A clinical trial to study the effects of four combinations of drugs for Procedural Sedation and Analgesia in Paediatric dental patients.

Phase 4

Recruiting

• Conditions: Diseases of oral cavity and salivary glands,

• Registration Number: CTRI/2021/02/030932
• Lead Sponsor: Dr Agarwal Abhilasha Kishanlal

Brief Summary

**“****A Comparative evaluation of Intranasal****combinations of Midazolam-Ketamine, Dexmedetomidine-Ketamine, Midazolam-Fentanyl and Dexmedetomidine-Fentanyl for Procedural Sedation and Analgesia in paediatric dental patients : Randomised Controlled Trial**

**INTRODUCTION :**

One of the most common challenges faced by a paediatric dentist in daily practice is to deal with emotional components of child like fear, anxiety, pain, and anger towards dental treatment procedures. It is already been witnessed that any past unpleasant dental experience will have a significant role and will be reflected through individual’s future dental attendance by creation of positive or negative memories.**(1)**

Dental treatment is a situation which has high potential for generating fear and anxiety which is even more for any painful or invasive dental procedure and those requiring the use of local anesthesia. For example, dental extraction seems to have a strong association to worsen child’s behavior in subsequent dental appointments.**(2,3)**

Various measures have been identified which can be used by the operator to overcome behavioural problems in absolute negative paediatric patients. Even an experienced pediatric dentist may find it difficult to render treatments to certain children when using conventional techniques. If non-pharmacological approach is insufficient for behaviour modification, procedural sedation and general anesthesia (GA) can be considered. Procedural sedation and analgesia (PSA) previously known as conscious sedation is a minimally invasive procedure of sedation providing relief of suffering and also, timely and successful completion of procedure.**(4)**

“Procedural Sedation and Analgesia (PSA) is a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardio- respiratory function.â€**(5)**

There are various routes that can be used for administration of these sedative drugs, among which the intranasal route has high popularity due to its many advantages, especially in pediatric patients. This route can bypass the need for invasive route like I.V (injection) and non invasive oral route (bitter tasting).**(6,7)**

There are a number of sedative drugs that can be used for dental procedures like midazolam, dexmedetomidine, ketamine *etc*.

Midazolam is a short-acting benzodiazepine that provides sedation, amnesia and anxiolysis. It is distinguishable from other benzodiazepines in that it is water soluble and has a short half-life and recovery time. It is also a very versatile medication, in that it can be given by many different routes and has effects that range from anxiolysis to moderate sedation. It has no analgesic properties, therefore it is generally administered in conjunction with an opioid for painful procedures.**(8,9)**

The resultant effects of midazolam in children under sedation for dental procedures have been studied in a number of projects and midazolam is now the standard agent for procedural sedation during paediatric dental treatments.**(10)**

Ketamine is a dissociative anesthetic with sedative, analgesic and amnestic properties. It is a versatile drug with the ability to produce dose-dependent effects. Ketamine provides anxiolysis and analgesia at lower doses, while providing dissociative sedation, amnesia and analgesia at higher doses. This medication typically allows maintenance of respiratory drive and airway reflexes and often causes increases in heart rate, blood pressure and cardiac output.**(8,9)**

Dexmedetomidine is an alpha2-adrenergic agonist. It has sedative and anxiolytic properties and is known for its analgesic potential owing to a reduction of sympathetic tone. It induces dose dependent effects, ranging from minimal to deep sedation. It is least likely to cause respiratory depression as compared to other commonly used sedative drugs. However, it can alter hemodynamic parameters at high doses and cause hypertension, hypotension and bradycardia.**(11,12)**

Fentanyl is a potent and highly selective opioid agonist that has a rapid onset and short duration of action, a lack of histamine release and fewer cardiovascular effects than do other opioids. Its most common side effect is respiratory depression which is often dose related.**(13)**It is a potent analgesic given on its own, with the ability to provide sedation and anxiolysis when used in combination with a sedative agent. It is preferable to other opioids as it has a shorter onset of action, a faster recovery time and tends to cause less nausea and vomiting.**(8,9)**

Many recent studies have been done using sedative drugs along with other anxiolytic and analgesic drug with a synergistic effect to reduce the required dose of main sedative component. Ketamine and midazolam combination has already been used successfully for the treatment of young fearful and anxious children.**(13)**

With this background, we have planned to conduct a study to compare intranasal combinations of Midazolam-Ketamine, Dexmedetomidine-Ketamine, Midazolam-Fentanyl and Dexmedetomidine- Fentanyl for Procedural Sedation and Analgesia in paediatric dental patients using various parameters.

**AIM :**

To evaluate and compare the efficacy of intranasal combinations of Midazolam-Ketamine, Dexmedetomidine-Ketamine, Midazolam-Fentanyl and Dexmedetomidine-Fentanyl for procedural sedation and analgesia as a pharmacological mode of behaviour management in uncooperative patients of age group 5-10 years for whom basic behaviour modification techniques are not successful for completion of invasive dental procedures.

**OBJECTIVES :**

To evaluate and compare the sedative effect of intranasal combinations of Midazolam-Ketamine, Dexmedetomidine-Ketamine, Midazolam-Fentanyl and Dexmedetomidine-Fentanyl used in uncooperative patients for dental treatment under procedural sedation and analgesia.

To minimize physical discomfort and pain during invasive dental treatment for patients under procedural sedation and analgesia.

To control anxiety and promote a positive psychological response towards dental procedures in uncooperative patients.

To complete the procedure safely under procedure sedation and analgesia.

**METHODOLOGY :**

**A) STUDY DESIGN :**

The present study is a randomised controlled clinical trial which will be conducted in the Department of Paediatric and Preventive Dentistry, Faculty of Dental Sciences, King George’s Medical University in association with Department of Anaesthesia, Faculty Of Medical Sciences, King George’s Medical University, and Department of Pharmacology & Therapeutics, Faculty Of Medical Sciences, King George’s Medical University, Lucknow, Uttar Pradesh.

 The rights of the patients will be protected and the parents/guardian accompanying the patients will be explained in detail about the purpose, methodology involved and the related risks and benefits, in a language well understood by them and written informed consent will be obtained. The study will be started only after the ethical approval by the Institutional Ethical Committee of King George’s Medical University, Lucknow.

**B) STUDY PARTICIPANTS :**

Paediatric patients in the age group of 5-10 years irrespective of gender and socioeconomic status will be enrolled in the study according to the following criteria -

**Inclusion Criteria :**

Patients who are in the age group of 5-10 years.

Patients requiring any invasive dental treatment.

Patients who are rated as positive and negative on Frankel’s behaviour rating scale.

Patients of physical status American Society of Anesthesiologists (ASA) class I and II.

Signed informed consent by the parents/guardians.

**Exclusion Criteria:**

Patients of physical status American Society of Anesthesiologists (ASA) Class III and IV.

Patients who have a history of any systemic diseases, like cardiorespiratory dysfunction and CNS dysfunction.

Patients who are allergic to any of the drugs considered for the present study or history of any adverse reactions to anesthetic/ sedative agents.

Patients with any intranasal pathology, nasal obstruction (obstructive sleep apnea) or with any congenital anomaly.

 **C) SAMPLING :**

**Sampling Population :**

The study participants will be selected from patients attending the outpatient department of Department of Paediatric and Preventive Dentistry, Faculty of Dental Sciences, KGMU, Lucknow. The children between the age group of 5-10 years those who are uncooperative, requiring any invasive dental treatment and for whom basic behaviour modification techniques are unsuccessful for completion of treatment.

**Randomization Technique :**

The patients enrolled for the study will be randomly allocated in one of the four groups by block randomization method.

 D) **STUDY PROCEDURE:**

All selected patients will be randomly divided into one of the four groups depending upon the intranasal combination of drugs used.

A comprehensive pre-anesthetic assessment will be performed by an experienced anesthesiologist. The pre-operative major vital signs like baseline heart rate, respiratory rate, blood pressure, oxygen saturation will be documented one day before the dental procedure and a joint decision of anesthesiologist and dental operator to provide treatment under procedural sedation and analgesia will be made. Patients weight (kg) will be measured and recorded for drug dosing.

 The finally enrolled patients in the study will be divided into one of the following groups depending upon the combination of drugs used for procedural sedation and analgesia :

**GROUP MK** - Intranasal combination of Midazolam (0.2 mg/kg, max5.0 mg)**(14)** and Ketamine (4.0 mg/kg, max 100 mg)**(15)**

**GROUP DK -** Intranasal combination of Dexmedetomidine ( 2 µg/kg, max 100µg)**(15)** and Ketamine ( 1mg/kg, max 100 mg)**(16)**

**GROUP MF** - Intranasal combination of Midazolam ( 0.2 mg/kg, max 10 mg)**(16,18)** and Fentanyl ( 2 µg/kg, max 100µg )**(16,18)**

**GROUP DF** - Intranasal combination of Dexmedetomidine (1 µg/kg, max 100µg)**(17,18)**  and Fentanyl ( 1.5 µg/kg, max 100µg )**(17,18)**

The drug will be given in atomized form with the help of LMA MAD NasalTM: “mucosal atomization device†(MAD)**(18)** which is attached to a standard syringe via Luer-Lock in order to turn an intravenous drug product into a fine mist for intranasal administration.

The procedure will be performed in the minor operation theatre (OT) of the institutional department, Paediatric and Preventive Dentistry. The on-site monitoring devices, rescue drugs and emergency resuscitation equipment appropriate for the pediatric patients according to American Academy of Pediatric Dentistry (AAPD) guidelines will be immediately available at the sedation procedure location.

The informed consent after explaining the procedure to the parents and giving the necessary instructions and information prior to sedation procedure will be documented. Fasting guidelines as reported by American Academy of Pediatric Dentistry (AAPD) will be practiced on the day of procedure. Patient monitoring will be performed in every 10-15 minutes before the administration of drug till the discharge point. During the procedure name of drugs, route, time of administration and dosage of all drugs administered will be recorded.

**E) Outcome parameters :**

1) Evaluation of hemodynamic parameters (like blood pressure, heart rate and oxygen saturation) of patients before, during and after undergoing dental treatment under procedural sedation and analgesia.

2) Evaluation of the onset of sedation and duration of action of different combinations of drugs used for procedural sedation and analgesia.

3) Evaluation of the depth of sedation in patients during treatment under procedural sedation and analgesia.

4) Behaviour changes in patients during treatment under procedural sedation and analgesia.

5) Observing relief in pain of patients during invasive dental procedure under procedure sedation and analgesia.

6) Comparing the ease of treatment completion under procedural sedation and analgesia.

  **F) DATA COLLECTION METHODS :**

1) **Hemodynamic parameters**- Sphygmomanometer and Pulse oximeter.

2) **Onset of sedation and Duration of sedation -** recording time from the start of sedation till the effect lasts after administration of drugs.

3) **Depth of sedation** - University of Michigan Sedation Scale (UMSS).**(19)**

4) **Behaviour scoring -** The Modified Observer’s Assessment of Alertness / Sedation Scale (MOASS) for behaviour scoring.**(20)**

5) **Relief in pain**-FLACC behaviour scale for pain assessment.**(21)**

6) **Ease of treatment completion -**HOUPT overall behaviour scale for ease of treatment completion.**(22)**

**G) STATISTICAL ANALYSIS :**

Data will be analysed and expressed in mean (SD) for quantitative variable and proportion/percentages for qualitative data. Categorical variables will be compared by using Chi-square test among the groups. The continuous variables will be compared by using one way analysis of variance (ANOVA) test among the groups. Other appropriate tests will be used for the statistical analysis. ‘p’ value < 0.05 will be considered significant.

 **RIVIEW OF LITERATURE :**

**AL Rafak*****et al.*****(23)** **(2001)** compared the effectiveness of sedation of 3  different doses of intranasal midazolam in paediatric dental patients respectively as Group A : 0.3mg/kg, Group B: 0.4mg/kg, Group C: 0.5mg/kgand concluded that all three doses were effective in behaviour modification of child for successful completion of treatment.

**Kaur and Singh****(24)****( 2011**) in their review article focussed on the unique properties of dexmedetomidine which has lead to its wide spectrum usage in the field of anesthesia, clinical settings and ICU. It offers sedation and analgesia along with hemodynamic stabilizing effects.

**Yang Liu** ***et al.*****(15)****(2018)** conducted a study where patients were administered a combination of Dexmedetomidine and ketamine intranasally for procedural sedation to evaluate the sedation success, rescue and failure. Intranasal sedation success, rescue and failure were respectively defined as sedation success with a single intranasal dose, additional bolus dose and the need for intravenous (IV) medications/inhalation agents. They concluded that the rate of intranasal sedation success was 93%, intranasal rescue was 1.8%, and intranasal sedation failure was 5.2% with the above combination.

**Patrick M. Ryan** ***et al.*****(16)** **(2018)** conducted a study to evaluate and report the safety and effectiveness of intranasal midazolam and fentanyl used in combination for procedural sedation in the paediatric department, where they found that this combination is a safe and effective strategy to be considered for procedural sedation in young patients.

**Astha Jaikaria** ***et al.*****(17)** **(2018)** evaluated and compared the sedative effect of oral combinations of midazolam ketamine (MK), dexmedetomidine fentanyl (DF) and dexmedetomidineketamine (DK) in a group of uncooperative children requiring dental treatment and concluded that oral DK had a comparable sedative property with oral MK combination and combination of  DF promises to be a potential sedative agent for  successful anxiolysis in procedural sedation in children.

**Veena Chatrath** ***et al.*****(25)****(2018)** conducted a study to compare the efficacy of intranasal fentanyl, midazolam and dexmedetomidine as premedication in pediatric patients. They concluded that Intranasal fentanyl in a dose of 1.5 µg/kg is better than intranasal midazolam 0.3 mg/kg and intranasal dexmedetomidine 1 µg/kg as far as premedication is concerned because of its early onset of action, and better anxiolysis. However with dexmedetomidine, the onset of action was delayed and duration of action was prolonged which helped the child to remain calm and sedated even after the surgery.

**Joji Sado-Filho*****et al.*****(14)** **(2019)** evaluated the efficacy of intranasal ketamine and midazolam as the main component of the behavioral guidance approach for preschoolers during dental treatment and came to the conclusion that combination of ketamine with midazolam appears to be more effective in managing the behavior of non-cooperative children during dental treatment in comparison to midazolam alone.

**Tania Vanhee** ***et al.*****(26)** **(2019)** did a study to determine the nature of dental anxiety-provoking stimuli in young patients and came to a conclusion that the dental environment is in general not causing fear rather the invasive part of the anaesthesia and the invasive dental procedures are normally related with the fear and anxiety of patients.

 **REFERENCES :**

1) Hosey MT. Anxious children: coping in dental practice. Dental update. 1995 Jun;22 (5): 210-5.

2) Baier K, Milgrom P, Russell S, Mancl L, Yoshida T. Children’s fear and behavior in private pediatric dentistry practices. Pediatric dentistry. 2004 Jul 1;26(4):316-21.

3) Versloot J, Veerkamp JS, Hoogstraten J. Pain behaviour and distress in children during two sequential dental visits: comparing a computerised anaesthesia delivery system and a traditional syringe. British dental journal. 2008 Jul;205(1):E2.

4) Lökken P, Bakstad OJ, Fonnelöp E, Skogedal N, Hellsten K, Bjerkelund CE, Storhaug K, öye I. Conscious sedation by rectal administration of midazolam or midazolam plus ketamine as alternatives to general anesthesia for dental treatment of uncooperative children. European Journal of Oral Sciences. 1994 Oct;102(5):274-80.

5) American College of Emergency Physicians Clinical Policies Committee. American College of Emergency Physicians Clinical Policies Subcommittee on Pediatric Fever Clinical policy for children younger than three years presenting to the emergency department with fever. Ann Emerg Med. 2003; 42(4):530-45.

6) Nooh N, Sheta SA, Abdullah WA, Abdelhalim AA. Intranasal atomized dexmedetomidine for sedation during third molar extraction. International journal of oral and maxillofacial surgery. 2013 Jul 1;42(7):857-62.

7) Agarwal V, Mishra B. Recent trends in drug delivery systems: intranasal drug delivery.

8) Mace SE, Barata IA, Cravero JP, Dalsey WC, Godwin SA, Kennedy RM, Malley KC, Moss RL, Sacchetti AD, Warden CR, Wears RL. Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department. Annals of emergency medicine. 2004 Oct 1;44(4):342-77.

 9) Krauss B, Green SM. Procedural sedation and analgesia in children. The Lancet. 2006 Mar 4;367(9512):766-80.

10) Gazal G, Fareed WM, Zafar MS, Al-Samadani KH. Pain and anxiety management for pediatric dental procedures using various combinations of sedative drugs: A review. Saudi Pharmaceutical Journal. 2016 Jul 1;24(4):379-85.

11) Lodenius Ã…, Ebberyd A, Cedborg AH, Hagel E, Mkrtchian S, Christensson E, Ullman J, Scheinin M, Eriksson LI, Fagerlund MJ. Sedation with Dexmedetomidine or Propofol Impairs Hypoxic Control of Breathing in Healthy Male VolunteersA Nonblinded, Randomized Crossover Study. Anesthesiology: The Journal of the American Society of Anesthesiologists. 2016 Oct 1;125(4):700-15.

12) Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Controlled clinical trials. 1996 Feb 1;17(1):1-2.

13) Golpayegani MV, Dehghan F, Ansari G, Shayeghi S. Comparison of oral Midazolam-Ketamine and Midazolam-Promethazine as sedative agents in pediatric dentistry. Dental research journal. 2012 Jan;9(1):36.

14) Sado-Filho J, Viana KA, Corrêa-Faria P, Costa LR, Costa PS. Randomized clinical trial on the efficacy of intranasal or oral ketamine-midazolam combinations compared to oral midazolam for outpatient pediatric sedation. PloS one. 2019 Mar 11;14(3):e0213074.

15) Yang F, Liu Y, Yu Q, Li S, Zhang J, Sun M, Liu L, Lei Y, Tian Q, Liu H, Tu S. Analysis of 17 948 pediatric patients undergoing procedural sedation with a combination of intranasal dexmedetomidine and ketamine. PediatricAnesthesia. 2019 Jan;29(1):85-91.

16) Ryan PM, Kienstra AJ, Cosgrove P, Vezzetti R, Wilkinson M. Safety and effectiveness of intranasal midazolam and fentanyl used in combination in the pediatric emergency department. The American journal of emergency medicine. 2019 Feb 1;37(2):237-40.

17) Jaikaria A, Thakur S, Singhal P, Chauhan D, Jayam C, Syal K. A comparison of oral midazolam-ketamine, dexmedetomidine-fentanyl, and dexmedetomidine- ketamine combinations as sedative agents in pediatric dentistry: A triple- blinded randomized controlled trial. Contemporary clinical dentistry. 2018 Sep;9(Suppl 2):S197.

18) Intranasal Medication Administration –Adult/Pediatric–Inpatient/ Ambulatory / Primary Care Clinical Practice Guidelines. 2017.

19) Malviya S, Voepelâ€Lewis T, Tait AR, Merkel S, Tremper K, Naughton N. Depth of sedation in children undergoing computed tomography: validity and reliability of the University of Michigan Sedation Scale (UMSS). British journal of anaesthesia. 2002 Feb 1;88(2):241-5.

20) Merkel S, Voepel-Lewis T, Malviya S. Pain Assessment in Infants and Young Children: The FLACC Scale: A behavioral tool to measure pain in young children. AJN The American Journal of Nursing. 2002 Oct 1;102(10):55-8.

21) Houpt MI, Weiss NJ, Koenigsberg SR, Desjardins PJ. Comparison of chloral hydrate with and without promethazine in the sedation of young children. Pediatr Dent. 1985 Mar;7(1):41-6.

22) Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, Siegel JL. Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: study with intravenous midazolam. Journal of clinical psychopharmacology. 1990 Aug.

23) Alâ€Rakaf H, Bello LL, Turkustani A, Adenubi JO. Intraâ€nasal midazolam in conscious sedation of young paediatric dental patients. International journal of paediatric dentistry. 2001 Jan;11(1):33-40.

24) Kaur M, Singh PM. Current role of dexmedetomidine in clinical anesthesia and intensive care. Anesthesia, essays and researches. 2011 Jul;5(2):128.

25) Chatrath V, Kumar R, Sachdeva U, Thakur M. Intranasal fentanyl, midazolam and dexmedetomidine as premedication in pediatric patients. Anesthesia, essays and researches. 2018 Jul;12(3):748.

26) Vanhee T, Mourali S, Bottenberg P, Jacquet W, Abbeele AV. Stimuli involved in dental anxiety: What are patients afraid of?: a descriptive study. International journal of paediatric dentistry. 2019 Nov 14.

**5. Subject selection**

Sample size is calculated on the basis of variation in sedation score at the end of treatment in two of the four study groups using the formula :

Where n = Sample size per group

s1= 0.522, The SD of sedation score in MK group

s2 = 0.492, The SD of sedation score in DK group

(ref. Asthaet al.)(17)

d = min (s1, s1) The minimum difference considered to be clinically significant

Type I error α = 5% significance level with 95% confidence interval

Type II error β = 10%

Power of study = 90%

Considering loss to follow-up = 10%,

The required sample size would be **n = 31 for each group**.

Number of subjects:

**Total 4 groups will be studied hence total number of subjects will be 124.**

Detailed Description

Not available

Study Timeline

• Last Update Posted: 2021-03-18
• Study Start: 2021-11-02

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 124

Inclusion Criteria

• 1)Patients requiring any invasive dental treatment.
• 2)Patients who are rated as positive and negative on Frankel’s behaviour rating scale.
• 3)Patients of physical status American Society of Anesthesiologists (ASA) class I and II.
• 4)Signed informed consent by the parents/guardians.

Exclusion Criteria

• 1)Patients of physical status American Society of Anesthesiologists (ASA) Class III and IV.
• 2)Patients who have a history of any systemic diseases, like cardiorespiratory dysfunction and CNS dysfunction.
• 3)Patients who are allergic to any of the drugs considered for the present study or history of any adverse reactions to anesthetic/ sedative agents.
• 4)Patients with any intranasal pathology, nasal obstruction (obstructive sleep apnea) or with any congenital anomaly.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
1)Evaluation of the onset of sedation and duration of action of different combinations of drugs used for procedural sedation and analgesia.	During the time of treatment.
2)Evaluation of the depth of sedation in patients during treatment under procedural sedation and analgesia.	During the time of treatment.

Secondary Outcome Measures

Name	Time	Method
1)Evaluation of hemodynamic parameters (like blood pressure, heart rate and oxygen saturation) of patients before, during and after undergoing dental treatment under procedural sedation and analgesia.	2)Behaviour changes in patients during treatment under procedural sedation and analgesia.

Trial Locations

Locations (1)

King George Medical University; 🇮🇳 Lucknow, UTTAR PRADESH, India

King George Medical University

🇮🇳Lucknow, UTTAR PRADESH, India

Agarwal Abhilasha Kishanlal

Principal investigator

8440924740

abhilasha08031994@gmail.com