US Pharm. 2008;33(3):HS2-HS8.

Each year, millions of infants and children require sedation and pain control for medical procedures. Over the past 25 years, great strides have been made to increase patient safety, including systematic reviews of adverse event (AE) prevalence and the institution of guidelines endorsed by several groups, including the American Academy of Pediatrics (AAP), the American Academy of Pediatric Dentistry (AAPD), and the American Society of Anesthesiologists (ASA). It has been observed that children younger than 6 years or those with developmental delay may require deeper sedation than other patient populations.1 The continual struggle faced by practitioners is achieving "successful sedation" while preventing or avoiding AEs. Previous reports have demonstrated the incidence of "failed sedation" to be anywhere from 0.2% to 50% of patients, although more recent reviews have shown this percentage to exist closer to the lower end of the range.2-5 However, the likely incidence of serious AEs resulting from pediatric sedation is less than 1 per 10,000.6 The actual incidence is difficult to determine due to volunteer reporting of events, which greatly decreases the validity of reported numbers. Any trial looking at AEs would require a large number of subjects to accurately assess.

In the mid 1980s, guidelines were created by several organizations with the intention to reduce AEs, specifically severe events such as permanent neurological injury and death. 7 These guidelines have been systematically updated and the reported incidence of morbidity from sedation has been reduced from 1 per 10,000 to 1 per 60,000.8 Even with the advent of continually updated guidelines, AEs are still a concern for any practitioner. This review will serve to identify and explain proposed theories that describe why AEs happen and how current guidelines reduce the risk in pediatric moderate sedation.

Definition of Sedation
Current guidelines, spearheaded by the AAPD and AAP, define sedation one of four ways: minimal sedation (anxiolysis), moderate (procedural or conscious) sedation, deep sedation, or general anesthesia.9,10 Moderate sedation is defined as a pharmacologically induced state that allows patients to tolerate painful procedures while maintaining protective reflexes (i.e., gag reflex and cough) and adequate airway control.5 Moderate sedation is the most commonly used form of sedation outside of the operating room and is frequently used in procedures such as MRI, CT, and dental work.

Prevalence of Adverse Events
There exist no multicentered, accurately powered trials to detect the frequency of AEs associated with sedation in pediatric patients. Data from several individual, retrospective studies indicate that the incidence of overall AEs due to pediatric sedation ranges from 0.6% to 25%5,8,11; however, these analyses have also found that close to 99% of events are considered mild to moderate in nature. The most common AE in pediatric sedation is hypoxia.8 The wide gap of reported events is likely due to inconsistency with several factors, including how trials define "complication" (e.g., O2 sat ?80% vs. ?90%) or "successful sedation," as well as the particular drugs used or studied. The newly formed Pediatric Sedation Research Consortium (PSRC), comprised of 35 institutions, is dedicated to improving sedation and anesthesia practices via a database where individual events can be shared by participating institutions.8 During the past four years, the PSRC has compiled over 30,000 encounters. The top three drugs utilized were propofol (50.1%), midazolam (27.1%), and ketamine (13.6%).8 One thousand and twenty events have been recorded (3.4%) since the launching of the PSRC, which is .336 of these events (33%) required some type of intervention, but only two (.2%) were considered serious (zero death, one cardiac arrest, one aspiration). According to the PSRC, one in 1,500 sedations will result in an event requiring unplanned admission. Events are reported to the PSRC voluntarily and are likely underreported. In terms of AEs based on age, Malviya et al found, in a study of 1,140 patients, that neonates experience significantly more events than 1- to 12-month-old infants (P =.04), 13- to 24-month-old children (P =.005), and 25-month- to 12-year-old children (P <.0001). They also found that infants 1 to 12 months of age experience more events versus 25-month- to 12-year-old children ( P =.0001).11 While comparing intravenous fentanyl and midazolam to intravenous ketamine, midazolam, and atropine, Pitetti et al found that patients in both groups who experienced an AE were likely to be older (7.4 y vs. 6.6 y, P =.02).5

Causes of Pediatric Adverse Events
Compared to adults, pediatric patients, in terms of moderate sedation, pose the highest risk and offer the lowest tolerance for error. In many cases, they need deeper sedation than adults, and this may contribute to the use of increased doses or polypharmacotherapy. Past studies have tried to identify possible mechanisms that may cause a patient to be at higher risk for developing an AE during sedation for outpatient procedures. Cote et al looked at 95 case reports compiled nationally, all defined as either death or permanent neurological injury.7 The authors found that 80% of these events presented initially as respiratory compromise, which has been previously described as the most common of AEs in pediatric sedation. Cote et al attempted to determine why some patients deteriorate to the point of needing emergency rescue care while undergoing sedation. The analysis by Cote et al posed seven possible causes of serious AEs due to sedation: 1) drug interactions; 2) high dose or drug overdose; 3) premature discharge; 4) prescription/transcription errors; 5) inadequate understanding of administered medications (pharmacokinetics/pharmacodynamics; 6) administration by unsupervised technicians; and 7) administration by parents or family member.12 The group also postulated that several events may have been due to multiple categories. Data are conflicting regarding whether certain drug classes are responsible for a larger number of events than others. The report by Cote et al found that there was no correlation between drug class or route of administration and events. Pitetti et al looked at 1,244 events occurring in 1,215 patients and found no difference between age, sex, race, ASA class (defined by level of systemic disease experienced by the patient), use of premedication, or level of consciousness achieved during sedation.5 These patients were only sedated with varying combinations of five drugs.



Drug Interactions: Cote et al found drug interactions to be associated with the highest incidence of adverse events.7 An analysis of 95 case reports found that there was a marked increased risk of events when three or more medications were used for sedation (18/20 patients experienced event vs. 7/70; P =.0006). Obtaining an accurate pharmacy history through medication reconciliation is a vital part of the health evaluation before sedation is initiated. Drug interactions are a continual concern, specifically drugs that interfere with hepatic metabolism of sedatives (ciprofloxacin, fluconazole, fluoxetine, amiodarone, antiretrovirals),13 medications causing delayed renal clearance of medications, and drugs that may cause synergistic effects. In addition, herbal medications such as St. John's wort may interfere with the CYP450 system, echinacea may prolong certain drug effects, and kava has the potential to increase the effects of sedatives. Nitrous oxide is commonly used in dental settings and, if diluted and used correctly, is very safe and efficacious; however, when combined with other sedatives, it can produce levels of deep sedation that the administrator/practitioner may not have anticipated.14 Local anesthetics (LAs), when used in combination with opioids, can cause a decrease in protein binding of the LA and increase arterial CO2, both of which could precipitate seizure activity.1

High Dose/Drug Overdose: Drug overdose is defined as greater than or equal to one drug administered in a dose greater than 1.25 times the maximum recommended dose.12 It has been shown that 71% of sedative-overdosed patients have suffered AEs.7 Pitetti et al found that patients given higher doses of opiates and benzodiazepines were more likely to experience an event (fentanyl 3.0 mcg/kg vs. 2.6 mcg/kg, P =.001; midazolam 0.13 mg/kg vs. 0.11 mg/kg, P =.01). They also found that patients receiving higher doses of midazolam in combination with morphine were more likely to experience events (0.27 mg/kg vs. 0.15 mg/kg, P =.03). The most common event that occurred in this study was vomiting (77%).5 Drug overdoses are recognized as the second most common cause of AEs in sedation; however, none of the reported cases involved a 10-fold increase in dose.7 This suggests a lack of knowledge of administered drugs, as the errors were not decimal in nature

Premature Discharge/Inadequate Understanding of Administered Drug: Practitioners should be familiar with the pharmacokinetics and pharmacodynamics properties of sedation agents. Certain drugs used in sedation (chloral hydrate, meperidine, pentobarbital, phenothiazines) have extended half-lives compared to other sedative drugs, and patients may require longer observation times so that the effects can completely wear off.13 Direct pharmacy involvement has been recognized to decrease medication errors, specifically in the areas of pharmacokinetics.16 Patient age can affect drug half-life; chloral hydrate has a half-life of approximately 28 hours in newborns and 10 hours in infants.17 Promethazine has vast differences in half-life between infants and adults (7.1 h vs. 20 h). Another consideration is intramuscular administration, as depot effects can significantly alter pharmacokinetics. Patient discharge prior to complete drug metabolism can be dangerous if prolonged effects persist after the patient has been discharged home. Depending on the half-life and time to secondary effect, patients may not have immediate access to resuscitative care

Prescription/Transcription Error: Cote et al found that it was not individual drugs that specifically caused events but rather a failure to follow procedure. Improper combinations, medication errors, faulty dosing, and inadequate monitoring were all targeted as possible systems breakdowns resulting in AEs. Direct pharmacy involvement may play a vital role in eliminating these errors, specifically in terms of mistranscription (tsp vs. tbsp) or drug calculations (mg/kg)

Administration by Unsupervised Technician/Parents/Family Member: Administration of drugs in an outpatient setting, either at a physician/dentist office or, more dangerously, at home by the family, has been an ongoing problem in relation to pediatric sedation. More deaths and neurological injuries have occurred in the outpatient than the inpatient setting (deaths: 82.1% vs. 30.2%, P <.001; neurological injury: 10.7% vs. 7.0%, P <.001).12 Lack of pulse oximetry plays a vital role in these statistics. In terms of predicting life-threatening events, pulse oximetry is by far the most important monitoring device.18 Even in a small subset of patients, better outcomes have been observed when some type of monitoring is available (14 events vs. 4, P <.001). Outpatient sedation leaves the potential for improper resuscitation due to inadequate equipment if a respiratory event should occur. When comparing inadequate resuscitation rates between inpatients and outpatients, only 2.3% of inpatients versus 57.1% of outpatients (P <.001) received inadequate resuscitation.12 Yet another risk factor for adverse sedation events is the coexistence of underlying disease states. Malviya et al found that children with ASA physical status III and IV experienced more events compared to children meeting ASA criteria for status I and II (P <.0001) and were more likely to have respiratory complications (P <.0001).11 ASA criteria evaluate patients based on severity of comorbid conditions and may help administrators identify those at higher risk for AEs. Some conditions may place a patient in a higher ASA class.

Prevention of Adverse Events

Direct pharmacy involvement, specifically having a trained pharmacy specialist present during sedation, could effectively help to decrease several of the identified causes of AEs. Drug interactions and drug overdoses can be minimized by providing an accurate patient medication history and properly examining drugs both before and while they are being administered to the patient. Accurate knowledge of drug pharmacokinetics could decrease the likelihood of a patient being discharged before a fully recovery is achieved. A systematic approach to medication administration should be utilized to eliminate transcription errors. Calculating mg/kg limits, using standard dosing regimens, and double- or triple-checking doses should be employed. Drs. Charles Cote and Theodore Striker developed the first set of pediatric sedation guidelines in 1983 after three deaths that occurred at one dental practice.19 The original guidelines were endorsed by the AAP, and over the past 25 years they have been updated numerous times, most recently in 2006 in conjunction with both the AAPD and the ASA. Several other organizations have also published guidelines on how to manage sedation in patients in a variety of settings. These guidelines have helped to properly define different levels of sedation as well as to provide recommendations for better administration of sedative drugs and monitoring both during and after procedures are performed. New requirements allow only properly trained, licensed practitioners to administer sedative medications. These practitioners, who at a minimum should be able to provide bag-mask-valve ventilation to oxygenate a patient, should be accompanied by other clinical staff who are all well versed in emergency protocols to minimize serious AEs from occurring.14,20 Emergency kits must be readily available. This is especially important for outpatient clinics or offices that continue to sedate patients.

Current AAP/AAPD guidelines specifically outline recommended discharge criteria to minimize the likelihood of AEs following sedation. The following six criteria are critical for achieving safe management of sedated pediatric patients: 1) cardiovascular function and airways are stable and satisfactory; 2) patient is easily arousable, with protective reflexes intact; 3) patient can talk (if appropriate based on age); 4) patient can sit up unaided (if appropriate based on age); 5) return to normal baseline responsiveness; and 6) hydration status is adequate.1 Documentation of sedation, the procedure, and recovery will help to minimize premature discharge. In addition, patients should be accompanied by at least two adults upon discharge and should have by-mouth intake evaluated to reduce the risk of aspiration.9 The administration of sedatives at the home is no longer an acceptable practice, as it poses too great a risk to the patient.9,20 If patients are sedated using certain drugs with extended half-lives, they may need longer, less-intensive observation to ensure that unwanted effects do not occur several hours after the procedure. The Institute of Medicine has stated that a national, mandatory reporting system should be in place to help improve awareness of adverse sedation events in terms of risk factors and causes. 21 The FDA currently administers MedWatch, a nonmandatory vehicle for collecting data involving AEs. Records of AEs are important to prompt root-cause analyses.

Management of Adverse Events
For several years there has been a great deal of debate as to which drugs should be used in pediatric sedation, who should be administering doses, and what type of setting is most appropriate. Is it appropriate to sedate a child for up to two hours for a radiological procedure that may only last five minutes? The lowest possible doses of the least number of medications that will produce the desired effects should be used. By using monotherapy or combinations of drugs that include reversible agents, we decrease the likelihood that a potentially harmful adverse event occurring. Drugs such as naloxone (Narcan) for opioid reversal or flumazenil (Romazicon) for benzodiazepine reversal can be used in possible overdose or synergistic situations.22 Both drugs can be titrated fairly quickly to achieve an adequate response: naloxone 0.1 to 0.4 mg IV every three to five minutes and flumazenil 0.2 to 1 mg IV every two to three minutes. Multiple dose forms (IV, IM [intramuscular], SL [sublingual]) also make these drugs favorable in rescue situations. Providers should use caution and avoid using these medications if drug dependence is an issue, as they may instill a rapid onset of withdrawal, which in some cases (with benzodiazepines, for example) could prove to be fatal. If airway obstruction is involved, the first step is to determine the cause. If laryngospasm is the cause and positive pressure using a bag-valve mask has not resolved the issue, succinylcholine 0.1 to 0.2 mg/kg IV (a neuromuscular blocking agent) should be added as adjunctive treatment. If anaphylactoid reaction has occurred, epinephrine 0.3 mg IM should be started. For severe reactions, 0.5 mg may be needed, and the drug can be titrated in 0.1-mg increments if the patient is refractory. Albuterol inhalation (2-3 inh q1-2min • 3 if needed ) should be used in conjunction with epinephrine if bronchospasm occurs. Sedatives will decrease sympathetic outflow from the heart, causing bradycardia and hypotension. Ephedrine (dilute 10 mg/mL; 5-10 mg IV q5min; max 50 mg) will directly stimulate the release of norepinephrine by acting on both alpha and beta receptors. It is considered the drug of choice due to its longer duration of action (60-90 min). Second-line agents atropine (0.5 mg IV, IM, SL q4-5min • 4-5) and phenylephrine (dilute to 0.1 mg/mL; 0.1 mg IV q3min • 5) may also be used but generally only produce effects for five to ten minutes. Caution must also be used with ephedrine and phenylephrine as they must both be diluted before use. Phenylephrine should be used for hypotension with tachycardia, as it works selectively as an alpha agonist and will not increase heart rate while producing venoconstriction and increased pressure. If hypertension occurs during sedation, nitroglycerin (1 tablet SL q5min • 3), morphine (2.5 mg IV q3-5min; max 10 mg) or aspirin (325 mg or four 81-mg tabs) are options. Labetalol (10 mg IV q5min, repeated if needed) can help to prevent reflex tachycardia but should be avoided in asthmatics due to nonselectivity. In these situations, esmolol is a better choice.

Discussion
Guidelines endorsed by several national organizations have helped to reduce the incidence and likelihood AEs in pediatric sedation; however, events still occur. Malviya et al found that 28 of 56 reported deaths due to complications related to sedation occurred after the first publication of AAP guidelines.11 In addition, 27% of the records that were reviewed did not include a sedation flowsheet, which is required per the guidelines. Strict adherence to published guidelines is essential to reducing the incidence of sedation-related AEs. Administration of sedatives should be done by licensed practitioners, assisted by staff members trained in emergency rescue protocol. New developments in human simulation are helping to improve sedation techniques, limit events, and promote safety.23 Accurate knowledge of drugs being used for sedation can decrease the incidence of adverse events. Pharmacists can play a vital role in completing medication reconciliation, calculating accurate mg/kg limits, and selecting appropriate drug therapy. Soft data suggests that drugs with reversible potential (opioids, benzodiazepines) may have advantages over other sedatives in reducing the incidence of events.7 Practitioners should be using the fewest number of drugs at the lowest efficacious dose. Dexmedetomidine (Precedex), a fairly new medication, may be considered in the future for sedation monotherapy. The current safety and efficacy profile is not adequate and further studies are needed to determine its value in moderate sedation.24 Documentation is the final key step in reducing the incidence of events. Proper reporting can help institutions as well as larger consortiums develop root-cause analyses, which can identify potentially hazardous practices and improve current guidelines.

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