Effect of IV midazolam premedication before anesthesia on post-recovery outcomes in orthognathic surgery: a double blind randomized clinical trial

Abstract

Objective

Orthognathic surgery is a complex maxillofacial procedure designed to correct skeletal jaw deformities, improving both functional and aesthetic outcomes. Despite its efficacy, the procedure carries risks of postoperative complications, including agitation, shivering, nausea, and intraoperative recall. Midazolam, a short-acting benzodiazepine with anxiolytic and amnestic properties, is frequently used as a premedication. This study aims to evaluate the effect of midazolam on postoperative recovery outcomes in patients undergoing orthognathic surgery.

Methods

In this double-blind randomized clinical trial, 56 healthy patients scheduled for orthognathic surgery were enrolled. The participants were assigned to receive either intravenous midazolam (0.1 mg/kg) or a normal saline placebo at the onset of anesthesia induction. A standardized anesthesia protocol using propofol and remifentanil was maintained for all patients. The measured outcomes included the incidence and severity of postoperative agitation, shivering, nausea, and surgical recall. Also, intraoperative blood loss, recovery duration, and ICU admission rates were evaluated. Statistical analysis was performed using Mann–Whitney U, Independent T-tests, and Chi-square tests as appropriate (P < 0.05).

Results

The two groups were comparable regarding demographic data, ASA classification, and surgical duration (p > 0.05). No significant differences were found in median intraoperative blood loss (350 mL in the midazolam group vs. 300 mL in the control group; p = 0.190) or median recovery duration (60 min for both groups; P = 0.204). Although the midazolam group showed lower frequencies of agitation, shivering, and nausea, these differences did not reach statistical significance (P > 0.05). Surgical recall was reported in 3.6% of the midazolam group compared to 10.7% in the control group (P > 0.05). No adverse pharmacological events or significant respiratory depressions were recorded in either cohort.

Conclusion

Pre-induction administration of IV midazolam did not decrease the incidence of postoperative complications such as agitation, shivering, or nausea.

Introduction

Orthognathic surgery is an elective surgical intervention performed to correct dentofacial skeletal discrepancies (Hosseini-Abrishami et al. 2025). Although it is generally considered safe, postoperative complications remain clinically significant. Among these, postoperative nausea and vomiting (PONV) is common and can substantially exacerbate patient discomfort. Beyond distress, PONV may precipitate serious sequelae, including fluid–electrolyte imbalance, wound dehiscence, aspiration, and delayed recovery (Ghosh et al. 2020; Mao et al. 2026). Emergence agitation (EA) represents another important postoperative complication, with a reported incidence ranging from 0.25% to 90.5%. EA poses a considerable challenge in perioperative management, as it increases the risk of self-extubation, accidental catheter removal, surgical site injury, and postoperative bleeding (Koo et al. 2022).

Enhanced Recovery After Surgery (ERAS) protocols have been developed to attenuate the physiologic stress response to surgery and facilitate accelerated recovery through opioid-sparing, multimodal approaches (Zarour et al. 2024; Amin et al. 2022). Within this framework, anxiolytic premedication has attracted increasing interest as a potential modulator of perioperative stress and recovery quality. Midazolam, a short-acting benzodiazepine, possesses well-established anxiolytic, sedative, and amnestic properties and demonstrates a favorable safety profile when administered as a low, single intravenous (IV) dose prior to anesthetic induction. Evidence indicates that perioperative IV midazolam reduces the incidence of PONV, nausea, vomiting, and antiemetic requirements, with meta-analyses reporting risk ratios between 0.45 and 0.51 (Grant et al. 2016; Ahn et al. 2016). Most investigations evaluating midazolam for EA have focused on pediatric populations receiving sevoflurane anesthesia for procedures such as strabismus or dental surgery. In these settings, low doses (e.g., 0.05 mg/kg administered postoperatively) have been shown to decrease EA incidence, albeit with some delay in recovery (Kim et al. 2011; Kawai et al. 2019). Limited data in adult populations also suggest that perioperative midazolam may reduce EA, with effects comparable to agents such as dexmedetomidine (Kurhekar et al. 2018).

Despite these findings, the role of pre-induction IV midazolam in patients undergoing orthognathic surgery has not been specifically evaluated with respect to PONV, EA, and overall recovery outcomes. Meanwhile, patients undergoing orthognathic surgery may be particularly vulnerable to these complications. Procedure-specific factors-such as intermaxillary fixation and nasal packing-can amplify the risk of airway compromise and aspiration, especially if vomiting or agitation occurs during emergence and early recovery (Au et al. 2024; Mingvoramethakul et al. 2024; Heidari et al. 2004). Consequently, optimizing perioperative strategies to mitigate PONV and EA is of particular relevance in this population. Moreover, contemporary anesthetic regimens frequently incorporate total IV anesthesia (TIVA), particularly with propofol (Yoo et al. 2012). It therefore remains uncertain whether pre-induction midazolam confers additional benefit beyond optimized TIVA techniques and multimodal ERAS strategies. Accordingly, the present study aimed to determine whether IV midazolam administered prior to anesthetic induction reduces the incidence of postoperative agitation, shivering, nausea, and surgical recall in patients undergoing orthognathic surgery. The null hypothesis was that administration of midazolam does not reduce the aforementioned complications compared with no midazolam administration.

Materials and Methods

This study was a prospective, randomized, double-blind, placebo-controlled clinical trial conducted at Shahid Rajaee Hospital, Shiraz, Iran, from January to December 2024. The protocol was approved by the Ethics Committee of Shiraz University of Medical Sciences (IR.SUMS.DENTAL.REC.1402.060) and registered with the Iranian Registry of Clinical Trials (IRCT20250118064423N1).

Sample size calculation

The sample size was determined based on a pilot study, assuming a Type I error (α) of 5%, a power (1 − β) of 80%, and a 37.5% difference in shivering incidence between the treatment (P2​ = 10%) and control (P1​ = 47.5%) groups. Accounting for a 12% potential attrition rate, a minimum of 25 patients per group was required. The final sample was set at 25 patients per group.

Participants

Participants were recruited from patients scheduled for orthognathic surgery (bimaxillary surgery, monomaxillary maxilla or mandible, or genioplasty) under general anesthesia. Eligible participants were healthy individuals aged 18 to 50 years, classified as American Society of Anesthesiologists (ASA) physical status I or II, and who were non-smokers with an expected surgical duration of less than 8 h. Conversely, patients were excluded if they had a history of motion sickness or postoperative nausea and vomiting (PONV), or if they had experienced nausea or vomiting within the 24 h preceding surgery. Additional exclusion criteria included morbid obesity (Body Mass Index (BMI) ≥ 35kg/m2), a history of psychiatric disorders, depression, hepatic cirrhosis, heart failure, or renal failure, and the current use of psychotropic medications, such as benzodiazepines, antidepressants, anticonvulsants, or antipsychotics.

A total of 56 patients met the criteria and were enrolled in the study after providing written informed consent. The CONSORT flow diagram is presented in Fig. 1. A maxillofacial surgery postgraduate student (H.A.) who did not participate in the surgical procedure enrolled the participants and assigned the interventions.

Fig. 1.

CONSORT 2025 flow diagram

Randomization and blinding

Participants were randomly assigned to two equal groups (n = 28 per group) using a block randomization scheme. The randomization sequence was generated via a specialized online platform (www.sealedenvelope.com), utilizing 12 blocks with varying sizes of four and six. The sequence was generated by a researcher who was not involved in surgical procedure (N.M.). To maintain strict allocation concealment, group assignments were placed in sequentially numbered, opaque, and sealed envelopes.

This study employed a double-blind design to minimize bias: an anesthesia technician, who was not involved in data collection or outcome assessment, prepared the syringes according to the allocation list. The medication was then administered by the attending anesthesiologist. Consequently, the patients, the maxillofacial surgeons, and the recovery room nurses remained blinded to the treatment assignments throughout the entire study period.

Study procedure

Following an 8-h preoperative fast, patients were transferred to the operating room where peripheral IV access was established. Standard hemodynamic monitoring was initiated, including continuous electrocardiography (ECG), non-invasive blood pressure (NIBP) measurement, and pulse oximetry (SpO2​). Vital signs were documented at 3–5-min intervals throughout the surgical procedure.

A standardized anesthetic technique was employed for all participants. Anesthesia was induced and maintained using propofol and remifentanil, with dosing protocols kept identical across both study groups.

Participants were allocated into two groups (n = 28 per group). At the onset of anesthesia induction, the intervention group received a premedication dose of IV midazolam (0.1mg/kg) administered via infusion. The control group received an equivalent volume of a placebo (normal saline) delivered through the same infusion method and at the same rate.

To evaluate the safety profile of the intervention, intraoperative vital signs were continuously monitored. Postoperatively, patients were admitted to the maxillofacial surgery ward and closely observed for the first 24 h. Safety assessments included the systematic documentation of any adverse drug reactions, untoward pharmacological events, and the recording of physiological parameters during the immediate post-anesthesia recovery phase.

Primary and secondary outcomes

Data were collected using a structured checklist encompassing demographic characteristics (age, gender, and weight), and the ASA classification. Perioperative variables included the specific surgical procedure (Monomaxillary Maxilla, Monomaxillary Mandible, Bimaxillary, or Genioplasty), the duration of surgery and anesthesia, intraoperative blood loss (mL), and the total length of the recovery room stay (minutes). Furthermore, the following clinical parameters were systematically assessed and recorded by a trained recovery room nurse who was blinded to the group assignments. The primary outcomes were as follows:

• Agitation:Postoperative agitation was monitored from recovery room admission until discharge. Using the Nursing Delirium Screening Scale (Nu-DESC), patients were assessed for agitation, inappropriate behavior, hallucinations, and psychomotor retardation. Each symptom was graded on a 3-point scale: 0 (asymptomatic), 1 (mild), and 2 (severe) (Gaudreau et al. 2005).

• Shivering:Shivering was graded according to the Crossley and Mahajan scale (Crossley and Mahajan 1994) on a 5-point basis: 0 = no shivering; 1 = peripheral vasoconstriction and piloerection without visible muscle activity; 2 = visible tremors limited to a single muscle group; 3 = visible tremors involving more than one muscle group; and 4 = intense, generalized shivering and tremors throughout the body.

• Severity of Nausea:The severity of nausea was assessed using a 4-point ordinal scale: 0 = no nausea, 1 = mild, 2 = moderate, and 3 = severe (Boogaerts et al. 2000).

Secondary outcomes included:

• Surgical Recall (Intraoperative Awareness): To evaluate for accidental awareness during general anesthesia, patients were interviewed postoperatively regarding their memory of any surgical stages. Data were recorded as a binary outcome (Yes/No recall).

• Requirement for Intensive Care: The necessity for a 24-h Intensive Care Unit (ICU) admission was recorded as a binary variable (Yes/No). This was defined as an unplanned admission based on clinical instability-such as respiratory distress, hemodynamic instability, or prolonged recovery-requiring advanced monitoring or ventilatory support beyond standard ward care.

Statistical analysis

Data were analyzed using SPSS software version 22.0 (IBM Corp., Armonk, NY, USA). The normality of the data was assessed using the Shapiro–Wilk test. Between-group comparisons were performed using the Mann–Whitney U test for age, bleeding volume, and recovery duration, due to not normal distribution. The independent samples t-test was employed for anesthesia duration and weight. Categorical variables-including gender distribution, postoperative agitation, shivering, nausea, surgical recovery, and the requirement for 24-h ICU admission-were compared between groups using the Chi-square test. A p-value < 0.05 was considered statistically significant.

Results

A total of 56 patients participated in the study, with a mean age of 24.41 ± 6.42 years. Intraoperative and postoperative vital signs, including blood pressure, respiratory rate, and SpO2​, were monitored continuously. No instances of significant respiratory depression, prolonged hypotension, or oxygen desaturation were observed in either group during the study period. All physiological parameters remained within normal clinical limits, and no adverse pharmacological events related to midazolam administration were recorded.

The demographic and clinical characteristics of the patients in both groups are shown in Table 1. Age, weight, ASA classification, and the duration of anesthesia and surgery were comparable between the two groups (P > 0.05). Additionally, there were no significant differences in gender distribution or the type of surgery between the groups (P > 0.05).

Table 1.

Demographic and clinical information of the participants

Variables		Midazolam group	Control group	P-value
Age (year)*		22 (20-26)	22.5 (19-27.5)	0.876
Gender †	Male	10 (35.7)	6 (21.4)	0.237
	Female	18 (64.3)	22 (78.6)
Weight (kg) ‡		66.14±9.45	61.55±10.03	0.087
BMI*		22.9 (18.5-24.9)	21.3 (18.6-24.7)	0.087
ASA Class†	I	7 (25)	10 (35.7)	0.379
	II	21 (75)	18 (64.3)
Anesthesia duration (hours)‡		5.01±1.71	4.92±2.11	0.863
Surgery duration (hours)*		3.75(2.62-4)	3.75(3-3.87)	0.961
Surgery Type†	Monomax Maxilla	9 (32.1)	7 (25)	0.922
	Bimax	9 (32.1)	11 (39.3)
	Monomax Mandible	7 (25)	7 (25)
	Genioplasty	3 (10.7)	3 (10.7)

BMI: Body Mass Index; ASA: American Society of Anesthesiologists *Values are presented as median (Q₁-Q₃). ^†Values are presented as number (percentage). ^‡Values are presented as mean ± standard deviation

Table 2 presents the comparison of intraoperative bleeding volume and recovery duration between the groups. The median intraoperative bleeding volume was higher in the midazolam group [350 mL (IQR: 262–637.5)] than in the control group [300 mL (IQR: 200–500)]; however, the Mann–Whitney U test indicated that this difference was not statistically significant (P = 0.190). The calculated effect size was r = 0.17, representing a small effect according to Cohen’s criteria. The median duration of the recovery room stay was 60 min for both groups, with no significant difference observed (P = 0.204, r = 0.169).

Table 2.

Comparing the amount of intra-operative bleeding volume and recovery duration between the groups

Variables	Intra-operative bleeding volume (cc)	Recovery duration (minutes)
	Median (Q1-Q3)	Median (Q1-Q3)
Midazolam group	350.00 (262-637.5)	60.00 (60-82.5)
Control group	300.00 (200-500)	60.00 (45-60)
P value	0.190	0.204
r	0.175	0.169

Table 3 summarizes the incidence and severity of postoperative agitation, shivering, nausea, surgical recall, and the requirement for 24-h ICU admission. According to the Chi-square test, none of the differences between the groups reached statistical significance (P > 0.05).

Table 3.

Comparing the incidence of postoperative agitation, shivering, nausea, surgical recall, and ICU stay for 24 hours between the studied groups

Outcome	Classification	Midazolam group	Control group	P-value
		N (%)	N (%)
Agitation	0	12 (42.9)	10 (35.7)	0.317
	1	11 (39.3)	16 (57.1)
	2	5 (17.9)	2 (7.1)
Shivering	0	10 (35.7)	8 (28.6)	0.149
	1	4 (14.3)	11 (39.3)
	2	0 (0.0)	0 (0.0)
	3	12 (42.9)	6 (21.4)
	4	2 (7.1)	3 (10.7)
Nausea	0	12 (42.9)	10 (35.7)	0.652
	1	7 (25)	12 (42.9)
	2	8 (28.6)	5 (17.9)
	3	1 (3.6)	1 (3.6)
Surgical recall	Yes	1 (3.6)	3 (10.7)	0.611
	No	27 (96.4)	25 (89.3)
ICU stay for 24 hours	Yes	3 (10.7)	5 (17.9)	0.705
	No	25 (89.3)	23 (82.1)

Discussion

The present study examined the efficacy of 0.1 mg/kg of IV midazolam on postoperative recovery outcomes. The findings indicated a high rate of agitation: 57.1% in the midazolam group and 64.2% in the control group. Although midazolam showed a downward trend, the difference was not statistically significant. This high incidence aligns with literature suggesting that orthognathic and nasal surgeries are independent risk factors for emergence agitation due to a "sense of suffocation" experienced upon awakening with a blocked airway or intermaxillary fixation (Kim et al. 2015; Posch et al. 2025). In adults, major risk factors for emergence agitation include younger age and the presence of a tracheal tube (Kim et al. 2015). While midazolam's anxiolytic effect at the GABAA​ receptor can allay preoperative distress (Philip et al. 2025), it may not adequately attenuate the intense physiological stress responses-such as sympathetic and endocrine activation-associated with airway manipulation during laryngoscopy and intubation, or the intense physical stimulus of a restricted airway during emergence (Rathod et al. 2024).

Shivering occurred in 64.3% of the midazolam group and 71.4% of the control group. The lack of significance suggests that, at a dose of 0.1 mg/kg, midazolam may not provide reliable protection against the redistribution of core heat common in lengthy procedures (Lopez 2018).

Postoperative nausea was reported in 57.1% of the midazolam group versus 64.3% of the control group, with no significant difference between the two. Several meta-analyses suggest that IV midazolam can reduce postoperative nausea and vomiting (Grant et al. 2016; Majumdar et al. 2019). Orthognathic surgery is associated with a high incidence of postoperative nausea (40–73%), often driven by the ingestion of blood during the intraoperative period; this acts as a potent gastric irritant and can precipitate nausea regardless of anxiolytic premedication (Ghosh et al. 2020; Phillips et al. 2015). However, no previous RCTs have directly compared IV midazolam against a placebo in this specific population. One retrospective study reported postoperative nausea at 31% with total intravenous anesthesia (TIVA) and the optional administration of midazolam, compared to 68% with volatile anesthesia (e.g., sevoflurane). This suggests an adjunctive benefit but fails to isolate midazolam as the primary factor (Aijima et al. 2024).

The trial observed a trend toward reduced surgical recall in the midazolam group (3.6%) compared to the control group (10.7%). Notably, the recall observed in the trial may be attributable to individual variation or the misinterpretation of emergence sensations as intraoperative awareness (Hari Keerthy et al. 2015). Midazolam is known for its potent anterograde amnesic properties, interfering with memory consolidation in the hippocampus and prefrontal cortex (Cascella 2015).

The assessment of intraoperative bleeding was performed to monitor perioperative safety and to ensure that pre-induction midazolam did not adversely affect intraoperative hemodynamics. The study found no significant difference in median blood loss (350 mL for midazolam vs. 300 mL for placebo). This confirms that while midazolam can reduce anxiety-induced sympathetic surges, it does not directly influence surgical hemostasis (Jerjes et al. 2005; Ravitskiy et al. 2011).

The recovery duration was similar between groups, with a median time of approximately one hour, suggesting that IV midazolam does not negatively impact early postoperative discharge. This is consistent with the study by Garcia et al., which found no significant differences in discharge time or postoperative adverse events among children receiving midazolam premedication for adenotonsillectomy compared to those who did not (Garcia et al. 2021).

The lack of a significant difference between the groups in the current study might be related to the use of propofol in both cohorts. Propofol is known to possess intrinsic antiemetic properties that significantly reduce the risk of early postoperative nausea (Yoo et al. 2012). It is possible that the antiemetic effect of propofol was potent enough across both groups to mask any potential minor benefit provided by a single 0.1 mg/kg dose of midazolam. Furthermore, research indicates that the antiemetic efficacy of midazolam may be influenced by the timing of its administration (Safavi and Honarmand 2009). Some studies suggest that midazolam is more effective at preventing postoperative nausea when administered toward the end of surgery rather than as a pre-induction premedication (Lim et al. 2023). Some studies suggest that midazolam is more effective at preventing postoperative nausea when administered toward the end of surgery rather than as a pre-induction premedication. At a dose of 0.1 mg/kg, midazolam may also be insufficient to counteract the intense emetic stimuli of orthognathic surgery without the support of a broader multimodal antiemetic protocol involving dexamethasone or 5 − HT3 ​ receptor antagonists (Yoo et al. 2012).

The findings of this study, alongside other investigations, suggest that midazolam might not be consistently suitable as routine prophylaxis for preventing recovery-related complications such as agitation, shivering, or nausea. It may be more appropriate for clinicians to consider its administration based on individual clinical assessment and the specific need for preoperative anxiolysis or amnesia (Kowark et al. 2024). Furthermore, given the frequent occurrence of agitation and nausea in this population, exploring multimodal ERAS protocols could be beneficial. These strategies may involve the use of scheduled non-opioid analgesics and tiered antiemetic prophylaxis to improve the recovery experience (Birbe 2025; Gao et al. 2024).

Several limitations of this study warrant acknowledgment. First, while randomization successfully balanced baseline characteristics-such as surgery type and anesthesia duration-the sample size was not powered to support multivariable adjusted modeling. Future large-scale trials should utilize logistic regression to further explore the influence of these perioperative factors on intraoperative bleeding and recovery outcomes. Second, the single-center design and relatively small sample size may have limited the statistical power to detect subtle, clinically relevant differences between groups. Finally, the scarcity of literature specifically investigating IV midazolam in orthognathic surgery restricted our ability to fully contextualize these findings within the broader surgical field.

Several limitations of this study warrant acknowledgment. First, although randomization balanced baseline characteristics-including surgery type and anesthesia duration-the inclusion of both monomaxillary and bimaxillary procedures may have introduced variability in operative complexity and physiological stress, potentially confounding outcomes such as PONV. While this inclusive approach was necessary to achieve the target sample size within the study period, it may have limited the internal validity. Future large-scale trials should consider restricting cohorts to specific procedure types (e.g., only bimaxillary surgery) or utilizing multivariable adjusted modeling to better isolate the effects of midazolam. Second, the single-center design and relatively small sample size may have limited the statistical power to detect subtle, clinically relevant differences between groups. Finally, the scarcity of literature specifically investigating IV midazolam in orthognathic surgery restricted our ability to fully contextualize these findings within the broader surgical field.

Conclusion

The present study demonstrated that 0.1 mg/kg IV midazolam did not adversely affect early postoperative discharge or surgical hemostasis. While the study observed minor downward trends in the frequency of recovery-related complications, midazolam failed to significantly reduce the incidence of postoperative agitation, shivering, or nausea. These findings suggest that a single pre-induction dose may be insufficient to counteract the intense physiological stress and specific triggers associated with complex maxillofacial procedures. However, the observed trend toward lower surgical recall (3.6% vs. 10.7%) might suggest the drug's value as an amnestic agent. Ultimately, since midazolam does not consistently prevent recovery complications in this population, anesthesiologists should prescribe it based on individual clinical assessments of the need for anxiolysis or amnesia.

Author contribution

Conceptualization: Shahsavari-Pour S., Eftekharian H.; Methodology: Shahsavari-Pour S.; Formal analysis: Askari H.; Investigation: Modaberi A., Askari H., and Morshedian N.; Writing- original draft preparation: Askari H., Morshedian N..; Writing – review and editing: Shahsavari-Pour S., Eftekharian H., and Modaberi A.; Supervision and project administeration: Shahsavari-Pour S., Eftekharian H.; Funding acquisition: Shahsavari-Pour S. All authors read and approved the final manuscript.

Funding

This manuscript has been extracted from a thesis submitted to the Shiraz Medical Dental School as a requirement for graduation in the Oral and Maxillofacial Surgery residency program by Dr. Ali Modaberi (thesis number: 3130). The financial support was provided by the Vice-Chancellery of Research, Shiraz University of Medical Sciences.

Vice-Chancellor for Research,Shiraz University of Medical Sciences,3130,Sheila Shahsavari-Pour

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author onreasonable request.

Declarations

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical consideration

The study protocol followed the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by the Ethics Committee of Shiraz University of Medical Sciences, Dental School (IR.SUMS.DENTAL.REC.1402.060). Written informed consent was taken from all the patients. This study was registered in the Iranian Registry of Clinical Trials (IRCT20250118064423N1).

Data sharing statement

The datasets will be available from the corresponding author upon reasonable request.