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 patients to continuous infusion of analgesia. setting of drug shortages, hydromorphone can be an appropri- Additionally, providing opioids and analgesics enterally can ate alternative to fentanyl and morphine. However, caution assist with conserving supply of IV agents.36 This strategy should be taken when using hydromorphone as an alternative should be limited to patients with adequate gastrointestinal analgesic agent as it has been associated with medication errors motility and function.15 Enteral opioids such as oxycodone and due to its potency. A retrospective analysis of an anonymous morphine are readily available in most critical care areas. Table 1. Analgesic Options for COVID-19 Patients.

Common adverse Mechanism of action Dosing Pharmacokinetics events Place in therapy Patient care considerations

Fentanyl16-18 Mu-opioid receptor Intermittent dosing: Onset: immediate Chest wall First-line Prolonged and unpredictable clearance agonist 0.35–0.5 mcg/kg IV Duration: 30-60 min rigidity with therapy can extend beyond infusion every 0.5–1 hr Large Vd: 4 to 6 L/kg rapid infusion Conventional discontinuation Infusion: 0.7–10 Context-sensitive care Risk of hypotension lower than morphine mcg/kg/hr IV t ½ > 100 min Accumulation in hepatic dysfunction Elimination t ½ of 2-4 h Fentanyl patch is an alternative but Three compartment consider absorption (delayed onset and distribution model offset) and efficacy issues Morphine15,19 Mu-opioid receptor Intermittent dosing: Onset: 5-10 min Hypotension First-line Metabolite can accumulate in kidney agonist 2–4 mg IV every 1–2 Duration: 3-5 hr Bradycardia therapy dysfunction hr Elimination t ½ 3-4 hr Conventional Accumulation of morphine-6-glucuronide Infusion: 2–30 mg/ Metabolized to morphine-6- care can cause sedation and morphine-3- hr IV glucuronide (active), glucuronide can cause neurotoxicity morphine-3-glucuronide Enteral morphine is an alternative during a (inactive) shortage but IV: PO conversion needs to be considered for equipotent dosages Hydromorphone20,21 Mu-opioid receptor Intermittent dosing: Onset: 15-30 min Hypotension First-line 5-7 times more potent than morphine agonist 0.2–0.6 mg IV every Duration: 3-4 hr therapy Accumulation of hydromorphone-3- 1–2 hr Elimination t ½ 2-3 hr Conventional glucuronide in kidney dysfunction can Infusion: 0.5–3 mg/ Metabolized to care cause neurotoxicity hr IV hydromorphone-3- glucuronide (inactive) Remifentanil22-24 Mu-opioid receptor Loading dose: 1.5 Onset: 1-3 min Hypotension Alternative Monitor for opiate withdrawal symptoms agonist mcg/kg IV Offset: 5-10 min Chest wall therapy for 24 hr after discontinuing remifentanil Infusion: 0.5–15 Duration: 3-10 min rigidity Contingency Use actual body weight. Use IBW if mcg/kg/hr IV Terminal t ½: 10-20 min care patient’s actual weight is 130% > IBW Metabolized by blood and No accumulation in hepatic/renal failure tissue esterases Can cause serotonin syndrome with concomitant use with serotonergic agents Sufentanil25,26 Mu-opioid receptor Infusion: 0.3 to 1.5 Onset: IV, 1-3 min and Bradyarrhythmia Alternative Can cause serotonin syndrome with agonist mcg/kg/hr sublingual, 30 min Hypotension therapy concomitant use with serotonergic agents Duration: IV, 2 hr and Crisis care 5-10 times more potent than fentanyl sublingual, 3 hr Enteral is available as an alternative (note t ½: IV, context-sensitive conversion for equipotent doses) >100 min and sublingual, 3 hr Alfentanil27 Mu-opioid receptor Loading dose: 50 Onset: 5 min Hypotension Alternative Use actual body weight. Use IBW if agonist mcg/kg IV Duration: 30-60 min therapy patient’s actual weight is 120% > IBW Infusion: 0.5 -1.5 t½:1.5–2hr Crisis care 5 times more potent than fentanyl mcg/kg/min Vd: 0.4- 1 L/kg Can cause serotonin syndrome with concomitant use with serotonergic agents (continued) 159 160

Table 1. (continued)

Common adverse Mechanism of action Dosing Pharmacokinetics events Place in therapy Patient care considerations

Oxycodone19 Mu-opioid receptor Oral dosing: 5 -20 Onset 10-15 min Hypotension Opioid Serum concentration increases by 50% in agonist mg every 4 to 6 hr Duration: 3-6 hr conservation patients with CrCl 60 mL/min t½:4hr and adjunct Drug interaction with CYP3A4 inhibitors therapy Do NOT crush controlled release Conventional formulation care Caution with conversion to equipotent dosages Methadone28,29 Mu-opioid receptor Oral dosing: 10–40 Onset: PO: 0.5 -1 hr/ IV: QTc Opioid Long half-life agonist, NMDA mg every 6–12 hr 10-20 min prolongation conservation Prolong effect with hepatic and renal receptor Intermittent dosing: Duration: 12-48 hr and adjunct dysfunction antagonist 2.5–10 mg IV every t ½: 8-59 hr therapy Can cause serotonin syndrome with 8–12 hr Reach steady state in 3-5 days Contingency concomitant use with serotonergic agents care Elimination half-life does not match short duration of analgesic effect Caution with co-administration with other QTc prolonging drugs Gabapentin30 Calcium-channel Oral dosing: 900– Slow onset of action Occasional Opioid Reduce dose based on CrCl modulation 3600 mg/day divided t½:6hr peripheral conservation TID-QID Renally eliminated edema and adjunct therapy Conventional care Carbamazepine15,31 Sodium channel 200-1200 mg/day Peak effect: 4-8 hr Dose-dependent Opioid Consider 25% dose reduction in severe inhibitor divided BID-TID Hepatic metabolism to hyponatremia conservation renal impairment (CrCl < 10 ml/min) carbamazepine-10,11- Transient and adjunct Consider dose reduction: undergoes epoxide (active metabolite) elevation of therapy extensive hepatic metabolism t½:24hr hepatic Conventional Major CYP3A4 substrate transaminases care Major CYP2C19/3A4 inducer (5–10%) Stevens-Johnson syndrome/toxic epidermal necrolysis Agranulocytosis Pregabalin15 Calcium-channel Oral dosing: 150- Slow onset of action Occasional Opioid Reduce dose based on CrCl modulation 600 mg/day divided t½:6hr peripheral conservation TID –QID Renally eliminated edema and adjunct therapy Conventional care (continued) Table 1. (continued)

Common adverse Mechanism of action Dosing Pharmacokinetics events Place in therapy Patient care considerations

Ketorolac15 Reversible inhibition Intermittent dosing: Onset: 30 min Risk of kidney Opioid Avoid NSAIDS in renal dysfunction, of 15-30 mg IV/IM t ½: 2-9 hr injury and conservation gastrointestinal bleeding and platelet cyclooxygenase-1 every 6 hr up to 5 Renally eliminated bleeding and adjunct abnormality and 2 enzymes days therapy Crisis care Ibuprofen15 Reversible inhibition Oral dosing: 400 mg Onset PO: 30 min Risk of kidney Opioid Avoid NSAIDS in renal dysfunction, of every 4 hr (max 2.4 t ½: PO/IV 2-3 hr injury and conservation gastrointestinal bleeding and platelet cyclooxygenase-1 g/day) Renally eliminated bleeding and adjunct abnormality and 2 enzymes Intermittent dosing: therapy 400-800 mg IV Crisis care every 6 hr (max: 3.2 g/day) Lidocaine32 Sodium channel Loading dose: 1.5 Onset: 45-90 sec Bradycardia Opioid Monitor drug levels (normal < 4 mcg/mL, blocker mg/kg Hepatically metabolized to Hypertension conservation toxic level >5 mcg/mL) Infusion: 0.5 – 2.5 active metabolite Hypotension and adjunct Half-life prolongs with congestive heart mg/kg/hr monoethylglycinexylidide and Blurred vision therapy failure, liver disease, shock, and renal glycinexylidide Tremors Crisis care impairment t ½: Biphasic, initially 7-30 Seizures min, terminal 1.5-2 hr Renally eliminated

BID: twice daily; CrCl: creatinine clearance; CYP: Cytochrome P450; hr: hours; IBW: ideal body weight; IV: intravenous; IM: intramuscular; min: minutes; NSAIDS: nonsteroidal anti-inflammatory drugs; NMDA: N-methyl- D-aspartate; PO: enteral; QID: 4 times daily; SSRI: Selective serotonin reuptake inhibitor, SNRI: Serotonin-norepinephrine reuptake Inhibitor; t½: half-life; TID: 3 times daily; TCA: Tricyclic antidepressants; Vd: volume of distribution 161 162 Journal of Intensive Care Medicine 36(2)

Given that opioids have equivalent analgesic properties with- recommend the routine use of non-steroidal anti- out significant difference in outcomes, supplementing a con- inflammatory drugs, due to risk of gastrointestinal bleeding and tinuous infusion opioid with equianalgesic doses of enteral kidney injury, nor IV lidocaine, due to lack of quality evidence oxycodone or enteral morphine is a reasonable approach.37-39 for pain management in the critically ill. In the setting of The use of controlled-release (CR) enteral opioids is also an extreme drug shortage, these therapies can play a role as alternative option. CR oxycodone has a fairly rapid onset of adjunct therapies in the appropriate patient population with action and a prolonged and constant duration of action.40-42 no hepatic and renal dysfunction and at lower risk for adverse A multicenter open-label study evaluated the use of CR oxy- events in crisis care.15,49-51 codone to convert post-operative patients receiving IV opioids to an enteral pain regimen reported a significant reduction in pain intensity within 6 hours after initial CR oxycodone admin- Sedation Strategies in COVID-19 43 istration. CR oxycodone is an extended release product, so it Currently there are no guidelines available for managing seda- cannot be crushed and administered through feeding tubes. As tion in COVID-19 patients requiring mechanical ventilation. such, the use of CR oxycodone should be reserved for COVID- However, the 2018 PADIS guidelines for sedation in critically 19 patients who are able to swallow. ill patients still pertain.15 Light sedation over deep sedation is Enteral methadone has a long half-life and can be used to recommended with emphasis on an analgosedation or an substitute patient’s IV opioids requirements in contingency analgesia before sedation approach. Additionally, the use of 28 care. A multicenter, double-blind randomized control trial non-benzodiazepine sedatives, propofol or dexmedetomidine, evaluated the use of enteral methadone in mechanically venti- are preferred over benzodiazepine sedatives (Table 2).15,52,53 lated critically ill patients who received fentanyl continuous Although light sedation is the recommended goal for patients 44 infusion for at least 5 days. In this study, after patients were requiring mechanical ventilation, as previously discussed, started on enteral methadone 10 mg every 6 hours, fentanyl COVID-19 associated pneumonia and ARDS may require infusion rates were reduced by 20% every 24 hours. The metha- moderate to deep levels of sedation to optimize the patient’s done dose was increased by 50% if patients exhibited opioid respiratory status.4,6-8 The remainder of this section will dis- 44 withdrawal intolerance. Methadone has a long half-life, but cuss the individual use of alternative sedatives with a focus on this half-life does not match the duration of analgesia (6-12 the practical application of these therapies based on whether hours) which can lead to drug accumulation with rapid titration. they should be considered for light or deep sedation (Table 2). As such, well-established protocols for conversion to enteral 28,29,45 methadone should be used. It is important to note that Recommended Therapies for Light Sedation methadone has the risk of prolonging QTc interval. As such, close monitoring of QTC interval once methadone is initiated is in COVID-19 Patients prudent.28 Propofol is often utilized for patients who require light seda- Transdermal fentanyl patches are not recommended for acute tion, but due to shortages, it may be reasonable to limit propo- pain management as it takes 12-16 hours after patch application fol use to those who require deep sedation. Thus, while to achieve therapeutic fentanyl blood concentrations. Addition- shortages remain an issue, in ICU patients, COVID-19 or oth- ally, the pharmacokinetics of absorption is not predictable as it is erwise, who require light sedation, dexmedetomidine should be affected by site of patch application and body temperature.46 recommended as the sedative of choice when there are no However, in the setting of opioid drug shortages, fentanyl trans- contraindications, such as bradyarrhythmia.71,72 In addition to dermal patches can be a reasonable option for non-opioid-naı¨ve potentially reducing the incidence of delirium, dexmedetomi- patients receiving opioid continuous infusions for several days in dine has demonstrated opioid sparing effects and may help contingency care. Several transition guides from continuous conserve shortened supply of analgesic agents.60 In critically infusion to transdermal patch have been evaluated with recom- ill patients receiving long-term infusions of dexmedetomidine mendations to overlap the infusion and fentanyl patch and there is a concern for withdrawal. This may be more proble- reduce the infusion dose within 6-12 hours.47,48 matic in COVID-19 patients who are known to require sedation A multimodal analgesia approach might facilitate better for prolonged periods of time.73 One study found that peak pain control and reduce patients’ opioid requirements. The doses greater than 0.8 mcg/kg/hr and cumulative daily doses 2018 Clinical Practice Guidelines for the Prevention and Man- greater than 12.9 mcg/kg/day were associated with a higher agement of Pain, Agitation/Sedation, Delirium, Immobility, incidence of withdrawal.74 Withdrawal effects may be amelio- and Sleep Disruption in Adult Patients in the ICU (PADIS) rated with the use of clonidine (Table 2).75 suggest using acetaminophen, ketamine, and neuropathic pain medications such as, gabapentin, carbamazepine, and pregaba- Alternative Therapies for Light Sedation in COVID-19 lin to decrease pain intensity and opioid use in critically-ill patients.15 The addition of these opioid-adjunct therapies to the Patients COVID-19 patient analgesia regimen would facilitate provid- Although not mentioned in the 2018 PADIS guidelines as a ing adequate analgesia in the setting of opioid drug shortages in sedation alternative, ketamine has been utilized in this manner contingency care. The 2018 PADIS guidelines do not for decades and can be considered as an alternative therapy in Table 2. Sedative Options for COVID-19 Patients.

Patient care Mechanism of action Dosing Pharmacokinetics Common adverse events Place in therapy considerations

Propofol54,55 GABA agonist Infusion: 5-50 mcg/kg/min Onset: 30 sec Propofol related First line for light Utilize alternative t ½: short term use, infusion syndrome or deep sedation agents if 3-12 hr and long term use, (rare) May be reserved triglycerides 50 + 18.6 hr Respiratory for deep sedation if exceed 800 mg/ Duration: 3-10 min depression there are shortage dL Large Vd Hypertriglyceridemia- issues Lipophilic greater likelihood in Conventional care COVID-19 patients (see text) Midazolam56 GABA agonist Infusion: 0.02-0.1 mg/kg/hr Onset: 3-5 min Respiratory Alternative therapy Caution with use (1-10 mg/hr) Large Vd depression for deep sedation in obese patients Intermittent dosing: 0.5-4 mg t ½: 3-11 hr, prolonged t ½ Contingency care and those with IV bolus doses every 15 min- in obese patients renal failure due 1 hr as needed Active metabolite 1- to drug hydroxy-midazolam accumulation accumulates in renal failure Can be used as intermittent doses for intermittent agitation/sedation requirements Oral doses can be used to wean off continuous infusion Lorazepam57 GABA agonist Infusion: 0.01-0.1 mg/kg/hr Onset: 3 min Respiratory Alternative therapy May be preferred (1-10 mg/hr) t ½:8-15 hr depression for deep sedation to midazolam in Intermittent dosing: 0.5-4 mg Inactive metabolites Propylene glycol Contingency care obesity and renal every 2-6 hr as needed (oral Duration: 6-8 hr toxicity (osmolar failure or IV bolus) anion gap metabolic Monitor for acidosis) with IV use development of propylene glycol toxicity Can be used as intermittent doses for intermittent agitation/sedation requirements Oral doses can be used to wean continuous infusion 163 (continued) 164

Table 2. (continued)

Patient care Mechanism of action Dosing Pharmacokinetics Common adverse events Place in therapy considerations

Diazepam58,59 GABA agonist Intermittent dosing: 2-10 mg Onset: 3 min Respiratory Alternative therapy Long acting every 3-6 hr as needed (oral Metabolized to multiple depression for light sedation intermittent dose or IV bolus) active metabolites Propylene glycol (intermittent agent t½*40 hr for parent toxicity (osmolar doses) Can be used as compound and up to 100 anion gap metabolic Contingency care intermittent hr for metabolite acidosis) with IV use doses for intermittent agitation/sedation requirements Oral doses can be used to wean continuous infusion 60,61 Dexmedetomidine a2-adrenoreceptor Loading dose (optional): 1 Onset 5-10 min after Bradycardia First line for light Cannot provide agonist in the brain mcg/kg over 10 min loading doses, 18-30 min Decreased cardiac sedation/ deep sedation stem that mediates Infusion: 0.2 -1.5 mcg/kg/hr with no loading dose output Conventional care Does not cause sedation through the Doses >1.5 mcg/kg/hr t ½: 2-3 hr Hypotension Weaning respiratory locus ceruleus unlikely to add clinical benefit Accumulates in hepatic Hypertension (with mechanical depression failure bolus dosing or high ventilation Analgesic; opioid Duration: 60 – 120 min infusion rates) Adjunct to reduce sparing effects or conserve opioids Ketamine62-66 Non-competitive NMDA Infusion, light sedation or Onset: within 30 min Hypersalivation Second line for Preserves receptor antagonist analgesia: 0.1 -1 mg/kg/hr t ½: alpha 5-17 min; beta Hypertension and sedation for light pharyngeal and Infusion, deep sedation: >1 2.5 hr (prolonged in tachycardia and deep sedation/ laryngeal mg/kg/hr critically ill (*5 hr) Hypotension and Contingency care protective Vd increases *3foldin decreased cardiac Adjunct to reduce reflexes the critically ill output in critically ill or conserve Lowers airway Duration: Dose and Psychotomimetic opioids resistance, duration dependent, 15 Monitor for Weaning increases lung min to 1 hr (prolonged in myocarditis in mechanical compliance renal or hepatic COVID-19 patients ventilation at low Analgesic; opioid dysfunction) (see text) doses sparing effects Metabolized to Can be norketamine (33% as concentrated (10 potent as parent mg/mL) to compound), minimize volume dehydronorketamine, Patient should be hydroxyketamine, monitored on hydroxynorketamine continuous telemetry (continued) Table 2. (continued)

Patient care Mechanism of action Dosing Pharmacokinetics Common adverse events Place in therapy considerations

Pentobarbital67 Binds directly to the Seizures or medically Onset 3-5 min Respiratory Last line in Decrease ICP GABAA receptor induced coma: loading dose: t ½: 15-50 hr depression extreme drug Therapeutic exerting its effects in 5-15 mg/kg Duration: 15-45 min Hypotension shortage serum levels the presence or Infusion: 0.5-5 mg/kg/hr Accumulation in severe Decreased myocardial Crisis care unnecessary if absence of endogenous Dosing for sedation likely to hepatic failure contractility being used for GABA be less; consider initiating Hypothermia sedation doses at 50% less than what Propylene glycol Often confused would be used for coma toxicity (osmolar with anion gap metabolic phenobarbital acidosis) Vesicant Volatile Gases68 Alter the activity of Dosed based on MAC, Rapid onset and offset of Malignant Reserved for last Data for use over neuronal ion channels general anesthesia: 0.2-0.3 action hyperthermia line therapy in 54 hr is severely particularly the fast- MAC (see Table 3) Cleared independently of Cerebral vasodilation extreme drug limited synaptic hepatic and renal function Hypotension shortage/Crisis Shown to cause neurotransmitter No metabolites Nausea, vomiting care pharmacologic receptors (nicotinic, Ideally used for pre- and post- acetylcholine, GABA, short periods of conditioning of and glutamate) time to get a the myocardium patient to more No development definitive therapy of dependence or such as ECMO tachyphylaxis Phenobarbital69 Binds directly to the Sedation: 200 mg every 6-8 Onset: Oral, 60 min and IV, Respiratory Primary or Monitor for drug GABAA receptor hr OR 7.5 mg/kg IV loading 5min depression adjunctive agent to interactions exerting its effects in dose followed by 1-2 mg/kg/ t ½: 53-118 hr Hypotension enhance or wean 1:1 PO to IV the presence or day divided every 12 hr Duration: Oral 10-12 hr IV: Hepatotoxicity sedation/Crisis conversion absence of endogenous Sedative withdrawal: 200 mg, >6 hr Laryngospasm with care Tapering not GABA followed by 100 mg every 4 Bioavailability 95% rapid IV administration Alcohol always necessary hr for 5 doses, 60 mg every 4 Metabolized via oxidation Propylene glycol withdrawal when given for a hr for 4 doses, and then 60 through CYP2C9 (major) toxicity (osmolar Seizures short period of mg every 8 hr for 3 doses Inducer of CYP3A4 and anion gap metabolic time CYP2C acidosis) IV use 69,70 Clonidine a2-adrenoreceptor Oral dosing (sedation): 0.3 - Onset: oral, 0.5-1 hr Hypotension Adjunctive agent to Opioid sparing agonist in the brain 1.6 mg/day divided into 3-4 t½*12 hr in healthy Bradycardia enhance or wean effects stem that mediates doses patients, prolonged to Xerostomia sedation, Taper off if used sedation through the Transition off *40 hr in patients with particularly for prolonged locus ceruleus dexmedetomidine: 0.2-0.5 renal dysfunction dexmedetomidine periods mg every 6 hr, taper Hepatic metabolism Conventional care clonidine every 24-48 hr by through CYP2D6 increasing dosing frequency, reduce dexmedetomidine infusion by 25% within 6 hr of each clonidine dose

165 CYP: Cytochrome P450; ECMO: extracorporeal membrane oxygenation; GABA: Gamma aminobutyric acid; hr: hours; IV: intravenous; ICP: intracranial pressure; MAC: minimum alveolar concentration; min: minutes; NMDA: N-methyl-D-aspartate; PO: enteral; sec: seconds; t ½: half-life; Vd: volume of distribution 166 Journal of Intensive Care Medicine 36(2) the setting of contingency care scenarios in the setting of drug pancreatitis and these patients had serum triglyceride concen- shortages.15,72,62 Ketamine is known to have analgesic proper- tration of 1000 mg/dl or greater.80 One potentially fatal adverse ties which may help conservation of IV opioids.62 Ketamine is effect of propofol use that clinicians should be aware of and not known to cause significant respiratory depression at mod- monitor for is propofol-related infusion syndrome. Overall erate doses which can be an advantage when trying to liberate a incidence is thought to be around 1.1% but increases in the patient from mechanical ventilation.76,77 setting of known risk factors including increased propofol Lastly, benzodiazepines can also be administered as inter- doses, use of vasopressors or corticosteroids, and critical ill- mittent doses or as a continuous infusion to achieve light seda- ness.81 If propofol is unavailable during times of contingency tion. Due to the improved benefit and better side-effect profile care, or is contraindicated, benzodiazepines, particularly as of non-benzodiazepine sedatives, benzodiazepines should only continuous infusions, remain a good alternative for deep seda- be considered as a first-line option sedative in settings of con- tion and have demonstrated safety in various patient popula- tingency care scenarios. When utilized, lorazepam, midazolam, tions.15 The use of benzodiazepine must be balanced against or diazepam, administered as IV scheduled or as-needed doses, risk of prolonged ICU length of stay, duration of mechanical can be prescribed to conserve drug supplies in the setting of ventilation and delirium.15 ongoing shortages. Additionally, this approach can limit over- all exposure of sedatives while still providing appropriate light Alternative Therapies for Deep Sedation in COVID-19 sedation conserving a need for high doses and continuous infu- sions known to be associated with accumulation. However, if Patients this is not sufficient to provide adequate sedation, continuous Ketamine may be an attractive alternative for patients with infusion lorazepam or midazolam can be initiated. Still inter- COVID-19 requiring deep sedation due to its dissociative anes- mittent doses can be reconsidered again when continuous infu- thetic properties and benefits on the respiratory system. One sion is no longer necessary and transitioning from continuous study that evaluated the use of ketamine as an adjunctive seda- infusion to a less aggressive dose is appropriate. tive in mechanically ventilated patients (n ¼ 91) reported that Nurse-protocolized targeted sedation should be used in an the addition of ketamine resulted in concomitant sedatives effort to minimize over-sedation. Oral benzodiazepines, such being reduced or discontinued within 24 hours in 63% of as oral lorazepam or diazepam can also be utilized to wean off patients, with propofol and benzodiazepines being the most continuous infusion sedatives.58 In a prospective evaluation of commonly discontinued sedatives.82 These benefits, however, diazepam as a component of a goal-directed sedation regimen are coupled with increased secretions that can lead to laryngos- in mechanically ventilated patients, 79% of patients received pasm, or clogging of the endotracheal tube and the need for enteral scheduled diazepam with the most common dosage aggressive suctioning. Hypersalivation can be treated with gly- being 10 mg every 6 hours and the majority of patients copyrrolate or sublingual atropine.76 In addition, ketamine can achieved the target sedation level.58 cause hallucinations and psychosis, which may be related to dose escalations and can be ameliorated with benzodiaze- 83 Recommended Therapies for Deep Sedation pines. Ketamine has also been associated with increases in intracranial pressure (ICP), however, studies in severe head in COVID-19 Patients injury patients who received ketamine showed no difference To provide deep sedation, propofol is often thought of as the in ICP or cerebral perfusion pressure (CPP).84-86 One study preferred sedative in conventional care because of its rapid found a significant increase in ICP by 2 mm Hg with conco- action and quick elimination.54 Propofol can cause hypertrigly- mitant increases in CPP by 8 mm Hg.87 Ketamine acts as a ceridemia due to its 10% fat emulsion containing product.54 sympathomimetic by facilitating adrenergic transmission and Traditionally, alternative agents are utilized in patients with inhibiting catecholamine reuptake. Interestingly though, in a triglyceride elevations exceeding 500 mg/dL to prevent the subset of critically ill patients, ketamine caused profound hypo- development of pancreatitis. However, patients with COVID- tension and reduced cardiac performance. However, patients 19 can present with a picture similar to a secondary hemopha- included in this analysis were critically ill septic shock patients gocytic lymphohistiocytosis (HLH) with hypertriglyceridemia. and most likely were volume and catecholamine depleted.63 HLH is a severe systemic inflammatory syndrome due to Ketamine should be used with caution in patients with cardiac absence of downregulation of activated macrophages and lym- dysfunction. In a trial evaluating mechanically ventilated phocytes.78,79 As such, triglyceride concentrations should be patients with heart failure and receiving vasopressors, ketamine more frequently monitored (every 24-48 hours) in patients with was associated with a decrease in cardiac output, an increase in COVID-19 who are receiving propofol. Since COVID-19 pulmonary capillary wedge pressure, and an increase in sys- patients may already present with elevated triglycerides not temic vascular resistance with no reduction in catecholamine due to propofol receipt, it is reasonable to have a more liberal dose.64 Of note, the development of myocarditis has been docu- cut off to consider alternative agents once the triglycerides mented in patients with COVID-19, and although there is no reach 800 mg/dL.55,80 A retrospective study evaluating data to suggest ketamine increases the risk of myocardial col- hypertriglyceridemia-associated pancreatitis, reported that lapse, close monitoring of cardiac function is warranted.88 Due only 10% of patients with hypertriglyceridemia had to lack of data and adverse effect profile, ketamine should be Ammar et al 167

Table 3. Pharmacodynamic Effects of Volatile Gases.98,99

Agent Pulmonary Cardiovascular Hepatic Renal

Isoflurane Depress ventilation # CO Minimal reduction in More resistant to defluorination # airway resistance # SVR, MAP hepatic blood flow Can be used for prolonged periods without significant "HR increases in serum fluoride levels91 Sevoflurane Depress ventilation $ CO Minimal reduction in Undergoes significant defluorination # airway resistance # SVR, MAP hepatic blood flow Patients with prolonged exposure had fluoride levels $HR >50 mmol/liter* 100 No increase in kidney injury Desflurane Depress ventilation $ CO Minimal reduction in Not significantly defluorinated $ airway resistance # SVR, MAP hepatic blood flow "HR

*Fluoride levels >50 mmol/liter can impair renal tubular concentrating ability leading to high output renal failure CO: cardiac output; HR: heart rate; MAP: mean arterial pressure; SVR: systemic vascular resistance reserved for contingency care situations when conventional overcome device dead space.68 Due to the lack of efficacy and therapies are in short supply. safety data with long-term use of pentobarbital and volatile Two uncommonly used alternative agents that are capable gases for sedation in ICU patients, the use of these agents of producing deep sedation include pentobarbital and volatile should be reserved for profound drug shortages in crisis care gases. Pentobarbital is used primarily for refractory status epi- scenarios.72 lepticus or medically induced coma. Data surrounding its use as Several concomitant agents are available to enhance or a sedative in mechanically ventilated patients is limited to the wean long term sedation. Phenobarbital may be an effective pediatric population.67 Dosing for sedation is likely to be less agent in maintaining sedation and comfort in ICU patients. One than doses utilized for coma and can be titrated to goal sedation case series included 40 patients who were transitioned from a levels.89 midazolam infusion to a fentanyl infusion with boluses of phe- Volatile gases, sevoflurane, desflurane, and isoflurane, are nobarbital (200 mg every 6-8 hours) and reported that depth of primarily used for general anesthesia in patients undergoing sedation was easily controlled, however, treatment duration surgery (Table 3). A study by Jabaudon and colleagues eval- and concomitant psychoactive medications were not uated the direct benefit of sevoflurane on pulmonary function reported.101 Another case series evaluated 7 ICU patients with in an open-label single-center study reported that by day 2, refractory agitation or propylene glycol toxicity. Patients were ARDS patients who received sevoflurane had significantly given a 7.5 mg/kg IV loading dose of phenobarbital followed higher partial pressure of arterial oxygen to fraction of inspired by 1-2 mg/kg/day IV or enterally divided every 12 hours with 102 oxygen ratio (PaO2/FiO2) than patients who received midazo- additional IV doses given hourly for breakthrough agitation. lam (mean + SD, 205 + 56 mm Hg versus 166 + 59 mm Hg, The quality of sedation based on the Riker Sedation-Agitation respectively; p ¼ 0.04).90 The use of volatile gases is limited by Scale remained similar before and after phenobarbital initiation extensive bedside equipment, unfamiliarity of these agents out- and there were no reports of over sedation. Although minimal, side of the operating theater, and lack of data for long term this data suggests that it could be utilized as a primary sedative sedation.68 Studies of volatile gases in ICU patients are primar- or in an effort to wean sedation. Phenobarbital may be an ily limited to short durations (less than 24 hours) in the post- effective agent in patients who are refractory to traditional operative setting. Trials that have evaluated volatile gases sedatives or for those requiring long-term sedation. Due to its versus traditional sedatives in mixed medical-surgical ICU long half-life, tapering is not generally necessary when given patients for more than 24 hours have demonstrated more time for a short period of time. Additionally, enteral or IV bolus within the targeted sedation range, a shorter time to extubation dosing may be advantageous in fluid-restricted patients. Due after cessation of sedation, and reduction in opioid consump- to the paucity of data, phenobarbital is best utilized during tion with volatile gases. The majority of patients received seda- contingency care scenarios when conventional resources are tion for 32-57 hours.91-94 These trials, however, are limited by limited. small sample sizes, inconsistency in agent, and relatively short Clonidine has been utilized for the management of agitation duration of sedation. There are a number of clinical considera- and pain due to its activity in the central nervous system. Due to tions when administering volatile gases. Although rare, they the reduction in sympathetic outflow, clonidine is likely to can cause malignant hyperthermia. Additionally, volatiles are cause hypotension and may not be suitable for patients with known to cause dose-dependent cerebrovasodilation. In a hemodynamic instability. Interestingly though, blood pressure cohort of patients with acute or subarachnoid hemorrhage, response to clonidine may follow a “U shaped” curve likely due sevoflurane led to a significant reduction in blood pressure and to the loss of a2-adrenoreceptor specificity at higher doses 95-97 cerebral perfusion pressure. Of note, when utilizing vola- resulting in peripheral a1-adrenoreceptor stimulation and sub- tile gases a minimal tidal volume of 350 mL is recommended to sequent vasoconstriction.75,103 Retrospective studies and case 168 Journal of Intensive Care Medicine 36(2) reports evaluating clonidine for treatment of sedation in ICU gradual reductions of cumulative sedative doses and may pre- patients have shown discontinuation of concomitant sedatives vent unnecessary increases in sedation rates. Daily awakening and decrease in mean daily dose of opioids and benzodiaze- trials should be done during all levels of surge capacity to pines with the use of clonidine.104,105 Gagnon et al. evaluated conserve medication supplies and improve patient outcomes. in a prospective single-center study the efficacy and safety of transitioning patients from dexmedetomidine to clonidine and reported that 75% of patients were successfully transitioned Paralysis Strategies in COVID-19 Patients from dexmedetomidine within 48 hours of clonidine initia- tion.75 Other studies evaluating clonidine to transition patients Recommended Therapies for Paralytics in COVID-19 off dexmedetomidine demonstrated successful weaning with Patients 75,106 no increase in agitation. Neuromuscular blocking agents (NMBA) have been shown to Finally, haloperidol and atypical antipsychotics (AA) work increase chest wall compliance, reduce patient-ventilator dys- through antagonism at various neurotransmitter receptors in the synchrony, facilitate lung recruitment, and reduce the inflam- brain (Supplemental Table 1). They are predominately used in matory response of ARDS.112,113 Two randomized controlled the ICU for the treatment of significant distress secondary to trials, ACURASYS and ROSE, evaluated NMBA for use in symptoms of delirium and, although not capable of providing early, moderate-to-severe ARDS (PaO2/FiO2 < 150 mm Hg) adequate sedation on their own, haloperidol and AA can be and used cisatracurium as a continuous infusion at a rate of 37.5 used as adjunctive treatment to reduce agitation in ICU mg/hr for 48 hours.114,115 Of note, these trials did not utilize 15 patients. Although long-term side effects are mitigated with peripheral nerve stimulators, or train-of-four (TOF), to monitor short duration of use, arrhythmias, QT interval, serotonin syn- depth of paralysis; furthermore, all patients in the NMBA arms drome, neuroleptic malignant syndrome, extrapyramidal symp- received deep sedation prior to the initiation of NMBA and did toms, and inadvertent continuation of therapy should be not utilize adjunctive measures of sedation (e.g. bispectral 107 monitored. index [BIS] monitors). Additionally, these studies had incon- sistent results for mortality rates and adverse effects of NMBA. Conservation Strategies for Sedatives in COVID-19 Based on the results of both studies, the role of continuous Patients infusion NMBA in moderate to severe ARDS has diminished and use is limited to patients with ventilator dyssynchrony or To conserve propofol supply and to decrease frequent entry to refractory hypoxemia.116 COVID-19 patient room, clinicians can consider priming pro- pofol lines with 20 mL propofol vials rather than using the 100 mL vials. These 20 mL vials are often utilized for IV push Alternative Therapies for Paralytics in COVID-19 Patients doses of propofol. Propofol is formulated as a nutrient-rich Many centers that use cisatracurium for continuous infusion emulsion and it is recommended that propofol vials and lines NMBA may need to consider alternatives. Although cisatracur- be changed every 12 hours to minimize risk of bloodstream ium is the only NMBA that has been studied in randomized infections.108,109 However, some institutions may be changing controlled trials, it is unknown if the benefit is confined to vials and lines more frequently. By extending tubing replace- cisatracurium, although one single-center retrospective study ment to every 12 hours, propofol supply and extension tubing that compared atracurium to cisatracurium for severe ARDS can be conserved. Unfortunately, at this time, there are no found no difference in clinical outcomes.117 Atracurium, rocur- safety data that indicate it is safe to extend propofol vial use onium, and vecuronium are other intermediate-acting NMBA and line exchanges past 12 hours. and can be given as continuous infusion and should be consid- Another major strategy to mitigate and reduce sedation ered in contingency care (Table 4).112 Pancuronium, a long- medication utilization as a whole include enforcing daily awa- acting NMBA, can also be considered for continuous infusion kening trials, including those requiring deep sedation.110,111 in crisis care.118 However, this agent should be used with an Daily awakening trials have been associated with reduced understanding of its adverse effects, particularly its vagolytic mechanical ventilation duration, decreased ICU length of stay, effects including increase in heart rate and arterial blood pres- and reduced sedative requirements.110,111 Daily awakening sure due to increased release and decreased reuptake of cate- trials force a reassessment of patient’s sedation needs and may cholamine at the adrenergic nerve terminal.119 It is important to result in a reduction in sedation requirements, thus conserving give an equivalent dose to achieve the same therapeutic effect drug supply, and minimizing overall exposure to these medica- based on TOF assessment when switching from one agent to tions. Daily awakening trials should not be conducted in the another. Additionally, it is important to consider that rocuro- setting of paralysis receipt.15 To ensure that sedation require- nium and vecuronium have renal and hepatic elimination, ments are minimized, another strategy that can be employed is unlike atracurium and cisatracurium which undergo Hoffman to reduce the maximum dose allowed on the titrated range for elimination, and thus may have prolonged elimination in cases sedation orders and supplementing with adjunct standing or as of organ dysfunction.112 In the setting of limited supply such as needed enteral and IV push sedatives to target adequate levels during contingency and crisis care surges, atracurium and cisa- of sedation. This can be done and reassessed daily to allow tracurium can be restricted for patients with organ dysfunction. Table 4. Paralytic Options for COVID-19 Patients.112

Mechanism of action Dosing Pharmacokinetics Common adverse events Place in therapy Patient care considerations

Atracurium Nondepolarizing Onset: 3-5 min Histamine release Alternative first- Hypotension with rapid NMBA Intermittent dosing: Bolus 0.4- t ½: initial, 2 min and (hypotension) line continuous administration Intermediate-acting 0.5 mg/kg terminal, 20 min Laudanosine metabolite infusion Not effected by renal and Infusion: 5-20 mcg/kg/min Duration: 20-35 min (flushing, seizure) Contingency care hepatic dysfunction Hoffman elimination Cisatracurium Nondepolarizing Onset: 2-3 min Bronchospasm (rare) First line Most commonly studied NMBA Intermittent dosing: Bolus 0.1- t ½: 22-29 min Bradycardia (rare) continuous infusion NMBA in ARDS Intermediate-acting 0.2 mg/kg Duration: 30-60 min Conventional care Not effected by renal and Infusion: 1-4 mcg/kg/min Hoffman elimination hepatic dysfunction Fixed dose infusion: 37.5 mg/hr Pancuronium Nondepolarizing Onset: 2-3 min Vagal blockade, Alternative Monitoring pupillary reflex NMBA Intermittent dosing: Bolus 0.05- t ½: 89-161 min sympathetic stimulation intermittent bolus unreliable due to Long-acting 0.1 mg/kg Duration: 60-100 min (hypotension, tachycardia) Crisis care antimuscarinic effects Infusion: 0.8 -1.7 mcg/kg/min 45-70% renal, 15% hepatic Active metabolite Rocuronium Nondepolarizing Onset: 1-2 min Vagal blockade at higher Intermittent bolus/ Preferred in renal NMBA Intermittent dosing: Bolus 0.6 - Alpha t ½, 1-2 min and doses Conventional care dysfunction over Intermediate-acting 1.2 mg/kg beta t ½, 1-2 hr Second-line vecuronium Infusion: 8-12 mcg/kg/min Duration: 20-35 min continuous 33% renal, < 75% hepatic infusion/ Contingency care Vecuronium Nondepolarizing Onset: 3-4 min Vagal blockade at higher Intermittent bolus/ Preferred in hepatic NMBA Intermittent dosing: Bolus t½:4min doses Conventional care dysfunction over Intermediate-acting 0.1 mg/kg Duration: 20-45 min Second-line rocuronium Infusion: 0.8 -1.7 mcg/kg/min 10-50% renal, 35-50% continuous hepatic infusion/ Active metabolite: Contingency care 3-desacetyl vecuronium (renally eliminated)

ARDS: Acute respiratory distress syndrome; hr: hours; min: minutes; NMBA: neuromuscular blocking agent 169 170 Journal of Intensive Care Medicine 36(2)

Conservation Strategies for Paralytics in COVID-19 effective drug conservation strategy.116 One strategy that has Patients been recommended to conserve NMBA when using flat-dose NMBA is to down-titrate or hold continuous infusion NMBA at COVID-19 patients develop respiratory failure in 2 different 55 120 least once daily until ventilator dyssynchrony occurs. An time-dependent patterns. The first is respiratory failure with alternative strategy for drug conservation is to utilize normal compliance that usually rapidly improves within the nursing-driven clinical titration to patient-ventilator dyssyn- first 12-24 hours of positive pressure mechanical ventilation. chrony or plateau pressures above 30 cm H20 and has been These patients are unlikely to benefit from interventions such described in the literature previously.124 However, this strategy as NMBA as they often respond quickly to traditional mechan- is not well validated and is outside the nursing scope of prac- ical ventilation strategies. However, some patients develop per- tice. Still, this has been a consideration during the extreme sistent moderate to severe ARDS despite optimization on resource limitations of the pandemic. mechanical ventilation; these patients likely require the use If BIS monitors are not utilized for sedation monitoring of rescue therapies for ARDS including continuous while on continuous infusion NMBA, it is important to target 120,121 NMBA. For these patients, there are several strategies deep sedation prior to initiation of continuous infusion that can be utilized to conserve supply of NMBA. First, as the NMBA; mimicking the strategy was utilized in ACUR- data for continuous infusion NMBA are conflicting, it may not ACSYS and ROSE studies for patients on NMBA.114,115 Once be prudent to start in every patient with patient-ventilator dys- deep sedation is achieved, sedation instructions should be synchrony. Instead, a more conservative approach may be to adjusted to flat-dose as traditional measures of sedation can- initiate intermittent bolus doses of NMBA initially to test if not be accurately performed while on NMBA. This sedation patient-ventilator dyssynchrony improves before initiating a strategy was compared to sedation monitoring utilizing BIS 122 continuous infusion. In fact, this strategy is recommended recently in a study of ARDS patients; the study found that by the Surviving Sepsis Campaign COVID-19 guidelines prior monitoring with BIS resulted in no difference in sedation 122 to initiation of continuous NMBA. If intermittent NMBA are utilization but increased titrations125 so removing these utilized, an intermediate-acting NMBA with a longer duration adjunctive monitors could likely be a good resource sparing 112 should be used such as rocuronium or vecuronium. Pancur- measure. However when considering the removal of these onium can also be considered for intermittent bolus dosing if devices, it is important to consider that studies of NMBA in 118 supplies are limited. If intermittent bolus doses of NMBA ARDS only continued NMBA for 48 hours therefore adjunc- are insufficient to control patient-ventilator dyssynchrony or tive sedation monitors may be necessary for prolonged worsening hypoxia or hypercapnia occurs, then a continuous NMBA due to concern for tachyphylaxis.114,115 Additionally, 122 infusion of NMBA for up to 48 hours could be considered. the risk for under-sedating patients should be evaluated to Some additional considerations for the use of paralytics prevent any long-term mood disorders such as post- during COVID-19 include removing depth of paralysis moni- traumatic stress disorder.126 toring (TOF) and adjunctive measures for monitoring sedation when utilizing continuous infusion NMBA. Although these monitoring devices are suggested in the guidelines, when Conclusion resources are limited such as during crisis care, removal of these monitors can be considered. As mentioned previously, The COVID-19 pandemic has made the existing supply of the studies for continuous infusion NMBA did not utilize TOF therapies needed for the care of mechanically ventilated monitoring or adjunctive measures for monitoring sedation patients vulnerable. In the meantime, clinicians are encouraged (e.g. BIS).114,115 Removing these monitors can decrease the to explore alternative therapies and conservation strategies for use of personal protective equipment used in the care of existing supplies of commonly used sedatives, analgesics and COVID-19 patients. Furthermore, adequate supplies of these paralytics. Periodic evaluation of goals of therapy and contin- peripheral nerve stimulators may be insufficient for the number ued need for sedation, analgesia and chemical paralysis in of COVID-19 patients requiring continuous infusion NMBA in COVID-19 patients is prudent for conserving existing supplies resource-limited areas. When TOF monitoring is removed, flat- of therapies. Further evaluation of these therapies in COVID- dose continuous infusion NMBA could be considered and the 19 patients is warranted and will better equip clinicians to rate increased or decreased based on clinical parameters such provide optimal patient care in the setting of drug shortages. as presence or lack of patient-ventilator dyssynchrony; addi- tional parameters include plateau pressures of less than 30-35 Declaration of Conflicting Interests cm H O or driving pressures less than 13-15 cm H 0.123 This 2 2 The author(s) declared no potential conflicts of interest with respect to dosing strategy for NMBA was utilized in ACURASYS and the research, authorship, and/or publication of this article. ROSE trials, where patients received a flat-dose rate of 37.5 mg/hr of cisatracurium.114,115 However, flat-dose continuous infusion of NMBA typically delivers more NMBA than most Funding patients require to improve patient-ventilator dyssynchrony The author(s) received no financial support for the research, author- andoxygenationwhenusingthatrateandmaynotbean ship, and/or publication of this article. Ammar et al 171

ORCID iD 17. Roan JP, Bajaj N, Davis FA, Kandinata N. Opioids and chest wall Mahmoud A. Ammar, https://orcid.org/0000-0002-3401-9960 rigidity during mechanical ventilation. Ann Intern Med. 2018; Gretchen L. Sacha, https://orcid.org/0000-0002-0070-8100 168(9):678. 18. Coruh B, Tonelli MR, Park DR. Fentanyl-induced chest wall Supplemental Material rigidity. Chest. 2013;143(4):1145-1146. 19. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing Supplemental material for this article is available online. opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49. References 20. Vallner JJ, Stewart JT, Kotzan JA, Kirsten EB, Honigberg IL. 1. Poston JT, Patel BK, Davis AM. Management of critically Ill Pharmacokinetics and bioavailability of hydromorphone follow- adults with COVID-19. JAMA. 2020. ing intravenous and oral administration to human subjects. J Clin 2. The Center for Systems Science and Engineering (CSSE) at Johns Pharmacol. 1981;21(4):152-156. Hopkins University. Accessed July 3, 2020. https://coronavirus. 21. Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology jhu.edu/map.html and clinical applications in cancer patients. Support Care Cancer. 3. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from 2001;9(2):84-96. patients with pneumonia in China, 2019. N Engl J Med. 2020; 22. Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of 382(8):727-733. the new short-acting opioid remifentanil (GI87084B) in healthy 4.HuangC,WangY,LiX,etal.Clinical features of patients adult male volunteers. Anesthesiology. 1993;79(5):881-892. infected with 2019 novel coronavirus in Wuhan, China. Lancet. 23. Joshi GP, Warner DS, Twersky RS, Fleisher LA. A comparison of 2020;395(10223):497-506. the remifentanil and fentanyl adverse effect profile in a multi- 5. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of center phase IV study. J Clin Anesth. 2002;14(7):494-499. covid-19 in New York City. N Engl J Med. 2020;382(24): 24. Wilhelm W, Kreuer S. The place for short-acting opioids: special 2372-2374. emphasis on remifentanil. Crit Care. 2008;12(suppl 3):S5. 6. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical 25. Monk JP, Beresford R, Ward A.Sufentanil. A review of its phar- characteristics of 99 cases of 2019 novel coronavirus pneumonia macological properties and therapeutic use. Drugs. 1988;36(3): in Wuhan, China: a descriptive study. Lancet. 2020;395(10223): 286-313. 507-513. 26. Reardon CE, Kane-Gill SL, Smithburger PL, Dasta JF. Sufentanil 7. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute sublingual tablet: a new option for acute pain management. Ann respiratory distress syndrome and death in patients with Corona- Pharmacother. 2019;53(12):1220-1226. virus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern 27. Scholz J, Steinfath M, Schulz M.Clinical pharmacokinetics of Med. 2020;180(7):1-11. alfentanil, fentanyl and sufentanil. An update. Clin Pharmacoki- 8. Bein T, Grasso S, Moerer O, et al. The standard of care of patients net. 1996;31(4):275-292. with ARDS: ventilatory settings and rescue therapies for refrac- 28. Fishman SM, Wilsey B, Mahajan G, Molina P. Methadone rein- tory hypoxemia. Intensive Care Med. 2016;42(5):699-711. carnated: novel clinical applications with related concerns. Pain 9. Hubmayr RD, Abel MD, Rehder K. Physiologic approach to Med. 2002;3(4):339-348. mechanical ventilation. Crit Care Med. 1990;18(1):103-113. 29. Gazelle G, Fine PG. Methadone for pain: no. 75. J Palliat Med. 10. FDA Drug Shortages [online]. Accessed April 26, 2020. https:// 2004;7(2):303-304. www.accessdata.fda.gov/scripts/drugshortages/default.cfm 30. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the phar- 11. ASHP Drug Shortages [online]. Accessed April 26, 2020. https:// macological treatment of neuropathic pain: 2010 revision. Eur J www.ashp.org/Drug-Shortages Neurol. 2010;17(9):1113-e1188. 12. Phuong JM, Penm J, Chaar B, Oldfield LD, Moles R.The impacts 31. Pandey CK, Raza M, Tripathi M, Navkar DV, Kumar A, Singh of medication shortages on patient outcomes: a scoping review. UK. The comparative evaluation of gabapentin and carbamaze- PLoS One. 2019;14(5):e0215837. pine for pain management in Guillain-Barre syndrome patients in 13. Drug shortages roundtable: Minimizing the impact on patient the intensive care unit. Anesth Analg. 2005;101(1):220-225, table care. Am J Health Syst Pharm. 2018;75(11):816-820. of contents. 14. Hick JL, Einav S, Hanfling D, et al. Surge capacity principles: 32. Weibel S, Jelting Y, Pace NL, et al. Continuous intravenous peri- care of the critically ill and injured during pandemics and disas- operative lidocaine infusion for postoperative pain and recovery ters: CHEST consensus statement. Chest. 2014;146(4 suppl): in adults. Cochrane Database Syst Rev. 2018;6:CD009642. e1S-e16S. 33. Dy SM, Shore AD, Hicks RW, Morlock LL. Medication errors 15. Devlin JW, Skrobik Y, Gelinas C, et al. Clinical practice guide- with opioids: results from a national reporting system. J Opioid lines for the prevention and management of pain, Agitation/Seda- Manag. 2007;3(4):189-194. tion, delirium, immobility, and sleep disruption in adult patients 34. Muellejans B, Lopez A, Cross MH, Bonome C, Morrison L, Kirk- in the ICU. Crit Care Med. 2018;46(9):e825-e873. ham AJ. Remifentanil versus fentanyl for analgesia based seda- 16. Peng PW, Sandler AN. A review of the use of fentanyl analgesia tion to provide patient comfort in the intensive care unit: a in the management of acute pain in adults. Anesthesiology. 1999; randomized, double-blind controlled trial [ISRCTN43755713]. 90(2):576-599. Crit Care. 2004;8(1):R1-R11. 172 Journal of Intensive Care Medicine 36(2)

35. Clotz MA, Nahata MC. Clinical uses of fentanyl, sufentanil, and 53. Devabhakthuni S, Armahizer MJ, Dasta JF, Kane-Gill SL. alfentanil. Clin Pharm. 1991;10(8):581-593. Analgosedation: a paradigm shift in intensive care unit sedation 36. Narayanan M, Venkataraju A, Jennings J. Analgesia in intensive practice. Ann Pharmacother. 2012;46(4):530-540. care: part 1. BJA Education. 2015;16(2):72-78. 54. DIPRIVAN (propofol injection, emulsion) [prescribing informa- 37. Anderson R, Saiers JH, Abram S, Schlicht C. Accuracy in equia- tion]. Lake Zurich, IL: Fresenius Kabi USA, LLC; 2020. nalgesic dosing. Conversion dilemmas. J Pain Symptom Manage. 55. Devlin JW, O’Neal HRJ, Thomas C, et al. Strategies to optimize 2001;21(5):397-406. ICU liberation (A to F) bundle performance in critically ill adults 38. de Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation for with coronavirus disease 2019. Crit Care Explor. 2020;2(6): toxicity reduction in terminal cancer patients. J Pain Symptom e0139. Manage. 1995;10(5):378-384. 56. Midazolam injection, USP [prescribing information]. Lake Zur- 39. American Pain Society. Principles of Analgesic Use in the Treat- ich, IL: Hospira, Inc; 2019. ment of Acute Pain and Cancer Pain. 6th ed. American Pain 57. Lorazepam injection, USP [prescribing information]. Eatontown, Society; 2008. NJ: West-Ward Pharmaceuticals Corp; 2008. 40. Sunshine A, Olson NZ, Colon A, et al. Analgesic efficacy of 58. Gesin G, Kane-Gill SL, Dasta JF, Birrer KL, Kolnik LJ, Chea- controlled-release oxycodone in postoperative pain. J Clin Phar- tham ML. Diazepam as a component of goal-directed sedation in macol. 1996;36(7):595-603. critically ill trauma patients. J Crit Care. 2011;26(2):122-126. 41.MandemaJW,KaikoRF,OshlackB,RederRF,StanskiDR. 59. Diazepam injection, USP [prescribing information]. Lake Forest, Characterization and validation of a pharmacokinetic model for IL: Hospira, Inc; 2019. controlled-release oxycodone. Br J Clin Pharmacol. 1996;42(6): 60. Naaz S, Ozair E. Dexmedetomidine in current anaesthesia prac- 747-756. tice—a review. J Clin Diagn Res. 2014;8(10):GE01-04. 42. Reder RF, Oshlack B, Miotto JB, Benziger DD, Kaiko RF. 61. Pertovaara A, Hamalainen MM, Kauppila T, Mecke E, Carlson S. Steady-state bioavailability of controlled-release oxycodone in Dissociation of the alpha 2-adrenergic antinociception from seda- tion following microinjection of medetomidine into the locus normal subjects. Clin Ther. 1996;18(1):95-105. coeruleus in rats. Pain. May 1994;57(2):207-215. 43. Ginsberg B, Sinatra RS, Adler LJ, et al. Conversion to oral 62. Patanwala AE, Martin JR, Erstad BL. Ketamine for analgoseda- controlled-release oxycodone from intravenous opioid analgesic tion in the intensive care unit: a systematic review. J Intensive in the postoperative setting. Pain Med. 2003;4(1):31-38. Care Med. 2017;32(6):387-395. 44. Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, Cavalcanti 63. Lippmann M, Appel PL, Mok MS, Shoemaker WC. Sequential AB, Westphal GA. Replacement of fentanyl infusion by enteral cardiorespiratory patterns of anesthetic induction with ketamine methadone decreases the weaning time from mechanical ventila- in critically ill patients. Crit Care Med. 1983;11(9):730-734. tion: a randomized controlled trial. Crit Care. 2012;16(2):R49. 64. Christ G, Mundigler G, Merhaut C, et al. Adverse cardiovascular 45. Ripamonti C, Bianchi M. The use of methadone for cancer pain. effects of ketamine infusion in patients with catecholamine- Hematol Oncol Clin North Am. 2002;16(3):543-555. dependent heart failure. Anaesth Intensive Care. 1997;25(3): 46. Weaver JM. Multiple risks for patients using the transdermal 255-259. fentanyl patch. Anesth Prog. 2014;61(1):1-2. 65. Erstad BL, Patanwala AE. Ketamine for analgosedation in criti- 47. Kornick CA, Santiago-Palma J, Khojainova N, Primavera LH, cally ill patients. J Crit Care. 2016;35:145-149. Payne R, Manfredi PL. A safe and effective method for convert- 66. Donnelly RF. Stability of diluted ketamine packaged in glass ing cancer patients from intravenous to transdermal fentanyl. vials. Can J Hosp Pharm. 2013;66(3):198. Cancer. 2001;92(12):3056-3061. 67. Tobias JD, Deshpande JK, Pietsch JB, Wheeler TJ, Gregory DF. 48. Nomura M, Kamata M, Kojima H, Hayashi K, Kozai M, Sawada Pentobarbital sedation for patients in the pediatric intensive care S. Six- versus 12-h conversion method from intravenous to trans- unit. South Med J. 1995;88(3):290-294. dermal fentanyl in chronic cancer pain: a randomized study. Sup- 68. Jerath A, Parotto M, Wasowicz M, Ferguson ND. Volatile anes- port Care Cancer. 2011;19(5):691-695. thetics. Is a new player emerging in critical care sedation? Am J 49. Insler SR, O’Connor M, Samonte AF, Bazaral MG. Lidocaine and Respir Crit Care Med. 2016;193(11):1202-1212. the inhibition of postoperative pain in coronary artery bypass 69. Gagnon DJ, Fontaine GV, Riker RR, Fraser GL. Repurposing patients. J Cardiothorac Vasc Anesth. 1995;9(5):541-546. valproate, enteral clonidine, and phenobarbital for comfort in 50. Kranke P, Jokinen J, Pace NL, et al. Continuous intravenous adult ICU patients: a literature review with practical considera- perioperative lidocaine infusion for postoperative pain and recov- tions. Pharmacotherapy. 2017;37(10):1309-1321. ery. Cochrane Database Syst Rev. 2015;(7):CD009642. 70. Sakamoto H, Fukuda S, Minakawa Y, Sawamura S. Clonidine 51. Wick EC, Grant MC, Wu CL. Postoperative multimodal analgesia induces sedation through acting on the perifornical area and the pain management with nonopioid analgesics and techniques: a locus coeruleus in rats. J Neurosurg Anesthesiol.2013;25(4): review. JAMA Surg. 2017;152(7):691-697. 399-407. 52. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond 71. Xia ZQ, Chen SQ, Yao X, Xie CB, Wen SH, Liu KX. Clinical Agitation-Sedation Scale: validity and reliability in adult inten- benefits of dexmedetomidine versus propofol in adult intensive sive care unit patients. Am J Respir Crit Care Med. 2002;166(10): care unit patients: a meta-analysis of randomized clinical trials. 1338-1344. J Surg Res. 2013;185(2):833-843. Ammar et al 173

72. Madhok J, Mihm FG. Rethinking sedation during prolonged 2019. Accessed July 3, 2020. https://www.ncbi.nlm.nih.gov/ mechanical ventilation for COVID-19 respiratory failure. Anesth books/NBK545288/ Analg. 2020. 90. Jabaudon M, Boucher P, Imhoff E, et al. Sevoflurane for seda- 73. Kotfis K, Williams Roberson S, Wilson JE, Dabrowski W, Pun tion in acute respiratory distress syndrome. A randomized con- BT, Ely EW. COVID-19: ICU delirium management during trolled pilot study. Am J Respir Crit Care Med. 2017;195(6): SARS-CoV-2 pandemic. Crit Care. 2020;24(1):176. 792-800. 74. Bouajram RH, Bhatt K, Croci R, et al. Incidence of dexmedeto- 91. Sackey PV, Martling CR, Granath F, Radell PJ. Prolonged midine withdrawal in adult critically Ill patients: a pilot study. isoflurane sedation of intensive care unit patients with the anes- Crit Care Explor. 2019;1(8):e0035. thetic conserving device. Crit Care Med. 2004;32(11): 75. Gagnon DJ, Riker RR, Glisic EK, Kelner A, Perrey HM, Fraser 2241-2246. GL. Transition from dexmedetomidine to enteral clonidine for 92. Mesnil M, Capdevila X, Bringuier S, et al. Long-term sedation ICU sedation: an observational pilot study. Pharmacotherapy. in intensive care unit: a randomized comparison between 2015;35(3):251-259. inhaled sevoflurane and intravenous propofol or midazolam. 76. Craven R. Ketamine. Anaesthesia. 2007;62(suppl 1):48-53. Intensive Care Med. 2011;37(6):933-941. 77. Bergman SA. Ketamine: review of its pharmacology and its use in 93. Trongtrakul K, Feemuchang C. Prevalence and association of pediatric anesthesia. Anesth Prog. 1999;46(1):10-20. vitamin D deficiency and mortality in patients with severe 78. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider sepsis. Int J Gen Med. 2017;10:415-421. cytokine storm syndromes and immunosuppression. Lancet. 94. Spencer EM, Willatts SM, Prys-Roberts C. Plasma inorganic 2020;395(10229):1033-1034. fluoride concentrations during and after prolonged (greater 79. George MR. Hemophagocytic lymphohistiocytosis: review of than 24 h) isoflurane sedation: effect on renal function. Anesth etiologies and management. J Blood Med. 2014;5:69-86. Analg. 1991;73(6):731-737. 80. Devlin JW, Lau AK, Tanios MA. Propofol-associated hypertri- 95. Purrucker JC, Renzland J, Uhlmann L, et al. Volatile sedation glyceridemia and pancreatitis in the intensive care unit: an anal- with sevoflurane in intensive care patients with acute stroke or ysis of frequency and risk factors. Pharmacotherapy. 2005; subarachnoid haemorrhage using AnaConDa(R): an observa- 25(10):1348-1352. tional study. Br J Anaesth. 2015;114(6):934-943. 81. Hemphill S, McMenamin L, Bellamy MC, Hopkins PM. Propofol 96. Kitano H, Kirsch JR, Hurn PD, Murphy SJ. Inhalational anes- infusion syndrome: a structured literature review and analysis of thetics as neuroprotectants or chemical preconditioning agents published case reports. Br J Anaesth. 2019;122(4):448-459. in ischemic brain. J Cereb Blood Flow Metab. 2007;27(6): 82. Groetzinger LM, Rivosecchi RM, Bain W, et al. Ketamine infu- 1108-1128. sion for adjunct sedation in mechanically ventilated adults. Phar- 97. Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthe- macotherapy. 2018;38(2):181-188. sia and learning disabilities in a population-based birth cohort. 83. Okamoto Y, Tsuneto S, Tanimukai H, et al. Can gradual dose Anesthesiology. 2009;110(4):796-804. titration of ketamine for management of neuropathic pain prevent 98. Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity. psychotomimetic effects in patients with advanced cancer? Am J A study of dose response in man. JAMA. 1973;225(13): Hosp Palliat Care. 2013;30(5):450-454. 1611-1616. 84. Bourgoin A, Albanese J, Leone M, Sampol-Manos E, Viviand X, 99. Kassiri N, Ardehali SH, Rashidi F, Hashemian SM. Inhala- Martin C. Effects of sufentanil or ketamine administered in target- tional anesthetics agents: the pharmacokinetic, pharmacody- controlled infusion on the cerebral hemodynamics of severely namics, and their effects on human body. Biomed Biotechnol brain-injured patients. Crit Care Med. 2005;33(5):1109-1113. Res J. 2018;2(3):173-177. 85. Bourgoin A, Albanese J, Wereszczynski N, Charbit M, Vialet R, 100. Rohm KD, Mengistu A, Boldt J, Mayer J, Beck G, Piper SN. Martin C. Safety of sedation with ketamine in severe head injury Renal integrity in sevoflurane sedation in the intensive care unit patients: comparison with sufentanil. Crit Care Med. 2003;31(3): with the anesthetic-conserving device: a comparison with intra- 711-717. venous propofol sedation. Anesth Analg. 2009;108(6): 86. Schmittner MD, Vajkoczy SL, Horn P, et al. Effects of fentanyl 1848-1854. and S(þ)-ketamine on cerebral hemodynamics, gastrointestinal 101. Fahron G, Martens F, Frei U. Phenobarbital: a good choice for motility, and need of vasopressors in patients with intracranial long-term sedation. Crit Care. 2001;5(suppl 1):P202-S295. pathologies: a pilot study. J Neurosurg Anesthesiol. 2007;19(4): 102. Fraser GL, Riker RR. Phenobarbital provides effective sedation 257-262. for a select cohort of adult ICU patients intolerant of standard 87. Kolenda H, Gremmelt A, Rading S, Braun U, Markakis E. Ketamine treatment: a brief report. Hosp Pharm. 2006;41(1):17-23. for analgosedative therapy in intensive care treatment of head- 103. Frisk-Holmberg M, Paalzow L, Wibell L.Relationship between injured patients. Acta Neurochir (Wien). 1996;138(10):1193-1199. the cardiovascular effects and steady-state kinetics of clonidine 88. Fried JA, Ramasubbu K, Bhatt R, et al. The variety of cardiovas- in hypertension. Demonstration of a therapeutic window in cular presentations of COVID-19. Circulation. 2020;141(23): man. Eur J Clin Pharmacol. 1984;26(3):309-313. 1930-1936. 104. Kariya N, Shindoh M, Nishi S, Yukioka H, Asada A. Oral clo- 89. Johnson AB, Sadiq NM. Pentobarbital. In: StatPearls [Internet]. nidine for sedation and analgesia in a burn patient. J Clin Anesth. StatPearls Publishing. Published 2020. Updated October 14, 1998;10(6):514-517. 174 Journal of Intensive Care Medicine 36(2)

105. Farasatinasab M, Kouchek M, Sistanizad M, et al. A randomized 116. Flannery AH, Moss M. Rescue neuromuscular blockade in acute placebo-controlled trial of clonidine impact on sedation of respiratory distress syndrome should not be flat dose. Crit Care mechanically ventilated ICU patients. Iran J Pharm Res. 2015; Med. 2020;48(4):588-590. 14(1):167-175. 117. Moore L, Kramer CJ, Delcoix-Lopes S, Modrykamien AM. 106. Terry K, Blum R, Szumita P. Evaluating the transition from dex- Comparison of cisatracurium versus atracurium in early ARDS. medetomidine to clonidine for agitation management in the inten- Respir Care. 2017;62(7):947-952. sive care unit. SAGE Open Med. 2015;3:2050312115621767. 118. de Lemos JM, Carr RR, Shalansky KF, Bevan DR, Ronco JJ. 107. Farlow MR, Shamliyan TA. Benefits and harms of atypical anti- Paralysis in the critically ill: intermittent bolus pancuronium psychotics for agitation in adults with dementia. Eur Neuropsy- compared with continuous infusion. Crit Care Med. 1999; chopharmacol. 2017;27(3):217-231. 27(12):2648-2655. 108. Cole DC, Baslanti TO, Gravenstein NL, Gravenstein N. Leaving 119. Punnen S, Gonzalez ER, Krieger AJ, Sapru HN. Cardiac vago- more than your fingerprint on the intravenous line: a prospective lytic action of some neuromuscular blockers. Pharmacol Bio- study on propofol anesthesia and implications of stopcock con- chem Behav. 1984;20(1):85-89. tamination. Anesth Analg. 2015;120(4):861-867. 120. Gattinoni L, Chiumello D, Caironi P, et al. COVID-19 pneumo- 109. Bourgoin A, Leone M, Delmas A, Garnier F, Albanese J, Martin nia: different respiratory treatments for different phenotypes? C. Increasing mean arterial pressure in patients with septic Intensive Care Med. 2020;46(6):1099-1102. shock: effects on oxygen variables and renal function. Crit Care 121. Payen JF, Chanques G, Futier E, Velly L, Jaber S, Constantin Med. 2005;33(4):780-786. JM. Sedation for critically ill patients with COVID-19: Which 110. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a specificities? One size does not fit all. Anaesth Crit Care Pain paired sedation and ventilator weaning protocol for mechani- Med. 2020;39(3):341-343. cally ventilated patients in intensive care (Awakening and 122. Alhazzani W, Moller MH, Arabi YM, et al. Surviving sepsis Breathing Controlled trial): a randomised controlled trial. Lan- campaign: guidelines on the management of critically ill adults cet. 2008;371(9607):126-134. with coronavirus disease 2019 (COVID-19). Intensive Care 111. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interrup- Med. 2020;46(5):854-887. tion of sedative infusions in critically ill patients undergoing 123. Murray MJ, DeBlock H, Erstad B, et al. Clinical practice mechanical ventilation. N Engl J Med. 2000;342(20):1471-1477. guidelines for sustained neuromuscular blockade in the 112. Greenberg SB, Vender J. The use of neuromuscular blocking adult critically ill patient. Crit Care Med. 2016;44(11): agents in the ICU: where are we now? Crit Care Med. 2013; 2079-2103. 41(5):1332-1344. 124. Baumann MH, McAlpin BW, Brown K, et al. A prospective 113. Forel JM, Roch A, Marin V, et al. Neuromuscular blocking randomized comparison of train-of-four monitoring and clinical agents decrease inflammatory response in patients presenting assessment during continuous ICU cisatracurium paralysis. with acute respiratory distress syndrome. Crit Care Med. 2006;34(11):2749-2757. Chest. 2004;126(4):1267-1273. 114. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers 125. Bass S, Vance ML, Reddy A, et al. Bispectral index for titrating in early acute respiratory distress syndrome. N Engl J Med. sedation in ARDS patients during neuromuscular blockade. Am J 2010;363(12):1107-1116. Crit Care. 2019;28(5):377-384. 115. The National Heart, Lung, and Blood Institute PETAL Clinical 126. Herridge MS, Moss M, Hough CL, et al. Recovery and outcomes Trials Network, Moss M, et al. Early neuromuscular blockade in after the acute respiratory distress syndrome (ARDS) in patients the acute respiratory distress syndrome. N Engl J Med. 2019; and their family caregivers. IntensiveCareMed. 2016;42(5): 380(21):1997-2008. 725-738.