According to the best available evidence, analagosedation remains the focus for managing COVID-19 ICU patients, according to Steven B. Greenberg, MD, FCCP, FCCM.
Dr. Steven B. Greenberg
“The choice of sedation and analgesia is important,” Dr. Greenberg, vice chair of education in the department of anesthesiology at Evanston Hospital, part of NorthShore University Health System, Chicago, said at a Society for Critical Care virtual meeting: COVID-19: What’s Next. “We know that the right choice of these two components may increase liberation from ventilators, earlier ICU discharge, and return to normal brain function and independent functional status.”
Analgesia first
Prior to the current pandemic, the approach to sedation of patients in the ICU was based on the PADIS Guidelines of 2018, which call for an assessment-driven, protocol-based stepwise approach to pain and sedation management in critically ill adults (Crit Care Med. 2018;46:e825-73). “” Dr. Greenberg said. “We know that pain management should be a priority of sedation, because pain may increase the risk of delirium, anxiety, and endocrine suppression, and may increase the risk of release of endogenous catecholamines, ischemia, and hypermetabolic states.”
Fentanyl appears to be the most common opioid analgesic used for patients in the ICU, “but fentanyl is a very lipophilic drug and has a long context-sensitive half-life,” he said. “There are components to fentanyl that allow it to become a very long-acting drug upon days and days of infusion. Another opioid used is remifentanil, which is typically short-acting because it is broken down in the blood by esterases, but may cause rigidity at higher doses. Dilaudid seems to be the least affected by organ dysfunction. In our very critically ill, prolonged mechanically ventilated COVID-19 patients, we’ve been using methadone for its NMDA [N-methyl-D-aspartate] antagonistic effect and its opioid-sparing effects.”
As for nonopioid analgesics, Dr. Greenberg said that clinicians have shied away from using NSAIDs because of their side effects. “Tramadol indirectly inhibits reuptake of norepinephrine and serotonin, and ketamine is being used a lot more because of its NMDA antagonist effect,” he said. “Lidocaine and gabapentin have also been used.”
In a recent systematic review and meta-analysis, researchers assessed 34 trials that examined adjuvant analgesic use with an opioid in critically ill patients versus an opioid alone (Crit Care Expl. 2020;2:e0157). They found that when using an adjuvant such as acetaminophen, clonidine, dexmedetomidine, gabapentin, ketamine, magnesium, nefopam, NSAIDs, pregabalin, and tramadol, there was a reduction in pain scores as well as a reduction in opioid consumption. “So, clinicians should consider using adjuvant agents to limit opioid exposure and improve pain scores in the critically ill,” Dr. Greenberg said.
ICU delirium: Risk factors, prevention
Delirium in COVID-19 patients treated in the ICU of particular concern. According to a systematic review of 33 studies, 11 risk factors for delirium in the ICU were supported by strong or moderate levels of evidence (Crit Care Med. 2015;43:40-7). These include age, dementia, hypertension, emergency surgery, trauma, APACHE score of II, need for mechanical ventilation, metabolic acidosis, delirium on prior day, coma, and dexmedetomidine use. Risk factors for ICU delirium among COVID-19 patients, however, “are far different,” Dr. Greenberg said. “Why? First and foremost, we are restricting visitation of family,” he said. “That family connection largely can be lost. Second, there are limitations of nonpharmacologic interventions. There is less mobility and physical therapy employed because of the risk of health care workers’ exposure to the virus. There’s also uncertainty about the global pandemic. Anxiety and depression come with that, as well as disruptions to spiritual and religious services.”
Strategies for preventing delirium remain the same as before the pandemic and in accord with recent clinical practice guidelines: Reduce the use of certain drugs such as benzodiazepines and narcotics, reorient the patients, treat dehydration, use hearing aids and eyeglasses in patients who have them, use ear plugs to cancel noise, mobilize patients, maintain sleep/awake cycles, and encourage sedation holidays (Crit Care Med. 2018;46[9]:e825-73).
A recent study from France found that among 58 patients with COVID-19, 65% had positive Confusion Assessment Method (CAM)–ICU findings and 69% had agitation (N Engl J Med 2020;382:2268-70). Most of the patients (86%) received midazolam, 47% received propofol, and all received sufentanil. “In the pre-COVID days, we would use midazolam as a second-line agent for many of these patients,” Dr. Greenberg said. “So, times really have changed.”
The fate of COVID-19 patients following discharge from the ICU remains a concern, continued Dr. Greenberg, clinical professor of anesthesiology at the University of Chicago. A recent journal article by Michelle Biehl, MD, and Denise Sese, MD, noted that post–intensive care syndrome (PICS) or new or worsening impairment in any physical, cognitive, or mental domain is of significant concern among COVID-19 patients following their ICU stay (Cleveland Clin J Med 2020 Aug doi: 10.3949/ccjm.87a.ccc055). The authors stated that COVID-19 patients may face a higher risk of PICS because of restricted family visitation, prolonged mechanical ventilation, exposure to higher amounts of sedatives, and limited physical therapy during hospital stay.
No ideal sedative agent
The 2018 PADIS Guidelines on the use of ICU sedation suggested strong evidence for modifiable risk factors producing delirium in the context of benzodiazepines and blood transfusion. They recommend a light level of sedation and the use of propofol or dexmedetomidine over benzodiazepines. They also recommend routine delirium testing such as using the CAM-ICU or Intensive Care Delirium Screening Checklist (ICDSC) and nonpharmacologic therapies such as reorientation, cognitive stimulation, sleep improvement, and mobilization.
Several sedation-related factors may be related to an increased risk of delirium. “The type, dose, duration, and mode of delivery are very important,” Dr. Greenberg said. “The ideal sedative agent has a rapid, predictable onset; is short-acting; has anxiolytic, amnestic, and analgesic properties; is soluble; has a high therapeutic index; and no toxicity. The ideal sedative is also easy to administrate, contains no active metabolites, has minimal actions with other drugs, is reversible, and is cost effective. The problem is, there really is no ideal sedative agent. There is inadequate knowledge about the drugs [used to treat COVID-19 in the ICU] available to us, the dosage, and importantly, the pharmacokinetics and dynamics of these medications.”
The classic types of sedation being used in the ICU, he said, include the benzodiazepines midazolam, lorazepam, and diazepam, as well as propofol. Alternatives include dexmedetomidine, clonidine, ketamine, and the neuroleptics – haloperidol, quetiapine, olanzapine, ziprasidone, and risperidone. “The advantages of benzos are that they are anxiolytics, amnestics, and they are good sedatives with minimal hemodynamic effects,” Dr. Greenberg said.
Advantages of propofol include its sedative, hypnotic, and anxiolytic properties, he said. It reduces the cerebral metabolic rate and can relieve bronchospasm. “However, small studies have found that its use may be associated with an increased risk of delirium,” he said. “It is a respiratory depressant, and it can cause hypotension and decreased contractility. It has no analgesic properties, and two of the big concerns of its use in COVID-19 are the potential for hypertriglyceridemia and propofol infusion syndrome, particularly at doses of greater than 5 mg/kg per hour for greater than 48 hours. It is being given in high doses because patients are requiring higher doses to maintain ventilator synchrony.”