By Bruce Buckley

The rate of delirium is rising sharply in many hospital ICUs as more mechanically ventilated patients with COVID-19 are kept under deep and prolonged sedation, often without the evidence-based interventions that could decrease their confusion and agitation and shorten ventilator time.

“We’ve been working for 20 years, and we’ve reduced delirium down from 70% in ventilated patients to around 40%,” said E. Wesley Ely, MD, MPH, a professor of medicine and critical care at Vanderbilt University Medical Center in Nashville, Tenn. “But COVID-19 has got it back up to 80%. So in three months, we’re erased 20 years of progress.”

A major factor in the resurgence is the growing shortage of first-line medications for managing the pain, agitation and confusion that patients on ventilators typically experience, and the increasing use of benzodiazepines for sedation.

“It’s going to be tough because of the prolonged nature of COVID-19 and because there are medication shortages, but when possible we need to get away from benzodiazepines,” Dr. Ely said.

In a New England Journal of Medicine case series that came out in April (doi: 10.1056/NEJMc2008597), 50 of 58 patients (86%) with COVID-19 received a benzodiazepine (midazolam), Dr. Ely noted. “We stopped using benzodiazepines years ago because of how deliriogenic they are,” he said. “To see 86% of people on a ventilator getting a benzodiazepine is like going back to how we practiced in 1995.”

Dr. Ely, who is also the co-director of Vanderbilt’s and Veterans Affairs’ Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center, is an advocate for a protocol known as the A2F (ABCDEF) Bundle, which focuses specifically on the prevention and treatment of delirium

“This is a six-step approach to taking care of patients in the ICU, where we modify sedation, try to avoid benzodiazepines, and try to wake people up and get them out of the bed,” Dr. Ely said.

The increasing number of COVID-19 patients with acute respiratory distress syndrome has stretched the ability of some hospitals to keep up with the shortages of drugs, personal protective equipment (PPE), and critical care physicians and nurses needed to treat them. Some hospitals find it easier to keep patients deeply sedated instead of implementing the A2F Bundle.

Another factor is fear of viral transmission at the bedside of COVID-19 patients.

“People are just scared,” said Joanna L. Stollings, PharmD, BCPS, BCCCP, a medical ICU critical care pharmacy specialist at Vanderbilt University Medical Center. “It’s a new virus and we don’t completely understand how it’s transmitted. Providers are sometimes afraid to go in and see the patients, not necessarily because they are afraid of contracting the virus but because they are afraid of transmitting it to someone else, and are trying to conserve PPE. Because of that, we’re having trouble implementing some of the letters in the bundle.”

These include the spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs) described in the letter B of the ABCDEF bundle, Dr. Stollings said, and the early mobility and exercise called for in letter E. Both steps have been shown to facilitate a reduced need for sedation and earlier removal from the ventilator.

The importance of family involvement and empowerment in ICU patient recovery (letter F) has been another casualty in the delirium reduction protocol, as hospitals with COVID-19 in their ICUs bar family visits out of fear of transmission. “When people become delirious [letter D in the bundle], we know medications typically don’t work to prevent or treat this,” Dr. Stollings said. “So one intervention that we might use is to have the family reassure and calm the patient.” But that option has been virtually eliminated by the need to curb transmission of the virus. “We have had to get creative and use things like phones and tablets to allow patients to communicate with their families,” she added.

Drug Shortages Force Substitutions

Dr. Stollings cited other factors in the resurgence of ICU delirium, including the growing shortage of medications used to induce sedation in ventilated patients. She noted that guidelines for managing pain, agitation and delirium recommend the use of dexmedetomidine or propofol for sedation, two drugs currently in short supply. Because of this, she added, critical care physicians are forced to use benzodiazepines, such as midazolam or lorazepam, to induce sedation. “We’ve done a fair amount of research to show that these agents can cause delirium,” Dr. Stollings said.

“Then there’s the shortage of PPE,” she added, including the N95 respirators and powered air-purifying respirators that reduce the risk for viral exposure among physicians and nurses when they enter patients’ rooms.

Dr. Stollings works in the medical ICU every day, rounding with physicians and helping them to decide what medications to prescribe and what not to prescribe. “I look for drug interactions and make sure everything is cost-effective,” she said. “I’m wearing scrubs for the first time and wearing a mask. We’ve had a shortage of fentanyl, for example, so I help them figure out different pain medications we can use so patients have adequate pain therapy.”

An Algorithm for Delirium Treatment

So far, Vanderbilt Medical Center has avoided the surge in critically ill COVID-19 patients that has struck other health systems. Dr. Stollings has developed a tiered algorithm for the use of ventilation medications “as we get more of these patients and experience more shortages.”

The algorithm, she said, has been submitted for publication and hopefully will be available soon for others to use to guide alternative treatment of pain and agitation. It suggests different options to consider, for example, when first-line sedation drugs and even less optimal second-line agents, such as the benzodiazepines, become unavailable. “When you get deeper into the algorithm,” Dr. Stollings said, “you’re thinking about things like antipsychotics,” such as haloperidol or drugs like ketamine, “which have limited data in medical, critically ill patients.”

Speaking of alternative therapies for delirium, Dr. Ely said: “What doctors in hotbeds of COVID-19 are telling me they are doing is transitioning to shorter-acting drugs for less time, even antipsychotics, though not for delirium—they don’t treat delirium—but at least they can calm the patient and they won’t cause respiratory suppression. They won’t keep patients on the ventilator longer. So, antipsychotics, the alpha-2 agonists—clonidine and dexmedetomidine—these choices will at least not suppress the respiratory drive and won’t build up as much.”