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.
References[AA] Alzheimer’s Association. 2021. 2021 Alzheimer’s Disease Facts and Figures. Chicago (IL): Alzheimer’s Association; [accessed 2021 Sept 8]. Report No.:17. https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf.
Alzheimer’s disease – plaques, tangles, causes, symptoms & pathology. 2016 Mar 22, 8:53 minutes. YouTube, Osmosis. [accessed 2021 Sept 19]. https://youtu.be/v5gdH_Hydes.
Askoldovich A. Party popper gif [digital illustration gif]. Dribbble. [accessed 2021 Sept 19]. https://cdn.dribbble.com/users/2983604/screenshots/8140241/media/d0905a1fd24438a96a158b355a72d0b8.gif.
Canada could face ventilator shortage within weeks. 2020 Mar 26, 1:59 minutes. YouTube, CBC News: The National. [accessed 2021 Sept 18]. https://youtu.be/1Z4EKMLDadM.
Cedars-Sinai. 2020. The Cedars-Sinai campus [digital photograph]. Cedars-Sinai. [accessed 2021 Sept 19]. https://content.presspage.com/uploads/2110/1920_sapersteinpanoramic1.jpg?10000.
COVID-19: life and death moments in an ICU. 2020 Apr 21, 6:27 minutes. YouTube, CBC News: The National. [accessed 2021 Sept 18]. https://youtu.be/WXpk0DwEaqw.
Critical ventilator shortage prompts health care workers, manufacturers to get creative. 2020 Mar 27, 2:39 minutes. YouTube, ABC 7 Chicago. [accessed 2021 Sept 18]. https://youtu.be/4aNQx3S6J8w.
Fakhoury M. 2018. Microglia and astrocytes in Alzheimer’s disease: Implications for therapy. Curr Neuropharmacol. [accessed 2021 Sept 11]; 16(5):508–518. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997862/. doi:10.2174/1570159X15666170720095240.
Gouras GK, Olsson TT, Hansson O. 2015. β-Amyloid peptides and amyloid plaques in Alzheimer’s disease. Neurotherapeutics. [accessed 2021 Sept 11]; 12(1):3–11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322079/. doi: 10.1007/s13311-014-0313-y.
Grimgram. 2020. Broken machine – vector illustration black silhouette icon [digital illustration]. iStock by Getty Images. [accessed 2021 Sept 19]. https://media.istockphoto.com/vectors/broken-machine-vector-illustration-black-silhouette-icon-vector-id1251531092?k=20&m=1251531092&s=612×612&w=0&h=Nb792ic0bO8WGeHFQfhAdX3Cyf-BWhYBGl4O0aPWnGk=.
How Trump and Kushner failed on testing and ventilators: a closer look. 2020 Apr 2, 16:21 minutes. YouTube, Late Night with Seth Meyers. [accessed 2021 Sept 18]. https://youtu.be/TmVqrJHrO-8.
Inside a Montreal ICU where COVID-19 patients are getting younger. 2021 Apr 27, 6:22 minutes. YouTube, CBC News: The National. [accessed 2021 Sept 18]. https://youtu.be/07XtzelHaT0.
Kahovsky. Sad suffering sick cute brain character vector image [digital illustration]. iStock by Getty Images. [accessed 2021 Sept 18]. https://cdn1.vectorstock.com/i/1000×1000/39/10/sad-suffering-sick-cute-brain-character-vector-25803910.jpg.
Kanivets I. 2019. Mouse, outline and flat [digital illustration]. iStock by Getty Images. [accessed 2021 Sept 19]. https://www.istockphoto.com/vector/mouse-outline-and-flat-design-elements-for-banners-for-chinese-new-year-vector-gm1187166705-335241427.\.
Lab mouse petri dish [digital photograph]. 2021. Medtech Insight. [accessed 2021 Sept 19]. https://medtech.pharmaintelligence.informa.com/-/media/editorial/medtech-insight/2021/01/mt2101_mouse_1200.jpg?w=790&hash=23AE532096962F5C409618F0FFB6F5B0.
Lahiri S, Regis GC, Koronyo Y, Fuchs D-T, Sheyn J, Kim EH, Mastali M, Van Eyk JE, Rajput PS, Lyden PD, et al. 2019. Acute neuropathological consequences of short-term mechanical ventilation in wild-type and alzheimer’s disease mice. Crit Care. [accessed 2021 Sept 1]; 23(1):63. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387486/. doi:10.1186/s13054-019-2356-2.
Mayalis. 2020. Cute nerd brain cartoon character with lightbulb stock illustration [digital illustration]. iStock by Getty Images. [accessed 2021 Sept 18]. https://media.istockphoto.com/vectors/cute-nerd-brain-cartoon-character-with-lightbulb-vector-id1249363489?k=20&m=1249363489&s=170667a&w=0&h=VLGv9-ZacD54s_E_eZ6f2rxIgQcYMDPOtSEptmoF7gI=.
Mechanical ventilation. 2017 Sept 28, 3:24 minutes. YouTube, MedStar Washington Hospital Center. [accessed 2021 Sept 20]. https://youtu.be/ALNdQ8YGwKI.
New York governor Cuomo stresses need for more ventilators. 2020 Mar 26, 2:29 minutes. YouTube, CBSN News. [accessed 2021 Sept 18]. https://youtu.be/qbSt8C7RnJM.
News monologue A. 2019 June 25, 1:50 minutes. Fesliyan Studios. [accessed 2021 Sept 22]. https://www.fesliyanstudios.com/royalty-free-music/download/news-monologue-a/362.
NYC doctor says hospitals need more ventilators | Morning Joe| MSNBC. 2020 March 31, 6:21 minutes. YouTube, MSNBC. [accessed 2021 Sept 18]. https://www.youtube.com/watch?v=8HP0Zkad3pM.
Overwhelmed: inside Oregon’s ICUs | ‘we see no end’ | full special report. 2021 Aug 6, 25:03 minutes. YouTube, KGW News. [accessed 2021 Sept 18]. https://www.youtube.com/watch?v=LU5HyKoAa20.
Paingineer. 2017. Sword and shield run cycle gif animation [digital animation]. Deviant Art. [accessed 2021 Sept 19]. https://images-wixmp-ed30a86b8c4ca887773594c2.wixmp.com/f/365b2bd6-b2da-4442-a813-d78d12a6f6f3/db2fdh0-ad391b69-8400-41da-ae81-97843b4a9e1b.gif?token=eyJ0eXAiOiJKV1QiLCJhbGciOiJIUzI1NiJ9.eyJzdWIiOiJ1cm46YXBwOjdlMGQxODg5ODIyNjQzNzNhNWYwZDQxNWVhMGQyNmUwIiwiaXNzIjoidXJuOmFwcDo3ZTBkMTg4OTgyMjY0MzczYTVmMGQ0MTVlYTBkMjZlMCIsIm9iaiI6W1t7InBhdGgiOiJcL2ZcLzM2NWIyYmQ2LWIyZGEtNDQ0Mi1hODEzLWQ3OGQxMmE2ZjZmM1wvZGIyZmRoMC1hZDM5MWI2OS04NDAwLTQxZGEtYWU4MS05Nzg0M2I0YTllMWIuZ2lmIn1dXSwiYXVkIjpbInVybjpzZXJ2aWNlOmZpbGUuZG93bmxvYWQiXX0.QXIXF045AYBunG8lsFBjDPvmKiO2R0K2b4lmtSt3zqQ.
Penn State Animal Research Program. Handling and restraint of mice. 2011 Mar 31, 4:46 minutes. YouTube, APRVideosful. [accessed 2021 Sept 19]. https://www.youtube.com/watch?v=VYdv6FNCdnI&t=84s.
Ranney ML, Griffeth V, Jha AK. 2020 Mar 25. Critical supply shortages – the need for ventilators and personal protective equipment during the covid-19 pandemic. N Engl J Med. [accessed 2021 Sept. 8]; 382(18):e41. https://www.nejm.org/doi/full/10.1056/NEJMp2006141#article_citing_articles.
Reitz S. 2019. Blood brain barrier diagram [digital illustration]. International Autoimmune Encephalitis Society. [accessed 2021 Sept 19]. https://i1.wp.com/autoimmune-encephalitis.org/wp-content/uploads/2019/12/PNK-Sleep-and-BBB.png?resize=698%2C675&ssl=1.
Scientists at work in laboratory. 2013 May 13, 1:01 minutes. YouTube, Educational Videos and Lectures. [accessed 2021 Sept 19]. https://youtu.be/tao0Aes5bko.
Steiner M. n.d., 2:36 minutes. Happy Business. Adobe Premiere Pro. [accessed 2021 Sept 22].
svt1992. 2019. Sad suffering sick cute human brain stock illustration [digital illustration]. iStock by Getty Images. [accessed 2021 Sept 18]. https://media.istockphoto.com/vectors/sad-suffering-sick-cute-human-brain-vector-id1154783437?k=20&m=1154783437&s=170667a&w=0&h=ezVUfDD0uJk4QtP8VK6GsuFM3q-bNsga550Htbniax8=.
Torjesen I. 2021 Jan 14. Covid-19: when to start invasive ventilation is “the million dollar question.” BMJ. [accessed 2021 Sept 8]. 372:n121. https://www.bmj.com/content/372/bmj.n121.
Trump orders ventilators, demands appreciation. 2020 Apr 1, 2:03 minutes. YouTube, AP Archive. [accessed 2021 Sept 18]. https://youtu.be/5PG2Lje20ds.
Ventilator shortage as Missouri virus hospitalizations spike. 2021 July 6, 1:28 minutes. YouTube, KCTV5 News. [accessed 2021 Sept 18]. https://youtu.be/_LnbbjjlXIM.
Ventilators and COVID-19: preventing a shortage. 2020 Mar 28, 5:05 minutes. YouTube, Los Angeles Times. [accessed 2021 Sept 18]. https://www.youtube.com/watch?v=xDwj9U7L14g.
What does a medical laboratory scientist do?. 2020 Jan 3, 1:35 minutes. YouTube, UNMCEDU. [accessed 2021 Sept 20]. https://youtu.be/FNTxRR1eGlY.
What is a ventilator and why is there a shortage? (coronavirus). 2020 Mar 27, 4:41 minutes. YouTube, CNET. [accessed 2021 Sept 18]. https://youtu.be/1MIIhWwTyy0.
Yamazaki Y, Kanekiyo T. 2017. Blood-brain barrier dysfunction and the pathogenesis of Alzheimer’s disease. Int J Mol Sci. [accessed 2021 Sept 11]; 18(9):1965-1966. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618614/. doi:10.3390/ijms18091965.
Zvezdina K. 2020. Artificial lung ventilation for covid patient, intensive care in hospital, woman infected by oronavirus in critical condition, vector illustration, cartoon character. Pulmonary ventilator stock illustration [digital illustration]. iStock by Getty Images. [accessed 2021 Sept 18]. https://media.istockphoto.com/vectors/artificial-lung-ventilation-for-covid-patient-intensive-care-in-by-vector-id1222526211?k=20&m=1222526211&s=612×612&w=0&h=Cc0CkXURRv3SYKwG5Ed_QUDJSKp06XYWLZjPek2glx4=.
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Man on Ventilator [Photograph]. 2012. American Nurse. [accessed 2021 Sept 13]. https://www.myamericannurse.com/top-10-care-essentials-for-ventilator-patients/.