The Neurological Effects of Sedation in COVID-19 Patients

Neurologic symptoms such as headache, confusion, altered alertness, prolonged unconsciousness and loss of smell have been identified as symptoms of COVID-19. Although researchers are starting to understand the symptoms behind neurological sequelae from SARS-CoV-2 infection, the direct and indirect effects of SARS-CoV-2 on the brain remain unclear.

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The COVID-19 pandemic has helped reveal the complex interaction between inflammation, sedation and neurological disorders. SARS-CoV-2 infection can lead to respiratory failure, which is often managed by intubation and mechanical ventilation, and subsequent prolonged sedation is necessary. Neurologists and neuroscientists at Massachusetts General Hospital are working to understand the effects of that long-term sedation on patients' neurological function.

"Prolonged anesthesia was clearly needed from a therapeutic standpoint to help the pulmonary status of COVID-19 patients," says Emery Brown, MD, PhD, anesthesiologist in the Department of Anesthesia, Critical Care and Pain Medicine and director of the Neuroscience Statistics Research Lab at Mass General. "But from a brain standpoint, you are paying a price for it. There are reports of patients who were not clearly waking up even after their respiratory system improved and sedation discontinued."

Early Treatment, Inflammation and Ventilation

SARS-CoV-2 readily infects the upper respiratory tract and lungs. The response to infection results in immune cells releasing pro-inflammatory molecules. Acute inflammation can become severe enough to cause organ damage and failure.

"The fundamental response to COVID-19 is inflammation," says Dr. Brown. "The body mounts an enormous inflammatory response, and it turns out to be pathologic as inflammation starts to damage tissues across all organ systems. Inflammation of the lungs, heart and blood vessel directly follows."

During the early outbreak of the pandemic, it was unclear how to best treat patients with extensive damage to their lungs and subsequent acute respiratory distress syndrome (ARDS).

"Physicians were describing patients with lungs like wet sponges," says Dr. Brown. "The emphasis was placed on just trying to get the patients ventilated properly. A number of different techniques were employed, such as turning patients prone and starting patients on ventilators as early as possible."

It was learned that an often-helpful option was to keep critically ill patients sedated for prolonged periods of time until they were able to breathe on their own. It also became clear that some patients required increased sedation to improve ventilation.

Prolonged Sedation is Linked to Hypoxia, Not Viral Infection

For those with COVID-19, sedation periods can last several weeks, much longer than those recovering from an operation or for someone with pneumonia in an intensive care unit (ICU).

Sedation is further impacted by the type of anesthetic given, as well as the inherent metabolism as a result of sedation.

"Some fat-soluble sedatives, such as propofol, may prolong anesthetization and contribute to patients not waking up," says Dr. Brown. "SARS-CoV-2 damages blood vessels, which affects blood pressure, inflammation and blood clotting. Patients have many emboli affecting their liver and kidneys, altering the metabolism of sedatives, which can affect the duration of sedation."

Because long-term sedation for COVID-19 patients could last several weeks, prolonged sedation increases the chance of hypoxia and causes neurological trauma.

A recent study in the New England Journal of Medicine by Shibani Mukerji, MD, PhD, associate director of the Neuro-Infectious Diseases Unit at Mass General, shows that post-mortem brains of ventilated COVID-19 patients have hypoxic injury. Dr. Mukerji and her collaborators found brain injury in several regions critical for cognitive function.

"You're more likely to have hypoxic-ischemic injury in prolonged ventilation patients. We found global injury in the frontal lobe, hippocampus and cerebellum," says Dr. Mukerji.

Clinical researchers thought that SARS-CoV-2 would infect the brain and that injury to the brain would be due, in part, to blood clots.

"We didn't find the virus in neurons using immunohistochemistry. We couldn't argue that hypoxic injury was due to direct infection," notes Dr. Mukerji. "There's no consistent report that shows direct central nervous system infection, looking at PCR assay in intubated patients with prolonged sedation."

SARS-CoV-2 potentially causes coagulability, thromboses and thus the risk for blood clots. It follows that the myriad of embolic events has the potential to send blood clots to any and all organs. "Blood clots have these very deleterious effects, essentially blocking off the circulation," says Dr. Brown.

"We didn't see a large number of clots to speak to the amount of hypoxic injury," says Dr. Mukerji. "That's still up for debate and that's still a consideration."

Anesthesia-induced Delirium

Prolonged sedation likely increases the incidence of delirium and cognitive dysfunction. Anesthesia-induced delirium has been highly prominent in medical literature over the past decade and is associated with ventilation.

"It is worse in older patients, those who are quite ill and is associated with certain drugs such as midazolam, haloperidol and opiates like hydromorphone," says Dr. Brown.

Now, many COVID-19 patients are struggling with delirium and cognitive dysfunction.

"We can likely mitigate this dysfunction by using the EEG to monitor brain state and guide anesthetic dosing," says Dr. Brown. "If we accelerate our emphasis on trying to use neuroscience in a more principled way, it will pay dividends for these ICU patients, whether they are being treated for COVID-19 or otherwise.

Eyal Y. Kimchi, MD, PhD, neurologist and primary investigator of the Delirium Lab at Mass General, seeks to determine the cause and find ways to treat delirium.

"We have studied brain rhythms in patients with COVID-19 using EEG, and have found that patients with COVID-19 have abnormal brain rhythms. At least some of the abnormalities appear to be linked with recent sedation," says Dr. Kimchi.

Researchers have made significant gains understanding the mechanisms of delirium.

"Physicians have made strides developing screening tools and decreasing burden on patients, primarily through the prevention of delirium, for example by limiting or fine-tuning the sedatives that patients receive," says Dr. Kimchi.

Still, those with COVID-19 present a unique challenge when treating delirium.

Dr. Kimchi relates that "the heavy sedation that we feel compelled to use in caring for patients with COVID-19, like other aspects of COVID-19 management, may be creating new challenges to prevent delirium."

Although the links between COVID-19, neurological symptoms and underlying brain dysfunction remain unclear, researchers are refining treatment plans for patients, clarifying the effects of SARS-CoV-2 on the brain and linking neurological symptoms like delirium to brain activity.

Dr. Brown is hopeful. "We now have a bit of perspective, and we can start to put the stories together, think about pathophysiologic mechanisms and help define the symptoms that we saw," he says. "That's what we're doing now."

Learn more about the Department of Neurology

Learn more about research in the Department of Neurology