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Estratégias diante da escassez de drogas durante a COVID 19 :'(

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Estratégias diante da escassez de drogas durante a COVID 19 :'(

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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.

Introduction

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen responsible for the 2019 coronavirus disease (COVID-19) pandemic which has affected over 10.5 million people and led to over 500,000 deaths as of June 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 common symptoms at onset of illness include fever, cough, and myalgia or fatigue.4 In a subset of patients, the disease can progress to pneumonia and acute respiratory failure requiring the need for ICU admission in up to 26% of patients with anywhere from 4-33% of patients requiring invasive mechanical ventilation.4-7

COVID-19 associated pneumonia can be complicated by the development of acute respiratory distress syndrome (ARDS) in up to 42% of patients.4,6,7 Patients with ARDS may need moderate to deep levels of analgesia and sedation to lower their respiratory drive in order to optimize their respiratory status.8 Additionally, neuromuscular blocking agents in ARDS facilitate ventilator synchrony.9 The surge in critically ill patients created an increased demand for these therapies, in addition to the extraordinary doses of sedatives and analgesics that individual COVID-19 patients are requiring, resulting in drug shortages10,11 which can significantly impact the quality of care and safety of patients.12,13 Currently, there are 10 sedative and analgesic agents on the FDA and American Society of Health-System Pharmacists shortage databases including propofol and dexmedetomidine.10,11 It is unfortunate, but these shortages are only likely to worsen as the pandemic progresses, making utilization of more costly alternatives and unfamiliar medications a reality. With any large-scale event including a pandemic that leads to critical care patient surges, surge capacity and response is measured based on 3 levels: conventional care, contingency care, and crisis care.14 Contingency care includes those practices that may be outside usual care but they attempt to maintain usual care, while crisis care practices are outside of standard of care but provide the best feasible care when resources are severely limited.14 The purpose of this narrative review is to provide recommendations for alternative drug therapies and suggested strategies to preserve existing medication supplies for the management of sedation, analgesia and paralysis in COVID-19 patients in the setting of drug shortages and patient surges. This article will mainly review drug therapies and medication practices to be considered in the setting of conventional, contingency, and crisis care. In addition, this will be a useful resource if future shortages occur.

Analgesia Strategies in COVID-19 Patients

Recommended Therapies for Analgesia in COVID-19 Patients

Critically ill patients, including COVID-19 patients, will experience pain and distress due to their underlying respiratory disease and invasive procedures, primarily mechanical ventilation.15 Opioids are the cornerstone of pain management in critically ill patients. Commonly used intravenous (IV) analgesics in mechanically ventilated patients include fentanyl, morphine, and hydromorphone ( Table 1).

Analgesic Options for COVID-19 Patients.

Fentanyl is the most commonly used synthetic opioid for analgesia in conventional care due to its distinctive pharmacokinetics. However, continuous infusions of fentanyl may lead to prolonged and unpredictable clearance that can extend beyond infusion discontinuation.16 Although, it is uncommon, clinicians should be cautious with the use of rapid bolus doses of fentanyl in COVID-19 patients as rapid IV fentanyl infusion has been associated with chest wall rigidity, which can decrease chest wall compliance and lead to inadequate spontaneous ventilation. This can lead to challenges in utilizing assisted ventilation.17

Morphine and hydromorphone are other commonly used opioids for analgesia in the ICU for conventional care. In the setting of drug shortages, hydromorphone can be an appropriate alternative to fentanyl and morphine. However, caution should be taken when using hydromorphone as an alternative analgesic agent as it has been associated with medication errors due to its potency. A retrospective analysis of an anonymous national medication error database reported that hydromorphone had significantly higher dose-related errors and these errors were significantly more likely to be overdoses.33

Alternative Therapies for Analgesia in COVID-19 Patients

Remifentanil is a selective mu-opioid receptor agonist with pharmacodynamic properties similar to fentanyl and should be considered in contingency care. Unlike fentanyl, remifentanil is rapidly metabolized by blood and tissue esterases; therefore, it has a very short duration of action independent of the duration of infusion.22 Remifentanil can be an alternative to fentanyl for analgesia, however, the use of remifentanil has been associated with a higher incidence of hypotension compared to fentanyl.23 A multicenter, double blind, randomized, control trial included mixed ICU mechanically ventilated patients compared the efficacy and safety of remifentanil to fentanyl for sedation and analgesia. This study reported no difference in the time spent in optimal sedation level, 88.3% in remifentanil versus 89.3% in fentanyl. Additionally, patients who received remifentanil exhibited significantly less between-patient variability in optimal sedation compared to fentanyl (p = 0.009). However, remifentanil patients experienced pain significantly longer during extubation, postextubation, and 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 half-life of remifentanil, it is prudent to ensure adequate pain management prior to discontinuation to prevent withdrawal symptoms.24

The ultra-short-acting opioids, sufentanil and alfentanil, are not commonly used in the ICUs but may be options in the setting of severe drug shortages and crisis care. Sufentanil and alfentanil are 5 to 10 times more potent than fentanyl. As such, in patients receiving high doses of fentanyl, sufentanil and alfentanil can conserve fentanyl infusion volume and dose requirements.25,35 Sufentanil is also available as sublingual tablet, with 53% bioavailability which blunts the high serum sufentanil levels seen with the IV route, decreasing the risk of adverse events with inappropriate use of high-dose IV sufentanil.26

Conservation Strategies for Analgesia in COVID-19 Patients

In critically ill, mechanically ventilated patients, IV administration of opioids is often preferred. One of the recommended strategies to conserve intravenous analgesic supplies during contingency care is to implement protocols where clinicians would initially utilize intermittent bolus analgesic doses prior to transitioning patients to continuous infusion of analgesia. Additionally, providing opioids and analgesics enterally can assist with conserving supply of IV agents.36 This strategy should be limited to patients with adequate gastrointestinal motility and function.15 Enteral opioids such as oxycodone and morphine are readily available in most critical care areas. Given that opioids have equivalent analgesic properties without significant difference in outcomes, supplementing a continuous infusion opioid with equianalgesic doses of enteral oxycodone or enteral morphine is a reasonable approach. The use of controlled-release (CR) enteral opioids is also an alternative option. CR oxycodone has a fairly rapid onset of action and a prolonged and constant duration of action. A multicenter open-label study evaluated the use of CR oxycodone 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 administration.43 CR oxycodone is an extended release product, so it cannot be crushed and administered through feeding tubes. As such, the use of CR oxycodone should be reserved for COVID-19 patients who are able to swallow.

Enteral methadone has a long half-life and can be used to substitute patient's IV opioids requirements in contingency care.28 A multicenter, double-blind randomized control trial evaluated the use of enteral methadone in mechanically ventilated critically ill patients who received fentanyl continuous infusion for at least 5 days.44 In this study, after patients were started on enteral methadone 10 mg every 6 hours, fentanyl infusion rates were reduced by 20% every 24 hours. The methadone dose was increased by 50% if patients exhibited opioid withdrawal intolerance.44 Methadone has a long half-life, but this half-life does not match the duration of analgesia (6-12 hours) which can lead to drug accumulation with rapid titration. As such, well-established protocols for conversion to enteral methadone should be used. It is important to note that methadone has the risk of prolonging QTc interval. As such, close monitoring of QTC interval once methadone is initiated is prudent.28

Transdermal fentanyl patches are not recommended for acute pain management as it takes 12-16 hours after patch application to achieve therapeutic fentanyl blood concentrations. Additionally, the pharmacokinetics of absorption is not predictable as it is affected by site of patch application and body temperature.46 However, in the setting of opioid drug shortages, fentanyl transdermal patches can be a reasonable option for non-opioid-naïve patients receiving opioid continuous infusions for several days in contingency care. Several transition guides from continuous infusion to transdermal patch have been evaluated with recommendations to overlap the infusion and fentanyl patch and reduce the infusion dose within 6-12 hours.47,48

A multimodal analgesia approach might facilitate better pain control and reduce patients' opioid requirements. The 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS) suggest using acetaminophen, ketamine, and neuropathic pain medications such as, gabapentin, carbamazepine, and pregabalin to decrease pain intensity and opioid use in critically-ill patients.15 The addition of these opioid-adjunct therapies to the COVID-19 patient analgesia regimen would facilitate providing adequate analgesia in the setting of opioid drug shortages in contingency care. The 2018 PADIS guidelines do not recommend the routine use of non-steroidal anti-inflammatory drugs, due to risk of gastrointestinal bleeding and kidney injury, nor IV lidocaine, due to lack of quality evidence for pain management in the critically ill. In the setting of extreme drug shortage, these therapies can play a role as adjunct therapies in the appropriate patient population with no hepatic and renal dysfunction and at lower risk for adverse events in crisis care.15,49-51

Sedation Strategies in COVID-19

Currently there are no guidelines available for managing sedation in COVID-19 patients requiring mechanical ventilation. However, the 2018 PADIS guidelines for sedation in critically ill patients still pertain.15 Light sedation over deep sedation is recommended with emphasis on an analgosedation or an analgesia before sedation approach. Additionally, the use of non-benzodiazepine sedatives, propofol or dexmedetomidine, are preferred over benzodiazepine sedatives ( Table 2).15,52,53 Although light sedation is the recommended goal for patients requiring mechanical ventilation, as previously discussed, COVID-19 associated pneumonia and ARDS may require moderate to deep levels of sedation to optimize the patient's respiratory status.4,6-8 The remainder of this section will discuss the individual use of alternative sedatives with a focus on the practical application of these therapies based on whether they should be considered for light or deep sedation ( Table 2).

Sedative Options for COVID-19 Patients.

Recommended Therapies for Light Sedation in COVID-19 Patients

Propofol is often utilized for patients who require light sedation, but due to shortages, it may be reasonable to limit propofol use to those who require deep sedation. Thus, while shortages remain an issue, in ICU patients, COVID-19 or otherwise, who require light sedation, dexmedetomidine should be recommended as the sedative of choice when there are no contraindications, such as bradyarrhythmia.71,72 In addition to potentially reducing the incidence of delirium, dexmedetomidine has demonstrated opioid sparing effects and may help conserve shortened supply of analgesic agents.60 In critically ill patients receiving long-term infusions of dexmedetomidine there is a concern for withdrawal. This may be more problematic in COVID-19 patients who are known to require sedation for prolonged periods of time.73 One study found that peak doses greater than 0.8 mcg/kg/hr and cumulative daily doses greater than 12.9 mcg/kg/day were associated with a higher incidence of withdrawal.74 Withdrawal effects may be ameliorated with the use of clonidine ( Table 2).75

Alternative Therapies for Light Sedation in COVID-19 Patients

Although not mentioned in the 2018 PADIS guidelines as a sedation alternative, ketamine has been utilized in this manner for decades and can be considered as an alternative therapy in the setting of contingency care scenarios in the setting of drug shortages. Ketamine is known to have analgesic properties which may help conservation of IV opioids.62 Ketamine is not known to cause significant respiratory depression at moderate doses which can be an advantage when trying to liberate a patient from mechanical ventilation.76,77

Lastly, benzodiazepines can also be administered as intermittent doses or as a continuous infusion to achieve light sedation. Due to the improved benefit and better side-effect profile of non-benzodiazepine sedatives, benzodiazepines should only be considered as a first-line option sedative in settings of contingency care scenarios. When utilized, lorazepam, midazolam, or diazepam, administered as IV scheduled or as-needed doses, can be prescribed to conserve drug supplies in the setting of ongoing shortages. Additionally, this approach can limit overall exposure of sedatives while still providing appropriate light sedation conserving a need for high doses and continuous infusions known to be associated with accumulation. However, if this is not sufficient to provide adequate sedation, continuous infusion lorazepam or midazolam can be initiated. Still intermittent doses can be reconsidered again when continuous infusion is no longer necessary and transitioning from continuous infusion to a less aggressive dose is appropriate.

Nurse-protocolized targeted sedation should be used in an effort to minimize over-sedation. Oral benzodiazepines, such as oral lorazepam or diazepam can also be utilized to wean off continuous infusion sedatives.58 In a prospective evaluation of diazepam as a component of a goal-directed sedation regimen in mechanically ventilated patients, 79% of patients received enteral scheduled diazepam with the most common dosage being 10 mg every 6 hours and the majority of patients achieved the target sedation level.58

Recommended Therapies for Deep Sedation in COVID-19 Patients

To provide deep sedation, propofol is often thought of as the preferred sedative in conventional care because of its rapid action and quick elimination.54 Propofol can cause hypertriglyceridemia due to its 10% fat emulsion containing product.54 Traditionally, alternative agents are utilized in patients with triglyceride elevations exceeding 500 mg/dL to prevent the development of pancreatitis. However, patients with COVID-19 can present with a picture similar to a secondary hemophagocytic lymphohistiocytosis (HLH) with hypertriglyceridemia. HLH is a severe systemic inflammatory syndrome due to absence of downregulation of activated macrophages and lymphocytes.78,79 As such, triglyceride concentrations should be more frequently monitored (every 24-48 hours) in patients with COVID-19 who are receiving propofol. Since COVID-19 patients may already present with elevated triglycerides not due to propofol receipt, it is reasonable to have a more liberal cut off to consider alternative agents once the triglycerides reach 800 mg/dL.55,80 A retrospective study evaluating hypertriglyceridemia-associated pancreatitis, reported that only 10% of patients with hypertriglyceridemia had pancreatitis and these patients had serum triglyceride concentration of 1000 mg/dl or greater.80 One potentially fatal adverse effect of propofol use that clinicians should be aware of and monitor for is propofol-related infusion syndrome. Overall incidence is thought to be around 1.1% but increases in the setting of known risk factors including increased propofol doses, use of vasopressors or corticosteroids, and critical illness.81 If propofol is unavailable during times of contingency care, or is contraindicated, benzodiazepines, particularly as continuous infusions, remain a good alternative for deep sedation and have demonstrated safety in various patient populations.15 The use of benzodiazepine must be balanced against risk of prolonged ICU length of stay, duration of mechanical ventilation and delirium.15

Alternative Therapies for Deep Sedation in COVID-19 Patients

Ketamine may be an attractive alternative for patients with COVID-19 requiring deep sedation due to its dissociative anesthetic properties and benefits on the respiratory system. One study that evaluated the use of ketamine as an adjunctive sedative in mechanically ventilated patients (n = 91) reported that the addition of ketamine resulted in concomitant sedatives being reduced or discontinued within 24 hours in 63% of patients, with propofol and benzodiazepines being the most commonly discontinued sedatives.82 These benefits, however, are coupled with increased secretions that can lead to laryngospasm, or clogging of the endotracheal tube and the need for aggressive suctioning. Hypersalivation can be treated with glycopyrrolate or sublingual atropine.76 In addition, ketamine can cause hallucinations and psychosis, which may be related to dose escalations and can be ameliorated with benzodiazepines.83 Ketamine has also been associated with increases in intracranial pressure (ICP), however, studies in severe head injury patients who received ketamine showed no difference in ICP or cerebral perfusion pressure (CPP). One study found a significant increase in ICP by 2 mm Hg with concomitant increases in CPP by 8 mm Hg.87 Ketamine acts as a sympathomimetic by facilitating adrenergic transmission and inhibiting catecholamine reuptake. Interestingly though, in a subset of critically ill patients, ketamine caused profound hypotension and reduced cardiac performance. However, patients included in this analysis were critically ill septic shock patients and most likely were volume and catecholamine depleted.63 Ketamine should be used with caution in patients with cardiac dysfunction. In a trial evaluating mechanically ventilated patients with heart failure and receiving vasopressors, ketamine was associated with a decrease in cardiac output, an increase in pulmonary capillary wedge pressure, and an increase in systemic vascular resistance with no reduction in catecholamine dose.64 Of note, the development of myocarditis has been documented in patients with COVID-19, and although there is no data to suggest ketamine increases the risk of myocardial collapse, close monitoring of cardiac function is warranted.88 Due to lack of data and adverse effect profile, ketamine should be reserved for contingency care situations when conventional therapies are in short supply.

Two uncommonly used alternative agents that are capable of producing deep sedation include pentobarbital and volatile gases. Pentobarbital is used primarily for refractory status epilepticus or medically induced coma. Data surrounding its use as a sedative in mechanically ventilated patients is limited to the pediatric population.67 Dosing for sedation is likely to be less than doses utilized for coma and can be titrated to goal sedation levels.89

Volatile gases, sevoflurane, desflurane, and isoflurane, are primarily used for general anesthesia in patients undergoing surgery ( Table 3). A study by Jabaudon and colleagues evaluated the direct benefit of sevoflurane on pulmonary function in an open-label single-center study reported that by day 2, ARDS patients who received sevoflurane had significantly higher partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO ₂/FiO ₂) than patients who received midazolam (mean ± SD, 205 ± 56 mm Hg versus 166 ± 59 mm Hg, respectively; p = 0.04).90 The use of volatile gases is limited by extensive bedside equipment, unfamiliarity of these agents outside of the operating theater, and lack of data for long term sedation.68 Studies of volatile gases in ICU patients are primarily limited to short durations (less than 24 hours) in the postoperative setting. Trials that have evaluated volatile gases versus traditional sedatives in mixed medical-surgical ICU patients for more than 24 hours have demonstrated more time within the targeted sedation range, a shorter time to extubation after cessation of sedation, and reduction in opioid consumption with volatile gases. The majority of patients received sedation for 32-57 hours.91-94 These trials, however, are limited by small sample sizes, inconsistency in agent, and relatively short duration of sedation. There are a number of clinical considerations when administering volatile gases. Although rare, they can cause malignant hyperthermia. Additionally, volatiles are known to cause dose-dependent cerebrovasodilation. In a cohort of patients with acute or subarachnoid hemorrhage, sevoflurane led to a significant reduction in blood pressure and cerebral perfusion pressure. Of note, when utilizing volatile gases a minimal tidal volume of 350 mL is recommended to overcome device dead space.68 Due to the lack of efficacy and safety data with long-term use of pentobarbital and volatile gases for sedation in ICU patients, the use of these agents should be reserved for profound drug shortages in crisis care scenarios.72

Pharmacodynamic Effects of Volatile Gases.98,99

Several concomitant agents are available to enhance or wean long term sedation. Phenobarbital may be an effective agent in maintaining sedation and comfort in ICU patients. One case series included 40 patients who were transitioned from a midazolam infusion to a fentanyl infusion with boluses of phenobarbital (200 mg every 6-8 hours) and reported that depth of sedation was easily controlled, however, treatment duration and concomitant psychoactive medications were not reported.101 Another case series evaluated 7 ICU patients with refractory agitation or propylene glycol toxicity. Patients were given a 7.5 mg/kg IV loading dose of phenobarbital followed by 1-2 mg/kg/day IV or enterally divided every 12 hours with additional IV doses given hourly for breakthrough agitation.102 The quality of sedation based on the Riker Sedation-Agitation Scale remained similar before and after phenobarbital initiation and there were no reports of over sedation. Although minimal, this data suggests that it could be utilized as a primary sedative or in an effort to wean sedation. Phenobarbital may be an effective agent in patients who are refractory to traditional sedatives or for those requiring long-term sedation. Due to its long half-life, tapering is not generally necessary when given for a short period of time. Additionally, enteral or IV bolus dosing may be advantageous in fluid-restricted patients. Due to the paucity of data, phenobarbital is best utilized during contingency care scenarios when conventional resources are limited.

Clonidine has been utilized for the management of agitation and pain due to its activity in the central nervous system. Due to the reduction in sympathetic outflow, clonidine is likely to cause hypotension and may not be suitable for patients with hemodynamic instability. Interestingly though, blood pressure response to clonidine may follow a "U shaped" curve likely due to the loss of α ₂-adrenoreceptor specificity at higher doses resulting in peripheral α ₁-adrenoreceptor stimulation and subsequent vasoconstriction.75,103 Retrospective studies and case reports evaluating clonidine for treatment of sedation in ICU patients have shown discontinuation of concomitant sedatives and decrease in mean daily dose of opioids and benzodiazepines with the use of clonidine.104,105 Gagnon et al. evaluated 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 from dexmedetomidine within 48 hours of clonidine initiation.75 Other studies evaluating clonidine to transition patients off dexmedetomidine demonstrated successful weaning with no increase in agitation.75,106

Finally, haloperidol and atypical antipsychotics (AA) work through antagonism at various neurotransmitter receptors in the brain (Supplemental Table 1). They are predominately used in the ICU for the treatment of significant distress secondary to symptoms of delirium and, although not capable of providing adequate sedation on their own, haloperidol and AA can be used as adjunctive treatment to reduce agitation in ICU patients.15 Although long-term side effects are mitigated with short duration of use, arrhythmias, QT interval, serotonin syndrome, neuroleptic malignant syndrome, extrapyramidal symptoms, and inadvertent continuation of therapy should be monitored.107

Conservation Strategies for Sedatives in COVID-19 Patients

To conserve propofol supply and to decrease frequent entry to COVID-19 patient room, clinicians can consider priming propofol lines with 20 mL propofol vials rather than using the 100 mL vials. These 20 mL vials are often utilized for IV push doses of propofol. Propofol is formulated as a nutrient-rich emulsion and it is recommended that propofol vials and lines be changed every 12 hours to minimize risk of bloodstream infections.108,109 However, some institutions may be changing vials and lines more frequently. By extending tubing replacement to every 12 hours, propofol supply and extension tubing can be conserved. Unfortunately, at this time, there are no safety data that indicate it is safe to extend propofol vial use and line exchanges past 12 hours.

Another major strategy to mitigate and reduce sedation medication utilization as a whole include enforcing daily awakening trials, including those requiring deep sedation.110,111 Daily awakening trials have been associated with reduced mechanical ventilation duration, decreased ICU length of stay, and reduced sedative requirements.110,111 Daily awakening trials force a reassessment of patient's sedation needs and may result in a reduction in sedation requirements, thus conserving drug supply, and minimizing overall exposure to these medications. Daily awakening trials should not be conducted in the setting of paralysis receipt.15 To ensure that sedation requirements are minimized, another strategy that can be employed is to reduce the maximum dose allowed on the titrated range for sedation orders and supplementing with adjunct standing or as needed enteral and IV push sedatives to target adequate levels of sedation. This can be done and reassessed daily to allow gradual reductions of cumulative sedative doses and may prevent unnecessary increases in sedation rates. Daily awakening trials should be done during all levels of surge capacity to conserve medication supplies and improve patient outcomes.

Paralysis Strategies in COVID-19 Patients

Recommended Therapies for Paralytics in COVID-19 Patients

Neuromuscular blocking agents (NMBA) have been shown to increase chest wall compliance, reduce patient-ventilator dyssynchrony, facilitate lung recruitment, and reduce the inflammatory response of ARDS.112,113 Two randomized controlled trials, ACURASYS and ROSE, evaluated NMBA for use in early, moderate-to-severe ARDS (PaO ₂/FiO ₂ < 150 mm Hg) and used cisatracurium as a continuous infusion at a rate of 37.5 mg/hr for 48 hours.114,115 Of note, these trials did not utilize peripheral nerve stimulators, or train-of-four (TOF), to monitor depth of paralysis; furthermore, all patients in the NMBA arms received deep sedation prior to the initiation of NMBA and did not utilize adjunctive measures of sedation (e.g. bispectral index [BIS] monitors). Additionally, these studies had inconsistent results for mortality rates and adverse effects of NMBA. Based on the results of both studies, the role of continuous infusion NMBA in moderate to severe ARDS has diminished and use is limited to patients with ventilator dyssynchrony or refractory hypoxemia.116

Alternative Therapies for Paralytics in COVID-19 Patients

Many centers that use cisatracurium for continuous infusion NMBA may need to consider alternatives. Although cisatracurium is the only NMBA that has been studied in randomized controlled trials, it is unknown if the benefit is confined to cisatracurium, although one single-center retrospective study that compared atracurium to cisatracurium for severe ARDS found no difference in clinical outcomes.117 Atracurium, rocuronium, and vecuronium are other intermediate-acting NMBA and can be given as continuous infusion and should be considered in contingency care ( Table 4).112 Pancuronium, a long-acting NMBA, can also be considered for continuous infusion in crisis care.118 However, this agent should be used with an understanding of its adverse effects, particularly its vagolytic effects including increase in heart rate and arterial blood pressure due to increased release and decreased reuptake of catecholamine at the adrenergic nerve terminal.119 It is important to give an equivalent dose to achieve the same therapeutic effect based on TOF assessment when switching from one agent to another. Additionally, it is important to consider that rocuronium and vecuronium have renal and hepatic elimination, unlike atracurium and cisatracurium which undergo Hoffman elimination, and thus may have prolonged elimination in cases of organ dysfunction.112 In the setting of limited supply such as during contingency and crisis care surges, atracurium and cisatracurium can be restricted for patients with organ dysfunction.

Paralytic Options for COVID-19 Patients.112

Conservation Strategies for Paralytics in COVID-19 Patients

COVID-19 patients develop respiratory failure in 2 different time-dependent patterns.120 The first is respiratory failure with normal compliance that usually rapidly improves within the first 12-24 hours of positive pressure mechanical ventilation. These patients are unlikely to benefit from interventions such as NMBA as they often respond quickly to traditional mechanical ventilation strategies. However, some patients develop persistent moderate to severe ARDS despite optimization on mechanical ventilation; these patients likely require the use of rescue therapies for ARDS including continuous NMBA.120,121 For these patients, there are several strategies that can be utilized to conserve supply of NMBA. First, as the data for continuous infusion NMBA are conflicting, it may not be prudent to start in every patient with patient-ventilator dyssynchrony. Instead, a more conservative approach may be to initiate intermittent bolus doses of NMBA initially to test if patient-ventilator dyssynchrony improves before initiating a continuous infusion.122 In fact, this strategy is recommended by the Surviving Sepsis Campaign COVID-19 guidelines prior to initiation of continuous NMBA.122 If intermittent NMBA are utilized, an intermediate-acting NMBA with a longer duration should be used such as rocuronium or vecuronium.112 Pancuronium can also be considered for intermittent bolus dosing if supplies are limited.118 If intermittent bolus doses of NMBA are insufficient to control patient-ventilator dyssynchrony or worsening hypoxia or hypercapnia occurs, then a continuous infusion of NMBA for up to 48 hours could be considered.122

Some additional considerations for the use of paralytics during COVID-19 include removing depth of paralysis monitoring (TOF) and adjunctive measures for monitoring sedation when utilizing continuous infusion NMBA. Although these monitoring devices are suggested in the guidelines, when resources are limited such as during crisis care, removal of these monitors can be considered. As mentioned previously, the studies for continuous infusion NMBA did not utilize TOF monitoring or adjunctive measures for monitoring sedation (e.g. BIS).114,115 Removing these monitors can decrease the use of personal protective equipment used in the care of COVID-19 patients. Furthermore, adequate supplies of these peripheral nerve stimulators may be insufficient for the number of COVID-19 patients requiring continuous infusion NMBA in resource-limited areas. When TOF monitoring is removed, flat-dose continuous infusion NMBA could be considered and the rate increased or decreased based on clinical parameters such as presence or lack of patient-ventilator dyssynchrony; additional parameters include plateau pressures of less than 30-35 cm H ₂O or driving pressures less than 13-15 cm H ₂0.123 This dosing strategy for NMBA was utilized in ACURASYS and 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 patients require to improve patient-ventilator dyssynchrony and oxygenation when using that rate and may not be an effective drug conservation strategy.116 One strategy that has been recommended to conserve NMBA when using flat-dose NMBA is to down-titrate or hold continuous infusion NMBA at least once daily until ventilator dyssynchrony occurs.55 An alternative strategy for drug conservation is to utilize nursing-driven clinical titration to patient-ventilator dyssynchrony or plateau pressures above 30 cm H ₂0 and has been described in the literature previously.124 However, this strategy is not well validated and is outside the nursing scope of practice. Still, this has been a consideration during the extreme resource limitations of the pandemic.

If BIS monitors are not utilized for sedation monitoring while on continuous infusion NMBA, it is important to target deep sedation prior to initiation of continuous infusion NMBA; mimicking the strategy was utilized in ACURACSYS and ROSE studies for patients on NMBA.114,115 Once deep sedation is achieved, sedation instructions should be adjusted to flat-dose as traditional measures of sedation cannot be accurately performed while on NMBA. This sedation strategy was compared to sedation monitoring utilizing BIS recently in a study of ARDS patients; the study found that monitoring with BIS resulted in no difference in sedation utilization but increased titrations125 so removing these adjunctive monitors could likely be a good resource sparing measure. However when considering the removal of these devices, it is important to consider that studies of NMBA in ARDS only continued NMBA for 48 hours therefore adjunctive sedation monitors may be necessary for prolonged NMBA due to concern for tachyphylaxis.114,115 Additionally, the risk for under-sedating patients should be evaluated to prevent any long-term mood disorders such as post-traumatic stress disorder.126

Conclusion

The COVID-19 pandemic has made the existing supply of therapies needed for the care of mechanically ventilated patients vulnerable. In the meantime, clinicians are encouraged to explore alternative therapies and conservation strategies for existing supplies of commonly used sedatives, analgesics and paralytics. Periodic evaluation of goals of therapy and continued need for sedation, analgesia and chemical paralysis in COVID-19 patients is prudent for conserving existing supplies of therapies. Further evaluation of these therapies in COVID-19 patients is warranted and will better equip clinicians to provide optimal patient care in the setting of drug shortages.

Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD
Mahmoud A. Ammar, https://orcid.org/0000-0002-3401-9960

Supplemental Material
Supplemental material for this article is available online.

Gretchen L. Sacha, https://orcid.org/0000-0002-0070-8100

References

1.

Poston, JT, Patel, BK, Davis, AM. Management of critically Ill adults with COVID-19. JAMA. 2020. |
Google Scholar Crossref | Medline

2.

The Center for Systems Science and Engineering (CSSE) at Johns Hopkins University . Accessed July 3, 2020. https://coronavirus.jhu.edu/map.html
Google Scholar

7.

Wu, C, Chen, X, Cai, Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):1-11. |
Google Scholar Crossref

10.

FDA Drug Shortages [online] . Accessed April 26, 2020. https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm
Google Scholar

11.

ASHP Drug Shortages [online] . Accessed April 26, 2020. https://www.ashp.org/Drug-Shortages
Google Scholar

24.

Wilhelm, W, Kreuer, S. The place for short-acting opioids: special emphasis on remifentanil. Crit Care. 2008;12(suppl 3):S5.
Google Scholar

66.

Donnelly, RF . Stability of diluted ketamine packaged in glass vials. Can J Hosp Pharm. 2013;66(3):198. |
Google Scholar Medline

72.

Madhok, J, Mihm, FG. Rethinking sedation during prolonged mechanical ventilation for COVID-19 respiratory failure. Anesth Analg. 2020. |
Google Scholar Crossref | Medline

89.

Johnson, AB, Sadiq, NM. Pentobarbital. In: StatPearls [Internet]. StatPearls Publishing. Published 2020. Updated October 14, 2019. Accessed July 3, 2020. https://www.ncbi.nlm.nih.gov/books/NBK545288/
Google Scholar

105.

Farasatinasab, M, Kouchek, M, Sistanizad, M, et al. A randomized placebo-controlled trial of clonidine impact on sedation of mechanically ventilated ICU patients. Iran J Pharm Res. 2015;14(1):167-175. |
Google Scholar Medline

106.

Terry, K, Blum, R, Szumita, P. Evaluating the transition from dexmedetomidine to clonidine for agitation management in the intensive care unit. SAGE Open Med. 2015;3:2050312115621767. |
Google Scholar SAGE Journals

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Sedation, Analgesia, and Paralysis in COVID-19 Patients in the Setting of Drug Shortages - Mahmoud A. Ammar, Gretchen L. Sacha, Sarah C. Welch, Stephanie N. Bass, Sandra L. Kane-Gill, Abhijit Duggal, Abdalla A. Ammar, 2021

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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.

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Na teoria este posicionamento permite que a ventilação seja mais homogênea devido a diferença entre as pressões transpulmonares  dorsal  e  ventral promoverem a redução da distensão alveolar ventral e a diminuição do colapso alveolar dorsal, além disso também ocorre a melhora da perfusão por diminuição da compressão pulmonar.

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Pronação em clientes com síndrome do desconforto respiratório agudo: caso simulado

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Genes humanos que lutam contra o Sars-CoV-2 são identificados em estudo

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Genes humanos que lutam contra o Sars-CoV-2 são identificados em estudo

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"Pesquisadores da Universidade da Colúmbia Britânica, no Canadá, registraram a ação de uma outra proteína, conhecida como lectina, que consegue se acoplar à spike e, assim, impedir que o novo coronavírus infecte nosso corpo."

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SARS-CoV-2 coronavirus spike protein under siege

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A Gasometria arterial é primordial para a realização de ajustes na ventilação mecânica, assim como ser o preditor do calculo que define a necessidade de pronação do paciente.

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O fisioterapeuta atua nos ajustes de parâmetros da ventilação mecânica de acordo com o encontrado em exames laboratoriais como a gasometria, e também de acordo com o estado clínico do paciente.

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Relação P/F

PaO2/FiO2

Peso Predito

(Alt. em cm – 152,4) X 0,91
Para Homens: +50
Para Mulheres: +45,5

PaCO2 desejada

(HCO3 Medida X 40) ÷ 24

FR desejada

PaCO2 (conhecida) X FR (conhecida) / PaCO2 (desejada)

VM desejado

VM atual X PaCO2 Atual / PaCO2 desejada

Vt desejado

Vt Atual X PaCO2 Atual PaCO2 desejada

FiO2 necessária

PaO2 (desejada) X FiO2 (conhecida) PaO2 (conhecida)

PaO2 Ideal

96 – (0,4 X Idade)

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A avaliação diária de exames de imagem também fazem parte da rotina do fisioterapeuta. Através dela são traçados objetivos tanto a nível de ventilação mecânica como de manobras ventilatórias e o uso de aparelhos.