US Pharm. 2020;45(7/8):HS9-HS16.
ABSTRACT: The role of the clinical pharmacist has expanded during the coronavirus disease 2019 (COVID-19) crisis. Pharmacists caring for hospitalized patients with pneumonia must simultaneously provide other team members with updated, COVID-19–specific best practices and ensure consistent application of evidence-based ICU practices, with responsibilities including optimizing medication shortages and keeping current with rapidly changing clinical information. It is also important for pharmacists to keep abreast of the unique pharmacotherapy challenges posed by COVID-19 pneumonia, understand the need for glycemic control and the controversial nature of anticoagulation, and be conversant with the medications used in mechanical ventilation. Objective data on COVID-19 therapy are lacking, and a definitive treatment algorithm will remain elusive so long as disagreement abounds.
Medicine finds itself in a very peculiar place right now. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2, the medical community has struggled to find effective therapies to combat this novel pathogen. Social media, mainstream media, and medical journals tout novel and/or repurposed drugs almost continuously. However, much of the information supporting these therapies is anecdotal or retrospective; limited data have been obtained from randomized, controlled trials. The formulation of decisive conclusions from the few existing clinical trials is also problematic given that sample sizes are very small, studies are from single centers, and public-health need pressures the release of preliminary results with inadequate peer review. Regardless, this process has provided accelerated access to novel therapies (remdesivir and convalescent plasma) through the FDA’s Emergency Use and Expanded Access programs.
Hallmarks of our accumulating understanding of the COVID-19 pandemic include an incredibly rapid pace of new information, fragmentation of the data being shared, and frequent contradictions between new information and data released only hours or days before. In this environment, clinical disagreements are common, and healthcare worker frustration is substantial. Given the lack of objective data, inconsistent guideline recommendations, and the rapid pace at which COVID-19 therapy is evolving, clinicians routinely rely on empirical, real-time recommendations shared by peers with more extensive experience—often through online channels including critical-care blogs and virtual guidelines.1,2 Multiple suggestions herein are not supported by rigorous data. Therefore, it is advisable for readers to view any recommendations lacking a customary citation with trepidation, as they are essentially expert opinion. This humbling observation also highlights that while expanding the understanding of COVID-19 is essential to optimizing the care of infected patients, it is equally important—perhaps more important—to adhere to long-standing, evidence-based ICU practices in treating hospitalized patients with COVID-19 pneumonia who are critically ill.
Experience gained thus far has led to two important realizations regarding pharmacists and COVID-19. First, the care of COVID-19–infected patients requiring mechanical ventilation is a resource-heavy endeavor for the pharmacy, with serious potential for shortages of commonly used medications. While the exact drugs with limited supply have varied regionally based on local practice and/or supply chains, heavily hit areas have consistently reported limitations.3 Second, pharmacists caring for these patients simultaneously fulfill the key roles of educator and enforcer: The educator provides other team members with updated, COVID-19–specific best practices (optimizing drug dosages, suggesting alternative routes/modes of administration, and recommending therapeutic exchanges), and the enforcer ensures consistent application of evidence-based ICU practices (fostering antimicrobial stewardship, minimizing the impact of shortages, and assisting with experimental therapies). It is not uncommon for physicians and nurses who do not routinely care for critically ill patients to take on this role during surges in COVID-19 patients; in this circumstance, the educator and enforcer roles of the clinical pharmacist become imperative. To that end, rather than focusing on rapidly evolving virus-specific therapies, this article summarizes the more durable lessons concerning pharmacotherapy and reviews ICU practices that should be modified during the COVID-19 pandemic.4
Medication administration should be consolidated to minimize the number of times nursing staff must enter a COVID-19–infected patient’s room. This lessens personal protective equipment (PPE) consumption and reduces the infection potential for healthcare workers. For medications being delivered via continuous infusion, consideration should be given to compounding larger bags than would typically be used and/or maximally concentrating medications to reduce the frequency of bag exchanges. Ready-to-use dosage forms should be used whenever possible because medications cannot be removed from a COVID-19 room to be reused elsewhere.
It is generally accepted that the delivery of medications via nebulizer is an aerosol-generating procedure and is associated with an increased risk of COVID-19 transmission in nonintubated patients.5,6 Accordingly, it is recommended that inhaled therapies be delivered to nonintubated COVID-19–infected patients via metered-dose inhaler (MDI) whenever practical, and clinicians should be reminded that one nebulized treatment is typically equal to roughly six to eight puffs on a conventional MDI.7 In the intubated patient, aerosolization via nebulizer is not a concern and medications should be given via in-line nebulization in order to preserve MDIs for use elsewhere.8
Acute kidney injury (AKI) and elevations in liver-function tests are common in critically ill patients, including those with COVID-19 pneumonia. This means that pharmacokinetic consultation may be required to assist with dosage adjustments for medications with renal and/or hepatic metabolism or clearance. In this setting, certain medications should be avoided whenever possible; both nonsteroidal anti-inflammatory drugs and vancomycin are discouraged because they contribute to AKI.9
Caution is warranted with medications that are known to prolong the QT interval. Although several of these agents are often necessary or recommended for use in COVID-19–infected patients, the astute clinician will periodically perform ECGs and assess for therapeutic substitutions if or when indicated.
Many COVID-19 patients develop an overreactive immune response—the so-called cytokine storm—that leads to dramatic increases in lactate dehydrogenase, ferritin, erythrocyte sedimentation rate, C-reactive protein, and d-dimer; a hypercoagulable state; and poorer clinical outcomes.10 Experts encourage caution in the prescribing of therapies with the potential to worsen the cytokine storm, and this is one rationale behind the recommendation for a restrictive blood-transfusion strategy.
The role of ACE inhibitors and angiotensin receptor blockers (ARBs) is controversial in COVID-19 patients. One early hypothesis was that ACE inhibitors and ARBs increase ACE2 expression by epithelial cells in the lung and that these receptors are the entry site for pathogenic coronarviruses.11 A subsequent curated literature review suggested that ACE2 may paradoxically protect against acute lung injury and that taking an ACE inhibitor or ARB might be protective.12 Without convincing data that these agents help or hurt during COVID-19 infections, multiple major professional societies endorse the continuation of these agents in patients previously taking them who have no contraindications to ongoing use (e.g., AKI, hyperkalemia).13,14
The major cause of death in COVID-19 patients is the development of acute respiratory distress syndrome (ARDS). Because the complications of ARDS are exacerbated by volume overload, a restrictive fluid strategy is uniformly endorsed. The guidelines that specifically address this topic recommend that fluids be given as frequent, small boluses, with reassessments made often via point-of-care ultrasound.15,16 In line with this rationale, hypotonic fluids, starches, and gelatins should be avoided; medications should be maximally concentrated; and medications should be given by IV push whenever possible, as opposed to infusing in a larger volume.
Finally, to date, no agent studied for postexposure prophylaxis has shown efficacy against COVID-19. Accordingly, pharmacists should be prepared to educate clinicians that, unlike the customary practice for influenza, postexposure prophylaxis is not currently endorsed for COVID-19.
As with other critically ill patients on mechanical ventilation, routine empirical antibiotic therapy is not recommended for COVID-19–infected patients. However, guidelines from the Surviving Sepsis Campaign, the World Health Organization (WHO), and the Veterans Health Administration (VHA) all endorse a low threshold to evaluate and prescribe empirical antibiotic therapy for secondary bacterial pneumonia in patients with COVID-19.5,15,17 A strategy of early lower respiratory tract cultures and procalcitonin measurement is based on experience from the outbreak in Wuhan, China. The Surviving Sepsis Campaign and Department of Defense guidelines for COVID-19 endorse an empirical regimen for community-acquired pneumonia consisting of ceftriaxone and azithromycin when mechanically ventilated patients with COVID-19 are suspected to have secondary bacterial pneumonia.5,16 If methicillin-resistant Staphylococcus aureus (MRSA) is a concern because of patient-specific risk factors, it is suggested that vancomycin be avoided owing to the risk of AKI. In this instance, MRSA coverage should include consideration of ceftaroline in place of ceftriaxone or linezolid in combination with ceftriaxone and azithromycin.18 As always, the pharmacist should advocate for good antimicrobial stewardship and antibiotic deescalation or cessation whenever appropriate.
Given the dramatic pace at which virus-specific therapies for COVID-19 are evolving, a discussion of these agents is intentionally avoided in this article. However, many experimental and/or compassionate-use therapies (e.g., remdesivir, convalescent plasma) require significant pharmacy engagement to procure and administer.
Sedation, Analgesia, and Paralytics
No COVID-19–specific recommendations have been published regarding sedation to facilitate mechanical ventilation. Patients with COVID-19 pneumonia commonly need more prolonged ventilator support—2 weeks on average—and often require deeper sedation in order to tolerate the uncomfortable ARDS-like ventilator settings that are typically used. Although anecdotal, many experts suggest a sedation “ladder” that incorporates multiple medications used at lower doses.1 These recommendations, which often include several agents (melatonin, diazepam, olanzapine, phenobarbital) that might be less commonly used in non–COVID-infected patients, are intended to avoid or minimize the impact of drug shortages.1,2,6,8
Although dexmedetomidine is the preferred sedative of some experts, given its favorable hemodynamic profile, others suggest that dexmedetomidine be reserved for weaning from ventilation.8 Another strategy includes using clonidine as an adjunct to dexmedetomidine.19 If deeper sedation is needed to facilitate vent synchrony, propofol is used. COVID-19 appears to potentiate the hypertriglyceridemia occurring with propofol, and triglycerides should be checked every 3 days; if the triglyceride level exceeds 500 mg/dL, an alternative sedative should be considered.1 Reliance on benzodiazepines is discouraged, given the potential for development of physical dependence and subsequent risk of withdrawal. During shortages or to avoid benzodiazepine use, it has been suggested that phenobarbital be considered at doses similar to those used for status epilepticus. Atypical antipsychotics are also an option, with olanzapine preferred over its predecessors because it does not prolong the QT interval. If benzodiazepine use is necessary, these agents should be given only on an as-needed basis by IV push.
Appropriate analgesia facilitates ventilator synchrony, minimizes oxygen consumption, and can potentiate the sedating effects of several medications.8 Opiates should be used judiciously, given their potential for dependence and withdrawal. Accordingly, scheduled acetaminophen should be considered for pain (and fever) in the absence of liver dysfunction. Fentanyl is generally the first-line opiate, followed by hydromorphone and morphine. All of these agents should be given as as-needed boluses, not as infusions. Ketamine has analgesic properties when properly dosed, and in times of shortage it can be administered as a continuous drip or as adjunctive boluses; its favorable hemodynamic profile is particularly appealing in patients with shock.20 Given that ketamine is a weak inhibitor of interleukin-6, some have suggested that it might mitigate the cytokine storm seen in later phases of COVID-19 pneumonia. Potential limitations to the use of ketamine for sedation include drug-induced hypertension and/or tachycardia, agitation with higher doses, and the unreliability of bispectral-index (BIS) monitoring of the depth of sedation with this agent.20
The use of neuromuscular blocking agents (NMBAs) is controversial in patients with COVID-19 pneumonia, just as in most other critically ill patients. The Surviving Sepsis Campaign guidelines recommend that NMBAs be considered only after other options have been exhausted.5 If a patient is dyssynchronous with the ventilator, has high ventilator pressures despite optimizing settings, and/or is not a candidate for prone ventilation, bolus doses of rocuronium or vecuronium may be given hourly as needed.8 Patients requiring more than five doses of a NMBA per 24 hours should be transitioned to a continuous infusion of cisatracurium.8 All patients receiving paralytics should be appropriately monitored for depth of paralysis (train of four) as well as for appropriate sedation and analgesia (BIS).
The use of systemic steroids is controversial in many critical-care disease states. Similarly, recommendations regarding the use of corticosteroids to blunt the cytokine storm and/or treat ARDS in COVID-19 are inconsistent across the various guidelines. The Surviving Sepsis Campaign suggests early corticosteroid use in patients who have ARDS secondary to COVID-19.5 This recommendation is extrapolated from a study of patients with ARDS not caused by COVID-19.21 In contrast, the WHO, the Infectious Diseases Society of America, the National Institutes of Health (NIH), and the VHA recommend against the use of corticosteroids in COVID-19 patients until more definitive data are obtained and out of concern that steroids may prolong viral shedding.15,17,22,23 The American Thoracic Society makes no recommendation for or against corticosteroids.24 Equally daunting is the fact that there is no clearly defined protocol for steroid prescription: Current strategies differ significantly regarding the timing of initiation, duration, dose, and withdrawal of steroid therapy. If steroids are being used, an argument has been made to avoid agents with significant mineralocorticoid activity in order to minimize sodium retention, thereby reducing fluid overload and the risk of ARDS. The pharmacist should be mindful of these pros and cons and should ensure that appropriate glycemic monitoring takes place when steroid therapy is prescribed.
Hyperglycemia is common in critically ill COVID-19 patients.8 The etiology appears to be multifactorial and potentially includes a combination of viral destruction of beta islet cells decreasing endogenous insulin release; insulin resistance; stress-induced hyperglycemia; and steroid-induced hyperglycemia.25 Although some experts have suggested placing all critically ill patients with hyperglycemia on an insulin drip, this results in more nursing time in the infected patient’s room (checking blood sugars frequently and titrating the drip) and attendant PPE consumption while also substantially increasing the daily fluid volume administered. Accordingly, many clinicians prefer a subcutaneous insulin regimen typically combining an intermediate- or long-acting agent with a sliding-scale short-acting agent. Regardless of the combination used, the pharmacist should assist in ensuring that a blood sugar level of 140 to 180 mg/dL is targeted.26
The role of anticoagulation in COVID-19 is one of the most contentious and heavily debated topics. The only agreed-upon paradigm in this realm is that the current ICU standard of care—regardless of COVID-19 status—is for mechanically ventilated patients to receive deep venous thrombosis (DVT) prophylaxis.5,27 After multiple postmortem case studies described an abundance of microthrombi in various organs of COVID-19–infected patients—even though the exact mechanism of microthrombus formation was not well understood—clinicians increasingly discussed liberal application of therapeutic anticoagulation.8 With the subsequent realization that elevated d-dimer concentration is a predictor of mortality, various institutions began to formally endorse aggressive anticoagulation in patients with COVID-19 despite a paucity of supporting evidence.28-30 Again, there was a general lack of consensus as to when anticoagulation should be started, the optimal agent(s), effective dosing, and when to discontinue therapy. This remains an area of significant disagreement, and the NIH recently suggested that any anticoagulation strategy beyond routine DVT prophylaxis should be used only in clinical trials, given “insufficient data.”31
Certain other therapies are considerations for institutions with the experience and capability to successfully employ them. Inhaled pulmonary vasodilators (nebulized epoprostenol, inhaled nitric oxide) are agents with a short half-life that, when delivered via the ventilator, cause vasodilation only in alveoli that are functional and participating in gas exchange. This effectively shunts blood flow away from atelectatic and consolidated alveoli and redirects it to functioning alveoli, thereby resulting in improved ventilation-perfusion matching and improved blood oxygenation. These medications have mixed recommendations because they are labor intensive; they accelerate the rate of replacement of ventilator filters, a potentially limited resource; tachyphylaxis develops; and their ability to improve oxygenation has never translated into improved clinical outcomes. Existing guidelines vary in their recommendations on the use of these medications, including using them as a temporary measure or as a bridge to extracorporeal membrane oxygenation (ECMO) treatment and making no comment on their use.5,6,16,32 The clinical pharmacist should ensure that these medications are used only in the appropriate clinical context by experienced prescribers.
The use of ECMO as salvage therapy in severe COVID-19 is controversial, as this is a personnel- and resource-rich endeavor that simply might not be practicable during times of COVID-19 surge. However, several guidelines endorse its consideration if it is available and feasible.6,15,16,24,32
Data regarding COVID-19 are evolving so quickly that much of the information in this review is anecdotal, and some of it is likely obsolete already. However, COVID-19 has imparted a host of lessons, many of which are not specific to this novel coronavirus and therefore provide opportunities to prepare for future pandemics. A definitive treatment algorithm for COVID-19 therapy will remain elusive so long as disagreement abounds—and disagreement is inevitable when objective data are lacking. Although FDA approval is being sought for a number of COVID-19–specific agents, the bulk of COVID-19 treatment is meticulous, evidence-based, and supportive. However, supportive therapies must be provided optimally, which is a challenging task when key drugs are unavailable, multiorgan failure is common, and nonintensivist physicians are caring for critically ill patients because of staffing limitations. Therefore, the clinical pharmacist must commit to the twin roles of educator and enforcer when assisting in the care of COVID-19 patients.
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14. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19. Accessed June 29, 2020.
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21. Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276.
22. National Institutes of Health. Care of critically ill patients with COVID-19. www.covid19treatmentguidelines.nih.gov/critical-care/. Accessed June 29, 2020.
23. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/. Accessed June 29, 2020.
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27. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026.
28. Emory Healthcare. Guidelines for the prevention and treatment of VTE in critically ill patients with COVID-19. www.emoryhealthcare.org/ui/pdfs/covid/medical-professionals/COVID%20Emory%20VTE%20Guidelines%20FINAL.pdf. Accessed June 29, 2020.
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31. National Institutes of Health. Antithrombotic therapy in patients with COVID-19. https://covid19treatmentguidelines.nih.gov/antithrombotic-therapy/. Accessed June 29, 2020.
32. Massachusetts General Hospital (MGH) COVID-19 treatment guidance. www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf. Accessed June 29, 2020.
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