Aim of review: Reconsideration of Benzodiazepines (BZDs) after many years’ widespread use, for development of recent new similar drugs and consideration about increased delirium with BZDs.
Methods: A comprehensive search in OVID MEDLINE, EMBASE and PubMed were performed from inception to Jan 31, 2016, the studies which involved pharmacological characteristics of BZDs and comparison among BZDs, placebo and some similar new drugs used for sedation and antianxiety in the perioperative period were included.
Recent findings: Routine use of BZDs as a sedative and antianxiety premedication is lack of benefits. BZDs did not improve the self-reported patient experience the day after surgery, but was associated with a lower rate of early cognitive recovery. Large numbers of using of other sedation drugs such as Propofol or Dexmedetomidine are replacing the using of BZDs for postoperative sedation. BZDs are important anesthesia-related predictors of postoperative delirium. Compared with those new drugs in sedation and anti-anxiety, BZDs has gradually lost its market.
Conclusion: As the developing of anesthesia monitoring technique and more beneficial pharmaceutical, the perioperative application of BZDs should be used with caution. (Funded by the National Natural Science Foundation of China.)
Citation: Yanzi Zhang, Yidan Tang, Jing Yang, Chunyu Gong, Zhuo Li. Perioperative Use of Benzodiazepines: A Reconsideration of Risks and Benefits. J Anesth Perioper Med 2018;5:34-40.
This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Benzodiazepines (BZDs), the benzodiazepine receptor agonists, has been widely used in the perioperative period for many years for their hypnotic, sedative, amnesia and anxiolytic effects. Dr. Leo Sternbach discovered BZDs after many years’ hard work (1-3). Firstly, in 1960, chlordiazepoxide was approved for internal medical use as the debut of BZDs. In the following years, more than one thousand sorts of BZDs had been synthesized (4). Of which, diazepam was firstly described for use as an intravascular anesthetic induction in 1963 (5). It was followed by the introduction of midazolam in 1983, which was also an intravascular BZDs and have a more rapid onset than other BZDs (6). Up to now, BZDs has been broadly used in the perioperative period to achieve two aims: one is to reduce anxiety (anxiolytic) and sedative-hypnotics for sleep, another is adjuncts to anesthesia to induce relaxation and amnesia (procedural memory loss). And midazolam (>75%), diazepam (7%) and lorazepam (2%) are being to the three most commonly used BZDs in the perioperative setting in the USA (7, 8).
Recently, however, as developing of anesthesia monitor technique and anesthetic drugs such as α2-adrenergic receptor agonists (Dexmedetomidine, for example) and Propofol, more and more pharmaceutical are further beneficial or replacing the role of BZDs in perioperative use. In this paper, we aim to revisit the BZDs by introducing them from aspects of pharmacological characteristics, perioperative uses and side effect, especially relationship with postoperative delirium.
Figure 1 showed the core structure and side chains of BZDs. "R" labels denote the common locations of side chains, which give different BZDs their unique properties (Figure 2). For example, Midazolam is approximately 3 to 6 times and lorazepam 5 to 10 times, as potent as diazepam (9). Midazolam and diazepam have a more rapid onset (usually within 30 to 60 seconds) of action than lorazepam (60 to 120 seconds) (9).
All BZDs have hypnotic, sedative, anxiolytic, amnesic, anticonvulsant, and centrally produced muscle-relaxing properties. The mechanism of action of BZDs is reasonably well understood (10-12). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the nervous system. The GABAA receptor is a chloride channel formed by 5 subunits. BZDs bind to sites distinct from GABA itself (allosteric modulation), increasing the receptor’s affinity for GABA, therefore enhance GABA action (13). The α-subunit of the GABAA receptor, of which there are six subtypes, is the predominant determinant of BZDS affinity and function (Table 1).
As the first BZDs antagonist antidote, Flumazenil (Anexate, Romazicon) can be given intravenously in the emergency setting to reverse the effects of a BZDs overdose (14). The structure of flumazenil is similar to midazolam and other classic BZDs except for the absence of the phenyl group, which is replaced by a carbonyl group (Figure 2). Therefore, Flumazenil can competitively bind on the BZDs site of GABAA receptor to blocks the central effect of BZDs.
Characterization of Physicochemical and Pharmacokinetics
Physicochemical characterization of BZDs (Table 2) is closely association with its pharmacokinetics (Table 3).
The more rapid redistribution of midazolam compared with diazepam and lorazepam (presumably because of the lower lipid solubility of diazepam and lorazepam) accounts for the more rapid onset and the shorter duration of its actions (16). The three BZDs are classified as short-lasting (midazolam), intermediate-lasting (lorazepam), and long-lasting (diazepam), according to their metabolism and plasma clearance (Table 3). And after long-term repeated administration, or after prolonged continuous infusion, blood concentration of midazolam decrease more rapidly than those of the other drugs because of greater hepatic clearance.
Biotransformation of the BZDs occurs in the liver. All of the three BZDs forms active metabolites, which add to and prolong the drug’s effects (17). It is excreted largely by the kidneys and can cause profound sedation in patients with renal impairment (18). In addition, because pH-dependent solubility of midazolam, it is water soluble as formulated in a buffered acidic medium (pH 3.5), which have its advantage over diazepam and lorazepam in clinical use.
The BZDs are usually used as premedication, intraoperation and postoperative adjuvant to reduce anxiety (anxiolytic) and sedative-hypnotics for sleep. However, as developing of some new anesthetic drugs and anesthesia monitor technique in sedation and antianxiety, BZDs has gradually lost its market.
Oral or intravenous BZDs were given for preoperative sedation for many years, but more and more evidence suggests a lack of benefit with routine use of BZDs as sedative and antianxiety premedication (Table 4).
BZDs VS. Placebo
Lorazepam is particularly unpredictable with regard to duration of amnesia. A randomized placebo-controlled clinical trial compared lorazepam (1 to 1.5 mg) intravenously vs. NaCl 0.9% as a premedication prior to day-case surgery. Lorazepam did not improve quality of recovery. Postoperative mean Quality of Recovery-40 scores were similar in both groups at first postoperative working day (174.5 vs. 176.4, P = 0.34) and 7th day after surgery (172.8 vs.176.3, P = 0.38). Furthermore, lorazepam may delay the decrease in postoperative anxiety and aggression (19).
Another randomized double-blind study compared 1 mg of lorazepam vs. placebo given orally before ERCP (20). Patients pretreated with lorazepam even needed more Propofol in the early phase of sedation (275+/-39 vs 159+/-37 microg/kg in minutes 5-10, P < 0.05) and the total amount of ketamine administered was higher in the lorazepam group (15.8+/-1.4 vs 11.3+/-1.2 microg/kg/min, P < 0.05).
There was also a randomized clinical trial that randomized patients into three groups each to receive 2.5 mg of lorazepam, no premedication, or placebo (21). The results were, premedication with lorazepam did not improve the Evaluation du Vécu de l'Anesthésie Generale (EVAN-G) mean global index for overall level of patient satisfaction compared with no premedication or placebo (P = 0.38). There were no significant differences found in the EVAN-G mean global index with the three groups (P = 0.18). And the rate of early cognitive recovery was 51%, 71% and 64%, respectively (P < 0.001). Among patients undergoing elective surgery under general anesthesia, sedative premedication with lorazepam compared with placebo or no premedication did not improve the self-reported patient experience the day after surgery, but was associated with a lower rate of early cognitive recovery.
BZDs VS. Other Anesthetics
Zopiclone is a nonbenzodiazepine hypnotic agent used in the treatment of insomnia, which increases the normal transmission of the neurotransmitter GABA in the central nervous system, as benzodiazepines do, but in a different way. A multi-center RCT compared zopiclone 7.5 mg, alprazolam 0.5 mg and controls received placebo as premedication for non-ambulatory consecutive surgical patients undergoing general surgery (22). Finally, in the operating room, anxiety and comfort were moderate and did not differ significantly among groups on a 1-10 scale: zopiclone: 2 [1-4] and 2.5 [1-5]; alprazolam: 2 [1,4] and 2 [1-5]; placebo: 3 [1-5] and 3 [1-5]. The patients who were more anxious preoperatively remained so in the operating room. Premedication of alprazolam and zopiclone in non-ambulatory surgery is no more effective than a placebo.
α2 - adrenergic receptor agonists
Otherwise, as anesthetic premedication, both α2-adrenergic receptor agonists have been compared with BZDs in many clinical trials (23). One of which, compared oral midazolam 0.5 mg/kg with oral clonidine 4 mg/kg in terms of drug acceptance, preoperative sedation, quality of mask acceptance, and recovery profile. They found the taste of clonidine is better and the onset of sedation is faster with midazolam, and the level of sedation is better with clonidine. The quality of mask acceptance was equally satisfactory, and they noted a trend toward an increased incidence of postoperative agitation after midazolam premedication (24). Moreover, a meta-analysis summarized 10 similar trials and found that clonidine, in comparison with midazolam, produced a more satisfactory level of sedation at induction (odds ratio, OR＝0.49), decreased emergence agitation (OR＝0.25), and produced more effective early postoperative analgesia (OR＝0.33) (25).
Dexmedetomidine is a more selective a2-adrenergic receptor agonist than clonidine with a faster onset of action, quicker time to reach the peak plasma concentration, and a shorter elimination half-life. Recently, two meta-analyses (26,27) found that dexmedetomidine was associated with more satisfactory sedation upon separation from parents and upon mask acceptance than midazolam as premedication. Furthermore, dexmedetomidine also decreased the severity of acute postoperative pain and reduce the number of requests for rescue analgesics after surgery, incidence of emergence delirium, and the incidence of postoperative shivering (26, 28).
Sedation in ICU
Sedation for longer periods, such as in the ICU, also is accomplished with BZDs. However, prolonged infusion results in accumulation of drug (midazolam) and significant concentration of the active metabolite. Recently, large numbers of using of other sedation drugs are replacing the using of BZDs in long care situation (Table 4).
BZDs VS. Propofol or Dexmedetomidine
For sedation, Propofol or Dexmedetomidine is generally similar with the amnesia and hemodynamic stability but with more rapid emergence or wake-up than midazolam (29). When lorazepam is compared with propofol for critically ill patients undergoing mechanical ventilation, propofol also has superior economic value (30). When midazolam is compared with dexmedetomidine for sedation during the early postoperative period in adolescents who underwent scoliosis surgery, dexmedetomidine was associated with the decreased postoperative fentanyl consumption, Numeric Visual Analog Scale (NVAS) pain scores, and a decreased incidence of delirium (31).
A systematic review and meta-analysis of six randomized trials enrolling 1235 patients suggest that use of a dexmedetomidine or propofol based sedation regimen rather than a benzodiazepine (midazolam or lorazepam) based sedation regimen in critically ill adults may reduce ICU length of stay and duration of mechanical ventilation (32).
Side effect of BZDs： Postoperative delirium
Delirium has recently been shown as a predictor of death, increased cost, and longer duration of stay especially in ventilated patients. Current evidence most strongly associates use of benzodiazepines with increased postoperative delirium, longer delirium duration, and possible transition to delirium in patients.
Long-term use of BZDs is closely related to postoperative delirium (POD). Recent research reported that premedication with BZDs is important anesthesia-related predictors for POD (OR, 1.8) (33-36), and the use of BZDs in the first 24 h after admission is also a risk factor related to delirium (OR, 2.28) (37).
Voepel-Lewis T, et al. (38) present a case of a 5-year-old boy who had severe agitation after PACU discharge after midazolam premedication for minor otologic surgery. Furthermore, a meta-analysis of seven RCTs with 466 children (24) demonstrated that dexmedetomidine premedication can decrease the incidence of emergence delirium, and the incidence of postoperative shivering (RR:0.59; 95% CI:0.40, 0.88). For elderly people, Marcantonio ER (39) presented a 76-year-old woman who developed delirium first after colectomy with complications and again after routine surgery. He concluded limiting use of sedating medications (especially BZDs) is the key strategy for successful prevention and treatment of delirium for elderly people.
In ICU patients, lorazepam has been an independent risk factor for transitioning to delirium (OR, 1.2; P = 0.003), whereas fentanyl, morphine, and propofol were associated with higher but not statistically significant odds ratios (40). Recent study also found that midazolam produces more delirium compared with dexmedetomidine in complicated post-surgical patients with sepsis and mechanical ventilation (41). Hence, it is important to underline that to avoid BZDs in ICU patients is associated with a reduced risk for POD.
For pharmacologic interventions used to treat postoperative delirium in older surgical patients, American Geriatrics Society strongly recommended that the prescribing practitioner should not use benzodiazepines as a first-line treatment of the agitated postoperative delirious patient who is threatening substantial harm to self and/or others to treat postoperative delirium. And healthcare providers should also not prescribe antipsychotic or benzodiazepine medications for the treatment of older adults with postoperative delirium who are not agitated and threatening substantial harm to self or others (42).
In conclusion, more and more pharmaceutical are further beneficial or replacing the role of BZDs in perioperative use. In addition, as the developing of anesthesia monitoring technique, amnesia effect of BZDs may not be that important. Therefore, the perioperative application of BZDs should be used with caution.