Medications And Drugs: Chronotherapy Study Finds That Usage Of The Sedative Midazolam At Night Increases Risk Of Myocardial Injury!

Medications - Drugs: 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!
https://www.dea.gov/sites/default/files/2020-06/Benzodiazepenes-2020_1.pdf
 
Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia and procedural sedation, and to treat severe agitation. It works by inducing sleepiness, decreasing anxiety, and causing a loss of ability to create new memories. Midazolam is classified as a short-acting benzodiazepine and is available in the United States as an injectable preparation, as oral tablets and as a syrup (primarily for pediatric patients).
 
Numerous animal studies have shown that midazolam can increase vulnerability to cardiac ischemia, potentially via circadian-mediated mechanisms.
 
The study team hypothesized that perioperative midazolam administration is associated with an increased incidence of myocardial injury in patients undergoing non-cardiac surgery (MINS) and that circadian biology may underlie this relationship.
 
The study team analyzed intraoperative data from the Multicenter Perioperative Outcomes Group for the occurrence of MINS across 50 institutions from 2014 to 2019.
 
The primary outcome was the occurrence of MINS. MINS was defined as having at least one troponin-I lab value ≥0.03 ng/ml from anesthesia start to 72 h after anesthesia end. To account for bias, propensity scores and inverse probability of treatment weighting were applied.
 
In all, a total of 1,773,118 cases were available for analysis.
 
The study findings showed that of these subjects, 951,345 (53.7%) received midazolam perioperatively, and 16,404 (0.93%) met criteria for perioperative MINS.
 
There was no association between perioperative midazolam administration and risk of MINS in the study population as a whole (odds ratio (OR) 0.98, confidence interval (CI) [0.94, 1.01]).
 
Shockingly however, the study findings showed a strong association between midazolam administration and risk of MINS when surgery occurred overnight (OR 3.52, CI [3.10, 4.00]) or when surgery occurred in ASA 1 or 2 patients (OR 1.25, CI [1.13, 1.39]).
 
The study findings shows that although perioperative midazolam administration may not pose a significant risk for MINS occurrence, midazolam administration at night and in healthier patients could increase MINS, which warrants further clinical investigation with an emphasis on circadian biology.
 
The study findings were published in the peer reviewed journal: Frontiers In Cardiology Medicine.
https://www.frontiersin.org/articles/10.3389/fcvm.2022.982209/full
 
The study findings provide more evidence that back up the idea that timing is important when giving medications.
 
The study findings shows that Midazolam, a drug that makes patients sleepy and less anxious before surgery is associated with an increased risk of heart damage when surgeries are performed at night.
 
The study findings provide further proof that a medication’s effectiveness might vary dependi ng on the time it is administered.
 
Senior author, Dr Tobias Eckle, MD, Ph.D., professor of anesthesiology at the University of Colorado School of Medicine told Medications - Drugs reporters, “We performed a large dataset analysis and demonstrated that administering midazolam is associated with an increased risk of myocardial injury in non-cardiac surgery when surgeries occurred at night and in healthier patients.”
 
He added, “This is significant because these findings could have tremendous implications for patient mortality.”
 
Dr Eckle is one of a select group of experts in chronotherapy, the practice of giving drugs at specific times of day to better align with circadian rhythms.
 
Past studies conducted by him has shown that intense light can aid in the healing of damaged hearts and that certain proteins that are favorable to health are expressed more strongly at certain times of the day.
 
The study team used the vast Multicenter Perioperative Outcomes Group to evaluate 1,773,118 instances in which the sedative midazolam was given to 951,345 patients.
 
A total of 16,404 of the patients satisfied the criteria for myocardial injury (MINS). Although there was no connection between giving the drug and the risk of heart damage in the overall study population, researchers determined that the time the drug was administered was significant.
 
Dr Eckle said, “We found a strong association between midazolam administration and risk of MINS when surgery occurred at night or with healthier patients.”
 
According to the study team, the mechanisms and reasons are unclear but may lie within the PER2 gene, a light-regulated protein that helps protect the heart from injury. In mouse studies, researchers found a link between midazolam, circadian protein expression, and heart ischemia.
 
Dr Eckle added, “That suggests midazolam interferes with the circadian system in humans.”
 
Midazolam increases the neurotransmitter GABA which inhibits certain brain signals to produce a calming effect. That in turn can lessen the expression of higher nighttime levels of PER2. As the levels decrease, the heart may become more susceptible to injury when the midazolam is given at night rather than during the day.
 
Dr Eckle further added, “This is the major focus of chronotherapy. Medications and Drugs can have different effects depending on when they are given. If you separate day and night there is a huge effect. For example, maybe we should not give anyone midazolam at night if it increases the risks of myocardial infarcts.”
 
Dr Eckle stressed that the entire field of chronotherapy is understudied and may hold clues to more effective use of routine therapies. He believes new drugs should be tested for the best time of day to be used. Blood pressure drugs, for example, tend to work best at night.
 
He added, “Drugs are often administered according to what’s most efficient. But what is most efficient, may in the end cause damage.”
 
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Read more about Chronotherapy:
 
https://health.selfdecode.com/blog/chronotherapy/
 
https://www.pnas.org/doi/10.1073/pnas.1916118116
 
https://www.mdpi.com/1999-4923/14/7/1424
 
https://www.mdpi.com/2073-4409/8/8/883
 
https://www.science.org/doi/10.1126/science.abb0738
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197224/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666849/
 
https://med.uth.edu/immpact-report/research-on-the-clock/
 
https://asja.springeropen.com/articles/10.1186/s42077-019-0035-9
 
https://www.sciencedirect.com/topics/medicine-and-dentistry/chronotherapy