the timing of induction of sedation and recovery without poking or prodding the child to determine their depth of sedation. These data can help to quantify the quality of sedation and best practices.
Simulations have been used to carefully examine rare adverse effects in pediatric sedation and ability to rescue.89,90 In a simulated scenario of a sedation complication, a standard reproducible event was introduced in which physiologic variables degraded with inappropriate interventions and improved when effective treatment was introduced. The simulation was distributed throughout the hospital and used with different sedation provider teams (e.g., postanesthesia care unit, emergency department [ED], radiology, and sedation unit). The event was videotaped and scored based on deviations from best practice; it quantifies episodes of hypoventilation, apnea, hypoxia, and cardiovascular collapse. Hypoxia and hypotension lasted 90 seconds in the pediatric sedation unit and 360 seconds in the ED and radiology setting.91 Such studies demonstrate that prospective and retrospective analysis of simulated but rare adverse events can identify areas within the hospital that are in need of improving their clinical skills, and have a positive impact on patient safety.
There has been a recent effort to capture information from the large numbers of pediatric sedation procedures necessary to understand the nature and frequency of adverse reactions to sedation. The Pediatric Sedation Research Consortium (PSRC) comprises a group of over 30 institutions in North America who share prospective data on pediatric sedation.14 Analysis of the first 30,000 records identified demographics, procedures, sedation techniques, outcomes, and adverse events: (1) there were no deaths and only one cardiac arrest reported; (2) unanticipated admission occurred infrequently, 1 per 1500 sedations; (3) vomiting occurred 1 per 200 sedations, including one aspiration; (4) stridor, laryngospasm, wheezing, and apnea occurred in 1 of 400 procedures; and (5) airway or ventilatory manipulations occurred in 1 time per 200 sedations.91 Risk factors included age younger than 3 months, ASA physical status 3 or greater, and multiple drug combinations for sedation. The PSRC has also reviewed the incidence of adverse events in 49,386 propofol sedation and/or anesthesia encounters for procedures outside of the OR.15 Propofol was delivered by multiple providers (anesthesiologists, intensivists, emergency medicine, pediatricians, and radiologists). No deaths were recorded. CPR was required in 2 children (anesthesiologists were not involved in their care) and aspiration occurred in 4 children. Desaturation of less than 90% for more than 30 seconds occurred 154 times per 10,000 sedations/anesthesias; central apnea or obstruction occurred 575 times per 10,000. Stridor, laryngospasm, excessive secretions, and vomiting occurred 50, 96, 341, and 49 times per 10,000, respectively. The most prominent type of complication was related to the airway and occurred 1 out of 65 sedations; 1 in 70 children required airway rescue. Unexpected admissions occurred 7.1 times per 10,000 sedations. When all possible adverse events are considered, anesthesiologists report fewer events than nonanesthesiologists, with an odds ratio of 1.38 (95% confidence interval [CI] of 1.21 to 1.57, P < 0.001).15 No difference, however, was noted when outcomes were limited only to major pulmonary complications. The authors concluded that propofol sedation and/or anesthesia when given under these strict organized conditions, i.e., following the AAP sedation guideline, with very well-trained providers, can result in effective sedation with a minimal incidence of severe adverse events. The safety of this practice is contingent on the ability to quickly and safely manage less serious events. In a prospective cohort study of 131,751 procedural sedations92 in radiology (62%), hematology–oncology (11%), and minor medical or surgical procedures (16%), in which sedation included primarily propofol (60%), midazolam (25%), and others provided by anesthesiologists, emergency physicians, intensivists, pediatricians, and “other” (pediatric residents, radiologists, dentists, surgeons, and nurses), the rate of major complications per 10,000 sedations (and 95% CIs) were: anesthesiologist 7.6 (4.6 to 12.8), emergency physician 7.8 (5.5 to 11.2), intensivist 9.6 (7.3 to 12.6), pediatrician 12.4 (6.9 to 20.4) and “other” 10.2 (5.1 to 18.3). There were no statistical differences between any providers before or after potential confounding variables (age, ASA status, fasting status, propofol use). A significant limitation of the study was the selection bias that was introduced because not all sedation areas within each hospital reported data and the providers were not randomized. The study did not track whether high-risk patients were referred to practitioners outside of their sedation practice (i.e., the anesthesia service). Only major complications and not minor but dangerous complications (i.e., desaturation, hypoventilation, and need for airway support) were monitored. The participants in these hospitals are highly motivated, and application of these data outside of the consortium requires rigorous evaluation of safeguards and training. The ASA thinks that anesthesiologist participation in all deep sedation is the best means to achieve the safest care. The ASA acknowledges that nonanesthesiologists administer or supervise the administration of deep sedation and has created guidelines to help anesthesiologists provide leadership in this area.93,94
Guidelines
The first sedation guidelines were published in 1985 from the Committee on Drugs, Section on Anesthesiology, American Academy of Pediatrics.95 These guidelines provided the first framework to improve safety for children requiring sedation for a procedure. The guidelines emphasized systems issues, such as the need for informed consent, appropriate fasting before sedation, frequent measurement and charting of vital signs, the availability of age- and size-appropriate equipment, the use of continuous physiologic monitoring, the need for basic life support skills, as well as proper recovery and discharge procedures. The guidelines stated that an independent observer whose only responsibility was to monitor the child was required for deep sedation. Advanced airway and resuscitation skills were encouraged but not required. In 1992, the guidelines were revised96 emphasizing that a child could readily progress from one level of sedation to another and that the practitioner should be prepared to increase vigilance and monitoring as indicated. In 2002, the same Committee on Drugs of the AAP updated and amended the guidelines.97 It eliminated the use of the confusing term conscious sedation and replaced it with the term moderate sedation. It also emphasized the application of these guidelines outside the hospital, in recognition of the relatively high complication rate in non–hospital-based settings. The ASA guidelines in use today were updated in 2002 and, in many respects, modeled after the AAP guideline.98 These guidelines were systematically developed by a task force of 10 members. The task force reviewed the strength of evidence and made recommendations that include the following:
Patient Evaluation: Clinicians should be familiar with the sedation-related aspects of the patient’s medical history. These include (1) abnormalities of major organ systems, (2) previous adverse effects with sedation and general anesthesia, (3) drug allergies, current medications, and drug interactions, (4) time and nature of oral intake, and (5) history of tobacco, alcohol, or substance abuse. A focused physical examination, including vital signs, auscultation of the heart and lungs, and evaluation of the airway, is recommended.
Physiologic Monitoring: All patients undergoing sedation/analgesia should be monitored by pulse oximetry with appropriate alarms. In addition, ventilatory function should be continually monitored by observation or auscultation. Monitoring of end-tidal carbon dioxide (etco2) should be considered for all patients receiving deep sedation and for patients whose ventilation cannot be directly observed during moderate sedation. Multiple studies have confirmed the usefulness in etco2 monitoring especially during deep sedation. Although not currently required, adverse events can be anticipated and corrected by using etco2 monitoring.99 It should be noted that ASA standards for basic monitoring have been amended to include etco2 monitoring for all sedated patients beginning in 2012.99,100 When possible, blood pressure (BP) should be determined before sedation/analgesia is initiated. Once sedation/analgesia is established, BP should be measured at regular intervals during the procedure, unless such monitoring interferes with the procedure (e.g., pediatric MRI, in which stimulation from the BP cuff could arouse an appropriately sedated child). Electrocardiographic (ECG) monitoring should be used in all children during deep sedation, and during moderate sedation in those with significant cardiovascular disease or those who are undergoing procedures in which dysrhythmias are anticipated.
Combinations of Sedative/Analgesic Agents: Combinations of sedative and analgesic agents may be administered as indicated for the procedure being performed and the condition of the child. Ideally, each component should be administered individually to achieve the desired effect (e.g., additional analgesic medication to relieve pain; additional sedative medication to decrease awareness or anxiety). The propensity for combinations of sedative and analgesic agents to cause respiratory depression and airway obstruction emphasizes the need to appropriately reduce the dose of each component, as well as the need to continually monitor respiratory function (Fig. 47-4).
Consultation and Availability of an Anesthesiologist: Whenever possible, appropriate medical specialists should be consulted before sedating children with significant underlying conditions. The choice of specialists depends on the nature of the underlying condition and the urgency of the situation. For severely compromised or medically unstable children (e.g., anticipated difficult airway, severe obstructive pulmonary disease, or congestive heart failure), or if it is likely that sedation to the point of unresponsiveness will be necessary to obtain adequate conditions, practitioners who are not trained in the administration of general anesthesia should consult an anesthesiologist (Table 47-6).
TABLE 47-6 Guidelines for the Consultation of an Anesthesiologist
2. Procedures requiring deep sedation in patients with a full stomach
ASA, American Society of Anesthesiologists; BMI, body mass index.
The above ASA guideline pertains to all age-groups. The AAP’s most recent guideline update was published in 2006.18 In general, their updated guideline reinforces the ASA guideline. The AAP updated revision retains the same definitions of the continuum of sedation that are identical to the ASA and Joint Commission definitions. The AAP guidelines emphasize a systematic approach to sedation that includes:
No administration of sedative medications without the safety net of medical supervision (i.e., no sedative medications given at home)
Careful presedation evaluation to include review of pertinent medical and surgical conditions
A “time out” should be performed before sedation
Understanding of the pharmacologic and PD effects of sedation medications and drug interactions
Immediate availability of size- and age-appropriate airway, monitoring, and resuscitation equipment
Appropriate medications and reversal agents
Sufficient numbers of sedation providers to carry out the procedure and monitor the child
Appropriate physiologic monitoring during and after the procedure; use of capnography is encouraged
Use of simulators to practice how to manage rare adverse events
Other organizations, including the American College of Emergency Physicians (ACEP), published their own sedation guidelines.101–105 The latter guidelines are distinguishable from the AAP and ASA guidelines in several respects, including the definition of the continuum of sedation. The ACEP guideline does not use the terms “moderate” or “deep” sedation but rather the term “procedural sedation.” It is defined “as a technique of administering sedatives, analgesics, dissociative agents, alone or in combination to induce a state that allows the child to tolerate unpleasant procedures while maintaining cardiopulmonary function.” It is intended to result in a depressed level of consciousness but one that allows the child to “independently and continuously” control their own airway. Unfortunately, the lack of uniform agreement on definitions and overlap of “procedural sedation” into “deep sedation” and “anesthesia” has led to considerable confusion and debate among practitioners. In 2006 the ASA asserted that “privileges to administer deep sedation should be granted only to practitioners who are qualified to administer general anesthesia.”93,94 Intensivists and emergency room physicians took umbrage with the ASA “usurping” control over their sedation practice.11 They pointed out that their specialties have been using drugs, such as propofol and ketamine, for procedural sedation with minimal complications at levels that are considered deep sedation or anesthesia for many years,106,107 and that they resent an outside organization imposing guidelines on their practices. In 2010 the ASA acknowledged that Medicare regulations permit some non–anesthesia practitioners to administer deep sedation and created guidelines to help hospital directors of anesthesia services grant privileges to such individuals.93 The guidelines include: formal training in administration of deep sedation during residency training (within 2 years) or an Accreditation Council for Graduate Medical Education accredited training program; experience and competency in managing sedated patients; clinical experience with more than 35 patients; knowledge of ASA guidelines; advanced cardiac life support training; and quality assurance tracking. Separate privileging is required for the care of children. The exact nature of these requirements are not specified, but are over and above baseline competencies and dependent on the hospital’s director of anesthesia services.
It is mandatory that sedation policies used in hospitals conform to Joint Commission standards that have been derived from the Department of Health & Human Services (DHHS) Centers for Medicare & Medicaid Services (CMS). In the 1990s, the Joint Commission recognized that there is considerable variation in the level of care provided to sedated children, depending on where the sedation is administered, even within one institution. They mandated that the standard of care for all sedated patients be uniform throughout any one institution Thus institutionally standardized documentation (e.g., medical history, physical status, and record-keeping during the procedure and the recovery from the procedure), fasting guidelines, and informed consent procedures are mandatory for all patients undergoing sedation, regardless of the nature, duration, patient’s history, and location of the procedure. Similarly, the sedation personnel, monitoring equipment, and recovery facilities must be standardized or uniform within an institution. All of this must be part of an active quality improvement process. Hospitals risk losing federal funding if they fail to comply. In 2004, 18% of hospitals were found noncompliant in planning the administration of moderate or deep sedation.108 In the most recent Joint Commission regulations, 2010,25 the leadership and responsibilities for the delivery of deep sedation fall on the shoulders of the anesthesia department (Fig. 47-5).
Specific standards for sedation are mentioned in Provision of Care, Treatment and Services (PC.03.01.01, .03, .05 .07), Improving Organization Performance (PI.01.01.01), and records (RC.02.01.03).23 These standards address moderate and deep sedation, as well as anesthesia services. The standards require that each hospital develop specific appropriate protocols for patients receiving sedation. These protocols must be consistent with professional standards and address the following:
1. Qualified individuals in sufficient numbers to perform and monitor patients during and after the procedure. A registered nurse must supervise perioperative nursing care.
2. Competency-based education, training, and experience in evaluating patients. These must include the following:
3. Appropriate equipment for care and resuscitation
4. The following must occur before moderate or deep sedation:
5. Appropriate monitoring of vital signs during and after the procedure, including, but not limited to, heart rate and oxygenation using pulse oximetry, respiratory frequency and adequacy of pulmonary ventilation, monitoring of BP at regular levels, and cardiac monitoring (by ECG or use of a continuous cardiac monitoring device) in patients with significant cardiovascular disease or when dysrhythmias are anticipated or detected
6. Documentation of care before, during, and after the procedure
7. Monitoring of outcomes. In particular, analysis of data is performed on adverse events or patterns of adverse events during moderate or deep sedation.
Implementation of Sedation Guidelines
The implementation of a successful institution-wide policy involves organization, education, record keeping, enforcement, and continuing quality improvement.109 A sedation committee must be carefully organized and involves many departments, practitioners, and geographic areas within the institution. The goal of the committee is to create a sedation policy that can facilitate patient care without placing undue burden on practitioners. Ideally, the committee should be composed of representatives from at least one and preferably two to three sedation practitioner services (e.g., an endoscopist, intensivist, dentist, surgeon, or emergency medicine physician) and departments: anesthesiology, nursing, pharmacy, hospital administration, and—very importantly—risk management. The responsibilities of the sedation committee include the creation of hospital- or institution-wide sedation policies, determination of hospital- or institution-wide personnel and equipment needs, creation of educational programs, monitoring of sedation problems, modification of policies as needed, and granting sedation privileges.
The department of anesthesiology (chairperson or their designee) must play a central role in formulating policy, educating nonanesthesiology sedation practitioners, acting as consultants for potentially complex cases, particularly those patients with a difficult airway, and determining when sedation by a nonanesthesiologist is or is not appropriate. The department of anesthesiology should approve sedation flow sheets and records, and be involved, along with the committee and the institution’s risk management department, in periodic review of the records and compliance with documentation and institutional policies and procedures. A member of the department of anesthesiology is responsible for the process of continuous quality improvement. Continuous quality improvement is needed to review complications, incident reports, and sedation flow sheets to ensure compliance with policy and recommend changes to the sedation committee. Finally, sedation and analgesia require a treatment plan. The department of anesthesiology must play a leading role in determining which sedatives, hypnotics, general anesthetics, and analgesics can be safely used alone and in combination in each institution. Several drugs in particular can easily produce deep sedation or general anesthesia, airway obstruction, an unprotected airway, and cardiorespiratory collapse, namely, methohexital, thiopental, nitrous oxide (when combined with other sedating medications), ketamine, propofol, and remifentanil. Which drugs can be used and by whom should be made on an institution-by-institution basis. Education is vital to maintain safety. An institution-wide ongoing educational program on sedation, emphasizing physician (and dentist) responsibility, nursing responsibility, guidelines, and the pharmacology of drugs, should be given frequently enough to train the staff and to accommodate staff turnover (usually one to two times a year). Teaching modules, videos, handouts, simulations, and hands-on supervision have been used to supplement such programs.87 One institution (CNMC) uses a computerized teaching module that includes a review of hospital policy, equipment, personnel, pharmacology of drugs used, and rescue from deeper levels of sedation (see Children’s Exchange [CHEX] course module). A quiz must be successfully completed at the end of the computerized teaching module. The module is part of the orientation and hospital privileging procedure for each physician and nurse, and must be successfully completed before they can administer sedation; the module must be reviewed and successfully completed every 2 years. Staff privileges also require training for Basic Life Support or equivalent for those providing moderate sedation and Pediatric Advanced Life Support or equivalent for those administering deep sedation. Each division chief or section supervisor must attest to the practitioner’s competency to provide the desired level of sedation.
Specialty organizations are also becoming involved in training of sedation providers. The Society for Pediatric Sedation provides an extensive “primer” on pediatric sedation on its web site at www.pedsedation.org. This organization also provides a credentialing course for pediatric sedation that uses a test of knowledge based on its written materials (see previous) and the completion of a full day “Sedation Provider Course,” which includes lectures, interactive sessions, and human patient simulation sessions (developed from data relating to pediatric sedation adverse events) to teach and test core competencies.
Education should also emphasize the limits of sedation and appropriate referral to an anesthesiologist. Of particular concern is upper airway obstruction that would likely become worse with the administration of sedatives (Table 47-6).54 Tonsil and adenoid hypertrophy is common in children aged 2 to 12 years, and is associated with loud snoring or obstructive sleep apnea. Obstructive sleep apnea occurs in 1% to 3% of all children, in up to 12% of adolescents, is threefold more frequent in African American children and fivefold more frequent in obese children.110 Parents will frequently report that their child snores loudly and then “stops breathing.” These children are at increased risk for airway obstruction and should be referred to an airway specialist (anesthesiologist, pediatric intensivist, pediatric emergency medicine specialist) if sedation will be required for their procedures. They may also require postsedation overnight admission and monitoring (see also Chapters 4 and 31).98,111–113 Children with developmental disabilities should raise concern for sedation because they have a high incidence of airway obstruction during sedation and anesthesia.114 Problems for which consultation with an anesthesiologist or other expert is suggested are listed in Table 47-6.
The performance improvement administrative part of sedation implementation is the final piece of the puzzle. Compliance can be monitored by the medical and dental staff office, the department of nursing, as well as a committee charged with the responsibility of continuing quality improvement. This committee should fall under the purview of risk management. Nursing and medical staff offices should monitor compliance with educational certification for appropriate credentialing. The medical staff office should report to the department chairman and nursing office a list of individuals who need to be recertified in sedation. It is the responsibility of the department chairman and nursing supervisors to secure individual staff compliance. Finally, variance reports should be generated when sedation policy is not followed or when a critical incident occurs. The appropriate institutional committee reviews the incident and informs the sedation committee. Educational and corrective action should take place as quickly as possible. This committee should not be viewed as “sedation police,” but rather as a resource to objectively and unemotionally review critical sedation-related events. The committee can then determine where the “system” broke down, to define what went wrong and why (e.g., inadequate history taking combined with sedation, inadequate monitoring combined with delay in problem recognition, or inadequate recovery procedures combined with re-sedation at home). Tracking common problems, such as desaturation events, the need for bag-mask ventilation, apnea, unplanned hospital admissions, unsatisfactory sedation, and so on, can provide direction for developing changes in policy that will prevent more severe but much less frequent events from occurring (Fig. 47-6). This type of critical incident analysis allows recommendations to be made for future prevention.115–117 An example of a successful hospital sedation policy is that of the CNMC (see Appendix 47-1).
Documentation
Although differing departmental procedures, practice requirements, patient needs, and location limitations produce unique problems, a unified systematic approach to sedation creates a safety net that will protect children while providing sedation/analgesia for procedures. A single sedation flow sheet that is used wherever sedation is given within the institution will allow for uniformity of care and compliance with sedation policy. The universal sedation flow sheet allows for nurses to rotate to different areas and feel familiar with sedation requirements in different locations. The sedation flow sheet should be organized such that the practitioners have a practical guide to the sedation policy. Following and completing the sedation flow sheet will ensure compliance with hospital policy (E-Fig 47-1). CNMC is in the process of converting to electronic records. As such we have an opportunity to move to an electronic paperless sedation document, which can “pull in” data from other databases and automatically add vital signs (Video 47-5)
. Our first draft will be available through this book. We still use the paper form when we are in areas that are remote or that do not have electronic record keeping (e.g., MRI, offsite locations) (see E-Fig 47-1). The flow sheet (both paper and electronic) is organized into Presedation, During Sedation, and Postsedation responsibilities of the registered nurse and licensed independent practitioner (physician or dentist) providing sedation. The electronic version has various dropdown menus which allows the practitioner to access rating scale information and automatically enter vital signs (see Video 47-5).
E-FIGURE 47-1 Sample hospital sedation flow sheet (four pages).
(Courtesy Children’s National Medical Center, Washington, D.C.)
Presedation responsibilities: During this time, the responsibilities of the registered nurse include evaluation of the child to include learning assessment, NPO (nothing by mouth) status, allergies, current medications, and review of medical problems. The licensed independent practitioner verifies this information with emphasis on airway assessment. A sedation plan is identified and informed consent is obtained. The licensed independent practitioner assigns an ASA physical status and reassesses the child immediately before the procedure.
During sedation: The time-based flow sheet identifies the type of stimulation needed to elicit a response, as well as what monitors and how frequently vital signs should be recorded for both moderate and deep sedation. A summary of monitoring, documentation, personnel, and equipment during sedation is given in Table 47-7.
TABLE 47-7 Recommended Intensity of Monitoring, Documentation, Personnel, and Equipment for Different Levels of Sedation
| Moderate Sedation | Deep Sedation | |
|---|---|---|
| Monitoring |
ECG, Electrocardiography; etco2, end-tidal carbon dioxide.
Individual departments may have special needs or situations that require addenda to the hospital sedation flow sheet. In addition, individual departments may find it helpful to create information sheets on presedation assessment, telephone interviews, and postsedation follow-up. The radiology–nursing database that consists of presedation telephone information, presedation instructions, NPO guidelines, health history, and postexamination telephone call information is shown in E-Figures 47-2 and 47-3. Samples of presedation and postsedation instruction sheets for pediatric dentistry are shown in E-Figures 47-4 and 47-5, respectively. These forms are available in Spanish and are explained via interpreters if necessary.
E-FIGURE 47-2 Sample department of radiology/nursing database patient sedation phone call and assessment form.
(Courtesy Children’s National Medical Center, Washington, D.C.) PIV, Peripheral IV.
E-FIGURE 47-3 Sample diagnostic imaging and radiology discharge teaching information sheet for parents or guardians of treated children.
(Courtesy Children’s National Medical Center, Washington, D.C.)
Specific Sedation Techniques
A sedation treatment plan analyzing the requirements for analgesics, anxiolytics, or both is necessary for each child and will vary depending on the procedure and the anxiety of the child and family. Psychological techniques to allay anxiety (cuddling, parental support, warm blankets, a gentle reassuring voice, and hypnosis) are extraordinarily useful adjuncts to the sedation plan.6–10
Although the FDA is responsible for approval of the use of drugs, for a variety of reasons many of the drugs used for sedation and analgesia in children are not approved by the FDA for use in young children (e.g., fentanyl less than 2 years; morphine less than 12 years, bupivacaine less than 12 years, propofol less than 2 months, and dexmedetomidine less than 18 years of age). Although midazolam is approved even in preterm infants, the reversal agent flumazenil is not approved in children younger than 1 year of age! The lack of “approval” by the FDA does not imply that a drug should not be used; rather, it only means that the manufacturer never carried out the appropriate studies to gain FDA approval.28,118–121 A number of legislative changes are intended to improve drug research in children and improve drug labeling; however, some of the drugs are no longer under patent protection and there is no motivation for drug companies to study their use in children.122–124 It is hoped that the continuing legislative efforts will improve drug labeling for children; see Chapter 6 for a more complete discussion of this issue.
It is important to review the child’s presedation medications. Particular note of the use of protease inhibitors (used by many patients with human immunodeficiency virus infection) must be sought. These protease inhibitors (e.g., nelfinavir, ritonavir, saquinavir) are potent inhibitors of the cytochrome P-450 CYP3A metabolic pathway. This pathway is responsible the metabolism of many sedatives, including midazolam, and may markedly prolong duration of action and may lead to life-threatening respiratory depression. Erythromycin and some calcium channel blockers may also inhibit the cytochrome system and delay metabolism of midazolam.125–127 Dexmedetomidine should not be combined with digoxin in infants because severe bradycardia has been reported.128 Another concern for the practitioner is the widespread use of herbal medicines that can enhance or shorten sedative medication activity.129–133 Herbal medicines (e.g., St. John’s wort or echinacea) may alter drug PK through inhibition of the cytochrome P450 system, resulting in prolonged drug effect and altered (increased or decreased) blood drug concentrations. Kava may increase the effects of sedatives, and valerian may itself produce sedation (see also E-Table 4-4).134
Local Anesthetics
Local anesthetics play a critical role in analgesia for painful procedures and greatly reduce requirements for systemic opioids. Unlike most drugs used in medicine, local anesthetics must be physically deposited at their site of action to produce their effect. Cessation of action often depends on the rapidity of removal of drug from this site. Systemic toxicity is related to how much and how rapidly local anesthetics are absorbed into the blood. Thus small amounts of local anesthetics can be toxic if injected intraarterially or IV. On the other hand very large amounts of local anesthetics can be safely administered in vascular-poor structures like fat. For most blocks and local skin infiltration, epinephrine (1 : 200,000 [5 µg/mL]) is used as a vasoconstrictor to lengthen the duration of blockade, decrease bleeding, and reduce systemic toxicity by decreasing vascular uptake. Local anesthetics should only be prepared in labeled syringes immediately before use. They should never be prepared before a procedure starts because of the possibility of inadvertent and catastrophic injection of the local anesthetic into an IV catheter or infusion. Finally, no more than the maximum allowable dose (mg/kg) should be prepared in the syringe to minimize the risk of an accidental overdose (Table 47-8). Epinephrine-containing local anesthetics can cause tissue ischemia and are contraindicated in end-arterial areas (digits, ear, and penis), as well as in Bier blocks. Local anesthetics can obtund airway reflexes when sprayed in the mouth for bronchoscopy or gastrointestinal endoscopy.
Specific blocks used in the sedated child include subcutaneous (SC) infiltration, field blocks, and IV regional anesthesia. A discussion of these topics and treatment of local anesthetic toxicity is found in Chapters 41 and 42. Topical administration of local anesthetics is useful in the sedated patient. EMLA cream is a eutectic mixture of local anesthetics (lidocaine 2.5% and prilocaine 2.5%) (AstraZeneca Pharmaceutical LP, Wilmington, Del.). When placed on the skin for 60 minutes,135,136 it is useful for reducing the pain of skin incision, IV cannula insertions, lumbar punctures, and circumcision.137–139 Absorption of large amounts of prilocaine can cause methemoglobinemia. It should be applied only to normal intact skin in appropriate doses31 (i.e., for children weighing less than 10 kg, apply to a maximum of approximately 100 cm2 surface area; for those 10 to 20 kg, apply to a maximum of approximately 600 cm2 surface area; and for those more than 20 kg, apply to a maximum of approximately 2000 cm2 surface area). The duration of action is 1 to 2 hours after the cream is removed. Adverse reactions include erythema, itching, rash, and methemoglobinemia. It also causes blanching of the skin, which can make IV access difficult. It is contraindicated in children younger than 1 month of age, in children with congenital or idiopathic methemoglobinemia, or in infants receiving methemoglobinemia-inducing drugs (e.g., phenytoin, phenobarbital, acetaminophen, and sulfonamides).
ELA-Max and LMX4 (Ferndale Healthcare, Ferndale, Mich.) are topical 4% liposomal lidocaine solutions whose effects occur in 30 minutes.140 The S-Caine patch (ZARS, Inc., Salt Lake City) is a eutectic mixture of 70 mg of lidocaine and 70 mg tetracaine in a bioadhesive layer that contains a heating element. The 20-minute application is effective in lessening pain from venipuncture procedures.141
Anxiolytics and Sedatives
Chloral hydrate is one of the most widely used sedatives in neonates and children younger than 3 years of age (Table 47-9).142–145 It is used as a sedative to facilitate nonpainful diagnostic procedures, such as EEG, CT, or MRI.144 It is rapidly and completely absorbed when given orally. Rectal administration is erratically absorbed and therefore not recommended. The onset of sedation is 30 to 60 minutes, and the usual clinical duration is 1 hour. Although it has a long safety record, it can cause respiratory depression as a result of airway obstruction. Deaths have been associated with its use alone and when combined with other sedating medications.54,113,146–149 One large series showed a 0.6% incidence of respiratory depression, especially at larger doses (75 to 100 mg/kg).150 Its effect is primarily mediated by the active metabolite trichloroethanol, which is formed by the liver and erythrocytes.151 Trichloroethanol has a half-life of 10 hours in toddlers, 18 hours in term infants, and 40 hours in preterm infants (see Fig. 47-3).152 The prolonged effects of chloral hydrate warrant a longer period of postsedation observation; chloral hydrate can also cause adverse effects after discharge, which include motor imbalance (31%), gastrointestinal effects (23%), agitation (19%), and restlessness (14%). Agitation and restlessness lasted more than 6 hours in more than one-third of children who experienced these effects, 5% of whom did not return to baseline activity for 2 days after the procedure!44,153 The unpredictable onset and active metabolites dictate that this drug (as well as all sedatives for sedation) is given only in facilities capable of resuscitation (AAP guidelines) and that discharge occurs when sedation is clearly lessening and the child meets discharge criteria. Airway obstruction and death occurred after chloral hydrate sedation in a child who was in a child’s car seat in the back of a car.54 Despite being restricted in some countries as a result of potential carcinogenicity, in the United States the AAP states that there is insufficient evidence to avoid single doses of chloral hydrate.154
The benzodiazepines are commonly used in pediatric sedation. They are anxiolytic, amnestic, sedative hypnotics with anticonvulsant activities but without analgesic properties. Their high lipid solubility at physiologic pH accounts for the rapid CNS effects. As opposed to diazepam, midazolam is delivered in a water-soluble form (pH 3.5), which markedly decreases the incidence of pain on injection and thrombophlebitis.151 However, the resulting decrease in fat solubility markedly delays transport into the CNS (peak EEG effect 4.8 minutes for midazolam vs. 1.6 minutes for diazepam; Fig. 47-7).155,156 Benzodiazepines exert their effects by occupying the benzodiazepine receptor that modulates γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. The clearance of benzodiazepines is decreased in neonates and also by liver enzyme inhibition that occurs during concomitant use of erythromycin, cimetidine, or protease inhibitors.126
The sedated child usually becomes compliant but does not lose consciousness. Children frequently move, and another agent, such as an opioid, may be necessary if the child must not move to successfully accomplish the procedure. Although many children initially act disinhibited and “drunk” after small doses of benzodiazepines, some have a true paradoxical response.157 Paradoxical responses, such as combativeness, disorientation, hyperexcitability, and agitation may appear in 1% to 15% of treated children.158 It is prudent to switch to a different sedative drug in these children, because increasing the dose of benzodiazepines may lead to severe agitation followed by unconsciousness and respiratory compromise. The benzodiazepines have the advantage of antegrade amnesia in a significant number of children.159,160 The markedly prolonged and variable elimination half-life and active metabolite of diazepam (desmethyldiazepam) make midazolam a superior sedative drug in children, particularly infants.161–166 The time to peak effect after IV administration of midazolam is 2 to 4 minutes, and its duration is 45 to 60 minutes. Midazolam can be given IV, intranasally, sublingually, orally, or rectally (see Table 47-9). It is the only drug in this class approved for neonates. A manufactured oral cherry-flavored form is available. The oral route has become very popular and is well tolerated. The oral route can lead to variable effects, dependent on gastric emptying and first-pass hepatic metabolism. Nasal administration causes nasopharyngeal burning and should be avoided.167,168 Rectal administration is usually well tolerated in children who have not been toilet trained (younger than approximately 1 year of age), but absorption may be irregular owing to many factors, including superior versus inferior hemorrhoidal vein absorption within the rectum. Benzodiazepines produce mild respiratory depression and upper airway obstruction.169–171 Even small doses of oral midazolam (0.3 mg/kg) that cause minimal sedation were associated with a 6.5% decrease in functional residual capacity and a 7.4% increase in respiratory resistance.172,172
Respiratory depression may become severe in compromised children or in children with tonsil hypertrophy. Benzodiazepines must be given according to appropriate guidelines.18,56,74 The combination of benzodiazepines and opioids is particularly troubling because they can produce a “super additive effect” on respiratory depression where the total depressant effect from the combination of drugs is much greater than the sum of their anticipated individual effects.173,174
Flumazenil is a specific benzodiazepine-receptor antagonist and will rapidly reverse the sedative and respiratory effects of benzodiazepines.175–179 It is the first specific reversal agent for benzodiazepines and rapidly reverses CNS-induced unconsciousness, respiratory depression, sedation, amnesia, and psychomotor dysfunction. Children who take benzodiazepines for seizures or drug dependency may have those symptoms rapidly recur if flumazenil is given.180 It should also be used with caution in children with benzodiazepine dependence, increased intracranial pressure, and in those taking drugs that decrease the seizure threshold (e.g., cyclosporine, theophylline, and lithium). The recommended dose of flumazenil is 10 µg/kg up to 0.2 mg every minute to a maximum cumulative dose of 1 mg IV. Antagonism begins within 1 to 2 minutes and lasts approximately 1 hour. Because re-sedation after 1 hour may occur, any child who receives flumazenil must be carefully monitored for at least 2 hours. Repeat flumazenil may be necessary. It should be noted that flumazenil will not antagonize respiratory depression caused by opioids.181 Flumazenil should not be administered for the routine reversal of the sedative effects of benzodiazepines, but reserved for reversal of respiratory depression.
Barbiturates
Pentobarbital is the most commonly used intermediate-acting barbiturate for sedation. It has no analgesic effect and produces sedation, hypnosis, and amnesia. It has a long history of use during radiologic procedures. Sedation starts in 3 to 5 minutes and peaks in 10 minutes. Studies have shown a low incidence of respiratory obstruction and transient desaturation, as well as hypotension.182,183 The barbiturates tend to make children more sensitive to pain and should be combined with analgesics when used during painful procedures. Pentobarbital’s relatively long duration of action (1 to 2 hours or greater) and slow recovery sometimes leaves children in a prolonged disinhibited state that necessitates prolonged recovery and restraint143; pentobarbital “rage” occasionally occurs. The alkaline pH of barbiturates can lead to local erythema and thrombophlebitis if subcutaneous infiltration occurs. Newer, shorter-acting, faster recovery drugs are quickly replacing pentobarbital (see Table 47-9).
Opioids
Opioid analgesics are rarely used alone for diagnostic and therapeutic procedures in children. These potent analgesics are important during painful diagnostic and therapeutic procedures. They bind with four primary opioid receptor types (µ, κ, δ, and σ) that are located in the brain, spinal cord, and periphery. Once opioids bind to the receptor, they trigger the production of signaling proteins (such as G proteins) whose end effects are modulation of pain neurotransmission.184 The µ1 subgroup is responsible for supraspinal analgesia and the development of dependence. The µ2 and κ receptors are responsible for sedation. Although the opioids provide some sedation, the sedation produced is usually inadequate, therefore requiring combination with a sedative. The “super-additive” respiratory depressant effects of the combination of opioids and sedatives must be reemphasized (see Fig. 47-1).173,185 This is especially true in infants and children with upper airway obstruction (e.g., tonsil and/or adenoid hypertrophy, trisomy 21, mucopolysaccharidosis). In addition, infants younger than 3 months of age and children who were born preterm have very large patient-to-patient drug metabolism variability.186 Other serious effects of opioids include bradycardia, hypotension, seizures, and opioid-induced glottic and/or chest wall rigidity.
Morphine may be considered for painful procedures (lasting more than 1 hour) or when the child will also be in pain after the procedure. The duration of action is 3 to 5 hours after IV administration.186 Morphine may be given orally (0.2 to 0.5 mg/kg), IV (0.05 to 0.1 mg/kg [maximum 0.3 mg/kg]), or IM (0.1 to 0.2 mg/kg). Rectal administration may cause delayed respiratory depression from erratic absorption and should be abandoned.187 Time to peak effect for oral, IV, or IM administration is 60 minutes, 3 to 5 minutes, and 10 to 30 minutes, respectively. Its slow onset and prolonged duration have caused it to be replaced by shorter-acting opioids when used for sedation and analgesia for procedures.
Meperidine (Demerol) was also once used for sedation for procedures. Its clinical duration of action is 2 to 4 hours.31 In addition to respiratory depression, the active metabolite of meperidine (normeperidine) may cause seizures, particularly after repeated doses of meperidine. Other adverse reactions include delirium, nausea, vomiting, urinary retention, pruritus, smooth muscle spasm, and hypotension (histamine induced). Special considerations include avoiding its use in children taking monoamine oxidase inhibitors (effects can include serotonin-induced hyperpyrexia and cardiovascular instability). CNS toxicity may occur in children taking tricyclic antidepressants and phenothiazines. Children taking phenytoin (Dilantin) may have a reduced analgesic effect. Reversal of meperidine-induced respiratory depression by antagonists may precipitate seizures caused by normeperidine. Because of these undesirable effects and prolonged duration, meperidine is not recommended for use as an analgesic or sedative in children.
DPT “lytic cocktail” is meperidine (Demerol [25 mg/mL]), promethazine (Phenergan [6.25 mg/mL]), and chlorpromazine (Thorazine [6.25 mg/mL]). Its long sedation duration (7 to 19 hours), hypotension, seizures, extrapyramidal reactions, and severe, prolonged, life-threatening respiratory depression143,188–191 have caused its use to be abandoned.189–195
IV fentanyl is a potent, pure opioid (i.e., approximately 50 to 100 times more potent than morphine) with no amnesic properties. Its high lipid solubility allows for onset within 30 seconds and a peak effect at 2 to 3 minutes. It has a brief clinical duration of 20 to 40 minutes when given in small doses, owing to its rapid redistribution to skeletal muscle, fat, and other inactive sites. Unlike morphine, it has no active metabolites. The clearance of fentanyl is decreased and its half-life increased in preterm and term infants compared with older infants.196 It is fully antagonized by naloxone. Fentanyl is frequently used with a short-acting anxiolytic (midazolam). IV doses usually start at 0.5 to 1 µg/kg and are titrated every 5 minutes to effect but not to exceed 5 µg/kg.197 Doses must be given in small aliquots and carefully titrated to avoid chest wall and glottic rigidity. When carefully titrated and appropriately monitored, fentanyl has few adverse effects. Chest wall rigidity is a centrally mediated idiosyncratic reaction that can interfere with respiratory function. The mechanism of action is partially modulated by GABA pathways at the spinal level. Chest wall rigidity can be reversed with either naloxone or muscle relaxants. The rigidity is quite rare and not described after these small doses were given in boluses for sedation in neonates.198–200 Other adverse reactions from fentanyl include bradycardia, dysphoria, delirium, nausea, vomiting, pruritus, urinary retention, hypotension, and smooth muscle spasm. Close postprocedural observation is required because respiratory depression can outlast analgesia (see Table 47-9).
Remifentanil an ultrashort-acting, rapid-acting, extremely potent, lipophilic opioid that is metabolized by plasma cholinesterase and must be administered as a continuous infusion. It has a context-sensitive half-life of 3 to 6 minutes that is independent of the duration of infusion. Remifentanil, when used as a sole agent in adults in the ED, caused a 17% incidence of respiratory complications that required bag mask ventilation or the placement of an laryngeal mask airway.201 This suggests a need to clearly understand the PK and PD when used outside of the OR.201
Remifentanil has been used for intraoperative and procedural sedation by anesthesiologists and in intubated children in the ICU.202–207 It has been suggested that children may develop opioid tolerance to this drug after several hours of infusion.208 Remifentanil is associated with a substantial incidence of apnea, hypoxemia, chest wall and glottic rigidity, and should not be used as a sole agent for pediatric sedation (see Table 47-9).204,206,209
Opioid antagonists specifically reverse the respiratory and analgesic effects of opioids, and should be readily available when opioids are used (see Table 47-9). Naloxone (Narcan) is the most commonly used antagonist.210 Opioid antagonists should not be used to routinely reverse the sedative effects of opioids, but reserved for reversal of respiratory depression or respiratory arrest. Naloxone may be given IV, IM, or SC.211 The initial dose for respiratory depression is 0.01 mg/kg titrated to effect every 2 to 3 minutes. A dose of 10 to 100 µg/kg up to 2 mg may be required for respiratory arrest. Adverse reactions from reversal of analgesia include nausea, vomiting, tachycardia, hypertension, delirium, and pulmonary edema.212–214 Children on long-term opioid therapy should be given opioid reversal agents in low doses and with extreme caution, because withdrawal seizures and delirium may occur. Children given naloxone may have recurrence of opioid effects after 1 hour. If naloxone is used, the child should be observed for a minimum of 2 hours. Repeat naloxone may be necessary. To avoid recrudescence of respiratory depression, some clinicians administer the same dose that was effective IV as an IM injection. Nalmefene (Revex) has a greater half-life (approximately 10 hours) than naloxone.215 Although experience in children is limited, it has been shown to accelerate recovery from sedation.216 Because of its relatively long half-life, it outlasts the effects of fentanyl and negates the treatment of pain with opioids for several hours.
α2-Adrenoceptor Agonist: Dexmedetomidine
Dexmedetomidine is the most recent addition to the list of sedative drugs used in pediatrics. Unlike other sedatives, it is an imidazole α2 agonist that is similar to clonidine but with an even greater α2– to α1-adrenoceptor specificity ratio of 1600 to 1. Clearance is predominantly by glucuronide conjugation, as well as by CYP2A6 action in the liver. The drug is highly lipid soluble and quickly crosses the blood-brain barrier. Its CNS effect is to stimulate receptors in the medullary vasomotor center, which decreases sympathetic tone. It also stimulates central parasympathetic outflow and decreases sympathetic outflow from the locus ceruleus of the brainstem. The decreased outflow from the locus ceruleus allows for increased activity of the inhibitory GABA neurons, which cause sedation and analgesia.217 Dexmedetomidine is approved for sedation of ventilated adult patients in the ICU, and for procedural sedation, but as of 2012, it is not approved for use in children younger than 18 years of age. In addition to IV use, it has been administered via the buccal and IM routes in adults.218 When administered in clinical doses, it causes limited effects on ventilation in adults and may mimic natural rapid-eye-movement sleep.219–221 Because rapid IV boluses can cause transient systemic hypertension, the initial loading dose must be given over 10 minutes, followed by an infusion. When given in the recommended fashion, it decreases BP and heart rate in a dose-dependent manner. It should be used with caution in children with preexisting bradycardia, atrioventricular conduction defects, hypotension, and decreased cardiac output.222,223 It has been associated with severe bradycardia in infants receiving digitalis.128 The minimal effects on ventilation have led to a surge in its use in children.224–227
Sedation after IV administration has a relatively rapid onset of 10 min and a half-life of 1.5 to 3 hours. It is unique among sedatives in that it mimics natural sleep. Its minimal effect on respiration has led to its use alone in nonpainful procedures (e.g., EEG, CT, and MRI), in children with Down syndrome, and children with obstructive sleep apnea. It has also been used in combination with ketamine and propofol for painful procedures and syndromes (e.g., cardiac catheterizations and complex regional pain syndrome)228,229; however, caution is advised in children with known congenital heart disease, as it depresses sinus and atrioventricular node function and may pose an increased risk for children prone to bradycardia.228–232 It has also been used as a novel approach to control the adverse effects of opioid and sedative withdrawal in children in the ICU.233–235 The minimal respiratory effects of dexmedetomidine has been demonstrated both anatomically and physiologically in healthy children. Analyzed by MRI, the dose-response effects of dexmedetomidine (1 to 3 µg/kg/min) on upper airway morphology in children without obstructive sleep apnea236,237 demonstrated minimal changes in upper airway dimensions in several planes, with no clinical evidence of airway obstruction. Infants and children 5 months to 16 years of age who were sedated with dexmedetomidine for nonpainful procedures (e.g., MRI, MRI plus EEGs, and nuclear medicine procedures) showed minimal effects on respiration.57 Boluses of 0.5 to 1.0 µg/kg dexmedetomidine were infused over 5 to 10 minutes, followed by an infusion of 0.5 to 1.0 µg/kg/hr. Heart rate, BP, and respiratory rate decreased but remained within normal limits for age. The etco2 exceeded 50 mm Hg in only 7 of 404 measurements. Maximum etco2 was 52 mm Hg; mean recovery time was 84 minutes. The minimal effect of dexmedetomidine on respirations has also been verified in children with obstructive sleep apnea.236,237
Initial studies demonstrated that standard doses of dexmedetomidine could not consistently provide optimal conditions for sedation for these procedures. Some clinicians increased the initial loading dose and maintenance infusion dose of dexmedetomidine, whereas others supplemented the original dosing regimen with midazolam 0.1 mg/kg, in search of a successful regimen for sedation for radiologic investigations. In the case of sedation for MRI,238 a loading dose of 3 µg/kg administered over 10 minutes IV followed by an infusion of 2 µg/kg/hr minimized the need for rescue with pentobarbital (2.4%). Mean arterial pressure was maintained in all children and oxygen saturation remained greater than 95% in all children. However, most importantly, in 30 of the 747 (4%) children, the heart rate decreased to less than the 20th percentile for age. Heart rates in the 1- to 3-year-old and 3- to 6-year-old age-groups were as low as the 30 to 40 beats per minute, although no adverse effects were noted, nor were any treatments required. Although not apparently harmful in this cohort, we do not recommend use of such large doses of dexmedetomidine, because heart rates of 30 to 40 beats per minute are well below the acceptable range of normal heart rates in children! Caution should also be used when administering glycopyrrolate to treat the bradycardia from dexmedetomidine in children, because severe and sustained hypertension after traditional doses of 5 µg/kg have occurred (e.g., BP 161/113 in a 3-year-old); the mechanism of this unusual response remains elusive.239 An alternative approach240 included a loading dose of 1 µg/kg dexmedetomidine over 10 minutes followed by an infusion of 0.5 µg/kg/min plus a 0.1 mg/kg bolus of midazolam after a sevoflurane inhalational induction for IV placement. With this regimen, all MRI scans were completed successfully, with only small changes in etco2 (maximum 57 mm Hg). Hemodynamically, systemic BP and heart rate were maintained, with the lowest systolic BP being 70 mm Hg and the lowest heart rate 64 beats per minute in 3 children. This regimen was compared with propofol at 300 µg/kg/min for 10 minutes and a dose of 250 µg/kg/min thereafter, with equivalent hemodynamic responses and no complications.
General Anesthetics
Ketamine has been available since the 1960s. It is one of the few sedatives that produce both amnesia and analgesia. It is structurally similar to phencyclidine and exerts its dissociative properties by interacting with the limbic and thalamic systems. Additional mechanisms postulated are antagonism of N-methyl-d-aspartate (NMDA) receptors and agonism of opioid subgroups.151 The clinical appearance is that of a child who has open eyes (usually with horizontal nystagmus) but does not respond to pain, the so called “dissociative” state. Ketamine preserves cardiovascular function and exerts limited effects on respiratory mechanics, allowing spontaneous respirations in most children.241 Although it is certainly not a new drug, ketamine has recently experienced a resurgence in popularity, particularly in the ED for procedural sedation. Some emergency medicine physicians suggest that ketamine not be considered an anesthetic, but rather a “dissociative sedation” drug with unique properties that warrant their own separate monitoring guidelines.242 New clinical practice guidelines for EDs have been written which emphasize this position107; however, given the fact that airway obstruction, apnea, and laryngospasm occur with some regularity (approximately 1% to 2%), we strongly disagree with attempts to reclassify the drug as a means of side-stepping the AAP sedation guidelines.107,243–245
IM and IV ketamine (with and without midazolam) are frequently used for closed fracture reductions and other painful minor procedures in the ED (see Table 47-9).245–247 In a review of 1022 children sedated with ketamine in the ED, there were no instances of aspiration, and airway reflexes were preserved, although complications included the need for airway management (0.7%), laryngospasm (0.4%), and apnea or respiratory depression (0.3%). Unpleasant reactions were rare and were not improved by prophylactic benzodiazepines.104 In a more recent review of 4252 children, respiratory complications occurred in 2.4%, with serious airway events occurring more frequently: of this 2.4%, laryngospasm occurred in 28%, hypoxia in 79%, and apnea in 10%.99,248 The risks in children younger than 2 years during ketamine with midazolam (62% of children) and morphine with midazolam (16% of children) showed a 6% incidence of complications in which all but one incident were related to ketamine with midazolam. Most were considered minor in severity, although one child required tracheal intubation.249 Ketamine (1 to 3 mg/kg) has also been studied in children undergoing gastroendoscopy procedures, with transient laryngospasm occurring in 8.2%, emesis in 4.1%, emergence agitation in 2.4%, partial airway obstruction in 1.3%, apnea and respiratory depression in 0.5%, and excessive salivation in 0.3%.83 The analgesic effects of ketamine make it very appealing for use during burn dressing changes. In one study, 4.9% of the sedations resulted in adverse outcomes, of which 2.9% required an intervention. Eight events were related to the airway.250 Ketamine sedation/analgesia has a very long history of safety, perhaps having advantage over other sedation regimens, although these studies indicate that potentially life-threatening events can and do occur during ketamine sedation. Ketamine is also associated with nonpurposeful motion, which limits its usefulness when immobility is necessary (e.g., use during CT).
Typical starting doses251 of ketamine are 1 to 2 mg/kg IM, 0.25 to 1.0 mg/kg IV, and 4 to 6 mg/kg orally.252–254 The onset after IM injection is 2 to 5 minutes, with a peak at ∼20 minutes; duration can be 30 to 120 minutes. Onset after IV administration occurs in less than 1 minute, with a peak effect in several minutes and duration of action of approximately 15 minutes. Oral doses of 4 to 6 mg/kg are usually combined with atropine and have an effect in 30 minutes and last up to 120 minutes.31 Larger doses or supplementation with other sedatives or opioids may produce deep sedation or general anesthesia. We advise that ketamine be administered with an antisialagogue (atropine, 0.02 mg/kg, or glycopyrrolate, 0.01 mg/kg) because copious secretions from ketamine alone may induce laryngospasm.255
Etomidate is a carboxylated imidazole that is primarily used as an induction agent for anesthesia. Its mechanism is thought to be potentiation of GABA inhibitory neurotransmission via alteration of chloride conductance. Loss of consciousness occurs in 15 to 20 seconds, and recovery results from redistribution and occurs in 5 to 10 minutes. It is hydrolyzed in the liver to inactive metabolites and excreted (90%) in the urine.151 Etomidate produces sedation and anesthesia, anxiolysis, and amnesia similar to the barbiturates and propofol. Its major advantage is its lack of adverse cardiovascular effects. Etomidate has been used in adults and children for procedural sedation, although the end point of sedation is not well described and often is a state of general anesthesia.79 Using data from the Pediatric Sedation Research Consortium, etomidate has been compared with pentobarbital for CT sedation. Adverse events were more common with pentobarbital (4.5%) than etomidate (0.9%); one child who received etomidate experienced apnea.256 Etomidate with fentanyl has been compared to ketamine with midazolam for reduction of limb fractures in children in the ED. Etomidate with fentanyl had a quicker recovery time but was less effective in reducing observed patient distress.257 Transient adrenal suppression can occur after multiple doses and has been described after single-dose administration in septic patients.258–262
Propofol is an anesthetic that is widely used for pediatric sedation and anesthesia. It is an isopropyl phenol derivative whose mechanism of action appears to be activation of the sodium channel of the β1 subunit of GABA receptors, thereby enhancing inhibitory transmission.263 Its onset is within 30 seconds. It is highly lipid soluble and is provided in a lipid solution that is the same as the lipid component in total parenteral solutions. The lipid solubility makes the drug effect diminish extremely quickly (5 to 15 minutes).264 It has no analgesic properties, but it does have antiemetic and antipruritic properties. Although small doses of propofol (25 to 50 µg/kg/min) can provide moderate sedation in adults, deep sedation and airway obstruction quickly occurs in some children at greater rates of administration. Dosing in adults for sedation is recommended at 25 to 200 µg/kg/min, whereas children, particularly infants and those with cognitive impairment, require larger doses (150 to 250 μg/kg/min). Propofol is also a profound respiratory depressant and can cause apnea. Respiratory complications have been reported in 8% to 30% of children.265 It is generally best administered by titration with an infusion pump. Other adverse reactions include increased salivary and tracheobronchial secretions, myoclonic movements, anaphylactic reactions, and bacterial contamination. Pain on injection can be lessened by several strategies, although the two most effective strategies are pretreatment with nitrous oxide by inhalation, or a mini–Bier block with 1 mg/kg lidocaine applied for 1 minute.266,267 Hypotension is mild and usually not clinically significant. Cases of fatal metabolic acidosis, myocardial failure, and lipemic serum have been reported in children who received propofol infusions for more than 48 hours at doses exceeding 5 mg/kg/hr (83 μg/kg/min), with sporadic cases, which may have been exacerbated by an underlying mitochondrial disorder, of the syndrome appearing after only 5 to 6 hours in some cases.268–273 Propofol should only be administered by practitioners with advanced sedation training and airway skills, because the propofol-sedated child will always be deeply sedated.
The use of all sedatives drugs in children continues to grow. All providers must be aware of the potency and risks of sedative drugs. There are many anecdotes and reviews with small numbers of incidents that attest to the risks of propofol. This is especially true when sedatives with general anesthetic potential are used by health care providers who are not specifically trained to use them in children. Propofol sedation frequently causes anesthesia with an inability to maintain and protect the airway. In a study of propofol sedation (2.5 to 3 mg/kg IV loading dose with an infusion up to 200 µg/kg/min) in 105 painful procedures in the pediatric ICU, 21% of the children required airway repositioning, 17% had apnea, 5% had hypotension, and 45% had events that required intervention.86 In the ED, propofol was administered to 113 children in a dose (4.5 mg/kg in addition to fentanyl 1 to 2 µg/kg)274 sufficient to ensure the children were motionless during the reduction of fractures. The net effect was an incidence of desaturation of 21%, laryngospasm in 1%, and a supplemental oxygen requirement in 25%. A study of sedation by nonanesthesiologists for bone marrow procedures, lumbar punctures, and esophagoscopies titrated propofol to a target of “not arousable”; 21 children 27 weeks to 18 years of age were studied. Only after a BIS score of 45 or less was 100% adequate sedation accomplished. Propofol total doses were 520 µg/kg/min for these short procedures.275 These responses to stimulation, effects on the airway, doses of propofol, and BIS levels are beyond the range of deep sedation, and more in keeping with the definition of general anesthesia, with the inherent risk of loss of the airway. More recent studies that reviewed the use of propofol by ED physicians specifically trained in sedation and performed in highly monitored environments, show that propofol can be used with much less severe adverse outcomes (and much smaller doses) than previously reported.15,92,106,276 The debate about who is best to provide sedation with all drugs and especially propofol will continue. The key to safety is training and environment.
The risks associated with propofol were brought into the international spotlight with the death of Michael Jackson in 2009. Michael Jackson’s physician who administered the propofol was tried for homicide and found guilty of involuntary manslaughter. This was not the first reported case of homicide using propofol.277
Fospropofol (Lusedra) is a water-soluble prodrug of propofol. Fospropofol is hydrolyzed by plasma alkaline phosphatase to propofol, formaldehyde, and phosphate.278,279 As fospropofol must first undergo dephosphorylation to propofol, time to onset of action is delayed (4 to 8 minutes).280,281 Because of its slower onset, it was proposed as a safe alternative to propofol with fewer restrictions on its administration. In December 2008, the FDA qualified fospropofol to be administered only by persons trained in the administration of general anesthesia (i.e., the same wording as propofol). Currently, there are no data on fospropofol use in children. The slow onset, adverse effect of perineal burning, and formaldehyde and formate byproducts may make this drug less appealing for sedation and only useful during general anesthesia.278,282 One possible advantage for this preparation may be for long-term sedation because it is free of any fatty acids and thus may avoid possible propofol infusion syndrome. Further studies are needed, particularly because preliminary PK data were flawed.283
There has been increasing use of a combination of ketamine (10 mg/mL) with propofol (10 mg/mL), so called “ketofol,” for painful procedures in the ED and for oncology patients.284–289 This combination is administered in incremental doses of 0.5 mg/kg of each drug at approximately 1-minute intervals. The limited number of prospective studies at this point preclude assessment of safety and efficacy. A literature review found insufficient evidence to recommend routine use of this combinaiton.288 A prospective study of adults found one patient in each group to require positive pressure ventilation.285
Methohexital is a short-acting oxybarbiturate that is rapidly metabolized and redistributed, and has a rapid recovery (see Table 47-9).290 Induction of anesthesia occurs with IV doses of 1 to 2 mg/kg. Apnea, hiccups, and methohexital-induced seizures in children with temporal lobe epilepsy have been reported.291 Methohexital has been used IM in doses of 8 to 10 mg/kg but has a slow onset292 and is not generally recommended. Rectal methohexital (20 to 25 mg/kg [from a 100 mg/mL solution]) can induce deep sedation in 7 to 11 minutes293 with a duration of action of about 30 to 45 minutes.294 Absorption through the rectal route is erratic.295 Children given methohexital (1 mg/kg) completed their head CT more quickly and needed less total sedation monitoring than those given pentobarbital (2 mg/kg).296 The variability of absorption, tendency to deep sedation, and airway problems have decreased the use of methohexital in favor of newer drugs. This medication is rarely used and should be used only by individuals with advanced airway skills, because upper airway obstruction and apnea may readily occur.297
Nitrous oxide (N2O) is a potent inhalation analgesic with a peak effect in 3 to 5 minutes and very rapid return to baseline when discontinued (see Table 47-9). A premixed tank of no more than 50% N2O is available (Entonox). Administration of N2O can be used for “minimal sedation” under the following AAP guidelines: (1) only ASA physical status I or II patients; (2) only 50% nitrous oxide or less is used; (3) inhalation equipment must have the capacity to deliver 100% oxygen and never less than 25% oxygen; and (4) a calibrated oxygen analyzer must be used. The child is able to maintain verbal communication throughout the procedure. Although N2O in 50% concentration with oxygen usually produces “minimal” sedation, the addition of any sedatives or hypnotic may rapidly produce a deeper level of sedation and require increased monitoring and vigilance.148,169 Nitrous oxide is frequently used by dentists for sedation. A recent questionnaire showed that all respondents performed dental treatment as a trainee, to patients who were under sedation, and the majority used nitrous oxide inhalation sedation.298,299 Extensive guidelines, following the ASA and AAP definitions and guidelines, have been written by the American Academy of Pediatric Dentistry that detail the accepted use of nitrous oxide.299 Adverse reactions, drug interactions, and special concerns are listed in Table 47-9.
Coté CJ, Notterman DA, Karl HW, Weinberg JA, McCloskey C. Adverse sedation events in pediatrics: a critical incident analysis of contributory factors. Pediatrics. 2000;105:805–814.
Cravero JP, Beach M, Gallagher SM, Hertzog JH. The incidence and nature of adverse events during pediatric sedation/anesthesia for procedures with propofol outside the operating room: report from the Pediatric Sedation Research Consortium. Anesthesia Analgesia. 2009;108:795–804.
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.
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