- Link to full chapter here (more complete – but longer).
- Preamble & caveats
- Initial tests to guide management
- Organ support
- Things that don't work
- Summary table
- Questions & Discussion
preamble & caveats
We're now almost a year into the COVID-19 pandemic. By this point, most of us are familiar with the basics of this disease. The purpose of this chapter is to provide an overview of the updated management of COVID patients admitted to either a stepdown unit or an ICU. A prior and more general chapter on COVID-19 is located here.
By now, you're probably well aware of the numerous controversies surrounding COVID-19 (e.g., when to intubate patients). This chapter will focus on available data, but there are innumerable grey zones in between available RCTs (indeed, most of our practice falls beyond answers which are clearly established by multicenter RCTs). Please don't misconstrue material in this chapter as irrefutable fact or dogma, since most of our management of COVID-19 remains a work in progress.
tests to guide management
- Chest X-ray
- Initial CXR is useful for prognostication and to avoid missing non-COVID pathology (e.g., pneumothorax).
- C-reactive protein (CRP) levels on admission and daily (discussed further in the immunomodulation section below).
- Other COVID labs
- It may be useful to check these once, upon admission (e.g., D-dimer, LDH, ferritin, fibrinogen).
- The value of repeating these labs is unclear.
- Avoid frequent lab draws (e.g., blood gas measurements or serial troponin), as these will promote anemia. If patients progress to develop severe hypoxemia, the coexistence of anemia will make that far more dangerous:
- Remember: (oxygen delivery) = (cardiac output) x (oxygen saturation) x (hemoglobin concentration)
chest CT scan
- CT scan is generally not needed solely for the purpose of diagnosing COVID (especially if there are characteristic abnormalities on chest x-ray and thoracic ultrasonography).
- Early CT scan is indicated if there is a specific clinical concern regarding pulmonary embolism (e.g., a patient who has recovered from COVID pneumonia, and then returns to the hospital with an acute respiratory deterioration weeks later).
- CT scan may have a greater role for patients who aren't responding to 1-2 weeks of therapy, where the differential diagnosis may be broader (including PE, fungal or bacterial pneumonia, or cryptogenic organizing pneumonia).
- Extreme hemodynamic instability isn't usually a feature of COVID (especially early on). For patients presenting with shock, evaluate for alternative causes (e.g., pulmonary embolism or myocardial infarction).
- Gentle volume resuscitation may be considered early after admission if:
- There is clinical history of volume depletion (e.g., days of reduced oral intake and diarrhea).
- Examination is consistent with volume depletion.
- Avoid bolusing patients (especially the 30 cc/kg fluid bolus which has been popularized for the management of sepsis). Available evidence shows that fluid boluses rapidly extravasate into the interstitial tissues. If patients are truly volume depleted, it may be optimal to repair this with a gradual fluid infusion.
- Once patients have reached a state of euvolemia, target an even fluid balance.
consider discontinuation of antihypertensives
- ACE inhibitors and angiotensin receptor blockers (ARBS) are potentially nephrotoxic and should be discontinued in patients with critical illness given the very high rate of renal failure. (These medications don't need to be discontinued in patients who are less severely ill, for example admitted on the ward).
- Consider holding or de-escalating other antihypertensives. Aiming for a high-normal blood pressure range may help avoid hemodynamic instability.
noninvasive respiratory support
- A major driver of hypoxemia in COVID-19 appears to be atelectasis. Once this begins happening, it may become a vicious spiral wherein lung architecture is distorted by collapsed alveoli – making it harder for neighboring alveoli to stay open.
- Lung recruitment may be achieved in one of two ways:
- Prone positioning or varying positions (e.g., from side to side) helps recruit the non-dependent lung tissue.
- Positive airway pressure (e.g., CPAP or BiPAP) directly promotes alveolar inflation.
non-intubated (“awake”) prone positioning
- Awake proning has emerged as a fundamental strategy to prevent atelectasis among COVID patients.
- This can be combined with simultaneous use of any other noninvasive support device (e.g., low-flow nasal cannula, high-flow nasal cannula, BiPAP, CPAP). The benefits of proning may be additive to the benefits of these devices.
- Awake proning requires cooperative patients with intact mentation.
- Many patients are able to do this with minimal assistance.
- For patients with morbid obesity, a pregnancy proning pillow may help.
- There is no single optimal way to achieve awake proning. In practice, this may be somewhat variable, depending on what patients are able to achieve comfortably. The overall goal is avoiding the supine position as much as possible.
- For patients who are comfortable sleeping on their abdomen, this could involve full proning for 12-18 hours/day.
- For patients unable to sleep on their abdomen, proning may be performed during the day (subsequently CPAP or BiPAP may be used at night to prevent derecruitment).
- For patients unable to lie on their abdomen, proning may involve alternating among a variety of positions (e.g., lying on alternate sides).
high-flow nasal cannula (HFNC)
- High-flow nasal cannula provides the following:
- (i) Precisely titrated oxygen support.
- (ii) Heated humidification (promotes comfort and may prevent airway obstruction by dried secretions).
- (iii) A very low level of PEEP.
- (iv) Washout of anatomic dead space (which facilitates CO2 clearance, thereby reducing the work of breathing).
- The combination of these benefits likely makes HFNC superior to using high levels of a conventional nasal cannula (e.g., running a standard nasal cannula at >6 liters/minute).
- HFNC by itself does not promote recruitment, so this may be inadequate to break the vicious spiral of derecruitment. Whenever possible, HFNC should be combined with awake proning.
CPAP or BiPAP
- These may be very effective modalities to recruit lung tissue, thereby improving oxygenation. CPAP or BiPAP are especially useful for:
- Patients with morbid obesity, sleep apnea, obesity hypoventilation syndrome, or COPD.
- Patients unable to tolerate awake proning at all.
- Patients unable to sleep comfortably in a prone position.
- CPAP or BiPAP are often useful at night, whereas patients may use HFNC during the day (in combination with periods of awake proning). The use of HFNC during the day allows patients to eat and communicate.
- Some patients may initially require a stabilization period of nearly continuous CPAP or BiPAP for ~24-48 hours to recruit alveoli and support the work of breathing (with intermittent breaks for secretion clearance).
- The key component of CPAP or BiPAP is the mean airway pressure – because this is what causes recruitment.
- For CPAP, the mean airway pressure is simply the PEEP level.
- For BiPAP, the mean airway pressure is most closely related to the expiratory pressure. Thus, for patients on BiPAP with severe hypoxemia, efforts usually center around up-titration of the expiratory pressure as tolerated (e.g., start at 10cm/5cm, escalate to 15cm/10cm, then escalate to 18cm/12cm).
- CPAP vs. BiPAP – which is best?
- BiPAP provides some mechanical support to aid the patient's work of breathing. This could be useful for patients with dyspnea. Additionally, some patients may perceive BiPAP as more comfortable because the pressure difference is helping them breathe.
- CPAP has the advantage that it doesn't increase the patient's tidal volume, which theoretically might facilitate more lung-protective ventilation. For patients who are comfortable on CPAP, this is probably the ideal modality.
- As long as you're setting the BiPAP with a low driving pressure (e.g., using 16cm/12cm, rather than 16cm/5cm), it probably doesn't matter whether you're using CPAP or BiPAP.
- The most important aspect is that the patient is comfortable. Some patients may find one modality more comfortable than the other. Settings should be titrated based on the patient's response.
- CPAP or BiPAP can be combined simultaneously with proning. The combination of CPAP or BiPAP plus prone positioning is probably the most powerful recruitment strategy for a non-intubated patient.
CPAP via helmet interface
- CPAP may be provided via a helmet interface.
- The low compliance of the helmet interface may make it difficult to synchronize with the patient when performing BiPAP. Thus, these devices might work a bit better with CPAP mode.
- Advantages may include the following:
- Superior mask seal (especially in patients with facial hair or unusual anatomy).
- Reduced aspiration risk (emesis will not immediately be aspirated).
- Reduced risk of skin erosions over the nose.
- No requirement for using a mechanical ventilator (e.g., can be run directly off wall oxygen).
safety of HFNC and BiPAP
- Neither HFNC nor non-invasive ventilation appear to increase virus aerosolization significantly, when compared to low-flow oxygen.(32838370, 33059983, 30336170)
- Speaking and coughing generate aerosols, so the distinction between “aerosol-generating procedures” and “non-aerosol generating procedures” is arbitrary and not evidence-based.
- Aerosol precautions should be maintained for all patients with COVID, regardless of whether they are being treated with HFNC or noninvasive ventilation (e.g., N95 masks, eye protection, and ideally negative pressure rooms with frequent air exchanges).
- For patients on CPAP or BiPAP, viral filters can help limit aerosol spread of the virus. This is possible with either a two-limb system involving a full-featured mechanical ventilator, or a one-limb system involving a dedicated BiPAP machine (e.g., Respironics V60). A discussion of how to configure this is located here.
invasive mechanical ventilation
when to intubate?
- This is highly controversial and largely unknowable due to the impossibility of designing adequate RCTs. Furthermore, these decisions are ultimately made at the bedside, based on serial evaluation of the patient's respiratory status over time. As such, the following are merely some rough guiding concepts.
- When possible, avoidance of mechanical ventilation is highly desirable. This may help avoid prolonged ICU stay, delirium, and complications of ventilation (e.g., ventilator-associated pneumonia, pressure ulceration).
- Potential indications for intubation usually center around:
- i) Patient is completely dependent on CPAP or BiPAP for >36-48 hours (i.e., unable to tolerate breaks on high-flow nasal cannula).
- ii) Inability to maintain saturations over roughly ~70-80% on noninvasive support, despite a period of recruitment. (The 70-80% number is arbitrary, with different centers having varying levels of comfort in tolerating hypoxemia. The degree of hypoxemia which a patient can tolerate will depend on their hemoglobin level and cardiopulmonary fitness, so a one-size-fits-all approach may not be ideal.)
- iii) Worsening respiratory distress (not isolated tachypnea, but true respiratory distress wherein the patient feels uncomfortably short of breath).(32281885)
- When in doubt, clinical trajectory can be a useful tie-breaker. If the patient is consistently deteriorating hour after hour, despite maximal supportive measures, then intubation may be more reasonable. If the patient has been fairly stable for a while, with some transient fluctuations up and down, then you may be more likely to be able to ride it out without intubation.
- For a discussion of the intubation procedure, see the COVID-19 Airway Page by Scott Weingart.
Either low tidal-volume ventilation or APRV may be used. This is largely dependent on institutional practice patterns.
airway pressure release ventilation (APRV)
- Early APRV could be very useful for these patients (i.e. when used as the initial ventilator mode, rather than a salvage mode).
- Benefits of APRV include:
- (1) A primary physiologic problem in COVID appears to be derecruitment, which is well managed by APRV. A drop in FiO2 requirement to ~50% is often seen within 6-12 hours on APRV (full recruitment takes time).
- (2) APRV often allows for improvement in hypoxemia without paralysis and/or proning. This may avoid iatrogenic complications from these interventions (e.g., delirium, myopathy).
- (3) APRV is a more comfortable mode than conventional volume-cycled ventilation. This may allow us to render patients comfortable and awake on the ventilator more easily, while using fewer medications (an especially important challenge as we run out of many sedatives).
- A practical guide to using APRV in COVID can be found here. APRV initiation can cause hemodynamic shifts, so pay careful attention to blood pressure during initiation.
- True failure to respond to APRV within 12-24 hours (e.g., with PaO2/FiO2 <100-150) would be a strong argument to move towards prone ventilation (discussed here). However, when started early APRV may be more likely to succeed – thereby avoiding the need for proning.
conventional low tidal-volume ventilation
- This will likely be the most commonly used mode of ventilation, given a strong evidentiary basis as well as widespread experience.
- Tidal volumes should be targeted to a lung-protective range (6 cc/kg ideal body weight, with some liberalization to 8 cc/kg if necessary).
- There is no consensus regarding exactly how to titrate PEEP. ARDSNet PEEP tables may represent a reasonable starting point. Titration to clinical effect may be useful if there is sufficient time and experience to do this.
- 👁 Image of ARDSNet low-PEEP & high-PEEP tables here.
- The concept of using unusually low levels of PEEP does not appear to be evidence-based and is not recommended for COVID. Low levels of PEEP may cause partial atelectasis of the lungs, leading to atelectotrauma (repeated opening and closing of the alveoli with each respiratory cycle). Substantial atelectotrauma may be even more dangerous than barotrauma.
permissive hypercapnia & optimization of metabolic acid/base status
- Regardless of the ventilator mode, permissive hypercapnia may be useful. The safe extent of permissive hypercapnia is unknown, but as long as hemodynamics are adequate, a pH above roughly ~7.15 is generally fine (hypercapnia is preferred over lung-injurious ventilation).
- A common error is to focus solely on respiratory parameters in order to improve the pH, while ignoring metabolic acid/base status. For example:
- ICU patients often have non-anion-gap metabolic acidosis (NAGMA). Treatment of NAGMA with bicarbonate may be the safest way to address a low pH (rather than increasing the intensity of mechanical ventilation and thereby threatening the lung).
- Even if the metabolic acid/base status is normal, IV bicarbonate may still be considered to improve pH, while simultaneously continuing lung-protective ventilation (discussed here). Targeting a mildly elevated serum bicarbonate can facilitate safe ventilation with low tidal volumes (more on different forms of IV bicarbonate here).
- Prior to consideration of proning, optimization on the ventilator for 12-24 hours is generally preferable (discussed here).
- For failure to respond to initial ventilator optimization (e.g., with persistent PaO2/FiO2 below 150 mm), prone ventilation should be considered.
- Proning is effective at increasing oxygenation, but it has the drawback of requiring deeper levels of sedation. Paralysis may be needed, but many patients can tolerate proning without paralysis (simply with deep sedation).
inhaled pulmonary vasodilators
- Inhaled pulmonary vasodilators offer potential efficacy with few drawbacks:
- i) Improved ventilation/perfusion matching may improve oxygenation.
- ii) Pulmonary vasodilation may off-load the right ventricle, avoiding cor pulmonale.
- Potential indications:
- (1) Refractory hypoxemia
- (2) Hemodynamic instability with evidence of cor pulmonale (e.g., right ventricular dilation on echocardiography)
- Aggressive noninvasive respiratory support following extubation may reduce the risk of reintubation.
- At a minimum, patients should receive ~24 hours of high-flow nasal cannula. This has been shown in RCTs to reduce the risk of reintubation among non-COVID patients with respiratory failure.(25003980, 26975498, 27706464)
- Addition of BiPAP or CPAP (e.g., at night – with high flow nasal cannula during the day) may be helpful for patients with morbid obesity, COPD, or worsening hypoxemia after extubation.
infectious disease & antibiotics
- Secondary or superimposed bacterial infection is uncommon in COVID, unless the patient has been intubated. Straightforward cases of COVID do not require treatment with antibiotics.
- If there is clinical concern regarding bacterial pneumonia (e.g., focal consolidation), empiric coverage for pneumonia may be initiated (e.g., ceftriaxone plus azithromycin). Testing for bacterial pneumonia may include blood cultures, procalcitonin, sputum Gram stain & culture, and urinary antigens. Based on the results of these tests, antibacterial therapy can usually be discontinued within <48 hours. Note that COVID itself may cause a mild increase in procalcitonin.
- Avoid vancomycin if possible, to avoid nephrotoxicity. Most patients with community-acquired pneumonia don't require MRSA coverage (further discussion here and here). If coverage of MRSA is legitimately required, linezolid or ceftaroline may be safer options.
- During influenza season, patients should be tested for both influenza and COVID. Coinfection is currently uncommon, but will vary depending on epidemiological trends.
- Coinfection may lead to increased disease severity.(33277660)
- Optimal management is unknown. A reasonable approach may be the treatment for COVID as described in this chapter, along with consideration for possibly adding oseltamivir. The presence of influenza isn't a contraindication to immunomodulation (note that influenza H1N1 can cause virus-induced hemophagocytic lymphohistiocytosis, which itself requires immunomodulation as discussed here).
- Patients have a tendency to develop renal failure, which is likely multifactorial in nature.
- Avoid nephrotoxins like the plague. Notable offenders are NSAIDs and vancomycin.
- COVID induces a state of hypercoagulability and heparin resistance. Traditional doses of prophylactic heparin for DVT prophylaxis often fail to achieve adequate inhibition of factor Xa among COVID patients, likely due to elevated levels of heparin-binding proteins.(32510975, 32920503, 33049598, 32445064, 32311843) This explains the clinical observation that ICU patients with COVID have high rates of venous thromboembolic disease, even despite prophylactic heparin.(32291094, 32485418)
- If renal function is adequate (GFR > 30 ml/min), an “intermediate” dose of low-molecular-weight heparin might be ideal (e.g., enoxaparin ~0.5 mg/kg twice daily).
- Prior to COVID there was already a growing body of evidence supporting the use of this dose for DVT prophylaxis among critically ill patients, especially surgical ICU patients.(26850200, 26658126, 22009998, 29699807, 24070664, 30954541, 26031274)
- It's likely that we've historically been underdosing many of our non-COVID ICU patients. Specifically, there is persuasive evidence that 40 mg enoxaparin daily for all critically ill patients will usually be inadequate.(19850587, 12771610, 23601744, 23487580, 31679829) Further discussion of this here.
- For patients with renal insufficiency (e.g., GFR <30 ml/min), somewhat generous doses of prophylactic heparin may be considered, especially for patients with morbid obesity (e.g., 7,500 units unfractionated heparin sq q8hr for larger patients).
- The most precise way to dose-titrate prophylactic low-molecular-weight heparin is based on anti-Xa levels (description of how to do that here). However, this is often logistically difficult.
- DVT prophylaxis should be continued if the patient has thrombocytopenia, as long as it isn't severe (e.g., platelets >30,000/uL).
therapeutic anticoagulation for COVID (without known DVT/PE) ??
- A press release from the ACTIV4 RCT stated that full dose anticoagulation given to moderately ill patients reduced the requirement for vital organ support (e.g. intubation). However, full-dose anticoagulation when started in the ICU was found not to be beneficial.
- Understanding the nuances of this study will need to await publication of results. For now, an augmented prophylactic strategy as described above seems reasonable for most patients.
therapeutic anticoagulation for known DVT/PE
- Due to issues with heparin resistance, use of a fixed dose of heparin may not be sufficient (e.g., 1 mg/kg enoxaparin BID).
- When possible, a heparin infusion with monitoring of anti-Xa levels may provide rapid assurance that heparin is achieving therapeutic efficacy. If low-molecular-weight heparin is used, then anti-Xa levels may be monitored after a few doses, to ensure adequacy (description of how to do that here).
- Available data is mixed and of low quality. A recent meta-analysis of retrospective studies detected no effect on mortality.(33417877)
- The RECOVERY trial is currently testing aspirin within a multicenter RCT.
- For patients previously on antiplatelet therapy, this should generally be continued.
analgosedation for intubated patients
- It may be challenging to maintain comfort among intubated COVID patients (e.g., due to medication shortages and prolonged duration of intubation).
- The key is often a multimodal strategy which utilizes lower doses of several medications. This may allow for synergistic efficacy, while avoiding dependency and withdrawal. For example:
- Multimodal analgesia often involves the use of scheduled acetaminophen and pain-dose ketamine infusions, to synergize with PRN opioids. More on this here.
- Multimodal sedation often involves using scheduled atypical antipsychotics to promote sleep and limit the dose of propofol required. More on this here.
- The use of melatonin agonists in critically ill patients has been a subject of ongoing controversy. Some RCTs have supported the ability of melatonin agonists to reduce the development of delirium, promote sleep, and decrease the requirement for sedatives.(20845391, 24554232, 25969139, 29595562, 33048904)
- One retrospective, preprint study from Columbia University found an association between melatonin use and improved mortality in COVID patients.(33083812)
- Nocturnal melatonin use (e.g., 5-10 mg q.h.s.) is a reasonable consideration for critically ill patients, regardless of whether it has any anti-COVID properties.(33048904)
- Currently, steroid is the cornerstone of immunomodulation. It should be utilized for any patient with new-onset hypoxemia due to COVID pneumonia.
- Various regimens have been utilized in RCTs:
- Dexamethasone 6 mg/day for up to 10 days improved mortality in the RECOVERY trial (equivalent to 32 mg methylprednisolone).(32678530) Consequently, this is the most commonly used steroid dose. However, this is a relatively low dose of steroid, which may be inadequate for patients with more severe disease.
- Dexamethasone 20 mg/day for five days followed by 10 mg/day for five days or until ICU discharge was the protocol utilized in the CODEX trial of intubated patients with COVID ARDS.(32876695) This regimen improved the number of ventilator-free days and also appeared to be safe (being associated with a decreased rate of infection). The same regimen was also found to reduce mortality in the DEXA-ARDS trial, a study of non-COVID ARDS.(32043986)
- Methylprednisolone 250 mg/day for three days was successfully utilized in one recent, very small RCT.(32943404)
- Currently the optimal dose of steroid is unknown and may vary between patients, depending on disease severity and the use of additional immunomodulating agents. A reasonable steroid dose might be somewhere between ~6-20 mg/day dexamethasone or its equivalent (e.g., ~32-125 mg/day methylprednisolone). If higher steroid dose is utilized initially, this may be tapered to 6 mg/day dexamethasone after the patient has improved.
- If dexamethasone supplies are exhausted, oral betamethasone sodium phosphate is nearly identical and could be a useful alternative.
IL-6 inhibitors (tocilizumab, sarilumab)
- Early studies involving tocilizumab monotherapy were negative.(33080005, 33085857) This is likely because tocilizumab affects only a single cytokine (IL-6) in the context of a storm involving numerous cytokines.
- The REMAP-CAP and RECOVERY trials demonstrated a mortality benefit when tocilizumab was added to low-dose dexamethasone. This is consistent with data from the EMPACTA trial, which found that tocilizumab reduced the risk of either death or intubation, among a population of COVID patients of whom 83% were receiving steroid.(33332779)
- Based on the RECOVERY trial, patients with hypoxemia and CRP levels >75 mg/L may benefit from adding tocilizumab to low-dose dexamethasone.(more on this trial here)
- In the RECOVERY trial, tocilizumab dosing was weight-based, as shown below. A second dose could be given after 12-24 hours, if there was no clinical improvement. However, only 29% of patients in the tocilizumab group received two doses.
- >90 kg: 800 mg IV
- 65-90 kg: 600 mg IV
- 40-65 kg: 400 mg IV
- <40 kg: 8 mg/kg IV
- Baricitinib is a JAK inhibitor which blocks multiple cytokine pathways (e.g., IL-2, IL-6, and IL-12), while potentially having fewer systemic side effects than steroid.(32542785)
- The ACTT-2 trial demonstrated that baricitinib reduced the risk of progressing to intubation (in a population of patients who were not receiving steroid).(33306283) Retrospective and propensity-matched studies have found a similar benefit among patients treated concurrently with steroid.(33187978, 33020836)
- Usual dosing is 4 mg/day (for GFR >30 ml/min) or 2 mg/day (for GFR 15-30 ml/day) for a two-week course.
- Notable contraindications are:
- Active severe infection (e.g., known tuberculosis or invasive fungal infection).
- Substantial immune dysfunction (e.g., AIDS, TNF inhibitors, chemotherapy).
- Pregnancy (little human data, some evidence of toxicity in animals).
- Absolute neutrophil count <500 cells/mm3 (although there isn't clear evidence that baricitinib reduces neutrophil count among COVID patients).
- (Lymphopenia is sometimes considered a contraindication, but studies have shown that the administration of baricitinib to COVID patients actually improves their lymphopenia.)(32592703, 32809969)
- Ruxolitinib is a similar JAK-1/JAK-2 inhibitor, showed some promise in one very small RCT. It likely has similar efficacy to baricitinib, but currently ruxolitinib is supported by less evidence.(32470486)
role of C-Reactive Protein (CRP) in titrating immunomodulation?
- CRP synthesis is largely modulated by IL-6, allowing it to be a clinically useful index of the cytokine storm (given that most hospitals lack the ability to measure IL-6 levels directly). CRP responds more rapidly to changes in inflammation than ferritin does.(32943404, 32341331)
- Rapidly rising CRP is a sign of uncontrolled inflammation, which is often a harbinger of subsequent clinical deterioration.(33212544) Thus, measuring CRP daily may be reasonable to detect uncontrolled inflammation early and rapidly intervene.(33216774)
- In the REMAP-CAP trial, only patients within the highest tercile of CRP levels derived statistically significant benefit from tocilizumab. Likewise, a retrospective study found that patients with higher CRP values seemed to derive more benefit from steroid.(32804611)
- CRP is not specific for COVID. If the CRP starts abruptly rising after more than ~5-7 days after admission, bacterial or fungal superinfection should be a primary consideration (particularly among intubated patients).
overall immunomodulatory strategy
- The optimal immunomodulatory strategy is unknown, with multiple trials ongoing. This may vary depending on the patient, especially with respect to the following variables:
- (1) Severity of hypoxemia & clinical course.
- (2) CRP level & trend over time.
- (3) Presence of baseline immunosuppression.
- The dose of steroid should usually be maintained within the dose ranges validated within RCTs (e.g., ~6-20 mg/day dexamethasone), to be consistent with published trials.
- The availability of baricitinib and tocilizumab is variable, and will likely decrease in the coming months (especially at smaller hospitals). Consequently, many centers may be left solely with steroid. However, steroid monotherapy probably works fine, if it's dosed adequately.
- The RECOVERY trial provides compelling evidence that patients with CRP >75 mg/dL may benefit from more potent immunomodulation than solely 6 mg/day dexamethasone.
- One potential approach to immunomodulation is shown below, to illustrate various combinations of agents which may be considered.
- Remdesivir does not affect mortality (based on a meta-analysis of four RCTs involving >7,000 patients). In the SOLIDARITY trial, it didn't affect the risk of intubation.(33264556)
- Remdesivir does not have a robust or reproducible effect on hospital length of stay.
- Remdesivir reduced the time to recovery by ~1-4 days in the ACTT-1 trial (e.g., duration of oxygen utilization).(32445440) This generated the popular misconception that remdesivir reduces hospital length of stay. However, it's actually unclear whether remdesivir caused a statistically significant reduction in length of stay within the ACTT-1 trial (extraneous factors often affect disposition, making hospital length of stay a difficult outcome to reduce). Furthermore, there were no benefits observed among patients on noninvasive or invasive mechanical ventilation.
- Remdesivir increased the hospital length of stay in the SOLIDARITY trial. This is likely because SOLIDARITY was an open-label trial (which may more closely mirror clinical reality in this situation). Open-label use of remdesivir likely prolonged length of stay because patients were kept in the hospital longer in order to receive remdesivir. The SOLIDARITY trial found that both remdesivir and hydroxychloroquine extended length of stay to the same extent, suggesting that both drugs are equally ineffective for COVID-19 (discussed further here).(33264556)
safety & side effects
- To date, published experience with remdesivir involves well under a thousand patients. As such, this is a very new drug which we don't fully understand. Little is known regarding side effects. Over time, it's likely that additional side effects will emerge.
- Known side effects at this point:
- Infusion-related reactions (may include hypotension, nausea/vomiting, diaphoresis).
- Renal failure is the single most concerning adverse event.
- Elevated liver enzymes (AST, ALT, hyperbilirubinemia).
- Another notable side effect is nausea and vomiting. This may be highly problematic among patients on noninvasive ventilation.
- Remdesivir is contraindicated in renal insufficiency. To date, studies involving remdesivir in COVID-19 have often excluded patients with GFR<50 ml/min due to concern that the intravenous vehicle sulfobutylether-beta-cyclodextrin could accumulate.(32445440)
- Given that remdesivir is a nucleoside analogue it might be teratogenic. In the ACTT-1 trial, women of child-bearing age were required to use contraception for a month after exposure to remdesivir.
dosing & monitoring
- 200 mg IV once, followed by 100 mg IV daily to complete a five-day course.
- Remdesivir should be stopped after five days. An RCT found that compared to the 5-day course, a 10-day course provided no clinical benefit but was associated with increased rate of renal failure.(32459919)
- Follow liver function tests.
⁍ bottom line on remdesivir?
- The World Health Organization currently does not recommend the use of remdesivir.(32887691) The above trials don't exclude a minimal benefit from remdesivir – but if a benefit exists it is likely to be small and restricted to patients who are mildly ill (i.e., not stepdown or ICU patients).
- Practitioners may continue to be pressured to administer remdesivir, especially in the United States. A five-day course is not unreasonable in patients without contraindications.
- Several RCTs have demonstrated that convalescent plasma is ineffective among patients admitted with COVID.(32492084, 33093056, 33232588)
- There are numerous reasons to explain why plasma fails:
- (1) Most of the illness among admitted patients is due to pathological inflammation, rather than direct viral replication.
- (2) By the time patients are admitted to the hospital, most are already producing antibodies and clearing the virus. In one study, the convalescent plasma tended to have lower antibody titers than the patient's own plasma! (33093056)
- (3) The volume of administered plasma is low compared to the patient's circulating blood volume (e.g., ~200 ml plasma vs. 5 liters of blood). Consequently, antibodies will be diluted considerably.
- Convalescent plasma exposes patients to numerous risks, including volume overload, transfusion-related acute lung injury (TRALI), and transfusion reactions including anaphylaxis.(32861333)
- 🛑 For patients admitted with COVID, convalescent plasma should only be used within the context of a randomized controlled trial.🛑
monoclonal antibodies fail for similar reasons that convalescent plasma does
- By the time of admission, patients are often producing their own antibodies and clearing the virus.
- Ongoing viral mutation may cause monoclonal antibodies to be ineffective.
- Bamlanivimab is a single monoclonal antibody against COVID. An RCT of bamlanivimab among patients admitted for COVID pneumonia was stopped due to futility.(33356051) Even when given very early in the disease course to outpatients, bamlanivimab still didn't affect any meaningful patient-centered endpoints.(33113295) The latest study on bamlanivimab confirms that it doesn't work.(33475701)
- Regeneron is a cocktail of two antibodies against COVID. It has been evaluated only in a single trial, wherein it had no effect on any clinical outcomes.(33332778)
⁍ Bottom line – Currently there is no good justification to give monoclonal antibodies to anyone. In particular, there is especially no justification to give it to patients admitted to the hospital.
The following considerations may be useful when admitting patients:
A fresh cast covering the revamped chapter will be released shortly! 😃
Update #7, 12/4:
Update #6, 5/17:
Update #5, 5/6:
Update #4, 4/21:
Update #3, 4/13:
Update #2, 3/30:
Update #1, 3/22:
First COVID cast, 3/11:
questions & discussion
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- Larger chapter on COVID-19 here.
- 12771610 Priglinger U, Delle Karth G, Geppert A, et al. Prophylactic anticoagulation with enoxaparin: Is the subcutaneous route appropriate in the critically ill? Crit Care Med. 2003 May;31(5):1405-9. doi: 10.1097/01.CCM.0000059725.60509.A0 [PubMed]
- 19850587 Zenáhlíková Z, Kvasnicka J, Kudrnová Z, et al. FXa inhibition and coagulation changes during DVT prophylaxis by enoxaparin over the course of a 15-day follow-up in septic patients. Clin Appl Thromb Hemost. 2010 Oct;16(5):584-90. doi: 10.1177/1076029609345686 [PubMed]
- 20845391 Al-Aama T, Brymer C, Gutmanis I, et al. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011 Jul;26(7):687-94. doi: 10.1002/gps.2582 [PubMed]
- 21249390 , , , , et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report [MedRxiv]
- 22009998 Ludwig KP, Simons HJ, Mone M, et al. Implementation of an enoxaparin protocol for venous thromboembolism prophylaxis in obese surgical intensive care unit patients. Ann Pharmacother. 2011 Nov;45(11):1356-62. doi: 10.1345/aph.1Q313 [PubMed]
- 23487580 Lim SY, Jeon K, Kim HJ, et al. Antifactor Xa levels in critically ill Korean patients receiving enoxaparin for thromboprophylaxis: a prospective observational study. J Korean Med Sci. 2013 Mar;28(3):466-71. doi: 10.3346/jkms.2013.28.3.466 [PubMed]
- 23601744 Robinson S, Zincuk A, Larsen UL, et al. A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: a double-blinded, randomised controlled trial. Crit Care. 2013 Apr 19;17(2):R75. doi: 10.1186/cc12684 [PubMed]
- 24070664 Bickford A, Majercik S, Bledsoe J, et al. Weight-based enoxaparin dosing for venous thromboembolism prophylaxis in the obese trauma patient. Am J Surg. 2013 Dec;206(6):847-51, discussion 851-2. doi: 10.1016/j.amjsurg.2013.07.020 [PubMed]
- 24554232 Hatta K, Kishi Y, Wada K, et al.; DELIRIA-J Group. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014 Apr;71(4):397-403. doi: 10.1001/jamapsychiatry.2013.3320 [PubMed]
- 25003980 Maggiore SM, Idone FA, Vaschetto R, et al. Nasal high-flow versus Venturi mask oxygen therapy after extubation. Effects on oxygenation, comfort, and clinical outcome. Am J Respir Crit Care Med. 2014 Aug 1;190(3):282-8. doi: 10.1164/rccm.201402-0364OC [PubMed]
- 25969139 Mistraletti G, Umbrello M, Sabbatini G, et al. Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol. 2015 Dec;81(12):1298-310 [PubMed]
- 26031274 Nunez JM, Becher RD, Rebo GJ, et al. Prospective Evaluation of Weight-Based Prophylactic Enoxaparin Dosing in Critically Ill Trauma Patients: Adequacy of AntiXa Levels Is Improved. Am Surg. 2015 Jun;81(6):605-9. [PubMed]
- 26658126 Stephenson ML, Serra AE, Neeper JM, et al. A randomized controlled trial of differing doses of postcesarean enoxaparin thromboprophylaxis in obese women. J Perinatol. 2016 Feb;36(2):95-9. doi: 10.1038/jp.2015.130 [PubMed]
- 26850200 Chapman SA, Irwin ED, Reicks P, et al. Non-weight-based enoxaparin dosing subtherapeutic in trauma patients. J Surg Res. 2016 Mar;201(1):181-7. doi: 10.1016/j.jss.2015.10.028 [PubMed]
- 26975498 Hernández G, Vaquero C, González P, et al. Effect of Postextubation High-Flow Nasal Cannula vs Conventional Oxygen Therapy on Reintubation in Low-Risk Patients: A Randomized Clinical Trial. JAMA. 2016 Apr 5;315(13):1354-61. doi: 10.1001/jama.2016.2711 [PubMed]
- 27706464 Hernández G, Vaquero C, Colinas L, et al. Effect of Postextubation High-Flow Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation Respiratory Failure in High-Risk Patients: A Randomized Clinical Trial. JAMA. 2016 Oct 18;316(15):1565-1574. doi: 10.1001/jama.2016.14194 [PubMed]
- 29595562 Nishikimi M, Numaguchi A, Takahashi K, et al. Effect of Administration of Ramelteon, a Melatonin Receptor Agonist, on the Duration of Stay in the ICU: A Single-Center Randomized Placebo-Controlled Trial. Crit Care Med. 2018 Jul;46(7):1099-1105. doi: 10.1097/CCM.0000000000003132 [PubMed]
- 29699807 Kay AB, Majercik S, Sorensen J, et al. Weight-based enoxaparin dosing and deep vein thrombosis in hospitalized trauma patients: A double-blind, randomized, pilot study. Surgery. 2018 Apr 23:S0039-6060(18)30094-1. doi: 10.1016/j.surg.2018.03.001 [PubMed]
- 30954541 Bethea A, Samanta D, Deshaies D, et al. Determination of Optimal Weight-Based Enoxaparin Dosing and Associated Clinical Factors for Achieving Therapeutic Anti-Xa Assays for Deep Venous Thrombosis Prophylaxis. J Am Coll Surg. 2019 Sep;229(3):295-304. doi: 10.1016/j.jamcollsurg.2019.03.018 [PubMed]
- 31679829 Rakhra S, Martin EL, Fitzgerald M, et al. The ATLANTIC study: Anti-Xa level assessment in trauma intensive care. Injury. 2020 Jan;51(1):10-14. doi: 10.1016/j.injury.2019.10.066 [PubMed]
- 32043986 Villar J, Ferrando C, Martínez D, et al.; Dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020 Mar;8(3):267-276. doi: 10.1016/S2213-2600(19)30417-5 [PubMed]
- 32281885 Tobin MJ. Basing Respiratory Management of COVID-19 on Physiological Principles. Am J Respir Crit Care Med. 2020 Jun 1;201(11):1319-1320. doi: 10.1164/rccm.202004-1076ED [PubMed]
- 32291094 Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Jul;191:145-147. doi: 10.1016/j.thromres.2020.04.013 [PubMed]
- 32311843 Beun R, Kusadasi N, Sikma M, et al. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol. 2020 Jun;42 Suppl 1(Suppl 1):19-20. doi: 10.1111/ijlh.13230 [PubMed]
- 32341331 Wang Y, Jiang W, He Q, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther. 2020 Apr 28;5(1):57. doi: 10.1038/s41392-020-0158-2 [PubMed]
- 32445064 White D, MacDonald S, Bull T, et al. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis. 2020 Aug;50(2):287-291. doi: 10.1007/s11239-020-02145-0 [PubMed]
- 32445440 Beigel JH, Tomashek KM, Dodd LE, et al. ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 – Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764 [PubMed]
- 32459919 Goldman JD, Lye DCB, Hui DS, et al.; GS-US-540-5773 Investigators. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020 Nov 5;383(19):1827-1837. doi: 10.1056/NEJMoa2015301 [PubMed]
- 32470486 Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020 Jul;146(1):137-146.e3. doi: 10.1016/j.jaci.2020.05.019 [PubMed]
- 32485418 Al-Ani F, Chehade S, Lazo-Langner A. Thrombosis risk associated with COVID-19 infection. A scoping review. Thromb Res. 2020 Aug;192:152-160. doi: 10.1016/j.thromres.2020.05.039 [PubMed]
- 32492084 Li L, Zhang W, Hu Y, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020 Aug 4;324(5):460-470. doi: 10.1001/jama.2020.10044 [PubMed]
- 32510975 Dutt T, Simcox D, Downey C, et al. Thromboprophylaxis in COVID-19: Anti-FXa-the Missing Factor? Am J Respir Crit Care Med. 2020 Aug 1;202(3):455-457. doi: 10.1164/rccm.202005-1654LE [PubMed]
- 32542785 Jorgensen SCJ, Tse CLY, Burry L, Dresser LD. Baricitinib: A Review of Pharmacology, Safety, and Emerging Clinical Experience in COVID-19. Pharmacotherapy. 2020 Aug;40(8):843-856. doi: 10.1002/phar.2438 [PubMed]
- 32592703 Cantini F, Niccoli L, Nannini C, et al. Beneficial impact of Baricitinib in COVID-19 moderate pneumonia; multicentre study. J Infect. 2020 Oct;81(4):647-679. doi: 10.1016/j.jinf.2020.06.052 [PubMed]
- 32678530 RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, et al. Dexamethasone in Hospitalized Patients with Covid-19 – Preliminary Report. N Engl J Med. 2020 Jul 17:NEJMoa2021436. doi: 10.1056/NEJMoa2021436 [PubMed]
- 32804611 Keller MJ, Kitsis EA, Arora S, et al. Effect of Systemic Glucocorticoids on Mortality or Mechanical Ventilation in Patients With COVID-19. J Hosp Med. 2020 Aug;15(8):489-493. doi: 10.12788/jhm.3497 [PubMed]
- 32809969 Bronte V, Ugel S, Tinazzi E, et al. Baricitinib restrains the immune dysregulation in patients with severe COVID-19. J Clin Invest. 2020 Dec 1;130(12):6409-6416. doi: 10.1172/JCI141772 [PubMed]
- 32838370 Miller DC, Beamer P, Billheimer D, et al. Aerosol Risk with Noninvasive Respiratory Support in Patients with COVID-19. J Am Coll Emerg Physicians Open. 2020 May 21;1(4):521–6. doi: 10.1002/emp2.12152 [PubMed]
- 32861333 Joyner MJ, Bruno KA, Klassen SA, et al. Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients. Mayo Clin Proc. 2020 Sep;95(9):1888-1897. doi: 10.1016/j.mayocp.2020.06.028 [PubMed]
- 32876695 Tomazini BM, Maia IS, Cavalcanti AB, et al. COALITION COVID-19 Brazil III Investigators. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 2020 Oct 6;324(13):1307-1316. doi: 10.1001/jama.2020.17021. [PubMed]
- 32887691 Siemieniuk R, Rochwerg B, Agoritsas T, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020 Sep 4;370:m3379. doi: 10.1136/bmj.m3379. Update in: BMJ. 2020 Nov 19;371:m4475 [PubMed]
- 32920503 Stattin K, Lipcsey M, Andersson H, et al. Inadequate prophylactic effect of low-molecular weight heparin in critically ill COVID-19 patients. J Crit Care. 2020 Dec;60:249-252. doi: 10.1016/j.jcrc.2020.08.026 [PubMed]
- 32943404 Edalatifard M, Akhtari M, Salehi M, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J. 2020 Dec 24;56(6):2002808. doi: 10.1183/13993003.02808-2020 [PubMed]
- 33020836 Rodriguez-Garcia JL, Sanchez-Nievas G, Arevalo-Serrano J, et al. Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study. Rheumatology (Oxford). 2021 Jan 5;60(1):399-407. doi: 10.1093/rheumatology/keaa587 [PubMed]
- 33049598 Trunfio M, Salvador E, Cabodi D, et al. e-COVID Study group. Anti-Xa monitoring improves low-molecular-weight heparin effectiveness in patients with SARS-CoV-2 infection. Thromb Res. 2020 Dec;196:432-434. doi: 10.1016/j.thromres.2020.09.039 [PubMed]
- 33216774 Sharifpour M, Rangaraju S, Liu M, et al.; Emory COVID-19 Quality & Clinical Research Collaborative. C-Reactive protein as a prognostic indicator in hospitalized patients with COVID-19. PLoS One. 2020 Nov 20;15(11):e0242400. doi: 10.1371/journal.pone.0242400 [PubMed]
- 30336170 Leung CCH, Joynt GM, Gomersall CD, et al. Comparison of high-flow nasal cannula versus oxygen face mask for environmental bacterial contamination in critically ill pneumonia patients: a randomized controlled crossover trial. J Hosp Infect. 2019 Jan;101(1):84-87. doi: 10.1016/j.jhin.2018.10.007 [PubMed]
- 33048904 Gandolfi JV, Di Bernardo APA, Chanes DAV, et al. The Effects of Melatonin Supplementation on Sleep Quality and Assessment of the Serum Melatonin in ICU Patients: A Randomized Controlled Trial. Crit Care Med. 2020 Dec;48(12):e1286-e1293. doi: 10.1097/CCM.0000000000004690 [PubMed]
- 33059983 Westafer LM, Soares WE 3rd, Salvador D, et al. No evidence of increasing COVID-19 in health care workers after implementation of high flow nasal cannula: A safety evaluation. Am J Emerg Med. 2021 Jan;39:158-161. doi: 10.1016/j.ajem.2020.09.086 [PubMed]
- 33080005 Salvarani C, Dolci G, Massari M, et al.; RCT-TCZ-COVID-19 Study Group. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021 Jan 1;181(1):24-31. doi: 10.1001/jamainternmed.2020.6615 [PubMed]
- 33083812 Ramlall V, Zucker J, Tatonetti N. Melatonin is significantly associated with survival of intubated COVID-19 patients. medRxiv [Preprint]. 2020 Oct 18:2020.10.15.20213546. doi: 10.1101/2020.10.15.20213546 [PubMed]
- 33085857 Stone JH, Frigault MJ, Serling-Boyd NJ, et al.; BACC Bay Tocilizumab Trial Investigators. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Dec 10;383(24):2333-2344. doi: 10.1056/NEJMoa2028836 [PubMed]
- 33093056 Agarwal A, Mukherjee A, Kumar G, et al. PLACID Trial Collaborators. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020 Oct 22;371:m3939. doi: 10.1136/bmj.m3939 [PubMed]
- 33113295 Chen P, Nirula A, Heller B, et al. BLAZE-1 Investigators. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. 2020 Oct 28:NEJMoa2029849. doi: 10.1056/NEJMoa2029849 [PubMed]
- 33187978 Stebbing J, Sánchez Nievas G, Falcone M, et al. JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Sci Adv. 2020 Nov 13;7(1):eabe4724. doi: 10.1126/sciadv.abe4724 [PubMed]
- 33212544 Valerio L, Ferrazzi P, Sacco C, et al.; Humanitas COVID-19 Task Force. Course of D-Dimer and C-Reactive Protein Levels in Survivors and Nonsurvivors with COVID-19 Pneumonia: A Retrospective Analysis of 577 Patients. Thromb Haemost. 2020 Nov 19. doi: 10.1055/s-0040-1721317 [PubMed]
- 33232588 Simonovich VA, Burgos Pratx LD, Scibona P, et al; PlasmAr Study Group. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med. 2020 Nov 24:NEJMoa2031304. doi: 10.1056/NEJMoa2031304 [PubMed]
- 33264556 WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, et al. Repurposed Antiviral Drugs for Covid-19 – Interim WHO Solidarity Trial Results. N Engl J Med. 2020 Dec 2:NEJMoa2023184. doi: 10.1056/NEJMoa2023184 [PubMed]
- 33277660 Covin S, Rutherford GW. Co-infection, SARS-CoV-2 and influenza: an evolving puzzle. Clin Infect Dis. 2020 Dec 5:ciaa1810. doi: 10.1093/cid/ciaa1810 [PubMed]
- 33306283 Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2020 Dec 11:NEJMoa2031994. doi: 10.1056/NEJMoa2031994 [PubMed]
- 33332778 Weinreich DM, Sivapalasingam S, Norton T, et al. Trial Investigators. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. N Engl J Med. 2020 Dec 17:NEJMoa2035002. doi: 10.1056/NEJMoa2035002 [PubMed]
- 33332779 Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021 Jan 7;384(1):20-30. doi: 10.1056/NEJMoa2030340 [PubMed]
- 33356051 ACTIV-3/TICO LY-CoV555 Study Group. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med. 2020 Dec 22:NEJMoa2033130. doi: 10.1056/NEJMoa2033130 [PubMed]
- 33417877 Salah HM, Mehta JL. Meta-Analysis of the Effect of Aspirin on Mortality in COVID-19. Am J Cardiol. 2021 Jan 6:S0002-9149(21)00003-5. doi: 10.1016/j.amjcard.2020.12.073 [PubMed]
- 33475701 Gottlieb RL, Nirula A, Chen P, et al. Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2021 Jan 21:e210202. doi: 10.1001/jama.2021.0202 [PubMed]