During March of 2020, as the devastating coronavirus began sweeping the nation, the healthcare community was sent into a tailspin as it became clear that the nation did not have enough ventilators to care for the skyrocketing number of COVID-19 patients (Ranney et al. 2021). These ventilators, which temporarily replace a patient’s natural breathing system with an artificial one, were at one point being used in a staggering 75% of COVID patients who entered the ICU (Torjesen 2021). With this lifesaving machine making headlines daily, the negative consequences associated with the technology are being brought into the limelight anew.
For a number of years, the link between mechanical ventilation and cognitive decline has been well-established within the medical community. The life support system is believed to promote the pathophysiology of Alzheimer’s Disease, a very common form of dementia that affects over one in nine Americans above the age of sixty-five (AA 2021). Studies have shown that up to 40% of patients on ventilators develop symptoms that align with those of this tragic disease. However, the exact mechanisms through which these similarities occur remain unclear. Additionally, the magnitude of these effects in individuals with pre-existing Alzheimer’s symptoms has yet to be examined – until now.
In 2018, researchers at the Cedars-Sinai Medical Center in Los Angeles, California set out to study these mechanisms in vivo (Lahiri et al. 2019). To do so, they utilized two types of mice in their study: the first group of twenty-one mice were genetically modified to present symptoms of Alzheimer’s Disease, while the second group of twenty was left unaltered. Twelve and eight of the mice from the Alzheimer’s and unaltered mice groups, respectively, were placed into the experimental group, where they were intubated and ventilated for 4 hours.
Specifically, the team was interested in studying the changes in the mice on three different fronts. First, brain tissue samples were analyzed to quantify the levels of beta amyloid accumulation. Although the exact molecular mechanisms through which beta amyloid causes Alzheimer’s remain unclear, evidence shows that the formation of plaques from this peptide is a signature of the disease (Gouras et al. 2015). Second, blood samples were searched for biomarkers that would point to neuroinflammation. While slight neuroinflammation can actually help to reduce the accumulation of amyloid beta in the brain, too much can worsen neurodegenerative processes (Fakhoury 2018). Finally, the mice were each given infusions after ventilation was complete, and the leakage of the infusion was assessed to determine the permeability of the blood-brain barrier. The blood-brain barrier is responsible for maintaining homeostasis within the central nervous system, and disrupting this homeostasis can cause neuronal damage and inhibit the clearance of amyloid beta from the brain (Yamazaki and Kanekiyo 2017).
After all data was collected, results were compared between the experimental and control groups for each variable tested. Correlation coefficients were calculated to determine the strength of the relationships between variables, and the statistical significance was found to ensure that results were not due to random chance. The study was blind, meaning that the data analysts were unaware of which mice were placed in the experimental and control groups, respectively; this is beneficial because it prevents conscious or unconscious bias when handling the results. All protocols aligned with the guidelines set by the Cedars-Sinai Medical Center Institutional Animal Care and Use Committee (IACUC).
The team hypothesized increases in beta amyloid accumulation, neuroinflammation, and blood-brain barrier permeability in both the Alzheimer’s and natural mice who were subjected to mechanical ventilation. Upon examining the results, this is nearly exactly what they discovered: statistically significant increases in beta amyloid accumulation and neuroinflammation were observed across both types of ventilated mice. The only unexpected result was a decrease in the blood-brain barrier permeability in ventilated Alzheimer’s mice and an increase in permeability in the ventilated wild-type mice. These unexpected results suggest that beta amyloid may provide a protective effect against the influx of neurotoxins. Overall, however, the results combined confirm the idea that breathing machines are linked to both the promotion of Alzheimer’s pathology in healthy mice and the worsening of symptoms in mice already living with the disease.
Of course, as with nearly all preliminary research studies, there are some limitations that must be taken into consideration. For starters, although the experimental results are consistent with prior knowledge, they reflect a strong correlation rather than a direct causation. While the statistically significant results do shed light on the mechanisms behind cognitive decline in mechanical ventilation patients, further experimentation is necessary to prove a cause-and-effect relationship. Furthermore, the authors of the study cite other limitations of their research – including the smaller-than-ideal sample size of only forty-one mice, the type of ventilation used (which may not align with the typical standard of care), and the young age of the mice – that possibly impacted the conclusions drawn. Replication of the study is thus suggested before any concrete conclusions can be made. Last but certainly not least, it is important for the public to remember that this experiment was performed on mice, not human beings. While mice are a great model organism for scientific studies, caution must be taken when translating these findings to human medical care.
That being said, if the study can be properly translated into humans, it can have significant implications for the future of mechanical ventilation and will make the decision to use the technology in patients even more difficult than it already is. The Cedars-Sinai research team hopes that additional studies will more closely examine the basis for these findings at a molecular level, and that this research can be used to develop better, less risky methods of mechanical ventilation. For now, however, medical professionals must struggle with the decision of whether or not to administer this lifesaving method of care, and patients must struggle with the life-altering consequences that they will pay in the long run.
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