Night-Time Use of Sedative Increases Heart Damage Risk

A new research study has found that midazolam – a sedative used before surgery to make patients relaxed and sleepy – is associated with a greater risk of heart damage when used at night.

The circadian clock affects more than our sleep–wake cycles

Professor Tobias Eckle, the senior author of the study, is an expert in chronotherapy. In previous research, he illustrated that proteins beneficial for heath health are expressed more strongly at different times of day and that intense light can promote heart healing.

In the study, published in Frontiers in Cardiovascular Medicine, a large-scale analysis was performed on data from 951,345 patient cases across 50 institutions where midazolam had been administered before non-cardiac surgery. Of these cases, 1.72% reached the criteria for myocardial injury after non-cardiac surgery (MINS). The researchers found no significant increase in heart injury risk when using midazolam overall, but the time of administration affected the risk of MINS.

“We found a strong association between midazolam administration and risk of MINS when surgery occurred at night or with healthier patients,” said Eckle. “This is significant because these findings could have tremendous implications for patient mortality.”

How does midazolam affect the heart?

In mouse studies, the research team identified that midazolam, circadian protein expression and heart injury were linked. The circadian gene PER2 may be particularly important in determining how midazolam affects the circadian system and the heart. PER2 protein expression increases at night and has previously been shown to protect the heart from injury by regulating the production of reactive oxygen species.

To calm a patient, midazolam increases the expression of the GABA neurotransmitter, which in turn can reduce the levels of PER2. When administered at night, midazolam may therefore decrease the protection against heart damage conferred by PER2, increasing the risk of heart injury during night-time surgeries.

“Drugs can have different effects depending on when they are given,” Eckle said. “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.”

The field is understudied says Eckle, but he believes chronotherapy could help identify ways to use routine or new therapies more effectively.

This article is a rework of a press release issued by the University of Colorado Anschutz Medical Campus. Material has been edited for length and content.

Reference: Prin M, Pattee J, Douin DJ, Scott BK, Ginde AA, Eckle T. Time-of-day dependent effects of midazolam administration on myocardial injury in non-cardiac surgery. Front Cardiovasc Med. 2022;9. doi: 10.3389/fcvm.2022.982209.