Propofol use in newborns and children: is it safe? A systematic review<sup>,</sup>

Mekitarian Filho, Eduardo; Riechelmann, Mariana Barbosa

doi:10.1016/j.jped.2019.08.011

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Review articles • J. Pediatr. (Rio J.) 96 (3) • May-Jun 2020 • https://doi.org/10.1016/j.jped.2019.08.011 copy

Propofol use in newborns and children: is it safe? A systematic review^☆ ☆ Please cite this article as: Mekitarian Filho E, Riechelmann MB. Propofol use in newborns and children: is it safe? A systematic review. J Pediatr (Rio J). 2020. https://doi.org/10.1016/j.jped.2019.08.011 ^,^☆☆ ☆☆ Study conducted at Universidade Cidade de São Paulo (UNICID), São Paulo, SP, Brazil.

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objectives:

To determine the main indications and assess the most common adverse events with the administration of hypnotic propofol in most pediatric clinical scenarios.

Sources:

A systematic review of PubMed, SciELO, Cochrane, and EMBASE was performed, using filters such as a maximum of five years post-publication, and/or references or articles of importance, with emphasis on clinical trials using propofol. All articles of major relevance were blind-reviewed by both authors according to the PRISMA statement, looking for possible bias and limitations or the quality of the articles.

Summary of the findings:

Through the search criterion applied, 417 articles were found, and their abstracts evaluated. A total of 69 papers were thoroughly studied. Articles about propofol use in children are increasing, including in neonates, with the majority being cohort studies and clinical trials in two main scenarios: upper digestive endoscopy and magnetic resonance imaging. A huge list of adverse events has been published, but most articles considered them of low risk.

Conclusions:

Propofol is a hypnotic drug with a safe profile of efficacy and adverse events. Indeed, when administered by non-anesthesiologists, quick access to emergency care must be provided, especially in airway events. The use of propofol in other scenarios must be better studied, aiming to reduce the limitations of its administration by general pediatricians.

KEYWORDS
Propofol; Pediatrics; Adverse events; Children; Propofol infusion syndrome

Level	Type of evidence
I	High quality, high power prospective cohort studies or systematic review and/or meta-analysis of these studies; good quality randomized, blinded clinical trials
II	Prospective cohort studies/lower quality clinical trials; untreated control patients of clinical trials; systematic reviews of these studies
III	Case-control studies or their systematic reviews; prospective studies without control group (when applicable); retrospective cohorts
IV	Series of cases
V	Experts' opinions; case reports or physiology-based evidence

Author	Patients and age range	Study design	Interventions	Results	Comments risk of biases	Level of evidence
Ulgey A et al. (2015)¹²12 Ulgey A, Güneş I, Bayram A, Aksu R, Biçer C, Uĝur G, et al. Decreasing the need for mechanical ventilation after surgery for retinopathy of prematurity: sedoanalgesia vs. general anesthesia. Turk J Med Sci. 2015;45:1292-9.	60 NBs	Prospective cohort	Surgery for ROP 20 NBs - ketamine (1 mg/kg) + propofol (1 mg/kg) 30 NBs - sevoflurane 1 mg/kg	The group that used sevoflurane had five-fold more episodes of postoperative mechanical ventilation (p = 0.01).	In this small group of patients, inhalation anesthesia brought significant additional morbidity. Few allocated newborns	II
Dekker et al. (2016)¹¹11 Dekker J, Lopriore E, Rijken M, Rijntjes-Jacobs E, Smits-Wintjens V, Te Pas A. Sedation during minimal invasive surfactant therapy in preterm infants. Neonatology. 2016;109:308-13.	38 NBs for sedation for minimally invasive surfactant administration; 23 used propofol and - 15 were not sedated Mean GA of 29 weeks in sedated NBs	Nonrandomized clinical trial	1 mg/kg or at the neonatologist's discretion	- Hypotension and bradycardia occurred in both groups without statistical difference -Hypoxemia (saturation < 80 % occurred three times more often in the intervention group) and intermittent CPAP as well (both with p < 0.05)	- Ethical questions regarding the control group	II
		Nonrandomized clinical trial	1 mg/kg or at the neonatologist's discretion		- Expected outcome of adverse events in sedated patients.	II
Smits et al. (2016)²⁰20 Smits A, Theiwessen L, Caicedo A, Naualaueres G, Allegart K. Propofol-dose-finding to reach optimal effects for (semi-)elective intubation in neonates. J Pediatr. 2016;179:54-60.	50 allocated NBs	Prospective cohort	To define the effective propofol dose for sedation - propofol administration - surfactant and extubation. The effective dose ranged from 0.71 to 1.35 mg / kg.	28.5 to 39.1 % showed hypotension regardless of GA, with mild blood and brain hypoxia.	Great advantage of a pharmacokinetic studyindicating lower doses than previously mentioned for propofol use in NBs	II
Grunwell et al. (2017)²¹21 Grunwell JR, Travers C, Stormorken AG, Scherrer PD, Chumpitazi CE, Stockwell JA, et al. Pediatric procedural sedation using the combination of Ketamine and Propofol outside of the emergency department: a report from the Pediatric Sedation Research Consortium. Pediatr Crit Care Med. 2017;18:e353-63.	- 3,660 children submitted to sedoanalgesia with ketamine + propofol outside the operating room	Prospective observational study	- Assessment of adverse events of the mixture. The text and tables do not show the doses used for both drugs.	9.8 % - adverse events (desaturation, coughing, apnea in most cases)	In most cases, there was no time and dose assessment of the mixture.	III
	- Only 1.5 % under 3 months (NBs not specified)	- Retrospective Cohort of the Pediatric Sedation Consortium				III
Piersigilli et al. (2017)²²22 Piersigilli F, Di Pede A, Catena G, Lozzi S, Auriti C, Bersani I, et al. Propofol and fentanyl sedation for laser treatment of retinopathy of prematurity to avoid intubation. J Matern Fetal Neonatal Med. 2019;32:517-21.	13 NBs allocated to laser therapy for grade III-IV retinopathy of prematurity (ROP), with an average gestational age of 26 weeks	Retrospective cohort	- Slow bolus of 2-4 mg/kg, followed by continuous infusion of 4-6 mg/kg/h	No cases of intubation, hypotension and significant bradycardia were reported.	High doses of induction and maintenance generating results bias, since all were ventilated with laryngeal mask.	III
		Retrospective cohort	- Laryngeal mask in all patients			III
Durrmeyer et al. (2018)²³23 Durrmeyer X, Breinig S, Claris O, Turneoux P, Alexandre C, Saliba C, et al. Effect of atropine with propofol vs atropine with atracurium and sufentanil on oxygen desaturation in neonates requiring nonemergency intubation: a randomized clinical trial. JAMA. 2018;319:1790-801.	173 NBs with an average gestational age of 30.6 weeks and average birth weight (BW) of 1,502g	Clinical trial	Two groups: atropine + propofol (15 mcg/kg and 1-2.5 mg/kg) vs. atropine + atracurium (0.3-0.4 mg/kg) + sufentanil (0.2 mg/kg) in several types of surgeries	Serious adverse events occurred in 11 % of the atropine + propofol group and 20 % of the other group, with no statistical significance and no deaths.	The power of the study may have been small enough to underestimate the outcome.	II
Dekker et al. (2019)¹⁰10 Dekker J, Lopriore E, van Zanten HA, Tan RN, Hooper SB, Te Pas AB. Sedation during minimal invasive surfactant therapy: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2019;104:F378-83.	78 NBs between 26-36 weeks of gestational age (GA)	Clinical trial	Sedation during minimally invasive surfactant infusion therapy with propofol (1 mg/kg) or without sedation	- Sedation group showed greater comfort during therapy (Comfort-Neo Scale <14-76% vs. 22% in the placebo group; p < 0.001) and greater need for transient noninvasive ventilation (93% vs. 47% in the control group; p < 0.001)	- Smallnumber ofpatients	II
Thewissen et al. (2018)²⁴24 Thewissen L, Caicedo A, Dereymaeker A, Van Huffel S, Naulares G, Allegaert K, et al. Cerebral autoregulation and activity after propofol for endotracheal intubation in preterm neonates. Pediatr Res. 2018;84:719-25.	22 NBs with GA between 28 and 37 weeks and BW ranging from 990 grams to 1415 grams	Single-center prospective cohort	Pre-OTI propofol infusion of 0.5-4.5 mg/kg and assessment of cerebral perfusion pressure, vital signs and cerebral oxygenation by near infrared spectrophotometry (NIRS) and EEG	50 % of patients had hypotension, but 95 % of them had no changes in CPP or cerebral oxygenation.	- Large propofol dose variation limits assessment of hypotension and CPP as markers of cerebral oxygenation.	III
		Single-center prospective cohort			- Low reach (little material available)	III
de Kort et al. (2019)²⁷27 de Kort EH, Andriessen P, Reiss IK, Van Dijk M, Simons SH. Evaluation of an Intubation Readiness Score to Assess Neonatal Sedation Before Intubation. Neonatology. 2019;115:43-8.	115 newborns with a median GA of 27.7 weeks and a median BW of 1005 g	Prospective cohort in two different centers	Infusion of 1-2 mg/kg of propofol pre-orotracheal intubation (OTI)	85 % of the NBs achieved sufficient sedation score to undergo OTI. No major adverse events	- High sedation failure rate	III
		Prospective cohort in two different centers			-The score used -Intubation Readiness Score (IRS) can be very subjective (assessment bias)	III

Author	Patients and age ranges	Study design	Interventions	Results	Levels of evidence
Chiaretti A et al. (2014)³³33 Chiaretti A, Benini F, Pierri F, Vecchiato K, Ronfani L, Agosto C, et al. Safety and efficacy of Propofol administered by paediatricians during procedural sedation in children. Acta Paediatr. 2014;103:182-7.	36516 sedations in children between 1 month and 10 years of age	Retrospective cohort	1-2 mg/kg depending on age and procedure	- Mean induction time was 3 min.	II
				- Mean wake-up time was 13 min.
				Proportion of adverse events:
				-0.05% - hypotension requiring intervention
				-0.4% - PAP
				-0.04-0.2 % - laryngeal or bronchospasm
Koriyama H et al. (2014)³⁴34 Koriyama H, Duff JP, Guerra GG, Chan AW. Sedation withdrawal and analgesia team. Is propofol a friend or a foe of the pediatric intensivist? Description of propofol use in a PICU. Pediatr Crit Care Med. 2014;15:e66-71.	210 children between 1 month and 17 years old (mean age 1.2 years)	Retrospective cohort	Safety and efficacy evaluation of propofol in pediatric ICU, continuous infusion up to 0.4 mg/kg/hour	- Minimum and maximum infusion rates (including bolus doses) were 0.5 and 7.8 mg/kg/h, respectively.	II
				- There was no mortality or occurrence of propofol infusion syndrome (PIS)
Costi D et al. (2015)³⁵35 Costi D, Ellwood J, Wallace A, Ahmed S, Waring L, Cyna A. Transition to propofol after sevoflurane anesthesia to prevent emergence agitation: a randomized controlled trial. Paediatr Anaesth. 2015;25:517-23.	230 children aged 1-12 years (mean age of control group: 4.1 years; propofol: 4.0 years)	Randomized clinical trial	3 mg/kg propofol vs. midazolam (up to 15 mg) to compare proportion of postoperative emergency agitation (EA)	The incidence of EA was lower in the propofol group at different scales (29-39 % vs. 7-15%; RR = 0.25; 95% CI: 0.12-0.62; p < 0.001)	I
Zhang JM et al. (2015)³⁶36 Zhang F, Wang Z, Xin TT, Zi HLV. Treatment of different-aged children under bispectral index monitoring with intravenous anesthesia with propofol and remifentanil. Eur Rev Med Pharmacol Sci. 2015;19:64-9.	40 ASA I-II children aged 2 months to 12 years old	Case series, without randomization or control group	- Induction with 3 mg/kg of propofol and maintenance with 6 mg/kg/h associated with remifentanil (loading dose: 1 mcg/kg; maintenance dose: 0.25 mcg/kg/min)	- From anesthetic induction to awakening, there were no clinically relevant adverse events.	V
			- Each group (four groups according to age range) was evaluated from the preoperative period to awakening at the same doses as above.
Jager MD et al. (2015)³⁷37 Jager MD, Aldag JC, Deshpande GG. A presedation fluid bolus does not decrease the incidence of propofol-induced hypotension in pediatric patients. Hosp Pediatr. 2015:85-91.	126 children (6-60 months)	Prospective, randomized, controlled, non-blinded study	- 1-6 mg/kg with or without previous SF infusion, 20 mL/kg for MRI sedation or auditory evoked potential assessment	- Hypotension was detected in 26 patients, with no difference between the two groups of patients who received or not SF (p = 0.26).	II
Kang J et al. (2017)³⁸38 Kang R, Shin YH, Gil NS, Kim KY, Yeo H, Jeong JS. A comparison of the use of propofol alone and propofol with midazolam for pediatric magnetic resonance imaging sedation - a retrospective cohort study. BMC Anesthesiol. 2017;17:138.	20 children aged 3-7 years (mean age 5.0 ± 1.45)	Prospective cohort	- Preoperative administration of 1 mg/kg midazolam IV; propofol-induced anesthesia (2 mg/kg) to assess pulse transit time (PTT) or time of propofol distribution according to changes in vascular tone	- PTT increased after propofol injection and peaked approximately 17 minutes after measurement (166.2 ± 25.9 vs. 315.9 ± 64.9 ms). This shows that propofol administration affected vascular tone.	III
Scheier E et al. (2015)³⁹39 Scheier E, Gadot C, Leiba R, Shavit I. Sedation with the combination of ketamine and propofol in a pediatric ED: a retrospective case series analysis. Am J Emerg Med. 2015;33:815-7.	429 children (median age of 6.8 years)	Retrospective cohort	- Propofol 1 mg/kg + ketamine 1 mg/kg in emergency room procedures	- 52 procedures (12.1 %) showed adverse events, including 39 hypoxic events (9.1 %), 12 apneic events (2.8 %), and one case of laryngospasm (0.2 %).	II
				- The increase in ketamine or propofol doses did not change adverse events (p = 0.63; 95 %CI 0.52-2.97)
Louvet N et al. (2016)⁴⁰40 Louvet N, Rigouzzo A, Sabourdin N, Constant I. Bispectral index under propofol anesthesia in children: a comparative randomized study between TIVA and TCI. Paediatr Anaesth. 2016;26:899-908.	62 children aged 4-14 years	Randomized clinical trial	-1 mg/kg in the induction, and 1 mg/kg/h in the maintenance, comparing different methods to identify the best BIS-guided plasma propofol concentration	- Propofol administration not using TCI, guided by clinical signs, is associated with a higher risk of overdose compared to BIS-guided administration; there was no great difference between TIVA and TCI (higher mean dose from 31% to 59% of cases).	I
Watt S et al. (2016)⁴¹41 Watt S, Sabouri S, Hegazy R, Gupta P, Heard C. Does dexmedetomidine cause less airway collapse than propofol when used for deep sedation?. J Clin Anesth. 2016;35:259-67.	40 children aged 3-7 years; mean age in propofol group: 5.1 years)	Randomized clinical trial	-3 mg/kg/h in continuous infusion during MRI vs. group receiving 1 mcg/kg/h dexmedetomidine to compare airway patency	- HR, SBP and PaCO2 (the latter after the procedure) did not differ between the two groups (p < 0.013 for each univariate analysis).	II
				- There was no difference regarding the degree of airway collapse between the two groups in sagittal or axial views.
Ozturk T et al. (2016)⁴²42 Ozturk T, Acikel A, Yilmaz O, Topcu I, Cevikkalp E, Yuksel H. Effects of low-dose propofol vs ketamine on emergence cough in children undergoing flexible bronchoscopy with sevoflurane-remifentanil anesthesia: a randomized, double-blind, placebo-controlled trial. J Clin Anesth. 2016;35:90-5.	68 children aged 1-8 years old (mean age of 3 years in the propofol group)	Randomized, double blind controlled trial	- Group C (0.5 mg / kg ketamine); Group P (0.5 mg/kg propofol) and Group S (SF 0.1 mL/kg) to evaluate cough and emergency agitation (EA)after sevoflurane administration in children undergoing bronchoscopy)	- The percentage of children with moderate or severe cough during emergency was similar in all groups.	II
				- The mean delirium scores at the emergency were significantly lower in group K than in group P and group S (p = 0.0001)
Sriganesh K et al. (2017)⁴³43 Sriganesh K, Saini J, Theerth K, Venkataramaiah S. Airway dimensions in children with neurological disabilities during dexmedetomidine and propofol sedation for magnetic resonance imaging study. Turk J Anaesthesiol Reanim. 2018;46:214-21.	72 children aged 1-6 years (mean age of propofol group (3.2 years)	Non-blinded, randomized trial	- To evaluate airway dimensions during sedation with propofol and dexmedetomidine in children undergoing MRI with neurological impairment (respective doses 2 mg/kg and 2 mcg/kg/min)	There was no significant difference in airway dimensions between the dexmedetomidine and propofol groups.	II
		Non-blinded, randomized trial		- Airway complications were less frequent and sedation quality was better with dexmedetomidine in children with neurological impairment.	II
Jain A et al. (2017)⁴⁴44 Jain A, Gombar S, Ahuja V. Recovery profile after general anaesthesia in paediatric ambulatory surgeries: desflurane versus propofol. Turk J Anaesthesiol Reanim. 2017;46:21-7.	80 children (3-10 years; propofol group: 39 patients)	Randomized controlled trial without blinding	- To compare the recovery profile in pediatric outpatients submitted to general anesthesia using desflurane (2-8%) and propofol (100-150 mcg/kg/min) as maintenance anesthetics.	- Desflurane and propofol provided similar recovery profiles in ASA I and II children.	II
				- Difference in HR in the propofol group was statistically significant during most of the surgical time (p = 0-0.02).
				- Awakening and hospital release time and respiratory events were statistically equal in both groups (p = 0.12).
Bhatt M et al. (2017)⁴⁵45 Bhatt M, Johnson DW, Chan J, Taljaard M, Barrowman N, Farion KJ, et al. Risk factors for adverse events in emergency department procedural sedation for children. JAMA Pediatr. 2017;171:957-64.	6,295 children <18 years old (mean age of 8 years)	Prospective, multicenter, observational cohort study	- 1.5-3.2 mg/kg propofol vs. ketamine 0.9-1.5 mg/kg vs. fentanyl 1 mcg/kg, comparing AEs in children undergoing various procedures outside the operating room	- Adverse events occurred in 736 patients (11.7 %). Oxygen desaturation (353 patients) and vomiting were the most common of these adverse events.	I
				- There were 69 severe adverse events (SAEs) (1.1 %) and 86 patients (1.4 %) required intervention.
				- SAEs - OR for propofol 5,6; OR for ketamine and fentanyl 6.5, both with p < 0.05
Indra S et al. (2017)⁴⁶46 Indra S, Haddad H, OʼRiordan MA. Short-term Propofol infusion and associated effects on serum lactate in pediatric patients. Pediatr Emerg Care. 2017;33:e118-21.	50 children (2-18 years; mean age of 9 years)	Prospective longitudinal study	2 mg/kg (1-9 mg/kg) to evaluate whether sedation of short-term procedures in children with propofol is related to propofol infusion syndrome (PIS) measured by serum lactate.	- The mean propofol dose per patient was 8.2 mg/kg	II
				- The highest measured lactate value was 1.8 mmol/L. Mean pre- and post-procedure lactate values were 1.0 (0.3) and 0.7 (0.2) (p < 0.001).

Karacaer et al. (2018)⁴⁷47 Karacaer F, Biricik E, Inginel M, Küçükbingöz Ç, Ağın M, Tümgör G, et al. Remifentanil-ketamine vs. propofol-ketamine for sedation in pediatric patients undergoing colonoscopy: a randomized clinical trial. Rev Bras Anestesiol. 2018;68:597-604.	70 children (2-16 years)	Randomized clinical trial in colonoscopy patients	Comparison between ketamine + remifentanil (2 mg/kg and 0.25 mcg/kg respectively) and propofol + ketamine (1 mg/kg and 2 mg/kg)	- Better intraoperative sedation and less need for rescue analgesia in the K + P group	II
Kang P et al. (2018)⁴⁸48 Kang P, Jang YE, Kim EH, Lee JH, Kim JT, Kim HS. Safety and efficacy of propofol anesthesia for pediatric target-controlled infusion in children below 3 years of age: a retrospective observational study. Expert Opin Drug Saf. 2018;17:983-9.	218 patients younger than 3 years (109 patients in the propofol group and 109 in the control group)	Retrospective study	- To assess the safety and efficacy of propofol for anesthesia maintenance using controlled infusion compared to inhalation anesthesia by evaluating clinical data of patients under 3 years of age.	- Difference in the proportion of patients who had decreased SBP (p < 0.001) and HR (p = 0.03) under propofol use, but there was no difference in DBP (p = 0.238) or MBP (p = 0.175) during surgery.	II
Narula et al. (2018)⁴⁹49 Narula N, Masood S, Shojaee S, McGuinness B, Sabeti S, Buchan A. Safety of propofol versus nonpropofol-based sedation in children undergoing gastrointestinal endoscopy: a systematic review and meta-analysis. Gastroenterol Res Pract. 2018:6501215.	5 months to 18 years	Systematic review and meta-analysis of 625 articles	- The aim of this study was to evaluate and compare the safety of sedation with propofol alone (0.5-3 mg/kg) for gastrointestinal endoscopy procedures with other anesthetic regimens in the pediatric population.	Subgroup analysis was not statistically significant between cardiovascular and respiratory complications. (total odds ratio: 1.31; 95 %CI: 0.57-3.04, p = 0.08)	I
Kang R et al. (2018)⁵⁰50 Kang R, Shin BS, Shin YH, Gil NS, Oh YN, Jeong JS. Incidence of tolerance in children undergoing repeated administration of propofol for proton radiation therapy: a retrospective study. BMC Anesthesiol. 2018;18:125.	58 children (mean of 4.5 years)	Retrospective cohort	Induction with 2 mg/kg followed by continuous infusion of 250 mcg/kg/min) to assess the development of tolerance to propofol used for repeated deep sedation in children undergoing proton radiation therapy (PRT).	-74% of patients did not develop tolerance after repeated propofol sedation during weeks	III
				- There were no significant differences between children who developed tolerance and children who did not develop tolerance regarding the mean propofol dose and awakening time over time (p = 0.887 and p = 0.652, respectively).
Kara D et al. (2018)⁵¹51 Kara D, Bayrak NA, Volkan B, Uçar C, Cevizci MN, Yılmaz S. Anxiety and salivary cortisol levels in children undergoing esophago-gastro-duodenoscopy under sedation. J Pediatr Gastroenterol Nutr. 2018;68:3-6.	Children aged 5-18 years (119 in propofol group)	Prospective, multicenter study	Initial propofol dose of 2 mg/kg and additional 0.5 mg/kg every 3-5 min to measure salivary cortisol level (SCL) and anxiety level in patients submitted to EGD	Post-EGD SCL was higher than baseline (p = 0.03). Patient anxiety levels were positively correlated with propofol dose by weight, propofol dose per minute and duration of sedation and recovery and negatively correlated with age.	I
Biricik E et al. (2018)⁵²52 Biricik E, Karacaer F, Güleç E, Sürmelioğlu Ö, Ilgınel M, Özcengiz D. Comparison of TIVA with different combinations of ketamine-propofol mixtures in pediatric patients. J Anesth. 2018;32:104-11.	75 children aged 3-12 years old	Randomized, prospective, double blind study	-Evaluate the effect of TIVA with different proportions of ketofol (ketamine-propofol) on the children's recovery. Ratios of 1:5, 1:6.7 and 1:10 mg/kg ketamine-propofol were prepared in the same syringe for groups I, II, and III, respectively.	- Extubation time was significantly shorter in group 1: 5 (mean 254.3 ± 92.7 sec. [p = 0.001]) in group I than in groups II and III (371.3 ± 153 sec. and 343.2 ± 123.7 sec, respectively)	II
				- Length of stay in the SRPA was shorter in group I [median 15 min (p = 0.001)] than in groups I and II: 20 min in both.
Hayes J et al. (2018)⁵³53 Hayes J, Matava C, Pehora C, El-Beheiry H, Jarvis S, Finkelstein Y. Determination of the median effective dose of Propofol in combination with different doses of ketamine during gastro-duodenoscopy in children: a randomised controlled trial. Br J Anaesth. 2018;121:453-61.	56 children aged 3-12 years old	Randomized clinical trial	Combination of 3 propofol doses (0.25, 0.5 and 1 mg/kg) associated with ketamine to assess adequate anesthesia level during endoscopy	The use of an adjuvant to propofol sedation at a dose of 1 mg/kg when compared to the groups was significantly lower (p < 0.008).	II
Kocaturk et al. (2018)⁵⁴54 Kocaturk O, Keles S. Recovery characteristics of total intravenous anesthesia with propofol versus sevoflurane anesthesia: a prospective randomized clinical trial. J Pain Res. 2018;11:1289-95.	120 children (3-6 years old, with a mean age of 4.67 years in the propofol group)	Randomized clinical trial	Two groups - induction with nitrous oxide and remifentanil 1.5 mcg/kg + maintenance with sevoflurane; another group induced with propofol 2.5 mg/kg and maintained with propofol (TIVA) during dental surgical procedures	- The incidence of AEs was higher after sevoflurane than after TIVA (65.5 vs. 3.4 %, p = 0.00).	I
				- Higher postoperative pain was observed in the SEVO group (median FLACC score 3 vs. 1, p = 0.000).
				- A higher level of parental satisfaction was observed in the TIVA group.
Karanth et al. (2018)⁵⁵55 Karanth H, Raveendra US, Shetty RB, Shetty P, Thalanjeri P. Comparative evaluation between sevoflurane and propofol for endotracheal intubation without muscle relaxants in pediatric cleft surgeries. Anesth Essays Res. 2018;12:434-9.	80 children (1-10 years; men age in the propofol group: 5.5 years)	Randomized clinical trial	3 mg/g vs. sevoflurane 8% in anesthetic induction to compare the proportion of orotracheal intubations (OTI) without neuromuscular blockers in palatoplasty	- Better OTI conditions in the sevoflurane group: less coughing and movement and lower OTI facility scores (p < 0.002)	II
				- No difference in BP, HR, or RR alterations
Koch S et al. (2018)⁵⁶56 Koch S, Rupp L, Prager C, Mörgeli R, Kramer S, Wernecke KD, et al. Incidence of epileptiform discharges in children during induction of anaesthesia using propofol versus sevoflurane. Clin neurophysiol. 2018;129:1642-8.	57 children aged 0.5-8 years (mean age in the propofol group - 57.6 months)	Observational prospective cohort	Induction with propofol 6 mg/kg or sevoflurane 6 % for later comparison in EEG tracing during surgical procedures	Epileptiform discharges were observed in 36 % of children in the propofol group, compared to 67 % in the sevoflurane group (p = 0.03).	II
Nagoshi M et al. (2018)⁵⁹59 Nagoshi M, Reddy S, Bell M, Cresencia A, Margolis R, Wetzel R, et al. Low-dose dexmedetomidine as an adjuvant to propofol infusion for children in MRI: a double-cohort study. Paediatr Anaesth. 2018;28:639-46.	306 children (1 month to 20 years; 74 children in the propofol group)	Retrospective cohort	Three groups - propofol only (P) 3.1 mg/kg; dexmedetomidine only (D) 0.5 mcg/kg; or both (PD) during MRI scans	- Total propofol dose was higher in group P compared to P + D (182 vs. 147 mcg/kg/min; p < 0.001)	II
				- Significantly lower MBP in group P compared to P + D (p = 0.004)
				- Transient saturation drop was more frequent in group B, without statistical significance (p = 0.174).
				- Mean sedation depth was greater in group A (modified Ramsay 4.89 vs. 4.1; p < 0.001)
				- Emergency symptoms were more commonly observed in group A (38 vs. 7 times; p < 0.001).
				- Sedation failure: nine cases, only in group B (p = 0.002)
Ramgolam A et al. (2018)⁵⁷57 Ramgolam A, Hall GL, Zhang G, Hegarty M, Ungern-Sternberg BS. Inhalational versus intravenous induction of anesthesia in children with a high risk of perioperative respiratory adverse events: a randomized controlled trial. Anesthesiology. 2018;128:1065-74.	300 children up to 8 years (mean age in the propofol group: 4.5 years)	Randomized clinical trial	Comparison between 8 % sevoflurane and 55 % N₂O in O₂ for 20-30 sec or propofol 3-5 mg/kg for assessment of perioperative respiratory adverse events	Best results in the propofol group (perioperative respiratory adverse events: 39/149 [26%] vs. 64/149 [43%], [RR]: 1.7; 95%CI: 1.2-2.3; p = 0.002; respiratory adverse events on induction:16/149 [11%] vs. 47/149 [32%], RR: 3.06; 95% CI: 1.8 - 5.2, p < 0.001)	I
Schmitz A et al. (2018)⁵⁸58 Schmitz A, Weiss M, Kellenberger C, O'Gorman Tuura R, Klaghofer R, Scheer I, et al. Sedation for magnetic resonance imaging using propofol with or without ketamine at induction in pediatrics-a prospective randomized double-blinded study. Paediatr Anaesth. 2018;28:264-74.	347 children (aged 1 month to 11 years)	Randomized double blind clinical trial	Group 1: 1 mg/kg of ketamine and 5 mg/kg/h of propofol; group 2 received only propofol 10 mg/kg/h for sedation for elective MRI	- Recovery time in group 1 was significantly shorter:38 (22-65) minutes compared to 54 (37-77) minutes in group 2 (difference between medians of 14 minutes (95 % CI: 8-20 min; p < 0.001)	II
				- Group 2 presented higher AEs
				- No significant adverse events in either group.

Author	Patient and age range	Study design	Interventions	Results	Comments and bias risks	Level of evidence
Bong C et al. (2015)⁶¹61 Bong CL, Lim E, Allen JC, Choo WL, Siow YN, Teo PB, et al. A comparison of single-dose dexmedetomidine or propofol on the incidence of emergence delirium in children undergoing general anaesthesia for magnetic resonance imaging. Anaesthesia. 2015;70:393-9.	120 children (mean age of propofol group: 4 years)	Randomized, placebo-controlled trial to assess AEs after general anesthesia for MRI	- Three groups - 1 - Doses of dexmedetomidine 0.3 mcg/kg, 2- propofol 1 mg/kg; SF 10 mL/kg	- Administering dexmedetomidine or propofol reduced the incidence or severity of emergency delirium (p = 0.02).	- Specific MRI sedation protocols are lacking	II
				- Median PAED (Paediatric Anaesthesia Emergence Delirium) score was higher in dexmedetomidine group compared to propofol group (p = 0.013)	- Arbitrary doses were chosen, although common to several authors
				- There were no adverse events.	- Only MRI scenario has been evaluated
Heard C et al. (2015)⁶²62 Heard C, Harutunians M, Houck J, Joshi P, Johnson K, Lerman J. Propofol anesthesia for children undergoing magnetic resonance imaging: a comparison with isoflurane, nitrous oxide, and a laryngeal mask airway. Anesth Analg. 2015;120:157-64.	150 children (mean age 1-10 years)	Randomized clinical trial	- Two groups - propofol alone (300 mcg/kg/min) or 80 % nitrous oxide	-The frequency of all adverse airway events and emergency after anesthesia were lower in the propofol group (12 %) was significantly lower than after N₂O/LMA (laryngeal mask airway) (49%) (95%CI for risk difference 23% - 50%; p = 0.0001)	- The propofol dose used was based on known anesthetic doses.	II
					- Non-blinding can limit external validation as well as generate result biases
Moustafa M et al. (2015)⁶³63 Moustafa AA, Abdelazim IA. Impact of obesity on recovery and pulmonary functions of obese women undergoing major abdominal gynecological surgeries. J Clin Monit Comput. 2016;30:333-9.	60 children aged 2-4 years	Prospective cohort study	- All children previously received sedation with midazolam IM 0.1 mg/kg before elective MRI	- Anteroposterior diameters of airways and area around the tongue increased, even after sedation	- The fact that only children without previous risk factors for VAD (vitamin A deficiency) were studied, as well as the naturally higher RR of the child (which prevents visualization on inspiration or expiration) may constitute selection and result biases.	III
			- Subsequently, they received propofol 1 mg/kg + continuous infusion of 50-100 mcg/kg/minute	- No adverse events were clearly observed
			- Objective: to evaluate post-midazolam airway diameter in children with cervical collar and complications arising from sedation
Gemma M et al. (2016)⁶⁴64 Gemma M, Scola E, Baldoli C, Mucchetti M, Pontesilli S, De Vitis A, et al. Auditory functional magnetic resonance in awake (nonsedated) and Propofol-sedated children. Paediatr Anaesth. 2016;26:521-30.	29 children (mean age: 5-8 years)	Prospective cohort	- Children undergoing MRI were evaluated for the need for sedation. Those who needed it, received induction with propofol 2 mg/kg and maintenance of 4-5 mg/kg/h	- The areas responsible for the stated objectives (mainly Broca Wernicke and posterior superficial temporal gyrus) were less activated in the group of sedated children (except the frontal lobe).	- Results were limited to sedation with propofol and not with other agents.	III
			- Objective: To evaluate post-anesthetic hearing, speech and memory function.		- Study carried out with children without diseases that affect the auditory pathway, which may positively interfere with the results.
Kang R et al. (2017)³⁸38 Kang R, Shin YH, Gil NS, Kim KY, Yeo H, Jeong JS. A comparison of the use of propofol alone and propofol with midazolam for pediatric magnetic resonance imaging sedation - a retrospective cohort study. BMC Anesthesiol. 2017;17:138.	897 children aged 3-16 years	Analytical retrospective cohort	Patients were divided into two groups: those receiving propofol alone (Group P - 1-2 mg/kg) and those receiving propofol with midazolam (PM group - 0.05 mg/kg midazolam + propofol 1-2 mg/kg) in children undergoing sedation for MRI	- Adverse events such as movement artifact (p = 0.818); bradycardia (p = 0.69) and hypotension (p = 0.651) were similar in both groups.	- A significant sample of patients did not establish a causal relationship between propofol administration with or without midazolam.	II
				- When there were adverse events, they were not significant (EA in the PM group and transient desaturation in group P)
Kamal K et al. (2017)⁶⁵65 Kamal K, Asthana U, Bansal T, Dureja J, Ahlawat G, Kapoor S. Evaluation of efficacy of dexmedetomidine versus propofol for sedation in children undergoing magnetic resonance imaging. Saudi J Anaesth. 2017;11:163-8.	63 children aged 2-10 years old	Randomized clinical trial in patients undergoing MRI	- Division into two groups: group D received dexmedetomidine 2 mcg/kg and group P received bolus propofol 1 mg/kg	- Patients receiving propofol had:	- Study demonstrates the safety and efficacy of propofol in children for MRI	II
				- Beginning of sedation - average 3.42 vs. 7 sec., p = 0.00	- Children most prone to AW events should preferably receive dexmedetomidine
				- Need for additional sedation bolus - 5 vs. 9; p = 0.005
				- Recovery time: 3.5 vs. 9 min; p = 0.00
				- Mild complications occurred in both groups; however, the four respiratory events occurred in group P
Boriosi J et al. (2017)⁶⁶66 Boriosi JP, Eickhoff JC, Klein KB, Hollman GA. A retrospective comparison of propofol alone to popofol in combination with dexmedetomidine for pediatric 3T MRI sedation. Paediatr Anaesth. 2017;27:52-9.	256 children (mean age in propofol group - 5.7 years	Retrospective analytical study to compare sedation for MRI	- Group A - propofol between 1-2 mg/kg/min	- Patients in group D + P had lower total and respiratory adverse events (5.9% vs. 26.4% in group P; OR 0.18 (95% CI 0.08-0.39; p < 0.001)	- Further evidence of the quality of the D + P combination for sedation in painless and short duration procedures	II
			- In group D + P, dexmedetomidine infusion of 1.2 mcg/kg/hour for 5-10 hours and maintenance of 1-2 mcg/kg/h with midazolam infusion of 0.05 mg/kg/additional IV dose if necessary.	- Time to discharge was longer in group P (mean difference - 17.7 min., 95 % CI 10.6-24.8, p < 0.001)
Sriganesh K et al. (2018)⁴³43 Sriganesh K, Saini J, Theerth K, Venkataramaiah S. Airway dimensions in children with neurological disabilities during dexmedetomidine and propofol sedation for magnetic resonance imaging study. Turk J Anaesthesiol Reanim. 2018;46:214-21.	72 children (mean age 1-6 years)	Randomized clinical trial to assess airway dimensions during sedation for magnetic resonance in children with neurological disabilities	- Patients divided into two groups: sedation with 2 mg/kg of propofol or 2 µg/kg dexmedetomidine	-Airway complications were less frequent, and the quality of sedation was better with dexmedetomidine.	- As in other studies, respiratory characteristics on inspiration or expiration cannot be observed in pediatric patients who are not in apnea.	II
				- From the statistical point of view, the dexmedetomidine group had better MBP values (p = 0.03)	- There was no comparison with the measurements of a control group, which would bring more accurate comparison information.
				- The main dimensions and measurements of AWs were similar in both groups.
Nagoshi M et al. (2018)⁵⁹59 Nagoshi M, Reddy S, Bell M, Cresencia A, Margolis R, Wetzel R, et al. Low-dose dexmedetomidine as an adjuvant to propofol infusion for children in MRI: a double-cohort study. Paediatr Anaesth. 2018;28:639-46.	201 children aged between 1 month and 20 years old	Retrospective cohort	Comparison between children receiving only propofol 2-3 mg / kg + maintenance of 150-300 mcg/kg/min or propofol + dexmedetomidine 1 mcg/kg for OTI (with the same propofol maintenance)	- The onset of induction with propofol alone occurred in the group that needed more additional doses; as well as used more propofol (215 vs. 147.6 mcg/kg/min in group D + P; p < 0.001)	- The use of dexmedetomidine was not randomized, but at the anesthesiologist's discretion and could constitute a selection bias.	III
				The need for some type of airway support was higher in group P (8.7 % vs. 2.3 %; p = 0.02)	- The maintenance doses, although high, have been described in other studies.
Schmitz A et al. (2018)⁵⁸58 Schmitz A, Weiss M, Kellenberger C, O'Gorman Tuura R, Klaghofer R, Scheer I, et al. Sedation for magnetic resonance imaging using propofol with or without ketamine at induction in pediatrics-a prospective randomized double-blinded study. Paediatr Anaesth. 2018;28:264-74.	347 children (mean age of 0.25-10.9 years)	Double-blind randomized clinical trial	Patients undergoing MRI received:	- The group induced with ketamine plus propofol showed faster normalization of the modified Aldrete score, resulting in a significantly lower recovery time of 38 (22-65) minutes, compared to 54 (37-77) minutes in the group induced only with propofol (median difference 14 min. (95 % CI: 8-20) minutes; p < 0.001)	- Single center study with specific study population including patients classified as ASA III but consisting of outpatients only	III
			- intervention group: ketamine 1 mg/kg + propofol 5 mg/kg/h.		- Even being less susceptible to sedation, there were no failures, even in previously ill children

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[1] * Corresponding author. E-mail:emf2002@uol.com.br (E. Mekitarian Filho).