Hemodynamic changes in third molar exodontia using, orally, midazolam versus diazepam: a systematic review of randomized clinical trials

Alterações hemodinâmicas em exodontia de terceiro molar utilizando, por via oral, midazolam versus diazepam: uma revisão sistemática de ensaios clínicos randomizados

ABSTRACT

Objective:  Compare the effect of Diazepam versus Midazolam on hemodynamic changes in oral conscious sedation in lower third molar exodontias.

Methods:  A systematic review was conducted, with registration in the International Prospective Register of Systematic Reviews (protocol CRD42020162953), using the databases from PubMed/MEDLINE, Embase, Cochrane Library, BVS Regional Portal and Grey Literature (Clinical Trial and OpenGrey), and also manual searches in Bucomaxillofacial Surgery journals, concluding the collections on November 3, 2020, updated on September 20, 2024. Randomized clinical trials comparing Diazepam with Midazolam were included, excluding those with incomplete information, which did not assess blood pressure, heart rate and peripheral oxygen saturation, and those which texts were not located. A risk of bias analysis was performed using the RoB 2.0 Cochrane Handbook for Systematic Reviews of Interventions tool. Subsequently, a narrative synthesis was conducted to show the results.

Results:  From the 2,017 records found, only two were included, aggregating 210 patients. Midazolam showed better results in blood pressure and peripheral oxygen saturation, while Diazepam showed more favorable values in heart rate.

Conclusion:  Due to limitations such as absence of data and failures in randomization, the evidences were considered fragile, requiring further randomized clinical trials, with a better scientific design.

Indexing terms
Conscious sedation; Diazepam; Midazolam; Systematic review; Third molar

RESUMO

Objetivo:  Comparar o efeito do Diazepam versus o Midazolam nas alterações hemodinâmicas após a sedação consciente por via oral em exodontias de terceiros molares inferiores.

Métodos:  Foi realizada uma revisão sistemática, com registro no International Prospective Register of Systematic Reviews (protocolo CRD42020162953), utilizando as bases de dados PubMed/MEDLINE, Embase, Cochrane Library, Portal Regional da BVS e Literatura Cinzenta (Clinical Trial e OpenGrey), assim como buscas manuais em periódicos de Cirurgia Bucomaxilofacial também foram realizadas, concluindo as coletas em 3 de novembro de 2020, com atualização em 20 de setembro de 2024. Foram incluídos ensaios clínicos randomizados comparando o Diazepam com o Midazolam, excluídos aqueles com informações incompletas, que não avaliaram pressão arterial, frequência cardíaca e saturação periférica de oxigênio, e aqueles que os textos não foram localizados. Uma análise de risco de viés foi realizada usando a ferramenta RoB 2.0 Cochrane Handbook for Systematic Reviews of Interventions. Posteriormente, foi realizada uma síntese narrativa para exposição dos resultados.

Resultados:  Dos 2.017 manuscritos encontrados, apenas dois foram incluídos, agregando 210 pacientes. O midazolam apresentou melhores resultados na pressão arterial e na saturação periférica de oxigênio, enquanto o diazepam apresentou valores mais favoráveis na frequência cardíaca.

Conclusão:  Devido às limitações como ausência de dados e falhas na randomização, as evidências foram consideradas frágeis, necessitando de novos ensaios clínicos randomizados, com melhor desenho científico.

Termos de indexação
Sedação consciente; Midazolam; Diazepam; Dente serotino; Revisão sistemática

INTRODUCTION

A high level of anxiety in the face of dental care is not uncommon, which can have a negative impact on the patient oral health due to poor adherence to treatment [¹]. Among the dental procedures that can cause increased anxiety, third molars exodontia stands out, especially lower molars, because it is constantly perceived by patients as a potentially more traumatic situation when compared to other procedures [²,³]. This high level of insecurity on behalf of patients can be considered one of the greatest challenges faced by surgeons during the surgical procedure.

Surgical extraction of impacted third molars is a procedure commonly performed by Oral-Maxillofacial Surgeons [³-⁶], and its frequent association with exacerbated anxiety in patients represents an important scenario for the investigation of the conscious sedation technique, which advantages are the fact of allowing the patient to autonomously open and close the mouth (allowing the extractor movement), rotate the head to allow a better view of the operative field, in addition to providing the maintenance of the cough reflex, which protects the airways from possible aspiration of fluids and foreign bodies [⁴,⁷].

There are several drugs proposed for the treatment of dental anxiety through the conscious sedation technique [⁴,⁸]. Among these, the benzodiazepine class is one of the most used to induce a conscious sedative state [⁵,⁸-¹⁰].

Regarding the administration route of these drugs, although the injectable form is the most used in this technique, the oral route (OR) has advantages that can stand out compared other administration routes, such as easier to access, less invasive, with greater acceptability by the patient, not requiring resources in equipment such as the inhalation and also because it is worldwide prescribed by Dental Surgeons, unlike, for example, the parenteral route that in countries such as Brazil cannot be prescribed by the Odontologist [⁷,⁸,¹¹]. Diazepam and Midazolam are the most widely used medicines [⁷,¹²-¹⁴].

Although Diazepam and Midazolam show similar sedative responses [⁸], these drugs have cardiovascular effects by different mechanisms [⁷], and may provide physiological changes, such as hemodynamic changes, with different intensities, making it valid to investigate which of these drugs promote fewer changes compared to normal levels.

Therefore, this study aimed to compare the effect of oral Diazepam versus oral Midazolam on changes in blood pressure, heart rate and peripheral oxygen saturation, when used in the conscious sedation technique in surgeries for the lower third molars extraction, through a systematic review of randomized clinical trials.

METHODS

Research question

Does oral Midazolam promote more stability in blood pressure (BP), heart rate (HR) and peripheral oxygen saturation (SpO₂) than oral Diazepam, compared to the conscious sedation technique for lower third molar exodontia in adult patients?

Protocol and registration

This systematic review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The used methods were recorded in the International Prospective Register of Systematic Reviews (PROSPERO), under the protocol number CRD42020162953, and data extraction only started after obtaining it.

Eligibility criteria

Randomized clinical trials comparing oral Diazepam with Midazolam as a form of conscious sedation for lower third molar extraction surgeries.

Exclusion criteria

As exclusion criteria, we have: information incompleteness on the dose and administration route of the used anxiolytic; studies that did not evaluate the hemodynamic responses of patients (BP, HR and SpO2), and studies which abstracts and/or full texts were not found.

Outcomes characteristics

The primary outcomes for this review were variations in Blood Pressure, Heart Rate and Peripheral Oxygen Saturation in third molars exodontia under the effect of conscious sedation with oral Diazepam and oral Midazolam.

Search strategy

Electronic surveys

The search for scientific papers was conducted by two researchers, independently, in the databases of PubMed/MEDLINE, Embase, Cochrane Library, BVS Regional Portal and Grey Literature (Clinical Trial and OpenGrey), developing specific search strategies for each researched database. These strategies were initially set up using the controlled vocabulary of the Medical Subject Headings (MeSH) dictionary, and later translated into the controlled vocabularies of Emtree and Health Science Descriptors (DeCS), for use according to the viability of each database. Official terms and synonyms were selected with reference to the population, intervention and control. And both for PubMed/MEDLINE and Embase research, validated filters for the type of study in a randomized clinical trial were added [¹⁵]. And it should be noted that official terms in each database were blown up. The complete strategy used on each database can be viewed in complementary file 1.

It must be emphasized that, with the exception of the BVS Regional Portal database, which aggregates other databases, the “Database” filter was used in it to select only those of interest (Lilacs, BBO - Odontology, IBECS and SciELO), and Embase, in which the “Sources” filter was used to select only the files contained in the Embase database and which were not contained in MEDLINE, since these papers had already been searched via PubMed, and there was no use of any other automatic filter in any of the searched databases.

Other resources

Manual searches were conducted in the following prominent journals in the Oral and Maxillofacial Surgery area: International Journal of Oral and Maxillofacial Surgery, Journal of Oral and Maxillofacial Surgery, British Journal of Oral and Maxillofacial Surgery and Journal of Cranio-Maxillo-Facial Surgery. All papers published in the aforementioned journals until the moment of data collection completion were analyzed.

The bibliographies of the included papers and relevant review papers were also verified for studies not identified by the above search strategies.

Data collection and analysis

Selection of studies

Papers found through the search strategies were exported from each data source to the online application Rayyan Wed (https://rayyan.qcri.org/welcome), where, through the application own resource, the possible duplicate studies were identified and then one of the evaluators made an individual comparative analysis of each paper accused by the software, so that the duplicate files were actually deleted. Sequentially, the selection process of the studies occurred in two different stages, the first was the titles and abstracts reading, when the papers judged in consensus as dissonant with the study objectives were eliminated. After that, the second selection stage included the critical reading of the full texts in order to perform a new round of exclusion of papers that were not compliant with the inclusion criteria or compliant with exclusion criteria. In both phases, two reviewers (A and B) performed the analyses independently and blindly, considering the eligibility and exclusion criteria, with a third evaluator (C) that was responsible for analyzing the cases of divergences of opinion between the first two evaluators. And finally, for each phase of papers selection, there was a common consensus among all evaluators on which papers should be excluded and which papers should be included in the subsequent phase. However, in case of any continued divergence, the study went ahead for more accurate analysis.

Risk of bias in each study

The risk of bias was verified by evaluators A and B individually, considering the evaluation criteria of the RoB 2.0 (https://www.riskofbias.info/welcome/rob-2-0-tool) instrument developed by the Cochrane Collaboration to evaluate randomized clinical trials. After each of the evaluators had made the analyses, both met and reached consensus for the formulation of a final judgment.

Data extraction

Through a specific form, an examiner performed the data extraction and the second evaluator verified the consistency of the information by tabulating the data on the study population, performed interventions, used anxiolytic, necessary dosage and results of interest (BP, HR and SpO2).

Data analysis

The narrative analysis of the included studies was performed due to the absence of quantitative data that did not allow conducting a Meta-analysis.

RESULTS

Selection of studies

With the collections completion on November 3, 2020, the research generated a number of 1,869 references.

After the exclusion of duplicate studies, a total of 1,450 papers from the searches in the databases were analyzed by the titles and abstracts by 2 evaluators, with the proper blinding. 9 papers were selected by evaluator A and 7 by evaluator B to read the full text, with 6 conflicts. After the analysis by evaluator C, there was a consensus among the three evaluators for the eligibility of 6 papers, however, one divergence remained, which was accepted by evaluators A and C and disregarded by evaluator B. So, as provided for in the methodology, this study was also selected for a more accurate analysis, totaling the number of 7 papers that passed to the study complete reading phase.

After the complete reading of the papers selected in the previous phase, and from the 3 papers tracked through manual searches in predetermined journals, with no divergence, evaluators A and B included 2 papers to be explored regarding the risk of bias and data extraction. The summary of the analyses can be seen in figure 1. We point out that the search was updated, and was redone on 09/20/2024, with a time frame from the date of the first collection of records (11/04/2020). In this new search, other 148 records were collected (79 from PubMed, 33 from Embase, 27 from BVS, 3 from Cochrane Library and 6 from gray literature), and 3 were excluded because they were duplicates, leaving 145 works to be screened by title and abstract, according to the methodology proposed in this paper. After this stage, all new records were excluded by evaluators A and B, individually and blindly, with no conflicts between the analyses.

Figure 1
Flowchart of the papers selection.

Characteristics of included studies

The study of Morais et al. [⁷] used the double blind method with split-mouth design, and in this study 128 patients were selected, while 8 were excluded for not returning for the second surgical procedure. Inclusion criteria were: healthy patients, according to the American Society of Anesthesiologists (ASA I) classification and absence of self-reported reactions or allergies to the drugs employed in the study. Exclusion criteria were: refusal to participate after reading the free and informed consent form, self-reported allergy to the drugs used, and no return for the second surgery on the contralateral side.

And the study by Chaia [¹⁶] had a sample of 120 patients for surgical removal of the third molars. Inclusion criteria were: ASA I patients, with orthodontic indication for the removal of the unenrupted third molars, patients with radiographic evidence of unenrupted and or impacted third molars. Exclusion criteria were: patients with a history of benzodiazepine hypersensitivity, pregnancy, narrow-angle glaucoma, narcotic drug-dependent, alcoholic patients, patients who use a sedative chronically and/or the following medications: cimetidine, ranitidine, erythromycin, diltiazem, verapamil, ketoconazole and itraconasole, patients who have previously undergone oral surgical treatment. A synthesis of the included studies characteristics can be seen in table 1.

Table 1
Summary of included studies.

SUMMARY OF INCLUDED STUDIES CHARACTERISTICS
Author/ Year	Country of origin	Study type	n	Conducted procedures	Interventions / controls	Presentation/Route	Variables of interest
Morais et al. [7]	Brazil	Paper published in a journal	120	Exodontias of upper and lower third molars	Diazepam 10 mg x Placebo; Midazolam 7.5 mg x Placebo; Midazolam 7.5 mg x Diazepam 10mg	Tablet/ Oral	BP; HR; SpO2; Pressure rate product and Pressure rate quotient
Chaia [16]	Brazil	Doctoral thesis	120	Exodontias of upper and lower third molars	Diazepam 10mg; Midazolam 15mg; Bromazepam 6mg; No drug	Tablet/ Oral	BP; HF and SpO2

Characteristics of interventions

In the study of Morais et al. [⁷] patients underwent two surgical moments, in the first both third molar elements were extracted (maxillary and mandibular) from one side of the patient, and in a second moment the exodontia of the other two third contralateral molars was made, showing the same degree of impaction on both sides, and three groups were formed: Group 1 (G1) received diazepam 10.0 mg and placebo, Group 2 (G2) received midazolam 7.5 mg and placebo, and Group 3 (G3) received midazolam 7.5 mg and diazepam 10.0 mg. All patients were instructed to take two tablets of dexamethasone 4mg 1 hour before surgery. The substances (diazepam, midazolam and placebo) were administered orally 45 minutes before the surgical procedure. Patients underwent local anesthesia (articaine 4%, adrenaline 1: 200.000).

In the study of Chaia [¹⁶], surgical removal of third upper and lower molars occurred in a single surgical moment and on only one side of the patients, which were unenrupted and/or impacted. Four groups were formed, including: Group I (GI) Diazepam 10 mg, Group II (GII) Bromazepam 6 mg, Group III (GIII) Midazolam 15mg and Group IV (GIV) that corresponded to the control group that received no anxiolytic medication. The substances (diazepam, midazolam and Bromazepam) were administered orally 1 h before the surgical procedure. Patients underwent local anesthesia (Lidocaine Hydrochloride 2% with adrenaline 1: 100.000).

Characteristics of measurements

In the study of Morais et al. [⁷] the dependent variables were systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), heart rate (HR) and peripheral oxygen saturation (SpO₂). The pressure rate product (PRP) and the pressure rate quotient (PRQ) were also analyzed. Blood pressure, HR and SpO₂ measurements were performed during the clinical examination (T0 = baseline), immediately before anesthesia (T1), five minutes after anesthesia administration (T2), ten minutes after anesthesia administration (T3), and at the end of the surgical procedure (T4). For the measurement of SBP and DBP, an aneric model sphygmomanometer (Premium®) was placed on the right arm at heart height, with the patient in semi-inclined supine position. HR and SpO2 were monitored at times predetermined by a pulse oximetry device, OXP-10 Emai®. The paired t-test was used to compare the means between the groups for each variable. All p <0.05 values were considered to have statistical significance.

And in the study of Chaia [¹⁶], a sphygmomanometer positioned in the proximal position of the left upper limb was used to obtain the values relevant to SBP and DBP, and to measure the heartbeat and oxygen saturation, the digital sensor of a pulse oximeter was positioned on the left index finger. The first data recording was performed five minutes before the anesthetic technique was applied, and was remade at five-minute intervals by the researcher until the end of the procedure. During the entire phase to record the data, the same devices and instruments were used. The author reported that data was analyzed through the following statistical tests: arithmetic mean, variance analysis and the Tukey test. All p <0.05 values were considered to have statistical significance.

Characteristics of outcomes of interest

Blood pressure

Morais et al. [⁷] found no statistically significant differences in SBP between the tested substances in any of the evaluated moments. However, they found statistically significant differences in Group 3 in T3 and T4, with lower DBP with the use of midazolam. While Chaia [¹⁶] found a p<0.05 in the SBP and DBP comparisons with the midazolam group showing results closer to clinically acceptable values compared to the diazepam group and the group that no drug was administered.

Heart rate

Morais et al. [⁷] found a p<0.05 in G2 at T2 and T3 with higher rate during midazolam administration and in G3 T3 with a higher rate occurring during midazolam administration. Chaia [¹⁶] found no statistically significant differences.

Peripheral oxygen saturation

Morais et al. [⁷] found no statistically significant differences in SpO2 between the tested substances in any of the evaluated moments. Chaia [¹⁶], in turn, found statistically significant differences between diazepam and midazolam compared to the group that received no medication, with the latter showing the lowest SpO₂ values, and also between midazolam and diazepam, with midazolam showing higher SpO₂ levels

Risk of bias analysis

The study by Morais et al. [⁷] shows a low risk of bias for the variables of interest, which are heart rate and peripheral oxygen saturation, but shows a high risk of bias to the blood pressure outcome. And the study of Chaia [¹⁶] shows a high risk of bias in all variables of interest (figure 2).

Figure 2
Evaluation of the risks of bias in each outcome using the RoB 2.0 instrument.

With the exception of the blood pressure outcome of the study by Morais et al. [⁷], the other outcomes had positive and negative evaluations common in each of their relevant studies. Some comments in different domains are needed.

In D1, Chaia [¹⁶] paper showed a high risk of bias, because it only reported that the patients were randomly and equally distributed, but without informing how this was done, and it was also possible to infer that there was no correct concealment of the allocation when it was understood that the drugs were not masked and that the control group did not take any medication (not even placebo). Another point that drew attention was the fact that Chaia [¹⁶] has not specified the distribution of men and women in each group, a factor that can interfere in the balance of the fundamental prognostic factor.

And in D3, the paper by Morais et al. [⁷], in all variables, brought no center and dispersion measurements to the groups that had no statistical difference; in addition, for those that had, these data were shown only in the form of charts, without the proper values clearly. In this domain, Chaia [¹⁶] also brought no dispersion measures to the groups. However, for both studies, it was considered that, due to these failures, there was probably no evidence that the results were biased by data from absent results, which generated a low risk of bias in this domain in all outcomes of interest of Chaia [¹⁶] study and for the heart rate and peripheral oxygen saturation outcomes of the study by Morais et al [⁷]. For the blood pressure outcome, in the study by Morais et al. [⁷], in addition to the problems already mentioned in D3, the results of the blood pressure variable mean were not shown, while it was one of the objectives of the paper in question, a fact that caused this outcome to be classified as showing a high risk of bias.

Another important issue is that the absence of center and dispersion measures, mentioned in the considerations on D3, made it impossible to perform a meta-analysis and consequently the evaluation of the evidence quality of this systematic review, and therefore, a narrative analysis was performed.

Narrative analysis

When we observed the results found in the included studies, it was possible to verify that both Chaia [¹⁶] and Morais et al. [⁷] had, at the end of the studies, a number of 120 patients who completed all the stages of the studies, which were divided into different groups. However, for the purpose of analysis in this systematic review, one of the Chaia [¹⁶] groups will be disregarded, because for this study, a benzodiazepine different from those of interest in this study was used. Therefore, this study includes a sample of 210 patients with 330 surgical procedures performed (since Morais et al. [⁷] used the split-mouth method), which are: 110 with diazepam; 110 with midazolam and other 110 surgical procedures with placebo or no medication. A summary of this distribution, with the available characterization of the sample, can be noted in table 2.

Table 2
Distribution of the number and percentage of patients by allocation and age groups (mean/standard deviation).

Sample characteristics and groups distribution
Groups	n	%	Age (mean / standard deviation)
Diazepam 10mg x Placebo (G1)*	40	19.0	22.7 ± 6.2
Midazolam 7.5mg x Placebo (G2)*	40	19.0	22.8 ± 3.4
Midazolam 7.5mg x Diazepam 10mg (G3)*	40	19.0	23.1 ± 5.3
Diazepam 10mg (GI)**	30	14.3	25#
Midazolam 15mg (GIII)**	30	14.3	22.7#
No medication (GIV)**	30	14.3	22.2#
Total	210	100

• Note:
• ^*
  Study of Morais et al.¹³;
• ^**
  Study of Chaia¹⁶;
• ^#
  Standard deviation not available.

Regarding the findings recorded in the outcomes of interest, it was possible to note, based on the results that showed statistically significant differences, that Midazolam had better results in blood pressure and peripheral oxygen saturation, while Diazepam showed more favorable values regarding heart rate. However, at different times of comparisons, these differences are not found. The summaries of the comparisons, which showed or not statistical difference, can be noted in tables 3 and 4, respectively.

Table 3
Variables of interest, comparison groups, moments of analysis and mean values of outcomes that showed a p<0.05.

Results with statistically significant differences
Variables			Comparisons	Comparisons moments					Mean values
Blood pressure p<0.05	Systolic blood pressure	Midazolam 15mg x No Drug or Placebo (NDP)			Mean of different moments (MDM)		Diazepam 10mg (135.27 mmHg); NDP (137.94 mmHg); Midazolam 15mg (126.16 mmHg).
		Midazolam 15mg x diazepam 10mg			MDM
	Diastolic blood pressure	Midazolam 15mg x NDP			MDM		NDP (81.70 mmHg); Diazepam 10mg (80.77 mmHg); Midazolam 15mg (72.66 mmHg). Midazolam 7.5mg with lower values compared to Diazepam 10mga.
		Midazolam 15mg x diazepam 10mgb			MDM
		Midazolam 7.5mg x diazepam 10mga			10 min after anesthesia administration and at the end of the surgical procedure
Heart rate p<0.05		Midazolam 7,5mga x placebo			5 and 10 min after anesthesia administration		Higher rates in those who used midazolama;b.
		Midazolam 7.5mgb x diazepam 10mg			10 min after anesthesia administration
Peripheral oxygen saturation p<0.05		Diazepam 10 mg x midazolam 15mg			MDM		Diazepam 10 mg (97%); Midazolam 15mg (99%); MNE (92%).
		NDP x Diazepam 10 mg			MDM
		NDP x midazolam 15mg			MDM

• Note: For different groups, but with the same drug and milligram, compared in the same variable, overwritten letters (a and b) were used to refer them to their relevant mean values.

Table 4
Description of the variables of interest, comparison groups and moments of analysis of the outcomes that showed p>0.05.

Results With No Statistically Significant Differences
Blood pressure	A p>0.05 was found when comparing systolic BP of G1, G2 and G3, during the clinical examination (T0), immediately before anesthesia (T1), 5 min after anesthesia administration (T2), 10 min after anesthesia administration (T3) and at the end of the surgical procedure (T4). A p>0.05 was also observed when comparing the diastolic BP of G1 and G2 in T0, T1, T2, T3 and T4, when comparing the values of G3 in T0, T1 and T2, when comparing GI with GIV.
Heart rate	A p>0.05 was found when comparing the HR of G1 in T0, T1, T2, T3 and T4, of G2 in T0, T1 and T4, of G3 in T0, T1, T2 and T4. There were also no statistical differences when comparing MDM between GI, GIII and GIV groups.
Peripheral oxygen saturation	A p>0.05 was found when comparing the means in groups G1, G2 and G3 in T0, T1, T2, T3 and T4.

• Note: G1: Diazepam 10mg x Placebo; G2: Midazolam 7.5mg x Placebo; G3: Midazolam 7.5mg x Diazepam 10mg; GI: Diazepam 10mg; GIII: Midazolam 15mg; GIV: No drug.

DISCUSSION

Regarding the drugs in question, even though both belong to the benzodiazepine group, these apparently have cardiovascular effects by mechanisms other than those mediated by gamaminobutyric acid receptors. Midazolam, for example, has a depressive effect of sympathetic response, which determines a decreased systemic vascular resistance, vasodilation and myocardial contractility, leading to hypotension. On the other hand, diazepam has an effect on cardiovascular stabilization, as it increases the inotropic response, probably because it inhibits phosphodiesterase-4 [⁷].

Regarding the primary outcomes of this systematic review, these have already been the subject of clinical evaluation regarding their variations in healthy patients during the surgical procedure for the extraction of lower third molars [¹⁷]. In the referred study, 60 healthy patients were evaluated to determine changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), HR and SpO₂ at different times. As a result, SBP and DBP showed significant changes with the highest values recorded at the time of osteotomy and tooth extraction, respectively. HR had statistically significant variations over time, with the maximum observed 4 minutes after local anesthetic injection and the lowest HR recorded during suture. There were also differences in gender, with the female showing a higher mean HR and the male gender with a higher SBP, both with statistically significant difference. And SpO2, on the other year, showed no statistical difference either regarding the observed moment or regarding the participants’ gender.

Following the same line of study, Tarazona-Ávarez et al. [²] also analyzed hemodynamic variations of SBP, DBP, and HR regarding the gender and anxiety of the patient during the surgical removal of the impacted lower third molar. Immediately before the operation, patients completed the Corah Dental Anxiety Scale and at the end of the surgery the pain was recorded by the Visual Analog Scale, with SBP, DBP, and HR recorded at different surgical moments. As results, the intraoperative pain score showed no significant difference between the genders (p = 0.104), but it was seen that regarding anxiety, women showed higher values (p = 0.00); SBP showed few alterations, with the highest value corresponding to the time of the incision and the shortest to the time of the suture. In turn, DBP was higher before the surgery and lower during extraction, with females showing higher values (p = 0.045), while HR was higher during the incision and lower at the time of suture and patients with anxiety, by the Corah Dental Anxiety Scale, showed higher HR than those with no anxiety, there was also a non-significant difference (p = 0.08).

Based on the last two studies mentioned above, it is valid accepting that hemodynamic stability, besides being an acceptable parameter for the measurement of anxiety level, is a factor to be controlled during the surgical procedure, and may suffer significant variations according to the operative moment and the patient gender. When analyzing these factors in the papers included in this systematic review, it was possible to note that both authors, Morais et al. [⁷] and Chaia [¹⁶], preconized the measurement at different times, however, it was not possible to make further analyses of these measurements due to the insufficient presentation of these data, given that Morais et al. [⁷] brought this information only in the form of charts (these with difficult precision regarding the real value of the center and dispersion measurements) and only in the variables in which there was an intraperiods statistical difference between diazepam and midazolam, which made it difficult to visualize the largest and smallest interperiods. And Chaia [¹⁶] only showed the values of the means among all the moments of measurement. Regarding the influence of the participants’ gender, Morais et al. [⁷] allocated similar numbers of men and women in each group, and it is not a factor that may have influenced the results, while Chaia [¹⁶] has not specified the number of men and women in each group.

Regarding the adverse effects associated with conscious sedation, these are due to the class of drugs used, and hallucinations are the adverse reaction most frequently observed linked to the use of benzodiazepines. However, the biggest disadvantage of conscious sedation is that it can mask the symptoms of a medical emergency [⁸].

In this regard, Corcuera-Flores et al. [⁸] conducted a systematic review which objective was to identify the safest and most effective sedative drugs to ensure the sedation success with minimum complications in Dentistry. In this study, the authors noted that, among the various drugs used, midazolam was the most used drug, and for this medication, the oral route was used in most of the studies, with all studies showing that midazolam can be used safely and effectively to induce mild or moderate sedation. On the other hand, diazepam, always administered orally, was present in three studies, one comparing with chloral hydrate and the other two with midazolam, with no differences between chloral hydrate and diazepam, and with midazolam showing greater effectiveness than diazepam, with no information regarding diazepam safety. However, making a more accurate analysis, it was observed that the three studies involving diazepam investigated behavioral alterations of children, and those that compared them with midazolam, Tyagi et al. [¹⁸] and Tyagi et al. [¹⁹] were, in fact, papers with duplicate publication. In the studies included in this systematic review, there were no accidents or complications for any of the groups.

Specifically regarding midazolam, this drug has already been investigated through a systematic review regarding its action on the extraction of third molars related to anxiolytic efficacy and the incidence of adverse reactions [²⁰]. In this study, the authors found the sedative superiority of midazolam compared to placebo, propofol compared to midazolam, diazepam compared to midazolam and lorazepam (however with diazepam showing more reports of injection pain and venous thrombosis, besides showing active metabolites with long plasma half-life), intravenous multidrug use compared to midazolam alone, and the combinations fentanyl-midazolam and fentanyl-midazolam-metoexital showed better results than midazolam administered without combinations, but with transient respiratory depression occurring in patients in both groups using fentanyl, with no other physiological changes detected. The authors emphasized that midazolam was more likely to be more efficient when considering anxiety relief and safety during third molar extraction surgery, but the review showed limitations regarding the heterogeneity of the studied papers.

Regarding the study immediately mentioned above, it must be emphasized that there were no studies included comparing midazolam and diazepam orally, only intravenously, as clearly intended in this paper, also valuing a greater homogeneity among the included studies as a way to overcome the limitation pointed out by Chen et al. [²⁰]. Another point to be highlighted is that, unlike midazolam, we found no systematic reviews in literature that aimed to investigate the action of diazepam on the extraction of third molars.

In the case of clinical trial, De Moraes et al. [¹³] compared three sedation protocols with diazepam (orally), midazolam (orally) and nitrous oxide in third molar extractions [²⁰]. As results no statistically significant differences were found in HR, SpO₂ and retrograde amnesia, but a statistically significant difference was seen in SBP and DBP 15 minutes after sedation, with lower values in the nitrous oxide group compared to the midazolam and diazepam groups, and also for anxiety levels in which the results showed a statistically significant difference between the mean value obtained at the first visit and that obtained at the end of the surgical procedure for the 3 sedation techniques, however, no difference was found between the techniques. This paper was not included in this systematic review because no lower third molar surgeries were performed, only upper ones.

When taking into account the differences between diazepam and midazolam, the study by De Moraes et al. [¹³] shows differing results from those of Morais et al. [⁷] in the HR and DBP findings, while the study of Chaia [¹⁶] had divergence in SpO₂, SBP and DBP. But, it is important to point out that although the study by De Moraes et al. [¹³] was not included in this systematic review and so was not subject to the risk of bias analysis, this paper was the subject of an assessment made by Brignardello-Petersen [²¹] which pointed out some strengths of limitations, which are the non-description of the appropriate methods for assigning participants to the groups or the provision of a description of baseline characteristics by different age and gender groups, the non-assurance that the 3 groups were balanced regarding prognostic factors, such as anxiety, at the beginning of the trial and no information if surgeons or participants were blind, with uncertainty of performance bias and if results detection were minimized. Therefore, Brignardello-Petersen [²¹] suggested that the evidences of De Moraes et al. [¹³] are of low quality due to the serious risk of bias.

Regarding the drugs efficiency in the outcomes of interest of this systematic review, both diazepam and midazolam showed statistically more advantageous results in different variables and moments. Nevertheless, it is important to point out that even in those results with statistically significant differences between the two drugs, there was no discrepancy between mean values of hemodynamic parameters of patients allocated in the groups and clinically acceptable values for HR, BP and SpO₂ [²²-²⁵] and that there was a risk of bias for most of the evaluated outcomes.

CONCLUSION

Even with midazolam showing better results in blood pressure and peripheral oxygen saturation and diazepam showing more favorable values regarding heart rate, there was no discrepancy between mean values of hemodynamic parameters of patients allocated in the studied groups and clinically acceptable values. However, scientific evidence can be considered fragile due to the small amount of research investigating the subject in question, and also the high risks of bias identified in the studies included in this review.

• How to cite this article
  Silva JA, Souza Junior EF, Andrade MF, Morais HHA. Hemodynamic changes in third molar exodontia using, orally, midazolam versus diazepam: a systematic review of randomized clinical trials. RGO, Rev Gaúch Odontol. 2025;73:e20250001. http://dx.doi.org/10.1590/1981-86372025000120240001

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Edited by

• Assistant editor:
  Luciana Butini Oliveira

Publication Dates

• Publication in this collection
  17 Feb 2025
• Date of issue
  2025

History

• Received
  01 Jan 2024
• Reviewed
  26 Sept 2024
• Accepted
  14 Nov 2024