A comparison of the effects of Ketamine-Midazolam and Ketamine-Propofol combinations on vital signs of uncooperative children with dental diseases in a crossover study with repeated measurements: The Bayesian approach

doi:10.21203/rs.3.rs-2963723/v1

Background: To calm non-cooperative children needing dental treatment, sedatives are used. Vital parameters must be monitored during sedation. This study aimed to evaluate the effects of Ketamine-Midazolam (KM) and Ketamine-Propofol (KP) combinations on the heart rate (HR) and oxygen saturation (SPO₂) of uncooperative children. The model parameters were estimated using the Bayesian approach.

Methods: The data were collected in a double-blind crossover study with repeated measurements (CSWRM). Twenty-two 3-6-year-old uncooperative children were included, and the linear mixed model was adopted for data analysis.

Results: A significant difference of 4.47 beats per minute (bpm) was found in the mean HR of KM recipients compared to KP recipients. The mean HR in KP was lower than that of KM, but it did not make a difference in SPO₂.

Conclusions: Although there was no difference in the two drug combinations regarding SPO2, they differed in HR. As such, the KP combination is recommended.

The study was registered in the Iranian Registry of Clinical Trials (IRCT20090506001882N10) at the date of 2021-03-08.

sedation

children

heart rate

linear mixed model

crossover study

Sedation drugs for uncooperative children undergoing dental treatment should provide adequate sedation and have fewer side effects.

What is New:

The KP combination increases the HR of children less than the KP combination, so the KP combination is preferred due to fewer side effects.

Reports from 195 countries and territories from 1990 to 2017 show that oral disorders are the most common cause of disease, and tooth decay contributes more than other problems to oral disorders [1]. According to the World Health Organization's (WHO) report, the prevalence of tooth decay in children is 60-90% [2]. The overall prevalence of caries in permanent and primary teeth in Iranian children is 78.6% and 62.8%, respectively [3].

During the treatment of dental problems, some children cannot cooperate with their dentist for some reason and, therefore, special arrangements must be made. One such arrangement is treatment under sedation. In general, sedation is a method of controlling stress and unwanted reactions using drugs, which differs from general anesthesia [4]. Unlike anesthesia, the use of drugs is less in sedation, and the person can breathe spontaneously without the need for any device [5]. However, the choice between anesthesia and sedation depends on factors such as the anatomy of the respiratory tract, [6] the child's age, the number of teeth that need treatment, the child's general health status, [7] and the time required for the treatment [8], the determination of which is the anesthesiologist's responsibility.

So far, different drugs have been used alone or in combination, and different doses have been recommended for sedation. The most effective way to use sedatives is intravenous injection because the absorption of drugs in the child's body is faster [5]. The comparison and review of sedatives with different combinations and doses is still a major research goal. Stabilization of vital parameters should also be characteristic of sedatives, including Ketamine, Midazolam, and Propofol.

In some studies, the combination of Ketamine with Midazolam (KM) and Propofol (KP) for sedation has been investigated, but no crossover study with repeated measurements (CSWRM) was found. CSWRM analysis using a mixed linear model provides useful interpretations for variables on a continuous scale. The Bayesian approach outperforms the classical approach in estimating parameters in a mixed linear model when the sample size is small [9]. The current study aimed to compare the effect of two drug combinations, KM and KP, on the heart rate (HR) and oxygen saturation (SPO₂) of uncooperative children with dental diseases using the Bayesian approach in a linear mixed model.

Study design and participants

This was a double-blind, crossover clinical trial with repeated measurements in each period. First, the study was registered in the Iranian Registry of Clinical Trials (IRCT20090506001882N10) and permission was obtained from the Ethics Committee of Shahid Beheshti University of Medical Sciences, Iran (IR.SBMU.RETECH.REC.1400.1176). The children's parents provided written informed consent for participation.

Twenty-two healthy children (ASA 1) of age 2 to 6 years who were uncooperative (completely negative on the Frankel scale according to two dentists), visited the Fellowship Department of Shahid Beheshti Dental School, and required two similar dental treatment sessions were non-randomly (conveniently) selected. Two treatment sessions were planned such that they were similar in terms of treatment time, the type of anesthesia, and the type of treatment. The exclusion criteria were systemic diseases, a history of allergy to drugs, colds and blocked nasal passages during the treatment session, and failure to complete two treatment sessions. The second treatment session was scheduled 2 to 3 weeks after the first.

Intervention

Midazolam 0.3 mg/kg was given to the children orally as premedication 30 minutes before the intravenous injection of the drugs. The aim was to compare two treatment regimens of intravenous Ketamine-Propofol (2-2 mg/kg, respectively) and intravenous Ketamine-Midazolam (2-0.2 mg/kg, respectively). In both groups, atropine 0.02 mg/kg was used to reduce secretions. Oxygen was administered through a nasal cannula at a rate of 5 lit/min. During the treatment, if needed, a maintenance dose of Propofol at a dose of 150 μg/kg/min and Ketamine at a dose of 10-15 μg/kg/min would be given to treatment groups KP and KM, respectively.

Outcome

Before the premedication injection, the patient's HR and SPO₂ were recorded in each session. In both sessions, SPO₂ and HR were recorded by the hospital's multi-purpose monitoring device at the time of venipuncture, after local anesthetic injection, every 15 minutes during treatment, and discharge.

Statistical analysis

The linear mixed model was adopted to compare the two drug combinations. Baseline measurements were also made in each period and entered as covariates into the model for handling. Due to the lack of exact times for measuring the response during anesthesia injection and discharge, the time was considered categorically and entered as a dummy variable into the model. Assume that the continuous response of the -th participant in sequence j, whose -th measurement is in period , is represented by ( ) and ، and and respectively indicate the treatment, period, sequence, and baseline variables. is a time dummy variable vector. Therefore, the model included the fixed effects of treatment (), period (), sequence (, and baseline (). The two parameter vectors and respectively correspond to the vector of dummy variables time and time x treatment interaction. Random effects in the model include the effect of the -th participant in sequence (), the effect of the -th participant in sequence in the -th period (), and the effect time for the -th participant (). The measurement error is indicated by . The linear mixed model for the CSWRM is as follows:

For Bayesian inferences, the noninformative normal prior distribution was used for the parameters. The normal distribution had a mean and variance of 0 and 1000, respectively, for the parameters related to the variables and inverse gamma distribution (0.01, 0.01) for the variance’s parameter. The Bayesian estimation of the parameters and their 95% credible interval were calculated in SAS 9.4.

Nine girls and 13 boys with an average age of 3.6 and a standard deviation (SD) of 0.97 years were recruited. Twelve participants randomly received the KP combination and 10 participants received the KM combination in the first period. The treatments were changed in the second period. The mean and SD by sequence, treatment, and time for HR and SPO₂ are presented in Tables 1 and 2, respectively. Of the five times that the HR was measured after the administration of the drug combination in the first sequence (KP in the first period and KM in the second period) and the second sequence (KM in the first period and KP in the second period), the mean HR of the KM was more than that of KP respectively 3 and 4 times. Figures 1 and 2 respectively depict the mean and SD of HR and SPO₂at different times in two periods for each drug. Figure 1 shows that in both treatments and both periods, the mean HR at the baseline is lower than at all times, and the changes have similar patterns. Based on Figure 2, the trends of variations in mean SPO₂ for both treatment groups in each period are almost the same.

The time ×treatment interaction effect was not significant for HR and SPO₂; as a result, the effect of the two treatments on both variables over time was not opposite (output not presented). This confirms the visual information in Figures 1 and 2. Due to the non-significance of interaction effects, they were removed from the model, and a model without interaction effects was fitted. The results of the model for HR are given in Table 3. The carry-over effect and period were not significant based on Table 3. Therefore, the non-significance of the carry-over effect enables us to check the treatment effect. Adjusting for the effect of the baseline measurement, in a KM recipient, HR was on average 4.47 beats per minute (bpm) lower than a KP recipient. This difference was statistically significant.

It can also be concluded that adjusting for the effect of the baseline measurement, KM recipients had a mean HR of 4.47 bpm lower than KP recipients. With 95% confidence, the mean HR of KP recipients was at least 1.41 bpm and at most 7.71 bpm lower than KM recipients. The mean HR of a participant at the time of local anesthesia injection and 15 minutes was, respectively, 8.55 bpm and 7.70 bpm higher (significantly) than the venipuncture time for both treatments. The mean HR of 30 minutes and discharge time were not significantly different compared to the venipuncture time for both treatments.

The results of fitting the model for the SPO₂ are listed in Table 3. Adjusting for the effect of the baseline measurement, there was no significant difference between the effects of the two treatments on the SPO₂ of the participant who experienced both treatments. In other words, there was no significant difference between KP and KM combinations in terms of the mean SPO₂. The mean SPO₂ for a participant at the time of anesthesia injection, 15 minutes, and 30 minutes after the start of the treatment was respectively 1.46%, 1.34%, and 1.71% higher (significantly) than the venipuncture time in both treatments. The mean SPO₂ for a participant at the time of injection was 1.09% lower (significantly) than the time of discharge for both treatments.

Using an efficient sedative can create good memories for children, relieve their fear and anxiety, and make it easier for them to visit the dentist in the future. A comparison of sedatives in terms of their effect on vital signs and hemodynamic variables is a key research goal. This paper investigated the effects of KM and KP on HR and SPO₂ with a CSWRM. Due to the small sample size, the Bayesian approach was adopted in the linear mixed model to better estimate the effects.

Modeling the data showed that the trend of SPO₂ was the same for both combinations; SPO₂ did not change significantly with the change in medication and remained somewhat stable during the treatment after venipuncture. The effect of Ketamine and Midazolam on the respiratory system is little, but Propofol may harm the respiratory system [5]. However, our finding can be due to the use of nasal cannula during treatment for all patients. If the nasal cannula was used only when needed, the results of the study might have been different. Similar findings were observed by Dal and Canpolat who used nasal cannulas. Dal investigated the sedation of Midazolam followed by Ketamine versus KP [10]. Canpolat recruited 3-9-year-old children to compare Propofol, Ketamine, and Propofol-Ketamine combination [11]. In both studies, there was no significant difference between the groups in terms of SPO₂ at any measurement time [10, 11], while in a study that did not use a cannula, the reduction in SPO₂ was greater in KP than KM [12].

We found that the HR trend was the same for both combinations, and the mean HR for KP was significantly lower than KM. The predominant effect of sympathetic and non-sympathetic properties in Midazolam and Propofol, respectively, increase the HR and does not change it during sedation compared to the baseline; however, HR during sedation with Propofol was significantly lower than with Midazolam [13]. On the other hand, Ketamine can increase HR due to its sympathomimetic property [11], and when combined with other sedatives, it can reduce the effects of this property [5]. These effects of drugs and their compounds on HR may be the main reason for our findings. In Dal's study, the HR in the KM group was significantly higher than in the KP group, only 10 minutes after the intervention [10]. In the comparison of KM and PM, HR was observed to be higher in the KM combination [14]; nevertheless, no significant difference was observed in the comparison of the mean HR with Propofol, KP, and PM [15]. This information is consistent with our findings.

Previous studies have compared KP and KM at different doses. It has been shown that both KM and KP combinations reduce salivary flow compared to pre-sedation, but there was no difference between these two compounds during treatment [16]. With the use of KM and KP for sedation during colonoscopy of adults (18 to 60 years), no significant difference in intraocular pressure was reported during the treatment. Still, in both groups, there was a significant difference in the first minute of sedation compared to pre-procedure. In the first minute of sedation, the mean blood pressure (MBP) of KP recipients was lower than that of KM recipients, and it was significantly reduced compared to the pre-procedure. At other times (3, 6, and 9 minutes after sedation and post-procedure), there was no difference compared to each other and compared to the pre-procedure [17]. In a study that used these two compounds for sedation in endobronchial ultrasound-guided transbronchial needle aspiration, there was no significant difference between the MBP of the two groups [10]. In children (under 12 years old), the number of times the MBP decreased or increased by more than 20% compared to the baseline at 5, 10, 15, 20, and 25 minutes post-administration for both drug combinations did not markedly differ [12].

There was a difference in the mean diastolic and systolic pressure in children (1 to 14 years). In terms of diastolic pressure, there was a significant difference between the two treatment groups, while there was no difference in systolic pressure [18]. Despite the use of different doses in the two combinations in the literature, the recovery time was less for KP recipients [10, 12, 19, 20]. Based on Ramsey's sedation score, a study by Adiban et al. revealed that KM resulted in better sedation at all times (5, 10, 30, and 60 minutes post-administration) [18], but in another study, KM was better than KP only at the 35^th minute [10]. Fattahi-Saravi et al. showed that KP recipients had lower scores on the Richmond Agitation-Sedation Scale [21]. In another study, where the level of sedation was based on the Observer Assessment of Alertness and Sedation Scale, there was no difference between the two compounds [17]. This difference in the results may be due to the difference in the scales. As a result, both combinations were found to be effective in different studies.

For data analysis in a CSWRM, a linear mixed model makes it possible to determine the rate of variations in the response variable by changing the treatment type and adjusting the effect of covariates. In a linear mixed model, the correlation structure of the data can be characterized by random effects [22]. By adopting the appropriate random effects of a CSWRM, the correlation structure between the responses can be taken into account. Unfortunately, after preparing the CSWRM data, parameter estimation with the Bayesian approach in the linear mixed model was more time-consuming than the classical approach. To model the data in this study, it was necessary to change the number of iterations and the number of burnings several times to achieve convergence. In future studies, the analysis of responses with a non-continuous scale or the simultaneous analysis of a combination of responses will be discussed to compare sedatives.

Our findings generally showed that the mean HR is significantly higher when using KM for sedation of uncooperative children needing dental treatment than with KP. However, the mean SPO₂ does not significantly differ between the two drug combinations. As a result, the KP combination is preferable in terms of HR.

Bmp beats per minute

CSWRM crossover study with repeated measurements

HR heart rate

KM Ketamine-Midazolam

KP Ketamine-Propofol

MBP mean blood pressure

SD standard deviation

SPO₂oxygen saturation

WHO World Health Organization

Funding No sources of funding were used to support the writing of this article.

Competing Interests: All authors declare that they have no competing financial and/or non-financial interests.

Ethics approval Approval was obtained from the ethics committee of Shahid Beheshti University of Medical Sciences, Iran (IR.SBMU.RETECH.REC.1400.1176). The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

Consent to participate Written informed consent was obtained from the children's parents.

Consent for publication Not applicable.

Availability of data and material The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Code availability This work has used the SAS software, the code is available from the corresponding author on request.

Author contributions Masoud Fallahinejad ghajari and Narjes Amiritehranizadeh contributed to the study conception, design, material preparation, and data collection. Analysis was performed by Tahereh Abbasi-Asl . The first draft of the manuscript was written by Tahereh Abbasi-Asl and all authors commented on previous versions of the manuscript. All authors have read and approved the final version of the manuscript.

Open Access Not applicable.

James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 2018;392(10159):1789–858.
Shitie A, Addis R, Tilahun A, Negash W. Prevalence of dental caries and its associated factors among primary school children in Ethiopia. International Journal of Dentistry. 2021;2021:1–7.
Vaisi Raygani A, Jalali R, Ghobadi A, Salari N. The prevalence of dental caries in deciduous and permanent teeth in Iranian children: A systematic review and meta-analysis. Res Dent Sci. 2018;15(3):180–9.
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;9(Suppl 2):S197.
Malamed SF. Sedation-e-book: a guide to patient management: Elsevier Health Sciences; 2017.
Baker S, Parico L. Pathologic paediatric conditions associated with a compromised airway. International Journal of Paediatric Dentistry. 2010;20(2):102–11.
Corcuera-Flores JR, Delgado-Muñoz JM, Ruiz-Villandiego JC, Maura-Solivellas I, Machuca-Portillo G. Dental treatment for handicapped patients; sedation vs general anesthesia and update of dental treatment in patients with different diseases. Medicina oral, patologia oral y cirugia bucal. 2014;19(2):e170.
Ibrahim H, Nelson T, Thikkurissy S, Xu Z, Scott J. Comparison of Procedures, Time and Fees Associated with Procedural Sedation and General Anesthesia in a Pediatric Dentistry Residency Program. Journal of Dentistry for Children. 2022;89(2):104–9.
Matranga D, Firenze A, Vullo A. Can Bayesian models play a role in dental caries epidemiology? Evidence from an application to the BELCAP data set. Community Dentistry and Oral Epidemiology. 2013;41(5):473–80.
Dal T, Sazak H, Tunç M, Şahin Ş, Yılmaz A. A comparison of ketamine-midazolam and ketamine-propofol combinations used for sedation in the endobronchial ultrasound-guided transbronchial needle aspiration: a prospective, single-blind, randomized study. Journal of thoracic disease. 2014;6(6):742.
Canpolat DG, Yildirim MD, Aksu R, Kutuk N, Alkan A, Cantekin K. Intravenous ketamine, propofol and propofol-ketamine combination used for pediatric dental sedation: A randomized clinical study. Pakistan journal of medical sciences. 2016;32(3):682.
Simsek M, Bulut M, Ozel D, Yucel I, Aykac Z. Comparison of sedation method in pediatrics cardiac catheterization. Eur Rev Med Pharmacol Sci. 2016;20(8):1490–4.
Win NN, Fukayama H, Kohase H, Umino M. The different effects of intravenous propofol and midazolam sedation on hemodynamic and heart rate variability. Anesthesia & Analgesia. 2005;101(1):97–102.
Wutzler A, Huemer M, Boldt L-H, Parwani AS, Attanasio P, Tscholl V, et al. Effects of deep sedation on cardiac electrophysiology in patients undergoing radiofrequency ablation of supraventricular tachycardia: impact of propofol and ketamine. Europace. 2013;15(7):1019–24.
Goel S, Bhardwaj N, Jain K. Efficacy of ketamine and midazolam as co-induction agents with propofol for laryngeal mask insertion in children. Pediatric Anesthesia. 2008;18(7):628–34.
Morse Z, Sano K, Kanri T. Decreased intraoral secretions during sedation-analgesia with propofol-ketamine and midazolam-ketamine combinations. Journal of anesthesia. 2001;15:197–200.
Bayraktaroglu M, Kurtay A, Horasanli E. Comparison of two sedation protocols on intraocular pressure and hemodynamic responses during colonoscopy. Eur Rev Med Pharmacol Sci. 2022;26(12):4295–302.
Adiban V, Matin S, Darghah M, Sadeghi M, Ghorbanzadeh K. Comparison of the Sedative Effect of Ketofol and The Combination of Midazolam-Ketamine in Upper GI Tract Endoscopy in 1–14 Years Childeren. Journal of Ardabil University of Medical Sciences. 2020;20:104–15.
Dalal PG, Taylor D, Somerville N, Seth N. Adverse events and behavioral reactions related to ketamine based anesthesia for anorectal manometry in children. Pediatric Anesthesia. 2008;18(3):260–7.
Sağır Ö, Özaslan S, Yaman İ, Demir HF, Köroğlu A. The comparison of the effects of propofol–ketamine and midazolam-ketamine in patients undergoing colonoscopy. 2014.
Fattahi-Saravi Z, Jouybar R, Haghighat R, Asmarian N. Comparison of the effect of ketamine, ketamine-midazolam and ketamine-propofol on post-tonsillectomy agitation in children. The Malaysian Journal of Medical Sciences: MJMS. 2021;28(5):72.
Fitzmaurice GM, Laird NM, Ware JH. Applied longitudinal analysis: John Wiley & Sons; 2012.

Table 1 Mean (SD) of HR by sequence, drug combination, and time

Sequence	Treatment	Time
		Baseline	Venipuncture	Injection	15 min	30 min	Discharge
KP_KM^a	KM	107.00(10.72)	126.42(8.46)	129.42(13.79)	130.58(14.96)	128.42(12.41)	121.08(11.42)
KP_KM^a	KP	111.67(11.57)	121.08(9.07)	130.00(13.40)	127.58(8.74)	120.83(9.72)	122.08(8.05)
KM_KP^b	KM	113.11(8.79)	126.60(8.38)	141.00(12.81)	141.80(11.31)	136.00(11.71)	126.56(8.69)
KM_KP^b	KP	111.89(8.37)	128.11(10.71)	136.20(14.85)	131.10(12.21)	128.10(11.93)	121.89(7.34)
a: Sequence where participants received KP in the first period and KM in the second period b: Sequence where participants received KM in the first period and KP in the second period

Table 2 Mean (SD) of SPO₂ by sequence, drug combination, and time

Sequence	Treatment	Time
		Baseline	Venipuncture	Injection	15 min	30 min	Discharge
KP_KM^a	KM	97.33(1.50)	97.75(1.29)	99.42(0.79)	99.17(1.34)	99.75(0.62)	96.75(0.75)
KP_KM^a	KP	97.33(1.07)	97.75(1.06)	98.92(1.44)	98.83(1.59)	99.17(1.11)	96.75(1.54)
KM_KP^b	KM	97.78(1.20)	97.60(0.84)	99.40(1.26)	99.60(1.26)	99.80(0.63)	97.11(1.05)
KM_KP^b	KP	97.67(0.87)	98.00(1.25)	99.50(0.85)	99.20(1.23)	99.50(0.97)	96.22(0.97)
a: Sequence where participants received KP in the first period and KM in the second period b: Sequence where participants received KM in the first period and KP in the second period

No competing interests reported.

A comparison of the effects of Ketamine-Midazolam and Ketamine-Propofol combinations on vital signs of uncooperative children with dental diseases in a crossover study with repeated measurements: The Bayesian approach

Status:

Version 1

Abstract

Figures

What is Known

Introduction

Materials and methods

Results

Discussion

Conclusion

Abbreviation

Declarations

References

Tables

Additional Declarations

Status:

Version 1