The Usage Of The Sedative Midazolam At Night Increases Risk Of Myocardial Injury


A study by researchers from the Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado-United States has found that the usage of the sedative midazolam at night increases risk of myocardial injury and heart damage!

The study findings were published in the peer reviewed journal: Frontiers In Cardiology Medicine.

In this study, we examined the relationship between perioperative midazolam administration and MINS. Overall, we did not find an association between midazolam administration and the rate of MINS. However, midazolam administration was associated with an increased risk of MINS when surgeries occurred at night or in healthier patients in the ASA 1+2 class. Interestingly, we found a MINS risk reduction when midazolam was given to higher risk patients (ASA 3+4 class). When assessing the time of day, however, the increased risk of MINS at night was present in both ASA 1+2 and ASA 3+4.

The endogenous circadian clock mechanism involves a cell autonomous transcription–translation feedback loop. During the day, the transcription factor CLOCK interacts with BMAL1 to activate transcription of the Per and Cryptochrome (Cry) genes, resulting in high levels of these transcripts. The resulting PER and CRY proteins translocate to the nucleus to inhibit their own transcription (30).

The entire cycle takes approximately 24 h. This process is also active without external cues and takes approximately 25 h in humans (31). Besides autonomous mechanisms, resetting of the circadian clock by photic induction of Per1 and Per2 genes is mediated by the binding of phosphorylated CREB (cyclic AMP responsive element-binding protein) to a cAMP-responsive element (CRE) in the respective promoters (32).

Since the circadian rhythm in humans is dominantly regulated by sunlight (33), circadian proteins cycle over a 24-h period, reaching their peak expression at night. The incidence of myocardial injury has been found to be lower at night in both mice and humans with an abrupt increase in the early morning hours (6 a.m.) (14).

Mouse studies have revealed a reciprocal relationship between myocardial injury and PER2 protein expression (13). In-depth genetic studies in mice have recently identified endothelial PER2 as an endogenous cardioprotective mechanism (14). In keeping with these findings, we found a lower baseline risk for MINS during the night when compared to the day.

We also found a correlation between the time of midazolam administration and the risk of MINS. This would support data from animal studies showing a link between midazolam, circadian protein expression, and ischemia, and suggests that midazolam also interferes with the circadian system in humans. Midazolam increases GABAA signaling, an important component of circadian rhythm protein regulation (34).

In fact, GABAA activation can inhibit the expression of circadian Per2 mRNA (35). As midazolam could lower the naturally occurring higher nighttime-PER2 levels, it is plausible that the heart could be more susceptible to injury when midazolam is given at night compared to the day. Further, as we also found that midazolam decreased the risk of MINS during the daytime, midazolam might also cause a reduction of the amplitude not only at the peak but also at the trough (Figure 5).

Figure 5. Proposed model of midazolam modifying myocardial injury in non-cardiac surgery (MINS) risk during a 24 h period. (A) At the peak of PER2 in the evening (p.m.), MINS occurs less frequent than during the PER2 trough in the morning (a.m.). (B) Midazolam administration at night might lower the PER2 peak which results in a higher occurrence of MINS. Midazolam administration during the daytime might have opposite effects and lower the PER2 trough resulting in less MINS occurrence. Dotted line indicates MINS risk in patients with midazolam.

The relationship between ASA class and risk of MINS after midazolam exposure may have a similar physiologic basis. Because most medical comorbidities increase in prevalence with age, ASA classes 3 and 4 presumably include an older patient population. Indeed, our ASA 1+2 had a mean age of 45.7 and our ASA 3+4 group had a mean age of 59.9 years.

In older adults, the amplitude and peak expression of circadian rhythms decreases by 20 to 40% (36). In addition, animal studies have shown that aging results in the diurnal rhythm amplitude of PER2 (37). Exposures that interfere with circadian protein expression might therefore be more harmful in younger patients who are accustomed to a higher circadian amplitude and baseline expression of circadian proteins.

Indeed, we identified a significant increase of MINS in the ASA 1+2 group when midazolam was given perioperatively. Surprisingly, we found a possible protective effect of midazolam in the ASA 3+4 group. Although small, this reduction in risk is harder to explain via circadian mechanisms.

One possibility is that administration in patients with many comorbidities resulted in lower cumulative anesthetic doses, reduced stress responses, and more hemodynamic stability during surgery which ultimately could have resulted in fewer cardiac complications.

Analyzing ASA 5 and 6 patients could potentially have given more insight into this phenomenon. However, since we excluded ASA 5 and ASA 6 patients due to their emergent and complex status, this will require future evaluation. Regardless, when we considered the time of day, an increased risk of MINS at night was present in both ASA 1+2 and ASA 3+4, suggesting that the time of day had a higher impact on the occurrence of MINS.

Benzodiazepines are medications used for the treatment of multiple conditions including anxiety disorders, insomnia, agitation, seizures, and induction of amnesia.[1] They are the most prescribed psychiatric medications and the third most misused drugs among adults and adolescents in the US.[2] Despite their efficacy, benzodiazepines are associated with an addictive potential and, if used inappropriately can lead to significant morbidity and mortality.

Benzodiazepines became increasingly prescribed in the late 1990s and early 2000s. According to Bachhuber et al,[3] benzodiazepine prescribing in the United States increased by 67% from the mid-1990s to 2013, with a 3-fold increase in the number of benzodiazepines prescribed.

This rise has been accompanied by accumulating evidence of the toxicity and addictive potential of benzodiazepines. According to Maust et al,[4] approximately 2.2% of the United States (US) population misused benzodiazepines in 2015 and 2016. Data from the National Institute on Drug Abuse[5] revealed that the number of benzodiazepine-related deaths has steadily increased from less than 1000 in 1999 to nearly 9000 in 2015.

The use and misuse of benzodiazepines have also contributed significantly to the current opioid overdose epidemic. It is reported that benzodiazepines were involved in ~30% of opioid overdose deaths in 2015 (National Institute on Drug Abuse, 2018). New concerns have recently emerged due to the increasing availability of highly lethal benzodiazepines on the illicit market (e.g., illicitly produced pills that combine benzodiazepines with fentanyl and potent “designer” benzodiazepines).[6]

The reasons for the increased use and misuse of benzodiazepines are multifaceted and are attracting increasing attention as fears of a benzodiazepine epidemic rise in different parts of the world. In addition to the pattern of increased prescribing of benzodiazepines by physicians, Lembke et al[7] showed that patients are not aware of the addiction potential is another factor. Additionally, patients who have developed a dependence on benzodiazepines do not get adequate support and guidance to help them discontinue their use of these medications.[8]

Benzodiazepine use and misuse are particularly problematic in many middle eastern countries where access to benzodiazepine is not controlled, but rather easily available at pharmacies without the need for prescriptions (Khalife et al). In Pakistan, benzodiazepine overdoses represented 84% of self-poisoning cases.[9] In Jordan, benzodiazepines were also frequently cited as a drug of abuse.[10] After excluding nicotine, benzodiazepines were the most abused substance among Egyptian adolescents.[11] In Lebanon, a study by Hitti et al[12] showed that benzodiazepine overdoses accounted for the most common pharmaceutical drugs of overdose along with sedatives, hypnotics, and antipsychotics.

In Lebanon, the literature on benzodiazepine uses and misuse is scarce. In 2000, Naja et al explored the prevalence of individuals who have used benzodiazepines within the last month in a sample of 1000 random participants. The authors noted that 9.6% of respondents had used benzodiazepines in the prior month. Additionally, they estimated that the dependence rate in 400 benzodiazepine users was ~50.2%.[13] In 2016, Ramadan et al[14] studied randomly selected Lebanese benzodiazepine users that were a sampled from 27 different pharmacies allocated across different regions of Lebanon and noted that a large proportion was using benzodiazepine as a long-term treatment for anxiety although it is recommended only for short-term use.

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