Most endoscopies in children can be performed only with appropriate sedation or anaesthesia. Various medical societies have published guidelines on children sedation (1–3); however, indications for endoscopic investigations should be carefully evaluated and invasive investigations must be replaced by noninvasive whenever applicable.
Probably the most appropriate sedation practice in hospitals is the one performed or supervised by anaesthetists. It enables the use of different sedatives or anaesthetics. When sedation is performed by nonanaesthetists, only limited selection of medications can be used safely (4). The scarcity of anaesthetists forces many endoscopists to perform sedation during diagnostic endoscopy by themselves. Medications usually used by nonanaesthetists are a combination of a benzodiazepine and an opioid analgesic (preferred are short-acting midazolam and fentanyl), ketamine with or without premedication with midazolam, and the still-controversial propofol (4,5), the latter raising some safety issues and being used in many countries only by anaesthetists (6). There are also other sedation practices in different centres. A survey in France, for example, showed that inhaled nitrous oxide, whose efficacy was proved in children (7), was used in up to 20% (8).
The depth of sedation is a continuum reaching from anxiolysis over conscious and deep sedation to general anaesthesia according to the American Society of Anesthesiologists. Different levels are defined by responsiveness, airway, spontaneous ventilation, and cardiovascular function, which are mostly unaffected in anxiolysis and mostly impaired in general anaesthesia (3).
Ketamine is a unique medication that does not produce any of the aforementioned states but dissociative anaesthesia characterized by sedation/anaesthesia, amnesia, and analgesia with a stimulative effect on cardiovascular and pulmonary system (9). This state is produced by the suppression of the association areas of the brain (9,10). The uses are many and one of them is sedation for gastrointestinal endoscopy in children (11). Studies and meta-analyses of ketamine safety for nonanaesthetists’ use in otherwise healthy or mildly ill patents (classification group I or II according to the American Society of Anesthesiologists) justify its use in the settings with a shortage of anaesthetists (12,13).
One of the particular properties of ketamine is that when the dissociative sedation state is reached, additional doses do not deepen the sedation. A lower starting dose (intravenously <1 mg/kg) produces analgesia and disorientation, which may be sufficient for some investigations, but because of their favourable safety profile, doses between 1 and 2 mg/kg are recommended (9,10,12,14). Emergence reactions of ketamine are defined as hallucinations, excitation, nightmares, and delirium, which could be followed by recurrent illusions (“flashbacks”) (9,14). Emergence reactions are more frequent in adults (5%–>30% (9), but premedication with benzodiazepines reduces its frequency (15,16).
The aims of our study were to establish the appropriate ketamine starting dose and to estimate differences in the frequency of adverse reactions and especially of emergence reactions when sedation for endoscopic procedures was performed with or without midazolam premedication.
The study was performed at the Department of Gastroenterology at the University Children's Hospital Ljubljana. Children scheduled for gastroscopy and/or colonoscopy during a 1-year period (February 20, 2007–February 21, 2008) were invited to participate. The study protocol was approved by the state ethical committee. Parents and/or patients (according to their age and cognitive development) were asked to sign an informed consent document.
Children who were admitted for diagnostic endoscopy were evaluated for suitability according to the guidelines for sedation by nonanaesthetists and the sedation with ketamine (3,12). The assessment consisted of a history and physical examination. Inclusion criteria were ages between 1 and 19 years and suitability for intravenous sedation with ketamine and/or midazolam by nonanaesthetists. Exclusion criteria were respiratory tract infection, untreated hypertension, glaucoma, eye injury, increased intracranial pressure, central nervous system mass lesion, psychosis, porphyria, and known allergy to ketamine or midazolam. Such patients were rescheduled, suggested to undergo another diagnostic procedure, or the endoscopy was performed with the sedation/anaesthesia supervised by an anaesthetist. The patients who had urgent or therapeutic endoscopies were not included in the present study. In such cases the procedure was performed under general anaesthesia supervised by an anaesthesiologist because the patients had to be intubated (eg, major bleeding, foreign body retrieval, PEG insertion).
The participants were randomly alternately assigned to the group A or the group B (see description of groups below). The study was designed as single blind. Before, during, and after the endoscopy oxygen saturation, heart rate and breathing frequency were monitored continuously, and blood pressure was measured before starting the procedure and every 5 minutes afterward.
Participants in group A (sedation with midazolam and ketamine; abbreviated as mid-ket) were given premedication with intravenous midazolam 0.1 mg/kg body weight (BW) up to a maximum of 2.5 mg followed by intravenous ketamine 0.75 mg/kg BW 1 minute afterward. Responsiveness was assessed by calling a child by his or her name and by tactile stimulation. If the patient responded, then ketamine 0.25 mg/kg was added at 2-minute intervals up to the total dose of 1.5 mg/kg. Response to verbal and tactile stimulation was reassessed after 2 minutes. When the child was unresponsive, the endoscopist started the endoscopy. The patient's response, if any, on introduction of the endoscope was noted. If the endoscopy lasted a long time or when a patient started to react, ketamine 0.5 mg/kg BW was added every 10 to 15 minutes and midazolam 0.05 mg/kg BW every 30 to 60 minutes. Doses of sedation medicaments, vital functions, and adverse reactions, if any, were recorded throughout the procedure. The sedation was led and supervised by the endoscopist. One nurse, experienced in sedations, provided sedatives and supervised vital functions.
Children in group B (sedation with ketamine only; abbreviated as ket) followed the same protocol but they received only ketamine without midazolam premedication. The sedation was categorized as optimal, appropriate, or unsuitable by the endoscopy team. After the investigation, children were supervised at the ward until they were in the same condition as before the sedation. Adverse reactions during awakening were recorded.
After at least 1 month, the investigator interviewed participants’ parents by telephone about the occurrence of any late adverse reactions. After randomisation and completed endoscopy, patients were categorized in 1 of the following subgroups:
- A1 (abbreviated as gastro/mid-ket)—gastroscopy, sedation with midazolam and ketamine
- B1 (abbreviated as gastro/ket)—gastroscopy, sedation with ketamine only
- A2 (abbreviated as gastro-colono/mid-ket)—gastroscopy followed by colonoscopy, sedation with midazolam and ketamine
- B2 (abbreviated as gastro-colono/ket)—gastroscopy followed by colonoscopy, sedation with ketamine only
Children who underwent colonoscopy only were excluded from further analysis because their numbers were too small for statistical analysis (Fig. 1). For some of the analyses, we united subgroups A1 and A2 together as group A (mid-ket) and B1 and B2 together as group B (ket).
Data were analysed using the PASW Statistics 18 software (SPSS Inc, Chicago, IL). The methods of descriptive statistics were used. Differences between the groups were analysed by the χ 2 test. In cases of expected frequency of <5, we used the Fisher test. The P value of 0.05 was regarded as significant.
Two hundred eleven patients were included in the study. Five were later excluded because of inappropriate age (1 patient too young, 1 too old) and incomplete documentation (3 patients). We also excluded 5 children who underwent only colonoscopy because of small sample size (Fig. 1). In the end, 201 patients remained for the analysis (111 girls, 90 boys); the median age was 8.2 years (range 1.0–18.9 years), and the median weight 31.5 kg (range 8.4–96.3 kg) (Table 1).
Fifty-seven percent of patients in the group A (mid-ket) received 1 and 5% received 2 supplemental doses of ketamine 0.25 mg/kg BW after the initial dose of 0.75 mg/kg BW. In group B (ket), those with 1 additional dose were 69% and those with 2 additional doses were 10%. The median starting doses at which the patients were sufficiently sedated to start the gastroscopy were 0.97 mg/kg (25th–75th percentile; P = 0.75–1.0) and 0.99 mg/kg TT (25th–75th percentile; P = 0.76–1.02), respectively. In group A (mid/ket), the appropriateness of sedation rated by the endoscopy team as optimal or acceptable was 96%, and in group B (ket), it was 99%. There were no statistical differences between the groups.
Adverse Reactions, Apart From Emergence Reactions
To assess the overall safety of both sedation protocols, we analysed all of the adverse reactions. The majority were short-term reactions and without any later implication. Those that could pose any risk to patients are described in more detail.
Laryngospasm was observed in 2 patients in group A1 (gastro/mid-ket), 4 in group B1 (gastro/ket), and none in groups A2 (gastro-colono/mid-ket) and B2 (gastro-colono/ket). All of the episodes were short-lived and self-limited because oxygen saturation normalized soon after the positioning of airways and the addition of oxygen through the nose catheter. We did not have to stop the endoscopy to intubate any patient.
Saliva aspiration during or immediately after gastroscopy was needed in 3 patients in the group A1 (gastro/mid-ket) and in 1 patient in the group B1 (gastro/ket). None of the patients in other groups needed it. We regarded this adverse reaction as a possible risk for aspiration. None of the patients showed any signs of aspiration pneumonia after the procedure or returned to the hospital because of this complication.
We noted laryngospasm and profound salivation in both groups A and B in the same percentage (5%) of patients without statistical difference in both groups (χ 2 = 0.013; P = 0.91).
The need for additional oxygen was defined by any drop of haemoglobin saturation <92%. The proportion of patients who needed additional oxygen was extremely high: 42% in group A1 (gastro/mid-ket), 43% in group A2 (gastro-colono/mid-ket), 46% in group B1 (gastro/ket), and 37% in group B2 (gastro-colono/ket). There were no statistical differences between the groups. After the positioning of airways and the addition of oxygen, saturation immediately normalised in all of the patients. No resuscitation with intubation or the transfer to the intensive care unit was needed.
Vomiting after endoscopy was observed in 10 patients in group A1 (gastro/mid-ket), in 11 patients in group B1 (gastro/ket) (χ 2 = 0.15; P = 0.90), in 10 patients in group A2 (gastro-colono/mid-ket), and in 4 patients in group B2 (gastro-colono/ket) (χ 2 = 3.354; P = 0.07).
We did not determine any statistical difference among subgroups in any described or other adverse reaction apart from emergence reactions during hospital stay as described below.
In group A1 (gastro/mid-ket), 2 parents reported that their children had probable emergence reactions after discharge from the hospital (in both cases severe disruption of night sleep with nightmares that were never observed before and that resolved spontaneously after a few nights). We observed marked irritability during recovery on the ward in 2 patients in group A2 (gastro-colono/mid-ket). One of them claimed to have unpleasant dreams. In group B1 (gastro/ket), 5 patients had emergence reactions in the hospital and 2 had them later at home (irritability and/or unpleasant vivid dreams), and in group B2 (gastro-colono/ket), 5 in the hospital and 1 after discharge (similar descriptions as in group B1 [gastro/ket]). Frequencies of emergence reactions are presented in Figure 2.
As expected, the frequencies of emergence reactions were small; however, we proved the statistical difference of emergence reactions at the hospital in total between groups A (endo/mid-ket) and B (endo/ket) (P = 0.02). There were no other statistical differences between the groups.
Our prospective single-blind randomised study proves that protocols using ketamine with or without midazolam for the sedation of children during gastrointestinal endoscopies by nonanaesthetists are both efficient and safe. A starting dosage of ketamine between 1 and 1.5 mg/kg should be used, and lower doses (0.75 mg/kg BW) do not lead to efficient sedation. This finding was in contrast to Bleiberg et al, who satisfactorily sedated 88% of patients at the emergency department using doses between 0.5 and 1 mg/kg (17) and to our previous observations (18). Other authors agree on the sufficient starting dose because of low dosage leads only to analgesia and disorientation (10,14).
Both sedation protocols can be regarded as safe because potentially dangerous laryngospasm or hypersalivation for which aspiration was needed was experienced by only 5% of patients. There was no difference between the groups. Moreover, none of our patients needed resuscitation or transfer to the intensive care unit. The frequencies of adverse reactions differ considerably among the studies. In the retrospective study by Green at al, 9.5% of 636 patients who underwent endoscopy under ketamine sedation experienced laryngospasm (19). In the same study, the number of patients who experienced hypersalivation was expectedly low (0.3%) as atropine was administrated in 87%.
The percentage of our patients who needed additional oxygen was high (37%–46%). Oxygen was routinely supplemented by nasal catheter in the study of Green et al (19), so the comparison between their and our study is not possible.
In another retrospective study laryngospasm was not present and oxygen was needed in only 1 of 128 patients (13) In the meta-analysis of 8282 children sedated with ketamine for procedures at emergency departments, 3.9% had airway or respiratory adverse reactions, but it could not be deduced how many others received the prophylactic addition of oxygen. In the same meta-analysis hypoxemia was defined as oxygen saturation ≤90% (20). In a study performed in adult patients undergoing endoscopies by Wang et al, addition of oxygen was needed in 6% of nonsedated and 16% of patients sedated with midazolam (hypoxemia defined as desaturation to ≤92% for at least 15 seconds) (21). Therefore, it is impossible to compare the results because different threshold and length of desaturation had been used as significant. In our study, we added oxygen faster and at higher haemoglobin saturation (immediately on desaturation ≤92%) than in some other studies. This explains the difference in oxygen addition in our and other studies. Most of the short-duration hypoxemias are physiologic because the passage of the gastroscope through the hypopharynx provokes hypoventilation. It is followed by mild transient haemoglobin desaturation, which is easily differentiated from possibly dangerous laryngospasm.
The overall incidence of vomiting in our study was 17%, with no differences between the groups. This is similar to the results of Langston et al (22), who reported vomiting in 18.9% of children with ketamine sedation but significantly less (7.8%) when they were additionally treated with ondansetron. In another study, postoperative vomiting after general anaesthesia was present in 13% to 42% of children (23). Because of the many factors influencing postoperative vomiting, the comparison with vomiting frequency after intravenous sedation is difficult.
In our study, emergence reactions occurred significantly more frequently during recovery in the hospital in patients who were sedated with ketamine only. This contrasts the results of the study of Sherwin et al in 2000 (24). They did not find any difference in emergence reactions in a group of 53 patients who received midazolam and 51 patients who received placebo. The number of patients who were agitated after sedation was higher than expected, but it did not have any clinical significance (24). Wathen et al studied a larger sample of 266 patients and noticed emergence reactions in 26.7% of the patients in the hospital and 22.4% at home (25). Significant emergence reactions were found in 7.1% in the ketamine group and in 6.2% in the ketamine-midazolam group without any statistical difference (25). Both studies were performed at paediatric emergency departments on a different population of patients than ours (endoscopy patients), which encumbers the comparison. In the retrospective study of Green et al, recovery agitation was seen in 2.4% of patients (19). Gilger and coworkers did not report any recovery agitation or emergence reactions in 128 retrospectively studied children sedated with midazolam and ketamine (13). A marked difference in the incidence of emergence reactions points towards the difficulty of exactly defining different emergence reactions.
The main difference between the studies mentioned above (24,25) and our study was that in our study ketamine followed midazolam, which is the usual way these medicines are given and not vice versa, as was done in the aforementioned studies, to enable a double-blind protocol. This may explain the effectiveness of midazolam's reducing the emergence reactions in our case. Probably even better results could be achieved by giving midazolam orally 30 minutes or intravenously 15 minutes before ketamine. In the present study, we deliberately decided not to follow this protocol, which is used on paediatric surgical departments at our hospital to enable our study being single blind. The limitation of our study was that because of the protocol it was impossible to make it double blind.
In conclusion, our study proves that the starting dose of ketamine should not be lower than 1 mg/kg BW. The frequency of adverse reactions did not differ between the groups, so there are no arguments against using midazolam as a premedication in ketamine sedation. Moreover, the frequency of emergence reactions in hospitals was reduced when midazolam was given before ketamine. A straightforward protocol and the unique ketamine property that the sedation is not deepened by increasing the dose make it suitable for endoscopists’ use after an education period. The described protocol of ketamine sedation with midazolam premedication allowed us to safely perform gastroscopies and colonoscopies in otherwise healthy children or those with mild chronic impairment and is suitable for sedation in paediatric endoscopy in settings with a shortage of anaesthetists’.
1. Kauffman RE, Banner W, Berlin CM, et al. Guidelines for monitoring of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics
2. Cote CJ, Wilson S. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update. Pediatrics
3. American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology
4. Schwartz SM, Lightdale JR, Liacouras CA. Sedation and anesthesia in pediatric endoscopy: one size does not fit all. J Pediatr Gastroenterol Nutr
5. Krauss B, Green SM. Procedural sedation and analgesia in children. Lancet
6. Fanti L, Testoni PA. Sedation and analgesia in gastrointestinal endoscopy: what's new? World J Gastroenterol
7. Michaud L, Gottrand F, Ganga-Zandzou PS, et al. Nitrous oxide sedation in pediatric patients undergoing gastrointestinal endoscopy. J Pediatr Gastroenterol Nutr
8. Michaud L, Francophone Pediatric Hepatology, Gastroenterology, and Nutrition Group. Sedation for diagnostic upper gastrointestinal endoscopy: a survey of the Francophone Pediatric Hepatology, Gastroenterology, and Nutrition Group. Endoscopy
9. White PF, Way WC, Trevor AJ. Ketamine—its pharmacology and therapeutic uses. Anesthesiology
10. Aroni F, Iacovidou N, Dontas I, et al. Pharmacological aspects and potential new clinical applications of ketamine: reevaluation of an old drug. J Clin Pharmacol
11. Cohen LB, Delegge MH, Aisenberg J, et al. AGA Institute review of endoscopic sedation. Gastroenterology
12. Green SM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation in children. Ann Emerg Med
13. Gilger MA, Spearman RS, Dietrich CL, et al. Safety and effectiveness of ketamine as a sedative agent for pediatric GI endoscopy. Gastrointest Endosc
14. Green SM, Roback MG, Kennedy RM, et al. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med
15. Reves JG, Fragen RJ, Vinik R, et al. Midazolam: pharmacology and uses. Anesthesiology
16. Sener S, Eken C, Schultz CH, et al. Ketamine with and without midazolam for emergency department sedation in adults: a randomized controlled trial. Ann Emerg Med
17. Bleiberg AH, Salvaggio CA, Roy LC, et al. Low-dose ketamine: efficacy in pediatric sedation. Pediatr Emerg Care
18. Brecelj J, Homan M, Sedmak M, et al. Safety of ketamine sedation by non-anesthesiologists for paediatric gastroenterology procedures. J Pediatr Gastroenterol Nutr
19. Green SM, Klooster M, Harris T, et al. Ketamine sedation for pediatric gastroenterology procedures. J Pediatr Gastroenterol Nutr
20. Green SM, Roback MG, Krauss B, et al. Predictors of emesis and recovery agitation with emergency department ketamine sedation: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med
21. Wang CY, Ling LC, Cardosa MS, et al. Hypoxia during upper gastrointestinal endoscopy with and without sedation and the effect of pre-oxygenation on oxygen saturation. Anaesthesia
22. Langston WT, Wathen JE, Roback MG, et al. Effect of ondansetron on the incidence of vomiting associated with ketamine sedation in children: a double-blind, randomized, placebo-controlled trial. Ann Emerg Med
23. Rose JB, Watcha MF. Postoperative nausea and vomiting in paediatric patients. Br J Anaesth
24. Sherwin TS, Green SM, Khan A, et al. Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized, double-blind, placebo-controlled trial. Ann Emerg Med
25. Wathen JE, Roback MG, Mackenzie T, et al. Does midazolam alter the clinical effects of intravenous ketamine sedation in children? A double-blind, randomized, controlled emergency department trial. Ann Emerg Med