What do you tell people?

[[Da...]]

Another old post from an article I was going to summarize anyway:

 

This study describes the increase in neuronal cell death as a result of combining caffeine and isoflurane (a positive allosteric modulator of the GABA-A receptor, similar to benzos) in fetal macaques.

 

https://www.nature.com/articles/s41598-018-23560-7

 

"Caffeine Augments Anesthesia Neurotoxicity in the Fetal Macaque Brain

 

Abstract

Caffeine is the most frequently used medication in premature infants. It is the respiratory stimulant of choice for apnea associated with prematurity and has been called the silver bullet in neonatology because of many proven benefits and few known risks. Research has revealed that sedative/anesthetic drugs trigger apoptotic death of neurons and oligodendrocytes in developing mammalian brains. Here we evaluated the influence of caffeine on the neurotoxicity of anesthesia in developing nonhuman primate brains. Fetal macaques (n = 7–8/group), at a neurodevelopmental age comparable to premature human infants, were exposed in utero for 5 hours to no drug (control), isoflurane, or isoflurane + caffeine and examined for evidence of apoptosis. Isoflurane exposure increased apoptosis 3.3 fold for neurons and 3.4 fold for oligodendrocytes compared to control brains. Isoflurane + caffeine caused neuronal apoptosis to increase 8.0 fold compared to control levels but did not augment oligoapoptosis. Neuronal death was particularly pronounced in the basal ganglia and cerebellum. Higher blood levels of caffeine within the range considered therapeutic and safe for human infants correlated with increased neuroapoptosis. Caffeine markedly augments neurotoxicity of isoflurane in the fetal macaque brain and challenges the assumption that caffeine is safe for premature infants."

 

Some excerpts:

 

"Analysis of the relationship between CAF blood levels and apoptotic brain injury revealed that ISO-induced brain injury increases sharply as CAF blood levels rise above 17 mg/L. This suggests that there may not be a wide safety margin for exposing very preterm infants to CAF in combination with other apoptogenic drugs. "

 

" It was recently reported that very preterm infants exposed to surgery have an increased risk for neurodevelopmental impairment22,23, and MRI evidence for structural brain injury22, which is particularly prominent in a region referred to as deep nuclear gray matter. "  (Just an additional note: they recently banned surgery that lasts for more than three hours using caffeine and sedatives because of this). 

 

"For procedural sedation very preterm infants are commonly exposed to a SAD in the benzodiazepine class, either intermittently or continuously for prolonged periods (days, weeks, months) while they are often also exposed continuously to CAF. Our previous research demonstrates that prolonged SAD exposures produce higher amounts of neurotoxicity in both the non-human primate3,43 and rodent44. These findings together with our newest observations suggest that intermittent or continuous SAD exposures when combined with CAF may be particularly dangerous to the developing infant brain. It has been demonstrated in infant mice that a 4-hour exposure to a sub-anesthetic dose of midazolam45 or diazepam33 induces a significant neurotoxic reaction, and when CAF is administered together with either drug, the neurotoxic action is significantly augmented33,34. "

 

"While recovering from ISO anesthesia, CAF exposed dams appeared more alert and active as compared to animals that did not receive CAF treatment. No lingering effects were noted during routine veterinarian evaluation 24 hours following the experiment. "

 

Caffeine in a regular cup of coffee: around 95mg

Caffeine blood levels at which neurotoxicity significantly increased in this experiment: 17mg/L

Number of litres of blood in the average human body: around 5L.

Apoptosis = programmed cell death."

SADs = Sedative, anesthetic, and anti-epileptic drugs

CAF = caffeine

ISO = isoflurane

 

http://www.benzobuddies.org/forum/index.php?topic=233481.msg2995429#msg2995429

[[Da...]]

Hello again, Data_Guy.  Please don’t go to any extra on my account.  I thought you had the refs easily at hand.  I’ll check out the links you provided.  Thank you so much.  Libertas

 

It's not a problem, Libertas. I can't believe I haven't done this at some point. There is a pretty strong case given the research available. I will just post a couple more studies and people can feel free to quote the posts whenever you see anyone saying "there is no injury" or "it's just anxiety". Of note, I did a neuropsychological exam showing significant impairment and my doctor tried to argue that people with anxiety can show cognitive impairment as well. When I looked it up, it turned out the most important predictor of whether someone with anxiety showed cognitive impairment was if they had been treated with a benzodiazepine. Also, as a group, long term benzo users show cognitive impairment that can last for months or years, regardless of whether they had anxiety or not. I'll post this study too. Most have already been posted here and there around the forum.

[[Li...]]

AOK. Thank you, Data_Guy.

[[Da...]]

https://www.ncbi.nlm.nih.gov/pubmed/29244060

 

"The Residual Medium and Long-term Cognitive Effects of Benzodiazepine Use: An Updated Meta-analysis.

Crowe SF1, Stranks EK1.

Author information

1

School of Psychology and Public Health, La Trobe University, Victoria, Australia.

Abstract

OBJECTIVE:

This study presents an updated meta-analysis of the effects of benzodiazepines on cognitive functioning in long-term, current users of these agents, those who have recently withdrawn and on those who have successfully abstained following withdrawal. The study represents an update of the previous meta-analyses published by our group.

 

METHOD:

A comprehensive search of the computerized databases Medline and PsycINFO was undertaken to identify studies that assessed the cognitive effects of benzodiazepines published up to 28 November 2016 (the date of the last update). Nineteen studies (eight studies published since the previous meta-analyses and 11 studies included in the previous studies) were included.

 

RESULTS:

The results of the analysis for current users revealed statistically significant, negative effects for the cognitive domains of working memory, processing speed, divided attention, visuoconstruction, recent memory, and expressive language. For those who had withdrawn and successfully abstained following withdrawal, deficits were observed for the domains of recent memory, processing speed, visuoconstruction, divided attention, working memory, and sustained attention.

 

CONCLUSIONS:

The results of the study are important in that they corroborate the mounting evidence that a range of neuropsychological functions are impaired as a result of long-term benzodiazepine use, and that these are likely to persist even following withdrawal. The findings highlight the residual neurocognitive compromise associated with long-term benzodiazepine therapy as well as the important clinical implications of these results."

 

________________________

 

 

I've got to say, I remember reading this study and thinking it was pretty badly written up. They don't do a great job of explaining or elaborating their findings, but they do find significant impairment in all domains of intelligence, if I remember correctly. If you want something a bit more clear, you can look through the references. The earlier meta-analysis from 2004 is a bit easier to understand. You can also look through some of the individual studies they are analyzing.

 

The prolonged neuropsychological impairment fits with the other evidence. Newborns exposed to the drugs for even a few hours show higher rates of neurodevelopmental disorders and actual visible brain deficits. You do not want to give these drugs to someone with a developing brain. Or adults for any extended period of time, for that matter. What is a brain injury if not prolonged impairment of problem solving, working memory, processing speed etc.?