To compare the efficacy of intravenous ketamine, fentanyl and dexmedetomidine infusions on hemodynamic control and overall outcome in paediatric infraumbilical surgeries: prospective randomized controlled study

INTRODUCTION

Pediatric surgery has made significant progress in recent years, with the advancement in surgical techniques and anesthesia. However, despite these advances, managing hemodynamic changes during surgery remains a significant challenge. Hemodynamic instability can lead to various complications, such as ischemia, hypoxia, organ dysfunction, prolonged recovery time, and increased hospital stays. Therefore, managing hemodynamics during surgery is crucial to minimize the risk of adverse outcomes. Hemodynamic instability during surgery is particularly problematic in pediatric patients, who have a smaller circulating blood volume and are more prone to hypovolemia. In addition, infants and children may have comorbidities that further increase their risk of hemodynamic instability, such as congenital heart disease or asthma.

Infraumbilical surgeries are common in pediatric patients, and they include procedures such as hernia repair, orchidopexy, and appendectomy. The effects of anesthesia and surgery on hemodynamics during these procedures are of particular interest, as they can have significant implications for patient outcomes.

While several studies have investigated the effects of ketamine, fentanyl, and dexmedetomidine on hemodynamics during adult surgeries, limited research has been conducted in pediatric patients undergoing infraumbilical surgeries. Thus, the aim of this study is to compare the effects of ketamine, fentanyl, and dexmedetomidine infusions on hemodynamics in pediatric patients undergoing infraumbilical surgeries

Ketamine, fentanyl, and dexmedetomidine are commonly used drugs in pediatric anesthesia. Each of these drugs has unique properties that make them suitable for use in different clinical scenarios. Ketamine, for example, is known for its analgesic and dissociative properties, while fentanyl is a potent analgesic that is often used to supplement general anesthesia. Dexmedetomidine, on the other hand, is a selective alpha-2 adrenergic agonist that produces sedation and analgesia while maintaining cardiovascular stability.

Ketamineis a dissociative anesthetic that has been used in pediatric anesthesia for several decades. Ketamine produces analgesia, amnesia, and dissociation from the surrounding environment while preserving cardiovascular stability. Ketamine is known to increase blood pressure and heart rate, making it particularly useful in patients with hypotension or bradycardia.

Fentanyl is a synthetic opioid that produces potent analgesia and sedation. Fentanyl is often used as an adjunct to general anesthesia to improve pain control and reduce the requirements for other anesthetic drugs. Fentanyl is known to cause respiratory depression, but it has a minimal effect on hemodynamics, making it an attractive option in patients with hemodynamic instability.

Dexmedetomidineis a selective alpha-2 adrenergic agonist that produces sedation and analgesia while maintaining cardiovascular stability. Dexmedetomidine reduces sympathetic tone, leading to a reduction in heart rate and blood pressure. Dexmedetomidine has been shown to reduce the requirements for other anesthetic drugs, making it an attractive option in patients who are at risk of hemodynamic instability

Hypothesis

Overall, we anticipate that each drug will have a distinct effect on hemodynamics, and that understanding these differences will be useful in guiding anesthetic management during pediatric infraumbilical surgeries.

Fahim HM e al. (2022) [7] aimed of this study was to compare the effect of dexmedetomidine versus ketamine when added to caudal bupivacaine on the incidence of emergence delirium (ED), postoperative sedation, and analgesia in pediatric patients undergoing inguinal hernia repair under sevoflurane anesthesia. Random assignment of 87 pediatric patients who underwent elective inguinal hernia repair under sevoflurane anaesthesia to one of three equal groups. Group B (bupivacaine, n = 29), Group BK (bupivacaine and ketamine, n = 29), and Group BD (bupivacaine and dexmedetomidine, n = 29) were all comprised of 29 participants. Patients in group B received caudal injectate of 1 ml/kg bupivacaine 0.25%, while patients in group BK received bupivacaine 0.25% mixed with ketamine 0.5 mg/kg and patients in group BD received bupivacaine 0.25% mixed with dexmedetomidine 1 μg/kg. The most important outcome measure was the incidence of postoperative ED. Secondary outcomes included postoperative sedation scores and Face, Legs, Activity, Cry, and Consolability (FLACC) pain scores, as well as time to initial postoperative analgesic administration and total postoperative analgesic consumption. Also evaluated was the incidence of perioperative complications. The incidence of ED was markedly lower in groups BD and BK than in group B (P <0.05), but there was no difference between groups BD and BK (P > 0.05). Postoperative sedation scores were significantly higher in groups BK and BD compared to group B at 30 minutes and 2 hours postoperatively (P <0.05 for both comparisons); they were also significantly higher in group BD compared to group BK at (10 min–2 hours) postoperatively (P <0.05 for both comparisons). The duration of analgesia and total postoperative paracetamol consumption were significantly prolonged and lower in groups BD and BK, respectively, than in group B (P <0.05); they were also significantly lower in group BD than in group BK. There was no significant difference between groups in terms of the incidence of perioperative complications. After sevoflurane anaesthesia, both dexmedetomidine (1 g/kg) and ketamine (0.5 mg/kg) added to pediatric caudal block were efficacious in controlling pediatric ED. Compared to ketamine, caudal dexmedetomidine patients had a longer time to first postoperative analgesia and lesspostoperative analgesic consumption, but longer postoperative sedation, with no significant difference in the incidence of perioperative adverse events between the two drugs.

Godbole R et al. (2020) [8] This study aimed to clinically evaluate and compare the efficacy of caudal epidural bupivacaine in prolonging the postoperative analgesia, with adjuvants like fentanyl or dexmedetomidine among children of Indian genotype. A prospective, randomized, double-blind comparison study. The study cohort of 68 Indian phenotype patients was selected at random from a random number table and divided into two groups of 34 patients each. Group A received 0.75 mL/kg of 0.25% bupivacaine plus 1 mcg/kg of fentanyl, while group B received 0.75 mL/kg of 0.25% bupivacaine plus 1 mcg/kg of dexmedetomidine. For both groups, the time from caudal injection to the first administration of rescue analgesia will be recorded as the Global Assessment of Anaesthesia. Results Either fentanyl or dexmedetomidine as adjuvants in caudal block provided excellent postoperative analgesia, with dexmedetomidine sedation lasting substantially longer (18.0 hours) than fentanyl (13.1 hours). In both groups, we observed adequate hemodynamic stability. Conclusion Addition of dexmedetomidine over fentanyl to bupivacaine for caudal epidural analgesia in children has multiple benefits, including improved intraoperative and postoperative hemodynamic control, significantly longer duration of postoperative analgesia, less bleeding during surgery, and good surgical satisfaction. As the children are pain-free, calm, silent, sedated, yet arousable, the parents’ contentment is rewarding. In the Indian population, the caudal epidural dose of 0.25% bupivacaine 0.75 mL/kg with adjuvants such as dexmedetomidine or fentanyl is efficacious for postoperative analgesia in lower abdominal surgeries without adverse effects.

Park SJ et al. (2017) [9] aimed of study was to compare the efficacy and safety of dexmedetomidine with that of fentanyl as an adjuvant to epidural ropivacaine in pediatric Orthopedic surgery. This study enlisted sixty (3–12-year-old) children scheduled for lower extremity orthopedic surgery and lumbar epidural patient-controlled analgesia (PCA). Children received either dexmedetomidine (1 μg/kg) or fentanyl (1 μg/kg) via epidural catheter along with 0.2% ropivacaine (0.2 mL/kg) 30 minutes prior to the conclusion of surgery. The children weremonitored postoperatively for ropivacaine consumption via epidural PCA, postoperative pain intensity, the requirement for rescue analgesics, emergence agitation, and other adverse effects. In the first six hours after surgery, the mean dose of bolus epidural ropivacaine was significantly lower in the dexmedetomidine group than in the fentanyl group (0.029±0.030 mg/kg/h vs. 0.053±0.039 mg/kg/h, p=0.012). The median pain score at six hours postoperatively was lower in the dexmedetomidine group than in the fentanyl group [0 (0–1.0) vs. 1.0 (0–3.0), p=0.039]. Throughout the duration of the investigation, the need for rescue analgesia did not differ between groups. In the early postoperative period, the use of dexmedetomidine as an epidural adjuvant had a substantially greater analgesic and local anesthetic-sparing effect than fentanyl in children undergoing major Orthopedic lower extremity surgery.

Elfawal SM et al. (2016) [10] Levobupivacaine is an effective local anesthetic agent with less systemic toxicity than racemic bupivacaine, but it has short postoperative analgesic duration. Dexmedetomidine and fentanyl are promising adjuncts for postoperative caudal analgesia that is both effective and long-lasting. This study compared the postoperative analgesia and sedation effects of caudal levobupivacaine plus dexmedetomidine and levobupivacaine plus fentanyl in minors undergoing lower limb orthopedic surgery. Ninety children aged 1 to 7 years, American Society of Anesthesiologists I-II, who underwent orthopedic lower limb surgery under general anaesthesia were administered caudal block for postoperative analgesia. Random assignment of the students to three groups: Group L (control) received 0.75 ml/kg levobupivacaine 0.25% diluted in saline. Group LD received 0.75 ml/kg levobupivacaine 0.25% with dexmedetomidine 1 µg/kg. Following drug administration, hemodynamic variables, total anaesthesia time, sedation score, Face, Legs, Activity, Cry, Consolability score, analgesia duration, and adverse effects were recorded. Both the baseline and intraoperative profiles of hemodynamic were comparable across all groups. In Group LD, the mean duration of analgesia and the mean sedation score were substantially greater than in the other two groups. Dexmedetomidine may be a superior additive to levobupivacaine than fentanyl for caudal postoperative analgesia and arousable sedation in children, with comparable hemodynamic and adverse effect profiles.

Bharti N et al. (2014) [11] This randomized double-blind study was conducted to evaluate the analgesic efficacy and safety of addition of three different doses of dexmedetomidine in caudal ropivacaine compared with plain ropivacaine for postoperative analgesia in pediatric day care patients. Included were eighty 1–8-year-old American Society of Anesthesiologists grade I–II minors undergoing lower abdominal and perineal surgery. Children were divided into four groups at random. Group 1 received 0.2% ropivacaine 0.75 ml.kg-1 without dexmedetomidine, while groups 2, 3, and 4 received dexmedetomidine in addition to 0.2% ropivacaine 0.75 ml.kg-1.5 µg.kg-1. With sevoflurane and 50% N2O in oxygen, anaesthesia was induced and maintained. Postoperative pain, nausea and vomiting, agitation, sedation, and adverse effects were monitored in children. Oral paracetamol was administered as rescue analgesia. All dexmedetomidine groups significantly prolonged postoperative analgesia compared to the ropivacaine group (P <0.001). In the first six postoperative hours, all patients in the ropivacaine group required rescue analgesia, whereas none in the other three groups did. No patient experienced delayed anaesthetic emergence. Four patients in the ropivacaine-alone group developed agitation, but none in the dexmedetomidine-alone group did. Patients receiving 1.5 µg/kg dexmedetomidine were more sedated than those in the other groups (P <0.01), but it did not impede their discharge. Conclusions: It appears that all three doses of caudal dexmedetomidine are efficacious for preventing postoperative pain in pediatric patients receiving day care. These doses of caudal dexmedetomidine appear to be safe for day surgery.

AIMS AND OBJECTIVES

AIM

â–ª        To compare the efficacy of ketamine, fentanyl and dexmedetomidine infusions on hemodynamic control and overall outcome in pediatric infraumbilical surgeries.

PRIMARY OBJECTIVE

·        To compare the effect of ketamine, fentanyl and dexmedetomidine infusions on hemodynamic control (PR, SBP, DBP, MAP, SpO2) in pediatric infraumbilical surgeries.

 SECONDARY OBJECTIVES

• To compare the time of emergence (TE)
• To compare the sedation score at the emergence**(RSS)**
• To compare the pain score**(CHEOPS)**

·         To compare of time of first rescue analgesic (TR)

• To compare the total number and doses of rescue analgesics

• To study the complications

• PONV

• Respiratory Depression

• Arrythmia

  MATERIAL AND METHODS

Study Setting:

·        The study will be conducted by Department of Anaesthesiology, King George’s Medical University, Lucknow in collaboration with Departments of Pediatric Surgery, KGMU, Lucknow after getting clearance from the ethical committee, Research Cell, KGMU, Lucknow.

Study Design:

·        Single Centre, Prospective, Randomized Controlled Study

Study Duration:

·        One and a half year

Sample Size:

N= 24 in each group (72)

The sample size formulae used are as follows: (Bernard, 5th edition) [12]

n=

 n= (20.512+9.22)/1(1.64+0.84)2

11.42

 n= (420.66+84.64)/1(6.15)

129.96

 n= (505.3001) (6.15)   = 3122.854 = 24.02 (in each group) ≈24

129.96            129.96

  n= Sample size

σ1 = Standard Deviation cases [=20.51] *

σ2 = Standard Deviation control [=9.2] *

∆ = Difference of means [=11.4]

κ= Ratio [=1]

Z1-α/2= Two-sided Z value [=1.64]

Z1-β= Power [=0.84]

*Assumed

 

Confidence Interval (2-sided)

90%

|Power

80%

  | |Mean Heart rate at 9 hr

(R Godbole et al., 2020) [13]

Group-A

Group-B

 Difference*

|Mean

111.7

 100.3

 11.4

|Standard deviation*

20.51

 9.2

  |Variance

420.66

 84.64

  |

---

|Sample size

72

   |

---

|Total Sample size                                   72 (24 in each group)

 Statistical Analysis:

Data will be entered in Microsoft Excel and analyzed using statistical software SPSS version 15 (Chicago, IL, USA). Statistical analysis will be performed using SPSS software (SPSS Inc., Chicago, IL, USA) for Windows program (15.0 version). The continuous variables will be evaluated by mean (standard deviation) or range value when required. The dichotomous variables will be presented in number/frequency and will be analyzed using Chi-square or Fisher Extract test. For comparison of the means between the two groups, analysis by Student t-test, Mann-Whitney U test, and Spearman correlation with 95% confidence interval will be used. A p-value of < 0.05 will be regarded as significant

Inclusion Criteria:

·        Patients of either sex and age group of 1-8 years

·        American Society of Anesthesiologists (ASA) I–II

·        Elective Pediatric Infraumbilical Surgeries

Exclusion Criteria:

·        Patient’s/ Guardian’s Refusal

·        Congenital Herat disease

·        Coagulation Disorders

·        Allergy to study drugs

·        Patients with mental developmental delay

·        Severe Systemic Diseases

           METHODOLOGY

After Institutional Ethics Committee approval &Informed Patient’s/Guardian’s Consent, total 72 patients (24 in each group), ASA I & II, of either sex and age group of 1 to 8years undergoing elective pediatric infraumbilical surgery will be included in the study.

As per institutional protocol, all patients will be examined on the night before surgery, and instruction regrading NPO, premedication will be given.

Total 72, patients will be randomly divided into three groups (24 in each group) using a computer-generated random table. Group Fwill be receiving intravenous fentanyl 2 mcg/kg bolus for induction and 1 mcg/kg/hr for maintenancewhereas Group K will be receiving intravenous ketamine 1.5 mg/kg for 10 minutes before induction and 0.5 mg/kg/hr for maintenance[18] and Group D will be receiving intravenous dexmedetomidine 1mcg/kg for 10 minutes before induction and 0.5 mcg/kg/hr for maintenance.[14, 15,16,17]

 

GROUP

DRUG

|Group F

(Fentanyl)

Induction: 2mcg/kg (bolus)

Maintenance: 1mcg/kg/hr (infusion)

|Group K

(Ketamine)

Induction: 1.5mg/kg (infusion)

Maintenance: 1mg/kg/hr (infusion)

|Group D

(Dexmedetomidine)

Induction: 1mcg/kg (infusion)

Maintenance: 0.5mcg/kg/hr (infusion)

  All children will be premedicated with midazolam 0.5mg/kg19 and atropine 0.03mg/kg19 orally 30 minutes before induction, and standard ASA monitor will be attached and intravenous access will be secured under inhalational anesthesia. Anaesthesia will be induced in Group Fwill be receiving fentanyl intravenous 2 mcg/kg bolus for induction whereas Group K will be receiving ketamine intravenous 1.5mg/kg for 10 minutes before induction and Group D will be receiving dexmedetomidine 1mcg/kg for 10 minutes before induction followed by intravenous propofol 2 -2.5mg/kg and myorelaxation will be achieved by intravenous atracurium 0.5mg/kg , and after 3 min of controlled ventilation, end tidal carbon dioxide will be maintained between 30-35 mm Hg, tracheal will be secured with endotracheal tube.Anaesthesia will be maintained with 60% Air and 40% in oxygen and 1.5-2.0% sevoflurane with desired MAC up to 0.8 to 1.0, along with continuous infusion of, fentanyl @ 1mcg/kg/hr intravenously, ketamine @ 0.5mg/kg/hr intravenously and dexmedetomidine @ 0.5mcg/kg in Group F, K & D respectively and atracurium at dose of 0.3-0.4mg/kg/hr intravenously.Myorelaxation will be monitored using train of four (TOF) monitoring.  At the end of the surgery, all infusion will be stopped and neuromuscular blockade will be reversed with neostigmine 0.05 mg/kg and glycopyrrolate 0.001 mg/kg, time of emergence**(TE)**will be noted as the time duration from stoppage of infusion to extubation. Patients will be extubated when they will able to obey simple commands (RSS>3).

During intra-operative period hemodynamics (PR, SBP, DBP, MAP, SpO2) will be recoded at T0 (before induction), T1 (just after intubation), T3 (5 minutes after T0), T4 (15 minutes after T0), and later on at the interval 15 minutes till end of surgery.  After discharge from the recovery room, the children will be transferred to the surgical ward. Sedation will be assessed after the extubation using Ramsay SedationScore and pain will be assessed at the time of extubation, 1 hour, 2 hour, 6 hour, 12 hour and 24 hour after extubation,by using the Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS), a multifactorial pain scale graded from 4 to 13, based on scores for cry, facial expression, verbal expression and movement in infants and children.20 If the CHEOPS score exceeded 7, additional intravenous boluses of rescue analgesics *(1. Paracetamol (10 mg/kg), 2. Ketorolac (0.5mg/kg), and 3. Tramadol (1mg/kg)*will be given. The number of CHEOPS exceeding 7 and the supplemental bolus dose of paracetamol will be recorded for 24 h. Potential side effects of fentanyl, ketamine and dexmedetomidine will also be recorded, including nausea, vomiting and psychomimetic side effects such as nightmares or hallucinations. At the end of the 24 h, the parents’ satisfaction will be assessed using Parents Satisfaction Score.

   HEMODYNAMICS

 

TIME/PARAMETER

PR

SBP

DBP

MAP

SPO2

|T0

      |T1

      |T2

      |T3

      |T4

      |TN

[T0 (before induction), T1 (just after intubation), T3 (5 minutes after T0), T4 (15 minutes after T0), and later on at the interval 15 minutes till end of surgery.]

PARENTS SATISFACTION SCORE

Grade

Level of Satisfaction

|I

Excellent

|II

Very good

|III

Satisfactory

|IV

Poor

CHILDREN’S HOSPITAL OF EASTERN ONTARIO PAIN SCALE (CHEOPS)

COMPLICATIONS & MANAGEMENT

Pain

Rescue Analgesics

Paracetamol 10-15 mg/kg IV

|Ketorolac 0.5 mg/kg IM/IV

|Tramadol 1-2 mg/kg IV

|Bradycardia

Atropine 0.05mg/Kg

|PONV

Ondansetron 0.15 mg/kg IV

|Respiratory depression

Oxygenation

|Naloxone 0.4 mg IV repeated to max. dose of 8 mg

ASSESSMENT

1.      HEMODYNAMICS**(PR, SBP, DBP, MAP, SpO2)**

2.      TIME OF EMERGENCE (TE)

3.      SEDATION SCORE AT EMERGENCE (RSS)

4.      PAIN SCORE (CHEOPS)

5.      TIME OF FIRST RESUCE ANALGESIC (TR)

6.      RESCUE ANALGESIC

a.       Paracetamol

b.      Ketorolac

7.      COMPLICATIONS

1. Pain
2. PONV
3. Respiratory Depression
4. Arrythmia
5. Ileus

REFERENCES

1.      Dahl JB, Kehlet H. Preventive analgesia. CurrOpinAnaesthesiol 2011;24(3):331–338

2.      Srouji R, Ratnapalan S, Schneeweiss S. Pain in children: assessment and nonpharmacological management. Int J Pediatr 2010; 2010:474838

3.      Caudal Epidural Block A, Review. Anaesthesia Today. December 19, 2010

4.      Polomano RC, Fillman M, Giordano NA, Vallerand AH, Nicely KL, Jungquist CR. Multimodal analgesia for acute postoperative and trauma –related pain. Am J Nurs 2017;117(3, Suppl 1): S12–S26

5.      Miller RD. Miller’s Anaesthesia. 8th ed. Philadelphia: Elsevier Saunders; 1600

6.      Lönnqvist PA. Adjuncts to caudal block in children–Quo vadis? Br J Anaesth 2005;95(4):431–433

7.      Fahim HM, Menshawi MA. Effect of caudal dexmedetomidine versus ketamine in prevention of emergence delirium in pediatric patients undergoing congenital inguinal hernia repair under sevoflurane anesthesia. Ain-Shams Journal of Anesthesiology. 2022 May 12;14(1):45.

8.      Godbole R, Gill J, Bhattacharya B, Shrotriya S, Shrivastava S, Bandari A. A Randomized Controlled Double-Blind Comparative Study between Bupivacaine 0.25% Plus Fentanyl and Bupivacaine 0.25% Plus Dexmedetomidine for Caudal Epidural Postoperative Analgesia in Pediatric Lower Abdominal and Urogenital Surgeries in Indian Genotype. International Journal of Recent Surgical and Medical Sciences. 2020 Jun;6(01):30-7.

9.      Park SJ, Shin S, Kim SH, Kim HW, Kim SH, Do HY, Choi YS. Comparison of dexmedetomidine and fentanyl as an adjuvant to ropivacaine for postoperative epidural analgesia in pediatric orthopedic surgery. Yonsei medical journal. 2017 May 1;58(3):650-7.

10.  Elfawal SM, Abdelaal WA, Hosny MR. A comparative study of dexmedetomidine and fentanyl as adjuvants to levobupivacaine for caudal analgesia in children undergoing lower limb orthopedic surgery. Saudi journal of anaesthesia. 2016 Oct;10(4):423.

11.  Bharti N, Praveen R, Bala I. A dose–response study of caudal dexmedetomidine with ropivacaine in pediatric day care patients undergoing lower abdominal and perineal surgeries: a randomized controlled trial. Pediatric Anesthesia. 2014 Nov;24(11):1158-63.

12.  Bernard Rosner. Fundamentals of Biostatistics (5th edition). (Based on equation 8.27).

13.  Godbole R, Gill J, Bhattacharya B, Shrotriya S, Shrivastava S, Bandari A. A Randomized Controlled Double-Blind Comparative Study between Bupivacaine 0.25% Plus Fentanyl and Bupivacaine 0.25% Plus Dexmedetomidine for Caudal Epidural Postoperative Analgesia in Pediatric Lower Abdominal and Urogenital Surgeries in Indian Genotype. International Journal of Recent Surgical and Medical Sciences. 2020 Jun;6(01):30-7.

14.  Lin R, Ansermino JM. Dexmedetomidine in paediatric anaesthesia. BJA Educ. 2020 Oct;20(10):348-353. doi: 10.1016/j.bjae.2020.05.004. Epub 2020 Jul 22. PMID: 33456916; PMCID: PMC7808041.

15.  Bong CL, Tan J, Lim S, Low Y, Sim SW, Rajadurai VS, Khoo PC, Allen J, Meaney M, Koh WP. Randomised controlled trial of dexmedetomidine sedation vs general anaesthesia for inguinal hernia surgery on perioperative outcomes in infants. Br J Anaesth. 2019 May;122(5):662-670. doi: 10.1016/j.bja.2018.12.027. Epub 2019 Mar 7. PMID: 30916007.

16.  Vaughns JD, Martin C, Nelson J, Nadler E, Quezado ZM. Dexmedetomidine as an adjuvant for perioperative pain management in adolescents undergoing bariatric surgery: An observational cohort study. J Pediatr Surg. 2017 Nov;52(11):1787-1790. doi: 10.1016/j.jpedsurg.2017.04.007. Epub 2017 Apr 19. PMID: 28465076.

17.  Tobias JD, Gupta P, Naguib A, Yates AR. Dexmedetomidine: applications for the pediatric patient with congenital heart disease. PediatrCardiol. 2011 Dec;32(8):1075-87. doi: 10.1007/s00246-011-0092-8. Epub 2011 Sep 10. PMID: 21909772.

18.  Bazin V, Bollot J, Asehnoune K, Roquilly A, Guillaud C, De Windt A, Nguyen JM, Lejus C. Effects of perioperative intravenous low dose of ketamine on postoperative analgesia in children. Eur J Anaesthesiol. 2010 Jan;27(1):47-52. doi: 10.1097/EJA.0b013e32832dbd2f. PMID: 19535988.

19.  Feld LH, Negus JB, White PF. Oral midazolam preanesthetic medication in pediatric outpatients. Anesthesiology. 1990 Nov;73(5):831-4. doi: 10.1097/00000542-199011000-00006. PMID: 2240672.

20.  McGrath PJ, Johnson G, Goodman JT, et al. CHEOPS: a behavioural scale for rating postoperative pain in children. Adv Pain Res Ther 1985; 9:395– 402