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According to the best available evidence, analagosedation remains the focus for managing COVID-19 ICU patients, according to Steven B. Greenberg, MD, FCCP, FCCM.
“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.”
Choosing the right drug
The keys to success for sedation of ICU patients are choosing the right drug at the right dose for the right duration and the right mode of delivery, and applying them to the right population. However, as noted in a recent study, the pandemic poses unique challenges to clinicians in how they care for critically ill COVID-19 patients who require sedation (Anesth Analg. 2020 Apr 22. doi: 10.1213/ANE.0000000000004887). The use of provisional work areas “has escalated because of the amount of patients we’ve had to care for over the past nine months,” Dr. Greenberg said. “We’ve used alternate providers who are not necessarily familiar with the sedation and analgesic protocols and how to use these specific medications. Drug shortages have been on the rise, so there’s a need to understand alternative agents that can be used.”
COVID-19 patients face the potential risk for an increase in drug-drug interactions and side effects due to the polypharmacy that is often required to provide adequate sedation during mechanical ventilation. He noted that these patients may have “unusually high” analgesia and sedation requirements, particularly when they’re mechanically ventilated. A hypothesis as to why patients with COVID-19 require so much sedation and analgesia is that they often have a high respiratory drive and ventilator dyssynchrony, which requires increased neuromuscular blockade. “They also have an intense inflammatory response, which may be linked to tolerance of specific opioids and other medications,” Dr. Greenberg said. “Many ventilated COVID-19 patients are of younger age and previously in good health, and therefore, have an excellent metabolism. Health care providers are concerned about self-extubation. This prompts bedside providers to administer more sedatives to prevent this unwanted complication. There may also be a reduction of drip modifications by health care workers because of the potential risk of contracting COVID-19 when going into the room multiple times and for long periods of time” (Anesth Analg. 2020;131[1]:e34-e35).
According to a sedation resource on the SCCM website, about 5% of COVID-19 patients require mechanical ventilation. “There has been a massive shortage of the usual drugs that we use,” Dr. Greenberg said. “The demand for sedatives has increased by approximately 91%, while the demand for analgesics has increased by 79%, and neuromuscular blocker demand has increased by 105%.”
A retrospective study of 24 COVID-19 patients who required ventilation in the ICU found that the median daily dose of benzodiazepines was significantly higher, compared with the median daily dose used in the OSCILLATE trial (a median of 270 mg vs. 199 mg, respectively; Anesth Analg. 2020;131[4]e198-e200. doi: 10.1213/ane.0000000000005131). In addition, their median daily dose of opioid was approximately three times higher, compared with patients in the OSCILLATE trial (a median of 775 mg vs. 289 mg). Other agents used included propofol (84%), dexmedetomidine (53%), and ketamine (11%).
“A potential strategy for COVID-19 ICU patient sedation should be analgesia first, as indicated in the 2018 PADIS guidelines,” Dr. Greenberg advised. “We should also apply nonpharmacologic measures to reduce delirium. In nonintubated patients, we should use light to moderate sedation, targeting a RASS of –2 to +1, using hydromorphone or fentanyl boluses for analgesia and midazolam boluses or dexmedetomidine for sedation,.”
For intubated patients, he continued, target a RASS of –3 to –4, or –4 to –5 in those who require neuromuscular blockade. “Use propofol first then intermittent boluses of benzodiazepines,” said Dr. Greenberg, editor-in-chief of the Anesthesia Patient Safety Foundation newsletter. “For heavy sedation, use midazolam and supplement with ketamine and other analgesics and sedatives such as barbiturates, methadone, and even inhalation anesthetics in some cases.”
For analgesia in intubated patients, use fentanyl boluses then infusion. “Patients can easily become tachyphylactic to fentanyl, and it has a long context-sensitive half time,” he said. “Hydromorphone may be least affected by organ dysfunction.”
Dr. Greenberg concluded his presentation by stating that more studies are required “to delineate the best analgesia/sedation strategies and monitoring modalities for COVID-19 ICU patients.”
In commenting on the presentation, Mangala Narasimhan, DO, FCCP, senior vice president and director of critical care services at Northwell Health, said that the recommendations regarding sedation highlight a struggle that ICU providers have been dealing with during the COVID-19 epidemic.
“There have been unique challenges with COVID-19 and intubated patients. We have seen severe ventilator dyssynchrony and prolonged duration of mechanical ventilation. I think we can all agree that these patients have extremely high metabolic rates, have required high levels of sedation, have an increased need for neuromuscular blockade, and have high levels of delirium for extended periods of time. The recommendations provided here are reasonable. Strategies to prevent delirium should be employed, pain management should be prioritized, analgesics can help reduce the need for opioids. Alternatives to sedation are useful in this patient population and are well tolerated. Drug shortages have provided additional challenges to these strategies and have required us to think about the use of alternative agents. The recommendations echo the experience we have had with large numbers of intubated COVID-19 patients.”
Dr. Greenberg disclosed that he receives a stipend from the Anesthesia Patient Safety Foundation for serving as editor-in-chief of the foundation’s newsletter.
According to the best available evidence, analagosedation remains the focus for managing COVID-19 ICU patients, according to Steven B. Greenberg, MD, FCCP, FCCM.
“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.”
Choosing the right drug
The keys to success for sedation of ICU patients are choosing the right drug at the right dose for the right duration and the right mode of delivery, and applying them to the right population. However, as noted in a recent study, the pandemic poses unique challenges to clinicians in how they care for critically ill COVID-19 patients who require sedation (Anesth Analg. 2020 Apr 22. doi: 10.1213/ANE.0000000000004887). The use of provisional work areas “has escalated because of the amount of patients we’ve had to care for over the past nine months,” Dr. Greenberg said. “We’ve used alternate providers who are not necessarily familiar with the sedation and analgesic protocols and how to use these specific medications. Drug shortages have been on the rise, so there’s a need to understand alternative agents that can be used.”
COVID-19 patients face the potential risk for an increase in drug-drug interactions and side effects due to the polypharmacy that is often required to provide adequate sedation during mechanical ventilation. He noted that these patients may have “unusually high” analgesia and sedation requirements, particularly when they’re mechanically ventilated. A hypothesis as to why patients with COVID-19 require so much sedation and analgesia is that they often have a high respiratory drive and ventilator dyssynchrony, which requires increased neuromuscular blockade. “They also have an intense inflammatory response, which may be linked to tolerance of specific opioids and other medications,” Dr. Greenberg said. “Many ventilated COVID-19 patients are of younger age and previously in good health, and therefore, have an excellent metabolism. Health care providers are concerned about self-extubation. This prompts bedside providers to administer more sedatives to prevent this unwanted complication. There may also be a reduction of drip modifications by health care workers because of the potential risk of contracting COVID-19 when going into the room multiple times and for long periods of time” (Anesth Analg. 2020;131[1]:e34-e35).
According to a sedation resource on the SCCM website, about 5% of COVID-19 patients require mechanical ventilation. “There has been a massive shortage of the usual drugs that we use,” Dr. Greenberg said. “The demand for sedatives has increased by approximately 91%, while the demand for analgesics has increased by 79%, and neuromuscular blocker demand has increased by 105%.”
A retrospective study of 24 COVID-19 patients who required ventilation in the ICU found that the median daily dose of benzodiazepines was significantly higher, compared with the median daily dose used in the OSCILLATE trial (a median of 270 mg vs. 199 mg, respectively; Anesth Analg. 2020;131[4]e198-e200. doi: 10.1213/ane.0000000000005131). In addition, their median daily dose of opioid was approximately three times higher, compared with patients in the OSCILLATE trial (a median of 775 mg vs. 289 mg). Other agents used included propofol (84%), dexmedetomidine (53%), and ketamine (11%).
“A potential strategy for COVID-19 ICU patient sedation should be analgesia first, as indicated in the 2018 PADIS guidelines,” Dr. Greenberg advised. “We should also apply nonpharmacologic measures to reduce delirium. In nonintubated patients, we should use light to moderate sedation, targeting a RASS of –2 to +1, using hydromorphone or fentanyl boluses for analgesia and midazolam boluses or dexmedetomidine for sedation,.”
For intubated patients, he continued, target a RASS of –3 to –4, or –4 to –5 in those who require neuromuscular blockade. “Use propofol first then intermittent boluses of benzodiazepines,” said Dr. Greenberg, editor-in-chief of the Anesthesia Patient Safety Foundation newsletter. “For heavy sedation, use midazolam and supplement with ketamine and other analgesics and sedatives such as barbiturates, methadone, and even inhalation anesthetics in some cases.”
For analgesia in intubated patients, use fentanyl boluses then infusion. “Patients can easily become tachyphylactic to fentanyl, and it has a long context-sensitive half time,” he said. “Hydromorphone may be least affected by organ dysfunction.”
Dr. Greenberg concluded his presentation by stating that more studies are required “to delineate the best analgesia/sedation strategies and monitoring modalities for COVID-19 ICU patients.”
In commenting on the presentation, Mangala Narasimhan, DO, FCCP, senior vice president and director of critical care services at Northwell Health, said that the recommendations regarding sedation highlight a struggle that ICU providers have been dealing with during the COVID-19 epidemic.
“There have been unique challenges with COVID-19 and intubated patients. We have seen severe ventilator dyssynchrony and prolonged duration of mechanical ventilation. I think we can all agree that these patients have extremely high metabolic rates, have required high levels of sedation, have an increased need for neuromuscular blockade, and have high levels of delirium for extended periods of time. The recommendations provided here are reasonable. Strategies to prevent delirium should be employed, pain management should be prioritized, analgesics can help reduce the need for opioids. Alternatives to sedation are useful in this patient population and are well tolerated. Drug shortages have provided additional challenges to these strategies and have required us to think about the use of alternative agents. The recommendations echo the experience we have had with large numbers of intubated COVID-19 patients.”
Dr. Greenberg disclosed that he receives a stipend from the Anesthesia Patient Safety Foundation for serving as editor-in-chief of the foundation’s newsletter.
According to the best available evidence, analagosedation remains the focus for managing COVID-19 ICU patients, according to Steven B. Greenberg, MD, FCCP, FCCM.
“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.”
Choosing the right drug
The keys to success for sedation of ICU patients are choosing the right drug at the right dose for the right duration and the right mode of delivery, and applying them to the right population. However, as noted in a recent study, the pandemic poses unique challenges to clinicians in how they care for critically ill COVID-19 patients who require sedation (Anesth Analg. 2020 Apr 22. doi: 10.1213/ANE.0000000000004887). The use of provisional work areas “has escalated because of the amount of patients we’ve had to care for over the past nine months,” Dr. Greenberg said. “We’ve used alternate providers who are not necessarily familiar with the sedation and analgesic protocols and how to use these specific medications. Drug shortages have been on the rise, so there’s a need to understand alternative agents that can be used.”
COVID-19 patients face the potential risk for an increase in drug-drug interactions and side effects due to the polypharmacy that is often required to provide adequate sedation during mechanical ventilation. He noted that these patients may have “unusually high” analgesia and sedation requirements, particularly when they’re mechanically ventilated. A hypothesis as to why patients with COVID-19 require so much sedation and analgesia is that they often have a high respiratory drive and ventilator dyssynchrony, which requires increased neuromuscular blockade. “They also have an intense inflammatory response, which may be linked to tolerance of specific opioids and other medications,” Dr. Greenberg said. “Many ventilated COVID-19 patients are of younger age and previously in good health, and therefore, have an excellent metabolism. Health care providers are concerned about self-extubation. This prompts bedside providers to administer more sedatives to prevent this unwanted complication. There may also be a reduction of drip modifications by health care workers because of the potential risk of contracting COVID-19 when going into the room multiple times and for long periods of time” (Anesth Analg. 2020;131[1]:e34-e35).
According to a sedation resource on the SCCM website, about 5% of COVID-19 patients require mechanical ventilation. “There has been a massive shortage of the usual drugs that we use,” Dr. Greenberg said. “The demand for sedatives has increased by approximately 91%, while the demand for analgesics has increased by 79%, and neuromuscular blocker demand has increased by 105%.”
A retrospective study of 24 COVID-19 patients who required ventilation in the ICU found that the median daily dose of benzodiazepines was significantly higher, compared with the median daily dose used in the OSCILLATE trial (a median of 270 mg vs. 199 mg, respectively; Anesth Analg. 2020;131[4]e198-e200. doi: 10.1213/ane.0000000000005131). In addition, their median daily dose of opioid was approximately three times higher, compared with patients in the OSCILLATE trial (a median of 775 mg vs. 289 mg). Other agents used included propofol (84%), dexmedetomidine (53%), and ketamine (11%).
“A potential strategy for COVID-19 ICU patient sedation should be analgesia first, as indicated in the 2018 PADIS guidelines,” Dr. Greenberg advised. “We should also apply nonpharmacologic measures to reduce delirium. In nonintubated patients, we should use light to moderate sedation, targeting a RASS of –2 to +1, using hydromorphone or fentanyl boluses for analgesia and midazolam boluses or dexmedetomidine for sedation,.”
For intubated patients, he continued, target a RASS of –3 to –4, or –4 to –5 in those who require neuromuscular blockade. “Use propofol first then intermittent boluses of benzodiazepines,” said Dr. Greenberg, editor-in-chief of the Anesthesia Patient Safety Foundation newsletter. “For heavy sedation, use midazolam and supplement with ketamine and other analgesics and sedatives such as barbiturates, methadone, and even inhalation anesthetics in some cases.”
For analgesia in intubated patients, use fentanyl boluses then infusion. “Patients can easily become tachyphylactic to fentanyl, and it has a long context-sensitive half time,” he said. “Hydromorphone may be least affected by organ dysfunction.”
Dr. Greenberg concluded his presentation by stating that more studies are required “to delineate the best analgesia/sedation strategies and monitoring modalities for COVID-19 ICU patients.”
In commenting on the presentation, Mangala Narasimhan, DO, FCCP, senior vice president and director of critical care services at Northwell Health, said that the recommendations regarding sedation highlight a struggle that ICU providers have been dealing with during the COVID-19 epidemic.
“There have been unique challenges with COVID-19 and intubated patients. We have seen severe ventilator dyssynchrony and prolonged duration of mechanical ventilation. I think we can all agree that these patients have extremely high metabolic rates, have required high levels of sedation, have an increased need for neuromuscular blockade, and have high levels of delirium for extended periods of time. The recommendations provided here are reasonable. Strategies to prevent delirium should be employed, pain management should be prioritized, analgesics can help reduce the need for opioids. Alternatives to sedation are useful in this patient population and are well tolerated. Drug shortages have provided additional challenges to these strategies and have required us to think about the use of alternative agents. The recommendations echo the experience we have had with large numbers of intubated COVID-19 patients.”
Dr. Greenberg disclosed that he receives a stipend from the Anesthesia Patient Safety Foundation for serving as editor-in-chief of the foundation’s newsletter.
FROM AN SCCM VIRTUAL MEETING