Six RCTs (N = 561 procedures) and 4 non-RCTs (N = 3322 procedures) examined the safety and/or effectiveness of propofol-based PS. The majority of published propofol sedations (3420/3883; 88.1%) were performed by nonanesthesiologists, that is, pediatric intensivists (14,15) or specifically trained pediatricians (4,16).
Propofol-based PS is safe. Mild respiratory events occur frequently and major complications may happen rarely, but adverse events do not occur more frequently compared with other sedation regimens. On a total of 3883 reported propofol-based sedations, major respiratory complications like total airway obstruction, deep hypoxia, or apnea occurred 11 times (0.3%). No cases of intubation, resuscitation, permanent sequelae, or death were reported. In the largest study (Larsen et al (15); N = 2332), the incidence was only 0.04%, but the retrospective design may have caused underreporting. In all of the studies, patients routinely received additional oxygen. Overall, the incidence of adverse events is not higher compared with other sedative regimens included in this systematic review. Minor respiratory events, such as temporary desaturation or hypoventilation, occurred more frequently (up to 24% in Kaddu et al's study), particularly in infants younger than 1 year (incidence 35% compared with 12.5% in children older than 10 years; P < 0.02) (15). Three of the 6 children needing assisted ventilation in the study by Barbi et al (4) (N = 811 procedures) were also younger than 1 year. The other 3 and all 14 children with laryngospasm (overall incidence 1.7%) were younger than 4 years. Disma et al (12) reported an incidence of laryngospasm of 3.75% in children sedated with propofol alone. Adding midazolam or fentanyl to propofol resulted in no cases of laryngospasm. Clinically relevant hypotension, hypoperfusion, or bradycardia has not been reported.
Propofol-based PS is greatly effective. None of the retrieved articles reported in itself on all aspects of effectiveness as defined in the methodology section of this systematic review. The reported incidences of incomplete or failed procedure ranged from 0% (14) over 0.05% (15) to 0.4% (4,15). Kaddu et al (17) showed that deep sedation with propofol is an equivalent alternative for general anesthesia (GA). The time to achieve adequate sedation, the mean procedure time, and the recovery time were significantly shorter in children sedated with propofol, compared with the combined sedation with meperidine + midazolam (14). Only 3 studies assessed patient comfort or the need for restraint as outcome parameters for effectiveness. Paspatis et al (18) reported an incidence of extreme discomfort of 14.2% if propofol was used alone. Premedication with oral midazolam improved significantly the level of patient comfort during the procedure (0% extreme discomfort). Khoshoo et al (14) showed that propofol + midazolam was associated with the need for restraint in only 3% of cases, compared with 57% in the meperidine + midazolam group (P < 0.01). Total absence of recall was observed more frequently in the propofol + midazolam group (88% vs 55%; P < 0.05). Elitsur et al (19) reported the absence of pain and recall in 96% of patients. Propofol injection pain was reported to occur in 53% of cases, despite the addition of lidocaine to propofol (4).
The addition of ketamine, midazolam, or fentanyl to propofol-based PS may have beneficial effects on PS quality. Tosun et al (20) compared propofol + ketamine with propofol + fentanyl. Both combinations provided equally effective sedation and similar low incidences of mild respiratory events. The use of ketamine was associated with a better tolerance of endoscope insertion but higher incidences of cough, vomiting, dizziness, and diplopia. A low dose of ketamine before propofol is more effective in reducing propofol infusion pain, compared with a lidocaine–propofol mixture (16). Disma et al (12) showed that the addition of either fentanyl or midazolam caused less adverse events compared with propofol alone. This effect was mainly caused by a lower incidence of coughs and laryngeal spasms. No differences were seen between these 2 additional medication regimes regarding effectiveness or adverse events. Both Disma et al and Elitsur et al (12,19) showed that adding midazolam or fentanyl significantly lowers the necessary dose of propofol.
Opioid + Benzodiazepine-based PS
The effectiveness and/or safety of opioid + benzodiazepine-based sedation were studied in 3 RCTs (N = 94 procedures) and 6 non-RCTs (N = 2326 procedures). The administrating professionals were intensivists (14), gastroenterologists/endoscopists (21–24), or were not reported (13,25,26).
Opioid + benzodiazepine-based sedation is safe. Mild respiratory events occur frequently and major complications may happen rarely. Of a total of 2420 opioid + benzodiazepine-based sedations, major respiratory complications such as apnea, total airway obstruction, or deep desaturation occurred only 5 times (0.2%). In all of the studies, patients received oxygen routinely, except for the studies by Fishbein et al, Chuang et al, and Gilger at al (21,22,26).
Khoshoo et al (14) showed that the use of meperidine + midazolam was associated with a higher need for supplemental oxygen and ventilatory support, compared with the use of propofol + midazolam (17% vs 7% and 7% vs 3%, respectively; P < 0.05 for both differences). Ali et al (25) showed in a small RCT that fentanyl + midazolam and meperidine + midazolam are equally safe. Chuang et al (21) came to the same conclusion in their retrospective comparative study. Fishbein et al (26) compared intravenous (IV) meperidine + midazolam with the combination of intranasal midazolam and IV meperidine. Both regimens were equally safe and none of the patients experienced major adverse events. In their prospective study on IV fentanyl + midazolam, Mamula et al (13) reported 9% respiratory adverse events (8% transient desaturation, 1% prolonged desaturation, 0.2% apnea), 11% mild cardiovascular adverse events (3% hypertension, 8% hypotension), 0.6% rash, 1% agitation, and 5% vomiting. The following rescue interventions were reported: 9.5% extra oxygen therapy, 1.3% tactile stimulation, 0.4% jaw thrust, 0.2% bag and mask ventilation, and 1.6% IV fluid bolus. In a smaller prospective study, Squires et al (24) compared PS using meperidine + midazolam with general inhalational anesthesia. No major adverse events or desaturations were reported. Gilger et al (22) compared retrospectively meperidine + midazolam with meperidine + midazolam + ketamine and midazolam + ketamine. Mild respiratory adverse events, especially desaturations, occurred most frequently in the meperidine + midazolam group (30.7% vs 10.9% [P < 0.001] and 0.6% [P < 0.001], respectively).
The evidence indicates that effectiveness of opioid + benzodiazepine-based PS is suboptimal, especially regarding time characteristics and the need for restraint. None of the retrieved articles reported in itself on all aspects of effectiveness as defined in the methodology section of this systematic review. In their comparative study between propofol + midazolam and meperidine + midazolam, Khoshoo et al (14) reported equally high procedural success rates (±100%); however, the time to achieve adequate sedation, the mean procedure time, and the recovery time were significantly longer if midazolam + meperidine was used. Furthermore, restraint was significantly needed more in the meperidine + midazolam group, suggesting suboptimal effectiveness of this regimen. Fishbein et al (26) reported high incidences of major negative behavior during EGD in children sedated with IV midazolam + meperidine (19/20) or intranasal midazolam + IV meperidine (18/20). The intensity of negative behavior was significantly lower in the group receiving intranasal midazolam premedication. Ali et al (25) could not show any significant difference in effectiveness between fentanyl- and meperidine-based PS, but patient comfort was not an outcome parameter in their study. In the Mamula et al study (13) on fentanyl + midazolam, 11% of the colonoscopies were incomplete because of inadequate sedation. Gremse et al (23) found similar figures in their study on meperidine + midazolam. Gilger et al (22) showed that, compared with ketamine + midazolam, the use of meperidine + midazolam resulted more frequently in inadequate sedation (8.6% vs 3.1%), although the difference was not significant (P = 0.07). Finally, a prospective comparison between meperidine + midazolam and GA showed a lower procedural failure rate (0% vs 4.8%), lower need for restraint (0% vs 13%), and less direct and indirect indications of discomfort in the GA group (24).
Three non-RCT trials (N = 1056 procedures) have examined the safety and/or effectiveness of ketamine. In 2 studies, gastroenterologists administered ketamine (22,27). Aggarwal et al (28) did not report the administrating professional.
Ketamine-based PS is probably safe, but data are limited. Especially in EGD, ketamine is associated with a high chance of laryngeal spasm. Compared with meperidine + midazolam, Gilger et al (22) reported less desaturation in the ketamine + midazolam group. Aggarwal et al (28) found no particular major adverse events or complications, but it is unclear how vital parameters were assessed. A retrospective study by Green et al (27) reported in more detail on adverse events (Table 2). All of the patients routinely received oxygen therapy. Laryngeal spasm occurred in 9.5% of EGDs. The only significant independent predictor of laryngospasm in a multivariate analysis was age: 13.9% in preschool-age (6 years or older) children and 3.6% in school-age (older than 6 years) children (difference 10.3%, 95% CI 5.5%–14.9%).
Ketamine-based PS is probably effective, but data are limited. Reliable data on patient comfort and the need for restraint are missing. According to Gilger et al (22), inadequate sedation occurs less frequently in ketamine + midazolam sedation compared with meperidine + midazolam. Incidences of failed sedation ranged from 0% to 1.1% (27,29); however, data on patient comfort, the need for restraint, or the ease of the procedure are missing.
One RCT (N = 61 procedures) and 2 non-RCTs (N = 275 procedures) have studied the safety and/or effectiveness of midazolam alone. Either anesthesiologists (30,31) or pediatricians (32) administered midazolam.
Data are too limited to draw conclusions on the safety of midazolam-based PS. Rafeey et al (31) compared oral and IV midazolam. Major adverse events did not occur. The mean oxygen saturation was lower in the IV group. Verhage et al (32) reported an overall incidence of adverse events of 3%. Nature and severity of events were not reported. Flumazenil was needed in 2.7% of cases. In a small comparative study, Lamireau et al (30) compared IV midazolam with halothane anesthesia. Desaturation below 90% occurred significantly more frequently in the midazolam group (50% vs 0%; P < 0.001). Midazolam-based PS is probably ineffective, but data are limited.
Lamireau et al (30) found that incomplete procedures and complete procedures under difficult conditions occurred significantly more frequently in patients sedated with IV midazolam compared with halothane anesthesia (50% vs 0% and 38.9% vs 0%, respectively). Rafeey et al and Verhage et al (31,32) reported procedural success rates of approximately 100%; however, both studies failed to report reliable data on patient comfort, adequacy of sedation, and ease of procedure. The significant increase in heart rate and blood pressure during endoscopy, as registered by Rafeey et al, suggests that midazolam is ineffective in reducing patient discomfort.
Sevoflurane Inhalation for PS
In a retrospective study, Montes and Bohn (33) compared inhaled sevoflurane (N = 67 procedures), administered by an anesthesiologist using an oropharyngeal tube, with 2 sedative regimens administered by pediatric intensivists: propofol alone (N = 114 procedures) and a combination of midazolam and/or fentanyl and/or ketamine and/or propofol (N = 67 procedures).
Sevoflurane-based PS may be safe, but data are limited. No severe adverse events were reported. Respiratory adverse events occurred rarely at similar incidences in the 3 groups. The incidence of hypotension was 0% in the sevoflurane group versus 13.2% and 7.5% in the other groups. None of these hypotensive episodes was considered relevant. Data are too limited to draw conclusions on the effectiveness of sevoflurane-based PS. Compared with the IV regimens, sevoflurane was characterized by a shorter recovery time, earlier discharge, and lower costs. The present study did not report on patient comfort, need for restraint, or overall procedural success; neither did it specify whether and how sevoflurane pollution in the ambient air was avoided (33).
Three RCTs (N = 107 procedures) specifically analyzed the safety and/or effectiveness of midazolam premedication. One RCT (N = 50 procedures) analyzed atropine premedication.
Midazolam premedication is probably safe for children undergoing PS for GIE, but data are limited. None of the studies recorded differences in safety between premedication and non–premedication groups.
Premedication with midazolam has positive effects on patient comfort. There is good evidence that oral midazolam premedication preceding a propofol- or an opioid-based PS improves significantly the ease and comfort of both IV catheter placement and separating the child from the parents. It also increases the level of patient comfort during the procedure (18,34). Following an opioid-based PS, the degree of partial or total amnesia is higher, compared with placebo, if oral midazolam premedication is given (83% vs 55%; P < 0.05) (34). In propofol-based PS, the addition of oral midazolam premedication lowers the propofol dose during the procedure but increases the recovery time (18). Fishbein et al (26) showed that premedication with intranasal midazolam before IV meperidine effectively reduces the intensity of negative behaviors; however, no effect was seen on the total number of negative behaviors. Furthermore, the intranasal administration itself was associated with negative behavior in 50% of cases.
Atropine premedication probably does not increase the safety or effectiveness of PS in children undergoing GIE, but data are limited. Hofley et al (35) compared atropine premedication with placebo in a small group of children sedated with fentanyl + midazolam or meperidine + midazolam. They concluded that atropine did not increase PS safety and provided no appreciable benefits on oral secretions, gastric motility, vomiting, facial flushing, or diphoria.
The available evidence suggests that propofol-based PS is the most effective regimen for PS during GIE in children (Table 4). Propofol guarantees an excellent level of procedural success, optimal timing, and maximal patient comfort, in particular if propofol is preceded by midazolam premedication. The addition to propofol of IV midazolam, fentanyl, or remifentanil may increase the effectiveness without generating more adverse events, provided that sedation is performed by trained PS practitioners under certain quality and safety conditions. Compared with GA, propofol-based PS seems to be an equally effective technique for selected cases of diagnosis and therapy. It must be noted, however, that there is a considerable risk that deep sedation with propofol may result in an actual sedative state close or similar to GA for a limited period of time with an increased risk. In a prospective study of children sedated with propofol by nonanesthesiologists, 90% of children reached a level of “anesthesia” albeit briefly (36). Nevertheless, this systematic review's search category was “sedation” and not “anesthesia,” so that irrespective of the actual sedation level, practitioners believed that they were sedating and not anesthetizing.
Propofol infusion–related pain can be prevented with a low dose of ketamine, which is, in children, a more effective approach compared with adding lidocaine to propofol. Opioid + benzodiazepine-based PS also results in high procedural success rates; however, the longer time needed to achieve sedation, the longer recovery time, and the significantly lower levels of patient comfort are substantial drawbacks compared with propofol-based PS. There is some evidence that the relatively high incidence of incomplete colonoscopies in opioid + benziodiazepine-based PS (up to 10%) is caused by ineffective sedation. We could find no study comparing the effectiveness of propofol and ketamine for GIE in children. The available evidence on ketamine suggests less inadequate sedation, compared with meperidine + midazolam; however, none of the articles reported data on patient comfort, the need for restraint, or the ease of the procedure. It is plausible that IV midazolam alone is not an effective way to provide PS for GIE in children; however, oral midazolam premedication preceding a propofol-based or an opioid-based PS improves significantly the ease and comfort of both IV catheter placement and separation of the child from the parents. It also increases the level of patient comfort during the procedure.
Comparing the safety outcome of propofol-based PS with the more traditional opioid + benzodiazepine-based PS does not reveal striking differences. Mild and transient hypoxia is reported as the most frequent adverse event in both strategies. Major respiratory adverse events, such as deep hypoxia, hypoventilation, apnea, and airway obstruction, seem to occur rarely but at similar rates. As a consequence, both regimens require the same safety precautions. In adult medicine, 3 recent meta-analyses did not show significant differences between propofol-based and traditional PS for hypoxemia and hypotension, except for fewer cardiorespiratory complications with propofol during colonoscopy (37–39). Khoshoo et al published the only available RCT comparing the safety of propofol-based versus opioid + benzodiazepine–based PS in children. In the propofol group, oxygen therapy and ventilatory support were significantly less needed. There is some evidence that laryngospasm occurs in about 9% of children sedated with ketamine for EGD (27), compared with 1.7% to 3.7% if propofol is used alone (4,12) and 0% if propofol is combined with midazolam or fentanyl (12). Therefore, it may be prudent to advise not to use ketamine for upper GIE and to add midazolam or fentanyl to a propofol PS.
The fact that, apart from 1 article (4), none of the studies made use of capnography monitoring may have caused underestimation of the real incidences of airway obstruction and hypoventilation. The relevance of capnography for early detecting imminent respiratory events during PS is well established (40–42). Its application during GIE was reviewed recently (43).
The similar low rate of adverse events in the different sedation regimens is not surprising. It has been shown that PS-related safety is determined by the circumstances, applied safety precautions, and professional skills rather than by specific pharmacological characteristics (10). In most studies included in this systematic review, competent and skilled professionals performed PS in accordance with widely accepted safety guidelines. Adherence to PS safety guidelines reduces the occurrence of PS-related adverse events (36,44,45).
The present review suggests the superior effectiveness of propofol compared with the more traditionally used opioid + benzodiazepine combination. The latter is generally considered safe in a nonanesthesiologist's hands, whereas the administration of the anesthetic propofol is usually restricted for safety reasons to anesthesiologists only. This distinction is remarkable given the results of this systematic review, showing a similar safety profile for both regimens. Furthermore, the vast majority of included propofol sedations were performed by nonanesthesiologists. Because of limited anesthesiology resources, propofol is being administered worldwide by nonanesthesiologists (specially trained nurses or endoscopists) for GIE in selected adult patients (46). An evidence-based guideline on this topic was published recently (47). Excellent evidence exists demonstrating that well-trained nonanesthesiologists may provide propofol sedation safely in children, including for gastrointestinal procedures (48). It has also been shown that within the setting of adequate training and strict safety measures, no differences exist in rates of major complications among different specialists (ie, anesthesiologists and nonanesthesiologists) (49). Appropriate safety precautions, monitoring, and professional skills, rather than professional title, are determinants for the safe and effective use of propofol for PS (50).
The present study has several limitations. At first, few RCTs compared different pharmacological techniques. The fact that different studies used different outcome measures or different definitions for safety and effectiveness is another important limitation. An objective or validated assessment of the more subjective measures such as satisfaction, ease of procedure, or patient comfort is missing in most studies. Consequently, it is presently impossible to summarize the available evidence in meta-analyses or to draw solid conclusions on best practices. Nevertheless, we believe that it is possible to draw prudent conclusions and to formulate practical recommendations. Because most of the studies reviewed included both upper and lower GIE, we choose not to differentiate between them. It is likely that optimal sedation characteristics and issues on safety and effectiveness are not the same for both procedures; however, we believe that the main conclusions would probably remain the same. Psychological distraction techniques may be useful adjuncts or partial alternatives for PS. We deliberately choose not to include these nonpharmacological methods in this systematic review. Finally, in individual patients, the optimal PS strategy may deviate from the conclusions of this systematic review. Although the benzodiazepine + opioid combination is not as good as propofol-based PS, it may be suitable for some children if they can tolerate moderate sedation. Also, unsedated endoscopy in selected greatly motivated children has been reported (51). In this respect, it is remarkable that in the Barbi et al (4) study among children older than 14 years, 26.6% preferred to have no sedation at all during upper GIE.
The limitations of this systematic review clearly identify a gap of scientific knowledge on this topic. Only well-designed, procedure-specific RCTs comparing validated outcome measures on effectiveness and safety between different sedative regimens in large numbers of children may yield a definite answer on our clinical question; however, given the results of this systematic review in general and the findings on patient comfort in particular, one may question whether setting up such trials is still ethically justifiable.
Despite the methodological limitations, the evidence gathered in this systematic review indicates propofol-based PS as the best practice for PS in children undergoing GIE. The addition to propofol of IV midazolam, fentanyl, or remifentanil may increase its safety and effectiveness. Oral midazolam premedication leads to a lower mean dose of propofol, less painful and easier IV access, easier separation from the parents, and greater patient comfort during endoscopy. A low dose of ketamine is effective in reducing propofol infusion pain. Propofol is likely to lead to an unconscious state in many children. Although this may not be unsafe, it does mean that it is not strictly sedation. Practitioners should be trained to manage this depth of sedation (ie, anesthesia) and parents and children warned that this may happen. Conversely, children who expect to be oblivious to the GIE during sedation with propofol should be told that they may be sedated (not anesthetized) and that they may recall some details of the procedure. Propofol can be safely administered to children by specifically trained nonanesthesiologists who provide PS in adherence to established safety guidelines. In the absence of these professionals and settings, it is advisable to refer children who need to undergo a GIE to an anesthesiologist for propofol-based PS or anesthesia.
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Keywords:Copyright 2012 by ESPGHAN and NASPGHAN
children; effectiveness; gastrointestinal endoscopy; procedural sedation; safety