The Local Route of Administration of Dexamethasone in Impacted Mandibular Third Molar Surgery: A Systematic Review and Meta-analysis of Randomised Controlled Trials and a Critical Narrative Review on the Claimed Advantages of the Local Route

Abstract

Introduction

The proponents of local route of Dexamethasone (DXM) administration for impacted mandibular 3rd molar (MM3) surgeries claim advantages over the traditional systemic routes. This systematic review and meta-analysis were aimed to determine whether the route of perioperative administration of DXM influences the inflammatory outcomes of MM3 surgeries.

Methodology

An electronic database search over a 25 year period of randomised trials of DXM in MM3 surgeries was conducted. The mean differences or standardised mean differences were extracted and pooled using the fixed or random-effects model.

Results

Of the sixteen selected trials, four were considered for a meta-analysis. There were no statistically significant differences in the inflammatory outcomes between the local and systemic routes of DXM.

Conclusion

The claimed advantages of the local route of DXM do not appear to be scientifically valid. Clinical trials supported with DXM plasma measurements are needed to confirm the absence of a systemic effect when DXM is administered locally.

Introduction

Corticosteroids (CS) are often used to minimise the post-operative inflammatory complications following impacted mandibular third molar (MM3) removal. Dexamethasone (DXM) with its long half-life, potency, and almost pure glucocorticoid activity makes it a safe and effective anti-inflammatory drug [1]. DXM is usually administered via the systemic routes viz; Intravenous, Intramuscular and Oral. With factors such as needle phobia and patient compliance, there have been a considerable number of trials that have investigated the efficacy of local injections of DXM for the control of inflammatory response following MM3 surgeries [2–6].

The local administration of DXM is claimed to have advantages such as localised action with minimal systemic effects, faster onset of action, need for a lower dose, and operator and patient comfort. Nevertheless, published systematic reviews and meta-analyses show conflicting conclusions on the efficacy of submucosal DXM compared to placebo/intramuscular routes in MM3 surgeries [7–10].

This article is aimed to examine the best available scientific evidence to determine if the route of administration of DXM (systemic or local routes) influenced the inflammatory complications of MM3 surgeries. Further, we also believe that the purported advantages of local administration of DXM may not be scientifically valid and need to be subject to critical scrutiny.

Materials and Methods

Search Strategy for Identification of Studies

The research question examined was “Is there a difference in inflammatory outcomes following the surgical removal of impacted MM3s when DXM is administered through a local or systemic route?”

The search strategy followed the PICOS format (Table 1).

Table 1.

Search strategy

Search strategy
Population	#1	"Molar, Third"[Mesh] OR “third molar surgery*”[tw] OR “mandibular third molar*”[tw] OR “third molar*”[tw] OR “wisdom teeth”[tw] OR “wisdom tooth”[tw] OR “impacted tooth”[tw] OR “impacted teeth”[tw]"Dexamethasone"[Mesh] OR "dexamethasone 21-phosphate" [Supplementary Concept] OR "Placebo Effect"[Mesh]
Intervention	#2	submucosal[tw] OR submucosal[tw] OR “pterygomandibular space”[tw]
Comparison	#3	oral[tw] OR intramuscular[tw] OR intramuscular[tw] OR intravenous[tw] OR intravenous[tw] OR intraosseous[tw] OR intraosseous[tw] OR “sublingual space”[tw]
Outcome	#4	"Oedema"[Mesh] OR "Trismus"[Mesh] OR “Post-operative" OR “inflammatory outcome*”[tw] OR “post-operative sequel*”[tw] OR “restricted mouth opening”[tw] OR swelling[tw] OR oedema[tw] OR oedema[tw]
Study design		Randomised control trial & Quasi Randomised control trial
Search combination		#1 AND #2 AND #3 AND #4
Language		English only
Electronic database		The Cochrane Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), Semantic Scholar & Google Scholar

Study Eligibility and Selection Criteria (Table 2)

Table 2.

Inclusion and exclusion criteria

Inclusion criteria	Exclusion criteria
Healthy adult patients (> 18 years) undergoing transalveolar extraction of impacted MM3	Perioperative administration of a CS other than DXM in any patient group
Only randomised or quasi randomised clinical trials including parallel-group or split-mouth studies with not less than ten patients in each group	MM3 clinical trials comparing DXM with other pharmacological agents such as NSAIDS, etc.
Studies in which DXM has been peri-operatively administered in at least two patient groups by a systemic route [IV/IM/PO/IO/SL] and a local route [EA/SM/Loc IM/PMS]	Clinical Trials where the comparisons of post-operative outcome are only amongst either the local or systemic DXM routes
72 h after surgery (Pain- VAS, Oedema- facial swelling measured by the distance between at least two facial points, Trismus- Reduced interincisal distance)	Clinical Trials where the post-operative outcome of local/systemic route of DXM are compared against a control/placebo
Restricted to publications in the English language over 25 years, viz. 1 January 1996—31 December 2020

Title and Abstract screening were performed independently by authors (RS and BK) for potential inclusion in the full-text review. Full-text articles were obtained for studies that seemed to satisfy the eligibility criteria from the initial screening or if there was inadequate information from the abstract alone that the inclusion or exclusion conditions had been met. Any disagreements were resolved by discussions between the two examiners. Also, if multiple publications from the same trial data were identified; and then, the selection of a single publication was again made through a consensus by discussion.

Data Extraction

The data collection was performed using a standardised form that was designed specifically for this systematic review. The data extraction form included authors country, year of publication, mean age, gender, nature of comparison group (parallel groups or split-mouth), number of patient groups, number of participants per group, DXM dose, DXM perioperative timing, DXM route of administration, outcomes measures (Pain, Trismus and swelling) at 72 h after surgery.

Risk of Bias and Quality of the Included Studies

The methodological quality of each included study was assessed using the Risk of Bias (ROB2) in randomised studies of interventions quality assessment tool [11].

Statistical Analysis

Meta-analysis was performed using RevMan Software (Version 5.3; Cochrane Collaboration). The effect size considered in the study was the difference in means (MD) for all the three outcomes; Oedema (facial swelling measured by the distance between at least two facial points in mm), Trismus (interincisal distance in mm), and VAS score for pain measured at third post-operative day. Meta-analysis was used to pool the difference in means between the systemic versus Local routes obtained from different studies separately for each outcome. Presence for heterogeneity was identified using Cochrane’s Q test and quantified using the I² statistic. The pooled effect sizes along with their 95% confidence interval (CI) were reported.

Results

Systematic Search

The search strategy resulted in 282 articles. Following the screening of title and abstracts and removal of duplicates, 229 articles were rejected. Of the 53 articles that underwent full-text assessment, 16 articles fulfilled the criteria for the qualitative and risk of bias assessment. Four articles were included for the meta-analysis (Fig. 1).

Fig. 1.

Study flow diagram (PRISMA format)

The characteristics of the 16 studies included in this systematic review are summarised in Table 3. The trials by Kaewkumnert et al. [21] and Moranon et al. [22] were the only crossover (split-mouth) RCTs. The sample sizes of the trials ranged from 20 to 80 participants, for a total of 631 randomised participants, excluding split-mouth studies. The age range of the pooled population was 18–50 years, with a mean age of 25.9 years. Gender distribution data were available for 13 studies, out of which only 6 provided the gender details amongst the patient groups. There was a skewed gender distribution towards male participants (M302; F208). Twelve trials reported the class and position of impacted third molars using the Pell and Gregory classification [4–6, 12–15, 17, 19–21, 24] and a single trial used the Pedersen difficulty index to select the participants. [18] Dosages of DXM ranged from 4 mg, [4, 6, 14–19, 21] 8 mg [5, 13, 20, 22, 24] combinations of different doses in different routes [12] and no dosage details in 1 trial [23]. A control/placebo group was included in 8 trials, with a majority of the control groups having no DXM administration [4, 6, 12–15, 17, 18].

Table 3.

Data extraction of the selected randomised trials

Sl. No	Author	Year	Country	Mean age (SD)	Type of study	Gender	No of groups	No of patients per group	Administration time	Administration route	Dose of dexamethasone	Pell & Gregory Classification
1	Pappalardo et al. [12]	2007	Italy	26.45 (4.2)	Parallel	52M;48F	A	20	Before suturing	EA	10 mg	Class I B
							B	20	(unclear)	SM	10 mg
							C	20	Intra-op	IV	4 mg
							D	20	Intra-op	IM (Unclear)	8 mg
							E	20	unclear	unclear	NA
2	Antunes et al. [13]	2011	Brazil	21 (5.4)	Parallel	13M;5F	A	18	Pre-op	IM (masseter)	8 mg	Class II B
						16M;4F	B	20	Pre-op	Oral	8 mg
						8M;14F	C	22	NA(Control)	NA(Control)	NA(Control)
3	Majid et al [6]	2011	Iraq	26.7 (6.3)	Parallel	5M;5F	A	10	Post-op	SM	4 mg	Class II/III A/B/C
						7M;3F	B	10	Post-op	IM (Unclear)	4 mg
						4M;6F	C	10	NA(Control)	NA(Control)	NA(Control)
4	Majid et al [14]	2013	Iraq	25.6(5.9)	Parallel	8M;4F	A	12	Post-op	IM (deltoid)	4 mg	Class II/III A/B/C
						8M;4F	B	12	Post-op	IV	4 mg
						4M;8F	C	12	Post-op	PO	4 mg
						4M;7F	D	12	Post-op	SM	4 mg
						3M;9F	E	12	Post-op	EA	4 mg (powder)
						4M;8F	F	12	NA(Control)	NA(Control)	NA(Control)
5	Bhargava et al. [4]	2014	India	24.1(4.3)	Parallel	34M;26F	A	10	NA(Control)	NA(Control)	NA(Control)	Class II B
							B	10	Pre-op	PTM(Twin mix)	4 mg
							C	10	Pre-op	SM	4 mg
							D	10	Pre-op	IM	4 mg
							E	10	Pre-op	IV	4 mg
							F	10	Pre-op	PO	4 mg
6	Sablhok et al [15]	2015	India	NR	Parallel		A	20	NA(Control)	NA(Control)	NA(Control)	Class II B
							B	20	Post-op	PO	4 mg
							C	20	Post-op	IM (Local)	4 mg
7	Gopalakrishnan et al. [16]	2015	India	30 (NR)	Parallel	22M;8F	A	30	Post-op	SM	4 mg	NR
						20M;10F	B	30	NR	IM (unclear)	4 mg
8	Saravanan et al. [17]	2016	India	NR	Parallel	NR	A	20	Pre-op	IM (unclear)	4 mg	Class II A/B
							B	20	Pre-op	SM	4 mg
							C	20	NA(Control)	NA(Control)	NA(Control)
9	Gopinath KA et al. [18]	2017	India	NR	Parallel	NR	A	40	Pre-op	SM	4 mg	Pederson’s difficulty score of 5 to 10 were included
							B	40	Pre-op	IV	4 mg
							C	40	NA(Control)	NA(Control)	NA(Control)
10	Kumar [19]	2017	India	29 (NR)	Parallel	9M;10F	A	19	Pre-op	SM	4 mg	Class II/III A/B/C
						11M;8F	B	19	Pre-op	IV	4 mg
11	Vivek et al. [20]	2017	India	27 (NR)	Parallel	28M;17F	A	15	Post-op	IV	8 mg	Class II B
							B	15	Post-op	SM	8 mg
							C	15	Post-op	IM (unclear)	8 mg
12	Kaewkumnert S et al. [21]	2019	Thailand	21.7(2.43)	Split-mouth	M13;F14	A	27	Post-op	IO	4 mg	Mesioangular/Horizontal
							B	27	Post-op	SM	4 mg
13	Moranon et al. [22]	2019	Thailand	21 (NR)	Split-mouth	M13;F17	A	30	Pre-op	SLS	8 mg	NR
							B	30	Pre-op	PMS	8 mg
14	Mahmoud [23]	2019	Egypt	27.6(4.8)	Parallel	M10;F5	A	15	Pre-op	SM	NR	NR
				29.8(5.2)		9M;6F	B	15	Pre-op	IM(Masseter)	NR
				28.5(5.9)		9M;6F	C	15	Pre-op	IM(Systemic)	NR
15	Vivek et al. [5]	2020	India	27 (NR)	Parallel	38M;22F	A	15	Post-op	IV	8 mg	Class II B
							B	15	Post-op	SM	8 mg
							C	15	Post-op	IM(Masseter)	8 mg
							D	15	Post-op	PO	8 mg
16	Hiriyanna et al. [24]	2020	India	28.67 (5.88)	Parallel	20M;10F	A	15	Pre-op	SM	8 mg	Class II/III A/B
				29.06 (5.73)			B	15	Pre-op	IV	8 mg

IV Intravenous; IM Intramuscular; PO Oral; IO Intraosseous; SL Sublingual; EA Endo-alveolar; SM Submucosal; Loc IM Local intramuscular (intramassetric); PMS Pterygomandibular space; VAS Visual analogue scale; M Male; F Female; SD Standard deviation; EA Endo-alveolar; IV Intravenous; IM Intramuscular; SM Submucosal; PO Peroral; PMS Pterygomandibular space; SLS Sublingual space; IO Intraosseous; NR Not reported; NA Not available

Quality Assessment

None of the trials had a low risk of bias across all domains. Following the exclusion of studies with a high risk of overall bias, there remained four studies with “some concern” of bias [6, 14, 21, 24] on whom a meta-analysis was performed (Fig. 2). Since there were fewer than ten studies, publication bias was not assessed.

Fig. 2.

Risk of Bias (ROB) assessment

Outcomes

Oedema

While 8 articles [4, 6, 14, 15, 17, 21, 22, 24] documented an equal response to post-surgical oedema following systemic or local dexamethasone administration, 3 articles [16, 18, 23] recorded oedema reduction with a systemic route and 1 article [19] with a local route. Pappalardo et al. [12] found that the IV and IM (systemic route) and EA (local) routes exerted better oedema control. Vivek et al. [5, 20] recorded comparable oedema control on day 1 with systemic and local routes, while on Day 3, IV and SM routes were better than the IM route.

Pain

Five articles [4, 6, 17, 21, 22, 24] documented an equal response to post-surgical pain following systemic or local dexamethasone administration. 4 articles [5, 19, 20, 23] recorded post-surgical pain reduction with a systemic route and 2 articles [16, 18] with a local route. However, an important point noticed in the study by Gopinath et al. [18] was that, while the local route was found superior in pain control compared to a control placebo group, no comparison between the systemic and local routes of DXM had been analysed. Likewise, Shablok et al. [15] provided no information on pain control achieved despite pain assessment being one of the outcome parameters in the methodology. Pappalardo et al. [12] found that the IV and IM (systemic route) and EA (local) routes exerted better pain control. Majid et al. [14] found that the IV route provided maximal pain relief, but the EA and SM routes exerted better pain control than the IM route.

Mouth Opening

Three articles [15, 18, 19] documented an equal response to post-surgical trismus following systemic or local DXM administration. Six articles [14, 16, 17, 21, 23, 24] recorded significant reductions on post-surgical trismus with a local route. Four articles [5, 6, 12, 20] recorded improved mouth opening with a systemic route of DXM.

As there were differences in mouth opening values on Day 1 and Day 3, certain additional points are given below for a better understanding.

• I.The study by Majid et al. [14] indicated that while all routes of DXM produced lesser trismus on D1 and D3 when compared to a control, on Day 1, the SM route of DXM was found to exert superior action on mouth opening, but on Day 3 the EA route had the least amount of trismus.
• II.The SM route in the study by Papillardo et al. [12] was found to exert the least effect on post-surgical trismus on Day 1. Further, on Day 1, the EA route had a similar impact to the IV and IM routes.
• III.Vivek et al. [20] on day 1 observed maximum benefit on mouth opening with the IM route compared to IV and SM routes, but the effect on day 3 was a reversal of Day 1.
• IV.Vivek et al. [5] on day 1 recorded a superior effect with the PO route, but on day 3 IV and SM routes exerted better outcomes than the Loc IM route.
• V.Gopinath et al. [18] found that SM and IV routes were better than control on day 2, but no comparison was done between the SM and IV groups.

Results of Meta-analysis

For the meta-analysis, all the routes of DXM administration in the four studies were clubbed into local or systemic routes, as explained in the study eligibility criteria. A random-effect (I² > 50%) / Fixed effect model (I² < 50%) was employed for outcome data of the 3rd post-operative day.

Oedema

Meta-analysis showed a pooled effect size of − 0.24 mm [95% CI; − 0.63, 0.14], indicating a reduction in oedema with the systemic route, albeit statistically insignificant (p − 0.22) (Fig. 3).

Fig. 3.

Forest plot showing the random-effect meta-analysis of mean difference in Oedema (mm), Trismus (mm) and fixed-effect meta-analysis of mean difference in Pain (VAS score) comparing systemic versus local routes of DXM on the third post-operative day

Trismus

Meta-analysis showed a pooled effect size of  − 1.17 mm [95% CI; − 6.34, 4.01], suggesting that the local route is better. However, the result was not statistically significant (p − 0.66) (Fig. 3).

Pain

Meta-analysis showed a pooled effect size of − 0.19[95% CI; − 0.69,0.31], indicating a slight reduction in pain with the systemic route, although the effect was not significant statistically (p − 0.46) (Fig. 3).

Discussion

A critical examination of the conclusions of studies that have claimed a better efficacy with local routes of DXM seem to be derived from comparison to the placebo/control groups and not against systemic routes [4, 6, 12–15, 17, 18]. Earlier published meta-analyses had concluded on the effectiveness of the local route from the information provided by these studies. There is enough evidence in the literature confirming the positive influence of DXM on inflammatory outcomes after MM3 surgery and it is but natural to observe that DXM shows better results than a placebo. Conversely, as our systematic review examines the results of only systemic and local DXM routes and excludes placebos/control groups, the findings are more likely to accurately reflect the influence of the route of DXM on the inflammatory outcomes after MM3 surgery. The results of our meta-analysis indicate that the effect of local routes of DXM administration on MM3 surgical inflammatory outcomes are not statistically significant when compared to the systemic routes. Further, the systemic routes provide better outcomes for oedema and pain following MM3 surgeries.

The claimed advantages of local routes of DXM in M3 surgeries are a rapid onset of action, minimal systemic absorption, thereby ensuring a prolonged localised action with minimal side effects, and comfort for both patient and operator. It is necessary to ascertain if the above assumptions are scientifically valid.

• a) Does the DXM injected directly into the site of action have a local action as intended with minimal systemic absorption and side effects?

Local delivery via injections is reserved for highly specialised therapies wherein the ability to accomplish systemic administration is hampered by poor perfusion or difficult-to-reach tissues [25]. Suppose a tissue site is either isolated or distinct from other nearby structures, then it may be possible to inject the drug directly into the tissue allowing a local therapeutic concentration to be reached. Since these sites have limited vascularity, only small amounts of the drug are transferred and diluted into the systemic volume of distribution [26]. However, the operative area in MM3 surgeries does not suffer from any of the above limitations. Moreover, the apprehension that a systemic route of DXM in MM3 surgery will cause side effects is unfounded as it is administered as a single dose. There are established guidelines that recommend intraosseous infusion in adults when intravenous access is unavailable. As the bioequivalence of intraosseous and intravenous routes are comparable, the presumption that intraosseous route exerts a purely local action is inaccurate [27].

• b) What would be the appropriate dosage of DXM when it is administered locally?

If a drug could be deposited directly into the site of action, a significant advantage would be that a lower dose can be used to achieve the clinical effect. Further, since the process of distribution throughout the entire body can be avoided, it would imply that clinically effective levels at the site of action could be obtained more rapidly [26]. Yet, in all the studies that have recommended the effectiveness of a localised administration of DXM in MM3 surgeries, dosages have ranged from the usual 4–8 mg (Table 2). While such dosages are necessary for systemic routes to overcome the expected dilution in blood volume, the continued use of similar dosages for local routes is inexplicable. In fact, Moraschini et al. [7], in their meta-analysis, indicate that there is no scientific evidence demonstrating the advantage of administering SM DXM in doses in excess of 4 mg. Nonetheless, they still recommend that when preoperative corticosteroids are used, more concentrated doses may be needed since the use of a flap and tissue displacement can affect the concentration of the drug and its absorption into the bloodstream. This recommendation by Moraschini et al. contradicts the evidence from their meta-analysis.

• c) Does the formulation of DXM matter?

Local drug administration requires specific formulations to allow the drug to remain at the application site for a sufficient length of time. The water solubility of glucocorticoids is very low, thus requiring their administration as a prodrug in the form of water-soluble esters such as DXM Sodium phosphate (DXMSP) [28]. Being a prodrug, the DXMSP must first undergo biotransformation by metabolic processes before becoming an active pharmacological agent for which entry into the systemic circulation is critical. Further, if a drug is intended to exert a local effect, absorption into the systemic vasculature would represent the loss of the drug from its primary site of activity [25]. Bhargava et al. compared the DXM plasma concentration using liquid chromatography following systemic gluteal IM and local PMS injections of 4 mg dexamethasone [29]. The mean plasma DXM concentration in the IM group was 226.41 + /48.67 ng/ml, and for the PMS group was 209.67 + /88.13 ng/ml and determined to be statistically insignificant. The interpretation that proximity administration of DXM is a “local route” is therefore erroneous from a pharmacological viewpoint. A purely localised action is not possible unless the DXM formulation is specifically altered such as DXM Acetate. In no study has there been a mention of altered formulations of DXM for local administration at the M3 surgical site. Despite a recommendation to evaluate the efficacy and safety of the acetate formulation of DXM in dentistry, there seems to be no published research on the use of DXM acetate in MM3 or dentoalveolar surgery even after two decades [1].

• d) Is injecting IM DXM close to MM3 have a more rapid action than distant IM injections?

Messer et al. [30] were amongst the earliest advocates for using the masseter muscle as a route of administration of DXM for MM3 surgeries. They opined that the masseter muscle was in the immediate area, anaesthetised, and injection into the muscle could be considered part of the operative procedure. They claimed to have used the local DXM in over 5000 patients with a considerable decrease in all inflammatory outcomes. However, their study did not provide any objective data on inflammatory outcomes and their conclusions appear to be derived from clinical observations. Likewise, their assertion that the masseter muscle was anaesthetised is incorrect as its innervation is not addressed in the local anaesthesia blocks for MM3 surgeries.

When a drug is injected through the IM route, the injected volume spreads through the interstitial spaces and comes into close proximity with the muscle capillary network [26]. This would mean that the absorption of IM drug is determined by the bulk of the muscle and its vascularity [31]. It is often assumed that injecting the drug close to the site of surgery will result in better and faster efficacy of the injected drug. The increased blood flow in the maxillofacial region can possibly contribute to the faster entry of DXM into the systemic vasculature when injected into the masseter muscle. Selvaraj et al. [32] assessed the efficacy of IM steroid injections administered through the gluteal and masseter muscles and found no significant differences in the inflammatory complications. Similarly, other studies have reported that administration of high dose steroids into the masseter muscle did not improve anti-inflammatory action over injections at a distant site [13, 33]. Additionally, iatrogenic muscle injury resultant from such direct injections can contribute to post-operative trismus confounding the effectiveness of DXM.

Studies have thrown up varied results with findings ranging from no differences between IM and Oral DXM [13, 34], more effectiveness with IM [12], lesser effectiveness with IM DXM than SM DXM [6]. A meta-analysis examining the efficacy of IM DXM vs a placebo/control in MM3 surgeries suggested that since the rate of absorption of DXM is highly related to blood flow in the muscle of administration, there was a need to select a standardised muscle for future clinical trials of IM DXM in MM3 surgeries [35]. The assumption that injecting the DXM into a muscle close to MM3 would have an enhanced activity than other muscle sites is not borne out by available evidence.

• e) Is the local route of DXM comfortable for operator and patient?

Dental surgeons who are not comfortable with performing IV/IM injections would find the local oral route more convenient. However, DXM injections, either SM or PMS, without a prior local anaesthesia injection can be quite painful and distressing to the patient. While Bhargava et al. [4] employed the use of Twin Mix injections into the PMS space before MM3 surgery, it is still likely to be causing some discomfort to the patient due to the time lag taken for the local anaesthesia to start acting. Another concern would be the effect of DXM on the disassociation constant (PKa and pH) of Lignocaine hydrochloride.

Conclusion

These results of the systematic review and meta-analysis cast doubt on the purported advantages of local routes of DXM in MM3 surgery. We hypothesise that the outcomes observed after local injections of DXM appears to be primarily due to systemic uptake and biotransformation rather than proximity to the MM3. An accurate picture can be obtained only with well-designed randomised clinical trials supported with DXM plasma measurements to confirm the absence of a systemic effect when DXM is administered locally.

Funding

This manuscript received no funding.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

The pre-specified protocol of this systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO): (Registration No. CRD 42020149687).

Consent for Publication

Authors have presented the findings of this review as Oral paper in Annual conference of AOMSI, Mangaluru, India.