Analytic Review Journal of Intensive Care Medicine 2021, Vol. 36(2) 157-174 ª The Author(s) 2020 Sedation, Analgesia, and Paralysis Article reuse guidelines: sagepub.com/journals-permissions in COVID-19 Patients in the Setting DOI: 10.1177/0885066620951426 of Drug Shortages journals.sagepub.com/home/jic Mahmoud A. Ammar, PharmD, BCPS, BCCCP1 , Gretchen L. Sacha, PharmD, BCCCP2 , Sarah C. Welch, PharmD, BCCCP2, Stephanie N. Bass, PharmD, BCCCP2, Sandra L. Kane-Gill, PharmD, MS, FCCM, FCCP3, Abhijit Duggal, MD, MPH, MSc4, and Abdalla A. Ammar, PharmD, BCPS, BCCCP1 Abstract The rapid spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a global pandemic. The 2019 coronavirus disease (COVID-19) presents with a spectrum of symptoms ranging from mild to critical illness requiring intensive care unit (ICU) admission. Acute respiratory distress syndrome is a major complication in patients with severe COVID-19 disease. Currently, there are no recognized pharmacological therapies for COVID-19. However, a large number of COVID- 19 patients require respiratory support, with a high percentage requiring invasive ventilation. The rapid spread of the infection has led to a surge in the rate of hospitalizations and ICU admissions, which created a challenge to public health, research, and medical communities. The high demand for several therapies, including sedatives, analgesics, and paralytics, that are often utilized in the care of COVID-19 patients requiring mechanical ventilation, has created pressure on the supply chain resulting in shortages in these critical medications. This has led clinicians to develop conservation strategies and explore alternative therapies for sedation, analgesia, and paralysis in COVID-19 patients. Several of these alternative approaches have demonstrated acceptable levels of sedation, analgesia, and paralysis in different settings but they are not commonly used in the ICU. Additionally, they have unique pharmaceutical properties, limitations, and adverse effects. This narrative review summarizes the literature on alternative drug therapies for the management of sedation, analgesia, and paralysis in COVID-19 patients. Also, this document serves as a resource for clinicians in current and future respiratory illness pandemics in the setting of drug shortages. Keywords sedation, analgesia, paralysis, ARDS, COVID, respiratory failure Introduction up to 42% of patients.4,6,7 Patients with ARDS may need mod- erate to deep levels of analgesia and sedation to lower their Severe acute respiratory syndrome coronavirus-2 (SARS- respiratory drive in order to optimize their respiratory status.8 CoV-2) is the pathogen responsible for the 2019 coronavirus Additionally, neuromuscular blocking agents in ARDS facili- disease (COVID-19) pandemic which has affected over tate ventilator synchrony.9 The surge in critically ill patients 10.5 million people and led to over 500,000 deaths as of June created an increased demand for these therapies, in addition to 2020.1,2 Early cases of the COVID-19 infection were reported in Wuhan, China, in December 2019 and have since spread around the world creating a global health threat.3 The most 1 Department of Pharmacy, Yale-New Haven Health System, New Haven, CT, common symptoms at onset of illness include fever, cough, 4 USA and myalgia or fatigue. In a subset of patients, the disease can 2 Department of Pharmacy, Cleveland Clinic, Cleveland, OH, USA progress to pneumonia and acute respiratory failure requiring 3 School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA theneedforICUadmissioninupto26% of patients with 4 Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA anywhere from 4-33% of patients requiring invasive mechan- 4-7 Corresponding Author: ical ventilation. Mahmoud A. Ammar, Department of Pharmacy, Yale-New Haven Health COVID-19 associated pneumonia can be complicated by the System, 20 York Street, New Haven, CT 06510, USA. development of acute respiratory distress syndrome (ARDS) in Email: [email protected] 158 Journal of Intensive Care Medicine 36(2) the extraordinary doses of sedatives and analgesics that indi- national medication error database reported that hydromor- vidual COVID-19 patients are requiring, resulting in drug phone had significantly higher dose-related errors and these shortages10,11 which can significantly impact the quality of errors were significantly more likely to be overdoses.33 care and safety of patients.12,13 Currently, there are 10 sedative and analgesic agents on the FDA and American Society of Alternative Therapies for Analgesia in COVID-19 Patients Health-System Pharmacists shortage databases including pro- pofol and dexmedetomidine.10,11 It is unfortunate, but these Remifentanil is a selective mu-opioid receptor agonist with shortages are only likely to worsen as the pandemic progresses, pharmacodynamic properties similar to fentanyl and should making utilization of more costly alternatives and unfamiliar be considered in contingency care. Unlike fentanyl, remifenta- medications a reality. With any large-scale event including a nil is rapidly metabolized by blood and tissue esterases; there- pandemic that leads to critical care patient surges, surge capac- fore, it has a very short duration of action independent of the ity and response is measured based on 3 levels: conventional duration of infusion.22 Remifentanil can be an alternative to care, contingency care, and crisis care.14 Contingency care fentanyl for analgesia, however, the use of remifentanil has includes those practices that may be outside usual care but they been associated with a higher incidence of hypotension com- attempt to maintain usual care, while crisis care practices are pared to fentanyl.23 A multicenter, double blind, randomized, outside of standard of care but provide the best feasible care control trial included mixed ICU mechanically ventilated when resources are severely limited.14 The purpose of this patients compared the efficacy and safety of remifentanil to narrative review is to provide recommendations for alternative fentanyl for sedation and analgesia. This study reported no drug therapies and suggested strategies to preserve existing difference in the time spent in optimal sedation level, 88.3% medication supplies for the management of sedation, analgesia in remifentanil versus 89.3% in fentanyl. Additionally, patients and paralysis in COVID-19 patients in the setting of drug who received remifentanil exhibited significantly less between- shortages and patient surges. This article will mainly review patient variability in optimal sedation compared to fentanyl drug therapies and medication practices to be considered in the (p ¼ 0.009). However, remifentanil patients experienced pain setting of conventional, contingency, and crisis care. In addi- significantly longer during extubation, postextubation, and tion, this will be a useful resource if future shortages occur. post-treatment (p < 0.05 for all comparisons) due to rapid offset of analgesia with remifentanil. There were no differences in hemodynamic instability or adverse events.34 Due to the short Analgesia Strategies in COVID-19 Patients half-life of remifentanil, it is prudent to ensure adequate pain Recommended Therapies for Analgesia in COVID-19 management prior to discontinuation to prevent withdrawal symptoms.24 Patients The ultra-short-acting opioids, sufentanil and alfentanil, are Critically ill patients, including COVID-19 patients, will expe- not commonly used in the ICUs but may be options in the rience pain and distress due to their underlying respiratory setting of severe drug shortages and crisis care. Sufentanil and disease and invasive procedures, primarily mechanical ventila- alfentanil are 5 to 10 times more potent than fentanyl. As such, tion.15 Opioids are the cornerstone of pain management in in patients receiving high doses of fentanyl, sufentanil and critically ill patients. Commonly used intravenous (IV) analge- alfentanil can conserve fentanyl infusion volume and dose sics in mechanically ventilated patients include fentanyl, mor- requirements.25,35 Sufentanil is also available as sublingual phine, and hydromorphone (Table 1). tablet, with 53% bioavailability which blunts the high serum Fentanyl is the most commonly used synthetic opioid for sufentanil levels seen with the IV route, decreasing the risk of analgesia in conventional care due to its distinctive pharmaco- adverse events with inappropriate use of high-dose IV kinetics. However, continuous infusions of fentanyl may lead sufentanil.26 to prolonged and unpredictable clearance that can extend 16 beyond infusion discontinuation. Although, it is uncommon, Conservation Strategies for Analgesia in COVID-19 clinicians should be cautious with the use of rapid bolus doses of fentanyl in COVID-19 patients as rapid IV fentanyl infusion Patients has been associated with chest wall rigidity, which can In critically ill, mechanically ventilated patients, IV adminis- decrease chest wall compliance and lead to inadequate sponta- tration of opioids is often preferred. One of the recommended neous ventilation. This can lead to challenges in utilizing strategies to conserve intravenous analgesic supplies during assisted ventilation.17 contingency care is to implement protocols where clinicians Morphine and hydromorphone are other commonly used would initially utilize intermittent bolus analgesic doses prior opioids for analgesia in the ICU for conventional care. In the to transitioning