Background

Women awaiting needle-guided breast biopsy procedures may experience high anxiety levels. A randomized, double-blind, placebo-controlled study was designed to evaluate the ability of midazolam and diazepam (in a lipid emulsion [Dizac]) to improve patient comfort during needle localization and breast biopsy procedures.

Methods

Ninety women received two consecutive doses of a study medication, one before the mammographic needle localization and a second before entering the operating room. Patients were assigned randomly to receive saline, 2.0 ml intravenously, at the two time points; midazolam, 1.0 mg intravenously and 2.0 mg intravenously; or diazepam emulsion, 2.0 mg intravenously and 5.0 mg intravenously, respectively. Patients assessed their anxiety levels before the needle localization, before entering the operating room, and on arrival in the operating room. Patients completed a questionnaire evaluating their perioperative experience at the time of discharge.

Results

Patient satisfaction during needle localization was significantly improved in both benzodiazepine treatment groups (vs. saline). The incidence of moderate-to-severe discomfort during needle localization was lower in the midazolam (20%) and diazepam emulsion (6%) groups compared with the saline group (70%) (P<0.05). The preoperative visual analogue scale anxiety scores were similar in all three groups. In the operating room, however, anxiety scores were 55% and 68% lower after midazolam (21+/-19) and diazepam emulsion (15+/-14) compared with saline (46+/-28). Finally, there was no difference in the time to achieve home-readiness or actual discharge time among the three groups.

Conclusions

Premedication with midazolam or diazepam emulsion improved patients' comfort during needle localization procedures and significantly reduced intraoperative anxiety levels before breast biopsy procedures without prolonging discharge times. Use of diazepam emulsion may be an effective alternative to midazolam in this population.

THE widespread use of screening mammography to detect nonpalpable breast lesions at an early stage has resulted in an increasing number of outpatients being scheduled for preoperative mammographic needle localization procedures before excisional breast biopsy. [1]Although anxiety is a common response to impending surgery, women undergoing breast biopsy procedures have additional concerns regarding the possibility of disfigurement and incurable disease. Therefore, it is not surprising that women awaiting breast biopsy procedures experience anxiety levels exceeding those of patients undergoing other types of elective surgery (e.g., cholecystectomy). [2-4]Although small doses of benzodiazepines have been used in ambulatory anesthesia to provide anxiolysis and sedation preoperatively without delaying recovery, [5]sedative-anxiolytic medications are not normally administered before needle localization procedures because of concerns regarding the risk:benefit of using these drugs in this setting. Although the intravenous administration of small doses of benzodiazepines has not been found to produce clinically important respiratory depression, [6]the benefits of this practice have not been demonstrated to date.

Midazolam is the most commonly used intravenous sedative premedicant because it is associated with a low incidence of venous irritation and perceived shorter duration of action compared with diazepam. [7]The newly available emulsion formulation of diazepam (Dizac; Baxter Pharmaceutical Products, Inc., Liberty Corner, NJ), however, has been reported to have an incidence of thrombophlebitis similar to that of midazolam and is less costly. [8]Despite its longer elimination half-life and active metabolites, early clinical recovery from diazepam has been reported to be similar or more rapid than midazolam. [9-11]

The objective of this study was to assess the safety and efficacy of administering small doses of midazolam or diazepam emulsion before needle localization and breast biopsy procedures. In addition to evaluating the patient's level of comfort and anxiety, the recovery profile and side effects of these two benzodiazepines were compared using a randomized, double-blind, placebo-controlled protocol.

## Methods

Before initiating this study, a survey was conducted to determine the level of discomfort associated with the needle localization and breast biopsy procedures (Appendix 1). Although most of the women we questioned in this pilot study were comfortable and highly satisfied with their intraoperative and postoperative anesthetic and surgical care, 54% complained of moderate to severe discomfort during the needle localization procedure. Several patients specifically mentioned that they would have preferred to receive sedative medication before the needle localization procedure. Therefore, after institutional review board approval, 90 consenting women, of American Society of Anesthesiologist physical status I-III, aged 18-79 yr who were scheduled for needle localization and breast biopsy procedures were invited to participate in this prospective study. Exclusion criteria included pregnancy, breastfeeding, long-term use of benzodiazepines, or allergic reactions to any of the study medications.

Patients were randomized to one of three premedication groups and received two separate doses of each study medication. The first dose was given 5 min before the patient was transferred from the Day Surgery Unit (DSU) to the radiology department, and the second dose was administered 5-10 min before entering the operating room (OR). The study medication was prepared by an anesthesiologist who was not involved in the data collection or patient assessments. The patients and investigators were unaware of which study medication was being administered because the study drug was prepared in a 3-ml syringe (which was wrapped with opaque tape), and the blinded observer (JMV) was not present during the injection of the study drug. Patients in the placebo group received saline, 2.0 ml intravenously, before the needle localization procedure and before entering the OR. Patients in the midazolam group received 1.0 mg and 2.0 mg intravenously, and the diazepam emulsion group was given 2.0 mg and 5.0 mg intravenously, respectively, all in a volume of 2 ml. All patients assessed their anxiety and sedation levels using a 100-mm visual analogue scale (VAS), with 0 = none and 100 = extreme, before the needle localization procedure, before entering the OR, and on arrival in the OR.

After recording the baseline VAS scores, patients received the first dose of study medication. The blinded observer noted the presence of any discomfort at the intravenous site after administration of the study drug. The patients were observed by the investigator for evidence of respiratory depression (i.e., respiratory rate < 8) or excessive sedation (i.e., OAA/S > 2) using the observer's assessment of alertness and sedation (OAA/S) scoring system, with 1 = awake to 5 = unarousable. Patients were transported in a wheelchair from the DSU to the radiology department accompanied by the blinded observer. Patients were required to walk unassisted to a special chair in the suite and remain seated and cooperative for the duration of the localization procedure. The patient's breast was placed between the compression paddles and remained compressed throughout the 15- to 20-min procedure. After administration of ethyl chloride spray, buffered lidocaine 1% was injected subdermally and subcutaneously with a 25-gauge needle, and the 22-gauge wire localization needle was subsequently inserted through the anesthetized area of breast tissue. Once the needle localization was complete, patients were returned to the DSU to await the breast biopsy procedure.

A second dose of the same study medication was administered 5-10 min before entering the OR, and the presence of pain on injection and the time between the two doses of study medication were noted. During the breast biopsy procedure, patients were monitored with a pulse oximeter, an electrocardiogram, and a noninvasive blood pressure cuff, and supplemental oxygen was administered through nasal prongs with a carbon dioxide monitoring port. In all three study groups, a variable-rate infusion of propofol (25-150 [micro sign]g [middle dot] kg-1[middle dot] min-1after an initial infusion rate of 50 [micro sign]g [middle dot] kg-1[middle dot] min-1) was used to provide intraoperative sedation, and fentanyl 25 [micro sign]g was administered intravenously to minimize pain during local anesthetic infiltration. After achieving a level of sedation at which the patient was resting comfortably with his or her eyes closed (i.e., OAA/S = 4), the surgeon infiltrated the incision site with a local anesthetic agent. Supplemental bolus doses of fentanyl 25 [micro sign]g were administered intravenously to treat pain not responding to additional local anesthetic infiltration. The infusion of propofol was subsequently titrated to maintain a stable level of sedation (OAA/S of 3 = sleeping but arousable with minimal stimulation).

The duration of surgery and anesthesia and the total amount of propofol and fentanyl administered were recorded. Once the incision was closed, the propofol infusion was discontinued, and patients returned directly to the Phase II (step-down) area in the DSU on a stretcher and were subsequently transferred to a reclining chair. Before discharge, patients completed a questionnaire (Appendix 1) evaluating their perioperative experience, and the times to ambulation and home-readiness were recorded. Patients were contacted by telephone 2 weeks postoperatively by one of the investigators to inquire about any signs of venous thrombophlebitis (i.e., pain, redness, swelling, or tenderness).

### Statistical Analysis

A power analysis was performed to determine the sample size required to detect a 50% decrease in anxiety levels after receiving the study drug. A baseline VAS anxiety level of 35 with a type I error ([small alpha, Greek]) of 0.05 and a type II error ([small beta, Greek]) of 0.2 were used in these calculations. [4]Continuous variables were compared using one-way analysis of variance and are presented as mean +/− SD. When a significant difference was noted using the analysis of variance, a Newman-Keuls test was performed for post hoc intergroup comparisons. Categorical variables were analyzed using chi-square and Kruskal-Wallis tests with data expressed as median values or percentages. Probability values < 0.05 were considered statistically significant.

## Results

### Demographic Profiles and Anxiety Scores

Ninety women were enrolled in the study, and only one patient did not complete the postoperative patient satisfaction questionnaire. The three study groups were similar in age, weight, height, American Society of Anesthesiologist physical status, and duration of surgery (Table 1). There was no difference in the baseline VAS anxiety scores among groups before the needle localization procedure (Figure 1). On arrival in the OR, however, the VAS anxiety scores for the midazolam and diazepam emulsion groups were significantly lower (55% and 68%, respectively) compared with the control group (21 +/− 19 and 15 +/− 14 mm vs. 46 +/− 28 mm; P < 0.01). The anxiety scores for patients in the control group increased to higher than baseline values on entering the OR and were significantly higher than in the DSU (46 +/− 28 mm vs. 29 +/− 27 mm; P < 0.05). Although the intraoperative fentanyl requirements were similar in all three groups, the mean infusion rate of propofol was significantly lower in both the midazolam and diazepam emulsion groups (Table 1).

Table 1. Patient Characteristics and Premedication and Surgery Times for the Three Treatment Groups

Figure 1. Visual analog scale (VAS) scores for anxiety (A) and sedation (B) before the needle localization in the Day Surgery Unit (DSU), before entering the operating room (OR), and at arrival in the OR. Grey bars represent the saline group; white bars represent the midazolam group; and the solid bars represent the diazepam emulsion group. Values are expressed as mean +/− SEM. *Significantly different from the saline group (P < 0.01).

Figure 1. Visual analog scale (VAS) scores for anxiety (A) and sedation (B) before the needle localization in the Day Surgery Unit (DSU), before entering the operating room (OR), and at arrival in the OR. Grey bars represent the saline group; white bars represent the midazolam group; and the solid bars represent the diazepam emulsion group. Values are expressed as mean +/− SEM. *Significantly different from the saline group (P < 0.01).

### Patient Satisfaction

The questionnaire completed before discharge revealed that most patients were highly satisfied with the anesthetic technique and were comfortable intraoperatively during the local anesthetic infiltration and surgical dissection (Table 2). Only one patient was dissatisfied with her level of comfort during the surgical procedure and that patient had received saline for premedication. One other patient in the saline group required induction of general anesthesia because of persistent anxiety and discomfort despite infiltration of a large volume of local anesthetic solution. With the diazepam emulsion premedication, more than 90% of patients considered the premedication before the needle localization procedure beneficial, and 97% would choose to have the same premedication again for a similar procedure (Table 2). Patient satisfaction was also high in patients receiving midazolam, with 74% considering the premedication helpful and 83% choosing the same premedication again. In contrast, only 38% of the patients in the saline group found the premedication helpful, and only 55% indicated that they would choose a similar premedication in the future. The patient's perception of the severity of discomfort during the needle localization procedure was significantly reduced by benzodiazepine premedication (Figure 2). Only 20% of the patients receiving midazolam and 6% of the patients receiving the diazepam emulsion experienced moderate-to-severe discomfort during the needle localization procedure compared with 70% of patients in the control group.

Table 2. Responses to the Patient Satisfaction Questionnaire in the Three Treatment Groups

Figure 2. Level of discomfort during the needle localization procedure. Grey bars represent the saline group; white bars represent the midazolam group; and the solid bars represent the diazepam emulsion group. Values are expressed as the percentage of the total number of patients in each group. *Significantly different from the saline group (P < 0.05).

Figure 2. Level of discomfort during the needle localization procedure. Grey bars represent the saline group; white bars represent the midazolam group; and the solid bars represent the diazepam emulsion group. Values are expressed as the percentage of the total number of patients in each group. *Significantly different from the saline group (P < 0.05).

### Patient Outcome

There was no clinical evidence of excessive sedation or respiratory depression during the transfer of patients from the DSU to the radiology suite. None of the patients had an OAA/S score > 2, and no patient had a respiratory rate < 8 breaths/min at any time during the needle localization or transit periods. The most serious adverse event was the occurrence of vasovagal episodes in the mammography suite. Although no patient in either of the benzodiazepine groups experienced vasovagal symptoms during the needle localization procedure, two patients in the control group (7%) had vasovagal reactions during the needle localization procedure. There were no significant differences in the times to achieve home-readiness and actual discharge among the three groups (saline, 69 +/− 23 and 88 +/− 32 min; midazolam, 71 +/− 26 and 85 +/− 30 min; and diazepam emulsion, 61 +/− 18 and 76 +/− 26 min, respectively).

All patients were transferred directly to the phase II (step-down) unit after their surgical procedure. One patient in the midazolam group was considered excessively drowsy in the DSU. This patient received flumazenil, 0.5 mg intravenously, and promptly awoke with no evidence of resedation during the early recovery or post-discharge periods. Injection of the study drug caused pain at the intravenous site in only one patient in the diazepam emulsion group (Table 3). When contacted 2 weeks after their surgical procedure, no patients complained of pain, tenderness, or redness at the intravenous injection site.

Table 3. Recovery Times, Adverse Events, and Premedication Drug Costs for the Three Treatment Groups

## Discussion

The baseline anxiety scores before the needle localization procedure confirmed that these women have high preoperative anxiety levels. It is reasonable to assume that the administration of anxiolytic medication before undergoing these procedures would reduce acute anxiety in this patient population. Although benzodiazepine premedication has been used to decrease anxiety before other ambulatory surgical procedures, [5]there has been a reluctance to administer sedative-anxiolytic drugs to outpatients undergoing preoperative radiologic procedures because of concerns regarding the safety of transferring premedicated patients to a remote location. The advantage of using intravenous benzodiazepines is that the effectiveness of the premedication can be assessed before transferring the patient to the mammography suite. More important, low doses of benzodiazepines do not appear to affect the ventilatory response to carbon dioxide and do not cause clinically significant respiratory depression. [6]

A study of breast-imaging procedures by radiologists found vasovagal reactions to be the most commonly observed complication. [12]The occurrence of this complication was the impetus that prompted the surgeons to request our assistance in the management of this rapidly growing patient population. The first step was to establish a policy for inserting an intravenous catheter in the DSU before transferring patients to the radiology department. This practice also allowed for the administration of intravenous fluids to replace fluid deficits, allowed for emergency administration of drugs, and facilitated intravenous administration of sedative premedication. In our study, two of the patients receiving saline for premedication experienced transient vasovagal reactions during the needle localization procedure compared with none in either of the benzodiazepine premedication groups (P > 0.05). Although these two patients did not require pharmacologic interventions to treat their vasovagal reactions, it is possible that patients suffering more prolonged or severe episodes might benefit from administration of an anticholinergic drug. These findings suggest not only that patients are more comfortable during the needle localization procedure when they received sedative premedication but also that patient safety may be enhanced.

Although many radiologists believe that the needle localization procedure is not painful and some have even suggested that the routine use of local anesthesia is unnecessary, [13]results of our preliminary survey demonstrated that most patients found this procedure to be associated with moderate-to-severe discomfort, and most felt it was the “worst part of the day of surgery.” In an effort to make the procedures less painful for the patients, all needle localizations were performed using ethyl chloride spray, [14]and buffered lidocaine was injected through a 25-gauge needle. [15]This technique is simpler and safer than the use of interpleural bupivacaine administered through an epidural catheter placed in the interpleural space, a procedure previously reported to provide effective analgesia for needle localization and breast biopsy procedures. [16]In our study, the patient's perception of the severity of discomfort during the needle localization procedure was significantly reduced by intravenous premedication with a benzodiazepine. Although benzodiazepines do not have analgesic properties, the reduction in discomfort during the needle localization procedure was presumably related to the well-known sedative and anxiolytic properties of the benzodiazepine compounds.

Dizac is a lipid-emulsion formulation of diazepam. It is associated with a markedly reduced incidence of pain on injection and thrombophlebitis compared with diazepam dissolved in propylene glycol. [17]Most comparative studies have reported that Dizac has a similar incidence of venous irritation to midazolam (Versed; Roche, Nutley, NJ). [8,18]Although diazepam has a longer elimination half-life (21-37 h) and active metabolites, the clinical recovery after small intravenous doses of these two benzodiazepines is similar. [10]In a study involving outpatients undergoing cataract extraction procedures, the investigators reported that early recovery was actually slower in patients receiving midazolam than with the diazepam emulsion. [19]In the current study, we did not specifically evaluate cognitive and psychomotor performance, and therefore, more subtle differences between the benzodiazepine groups during the recovery period may have gone undetected. The direct costs of the preanesthetic doses of the study drugs were $1.87 for the diazepam emulsion (Dizac), 7 mg intravenously, and$7.44 for midazolam (Versed), 3 mg intravenously. As there were no differences in patient satisfaction, anxiety scores, or discharge times between the two groups, the diazepam emulsion may be a cost-effective alternative to midazolam in this outpatient population. We did not perform a formal cost analysis, however, and it is possible that less obvious differences between the drugs might offset this difference in acquisition costs.

The decision to use standard clinical doses of the study drugs rather than calculating dosages based on actual body weight may be criticized. Although the population consisted entirely of adult women aged 21-79 yr, the body habitus of this female population does vary widely. If the overweight patients were given doses on a milligram-per-kilogram basis, it is possible that a large proportion of those patients would have become excessively sedated. The dosages selected were based on the equivalent dosage ratios and clinically effective dosages of midazolam and diazepam emulsion previously reported in the anesthesia literature. [11,19]The 1.0:2.5 dosage ratio of midazolam:diazepam was also chosen in part for ease of administration.

It is noteworthy that there were no significant differences among the three groups in the VAS anxiety scores before entering the OR; however, the similar VAS anxiety scores before entering the OR may reflect the long time interval (2.5-3.0 h) between the two doses of the study medications. There would be little residual effect from the first dose of study medication after this prolonged period of time, and patients' anxiety would be expected to increase in anticipation of the impending surgical procedure. Patients receiving benzodiazepine premedication were more comfortable during the needle localization and had improved patient satisfaction as determined by the postoperative patient questionnaire.

One of the major concerns raised by the nursing and radiology staff related to the possible need for additional monitoring or supplemental oxygen if the patients received intravenous sedative medication before the needle localization procedure. A pilot study was performed using similar dosages of the benzodiazepines, and no changes were found in either oxygen saturation values or respiratory rate 5-15 min after intravenous administration of midazolam (1-2 mg) in a similar patient population receiving no supplemental oxygen (data unreported). In addition, oxygen saturation values on arrival in the radiology suite were unchanged from baseline values. The situation is analogous to the concerns initially expressed when patient-controlled analgesia was introduced in the early 1980s. [20]

Patients undergoing needle localization and breast biopsy procedures have high anxiety levels. Premedication with small doses of an intravenously administered benzodiazepine can significantly improve patient satisfaction with the procedure by decreasing their perceived levels of discomfort during the needle localization and their anxiety levels on entering the OR. As expected, the benzodiazepine premedication did not prolong discharge times. Most important, the routine use of sedative premedication may improve patient safety by reducing vasovagal episodes in the mammography suite.

## Appendix 1

### Patient Discharge Questionnaire

In an effort to improve the care of patients undergoing breast biopsy procedures, we would appreciate your responses to the following questions. Please mark all boxes which apply (X).

1. The preoperative registration process was:

() Smooth and efficient

() Acceptable but rather lengthy

() Disorganized and inefficient

2. The preoperative preparation in the Day Surgery Unit was:

() Better than expected

() Acceptable

() Below expectations

3. Did you feel that the sedative mediation you received before the needle localization procedure was beneficial?

() Yes

() No

() Uncertain

4. Please indicate the degree of discomfort you experienced during the needle localization procedure in the x-ray department:

() None

() Mild

() Moderate

() Severe

5. What was the cause of the discomfort?

() Position

() Needle

6. How satisfied are you with the drugs that were used in the operating room to make you feel comfortable while the surgeon was injecting the numbing medication?

() Extremely satisfied

() Satisfied

() Somewhat satisfied

() Neither satisfied nor dissatisfied (ambivalent)

() Somewhat dissatisfied

() Dissatisfied

() Extremely dissatisfied

7. Overall, how satisfied are you with the drugs that were used to make you comfortable during the actual operation itself?

() Extremely satisfied

() Satisfied

() Somewhat satisfied

() Neither satisfied nor dissatisfied (ambivalent)

() Somewhat dissatisfied

() Dissatisfied

() Extremely dissatisfied

8. What is the main reason for your dissatisfaction with the drugs used to make you comfortable during your operation (check all that apply)?

() Drugs did not provide adequate comfort

() Didn't like the way the drugs made you feel

() The medication did not provide adequate relief of your anxiety in the operating room

() The medication did not provide adequate sedation (sleepiness) during the operation

() The medication did not provide adequate pain relief

9. If you were to have the same operation performed again, would you want to receive the same medications before the operation?

() Yes, would prefer the same drugs

() Not sure, may or may not prefer the same drugs

() No, would ask for something different

10. If you were to have the same operation performed again, would you want to receive the same medications during the operation?

() Yes, would prefer the same drugs

() Not sure, may or may not prefer the same drugs

() No, would ask for something different

11. What was the worst aspect of the day of surgery?

() Waiting for the procedure

() Needle localization procedure

() Operating room activities

a. before surgery

b. during surgery

c. after surgery

() Postoperative recovery period

a. pain

b. nausea

c. drowsiness/tiredness

() None of the above

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