- Rapid Reference 🚀
- Initial tests to guide management
- Organ support
- Things that don't work
- Questions & Discussion
checklist for COVID admission to ICU/stepdown ✅
Review medication list & orders (more)
- Discontinue nephrotoxins if possible.
- Consider discontinuing or dose-reducing antihypertensives.
- D/C unnecessary serial lab draws (e.g., scheduled troponin, ABGs).
- Consider trending CRP daily (if not receiving tocilizumab).
DVT prophylaxis (more)
- Standard DVT prophylaxis is generally adequate.
- For morbid obesity, consider weight-based dosing:
- GFR >30 ml/min: ~0.5 mg/kg enoxaparin BID.
- GFR <30 ml/min: 7,5000 U UFH sq q8hr
- The optimal regimen is unknown, but most patients will benefit from something more than dexamethasone 6 mg/day (at least initially, until CRP is down-trending and patient is improving). Options may include:
Respiratory support – nonintubated patients (more)
- Encourage awake proning or repositioning if possible.
- Positive airway pressure (CPAP or BiPAP) is the front-line modality to avoid intubation.
- High-flow nasal cannula may be used for patients unable to tolerate CPAP/BiPAP, or to provide breaks.
Respiratory support – intubated patients (more)
- Attempt recruitment with high PEEP or APRV.
- More on management of ARDS here.
- For intubated patients:
- Multimodal analgesia (e.g., scheduled acetaminophen, pain-dose ketamine infusion, PRN opioids).
- Multimodal sedation (e.g., moderate-dose propofol, atypical antipsychotic).
- For non-intubated patients: Dexmedetomidine infusion may be helpful to promote rest and use of CPAP/BiPAP (especially at night).
🛑 Do not use remdesivir (more)
- Despite numerous high-quality RCTs, remdesivir has failed to demonstrate any reproducible meaningful clinical benefits.
tests to guide management
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 (more below 📖).
- Other COVID labs: It may be reasonable to check these upon admission (e.g., D-dimer, LDH, ferritin). 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).
chest CT findings in COVID-19
chest CT findings in COVID-19
Chest CT findings in COVID are diverse. A useful framework is to classify findings as typical, indeterminant, or atypical of COVID-19.(32324653) Atypical features would suggest an alternative diagnosis, or the combination of COVID-19 plus another simultaneous process (e.g., heart failure).
typical appearance of COVID-19
- Peripheral, bilateral ground glass opacities (with or without consolidation or visible intralobular lines (crazy-paving)).
- Multifocal ground glass opacities of rounded morphology (with or without consolidation or visible intralobular lines (crazy-paving)).
- Reverse halo sign or other findings of organizing pneumonia (seen later in the disease).
indeterminate appearance of COVID-19
- Multifocal, diffuse, perihilar, or unilateral ground glass opacities (with or without consolidation, lacking a specific distribution).
- Few very small ground glass opacities with a non-rounded and non-peripheral distribution.
atypical appearance for COVID-19
- Isolated lobar or segmental consolidation without ground glass opacities.
- Discrete small nodules (e.g., centrilobular, tree-in-bud opacities).
- Lung cavitation.
- Smooth interlobular septal thickening with pleural effusion.
- 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
noninvasive respiratory support
general concept: lung recruitment
- 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.
- Patients unable to sleep comfortably in a prone position.
- The RECOVERY-RS trial demonstrated that CPAP can reduce the rate of intubation.🌊 Thus, CPAP (or BiPAP with a low driving pressure) seems to be the front-line support modality in COVID patients. However, tolerability may be limited (especially for prolonged periods of time), so some patients will be best served by a combination of CPAP/BiPAP with breaks on high flow nasal cannula.
- 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).🌊
invasive mechanical ventilation
invasive mechanical ventilation
To date there is no high-quality evidence regarding best practices for intubated COVID patients. In the absence of such data, these patients may be managed similarly to other ARDS patients.📖
infectious disease & antibiotics
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.📖 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 administration of oseltamivir. The presence of influenza isn't a contraindication to immunomodulatory therapy for COVID (note that influenza H1N1 can cause virus-induced hemophagocytic lymphohistiocytosis, which itself requires immunomodulation 📖).
- 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 may 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)
- For most patients, standard dosing of DVT prophylaxis is probably adequate.
- For morbidly obese patients, weight-based dosing may be more appropriate:
- If GFR >30 ml/min, then enoxaparin ~0.5 mg/kg sq BID may be used. 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 within the surgical ICU.(26850200, 26658126, 22009998, 29699807, 24070664, 30954541, 26031274)
- If GFR <30 ml/min, then heparin 7,5000 IU sq q8hr may be reasonable.
- 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 is indicated for patients with known or suspected DVT and/or PE.
- Many patients with COVID are too unstable to transport to the CT scanner to evaluate for PE. If PE is suspected clinically, then empiric anticoagulation may be reasonable.
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:
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.
- (4) Availability of various agents.
- The dose of steroid should usually be maintained within the dose ranges validated within RCTs (e.g., ~6-20 mg/day dexamethasone).
- 6 mg/day currently seems reasonable for patients who are receiving additional immunomodulators (e.g., tocilizumab or baricitinib).
- 12 mg/day may be reasonable for patients on dexamethasone monotherapy. The COVID-STEROID-2 trial as well as numerous RCTs involving tocilizumab and baricitinib suggest that dexamethasone 6 mg alone is inadequate for sicker patients.
- Below is one schema for approaching immunomodulation. In the absence of head-to-head trials, it's impossible to know whether this is the best approach. However, this may currently serve as a reasonable guide.
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 tertile 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).
Currently, steroid is the cornerstone of immunomodulation. It should be utilized for any patient with new-onset hypoxemia due to COVID pneumonia.
various steroid regimens that have been utilized:
- Dexamethasone 6 mg/day for up to 10 days improved mortality in the RECOVERY trial (equivalent to 32 mg methylprednisolone).(32678530) However, this is a relatively low dose of steroid, which alone is probably suboptimal for patients with more severe disease.
- Dexamethasone 12 mg/day: The COVID-STEROID 2 trial compared 6 vs. 12 mg dexamethasone among hospitalized patients requiring 10 liters/minute oxygen or more intensive support. Mortality was 5% lower in patients treated with 12 mg dexamethasone, but this didn't reach statistical significance (p=0.09). However, when combined with numerous other RCTs suggesting that 6 mg/day dexamethasone alone is suboptimal, this study supports the use of 12 mg/day dexamethasone for patients who aren't also receiving baricitinib or tocilizumab.🌊
- 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) For extremely sick patients who have very high inflammatory markers and are being treated with dexamethasone alone, induction of therapy with 20 mg/day dexamethasone may be reasonable until some improvement is seen (after which transitioning to lower doses of dexamethasone might be considered).
- Methylprednisolone 250 mg/day for three days was successfully utilized in one recent, very small RCT.(32943404) This could be a consideration for the absolute sickest patients, if additional agents were not available (e.g., tocilizumab or baricitinib).
conclusion on steroid dose?
- 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.
- Current guesses regarding the optimal steroid dose:
- For patients receiving tocilizumab or baricitinib: 6 mg/day dexamethasone.
- For patients treated with dexamethasone alone: 12 mg/day dexamethasone for most patients (perhaps with some flexibility within a range of 6-20 mg/day, depending on individual patient characteristics).
- If dexamethasone supplies are exhausted, oral betamethasone sodium phosphate is nearly identical and could be a useful alternative.
- 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, if administered promptly after ICU admission.🌊
- 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
- Sarilumab is another IL-6 inhibitor which may be considered if tocilizumab is unavailable.
- 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)
- The COV-BARRIER trial found that baricitinib reduced all-cause mortality. This result was robust, regardless of whether patients received dexamethasone (thereby supporting the combination of baricitinib and dexamethasone). Most patients in the trial didn't receive remdesivir, so this trial debunks the misconception that baricitinib must be co-administered with remdesivir. Finally, there was no increase in thromboembolic events or infections among patients treated with baricitinib, which should address fears that baricitinib would promote thrombosis or infection.(34480861)
- An addendum RCT to the COV-BARRIER trial also detected a mortality benefit from baricitinib among patients receiving mechanical ventilation or ECMO.📄
- Comparison of data from ACTT-2, COV-BARRIER, and COVID-BARRIER addendum trials suggests a consistent and clinically meaningful mortality benefit:
- (1) Hospitalized COVID patients with an oxygen saturation ≤ 94% on room air (or the requirement for supplemental oxygen).(33306283, 34480861)
- (2) COV-BARRIER also required patients to have at least one elevated inflammatory marker (including CRP, D-dimer, LDH, or ferritin above the upper limit of normal).
- Active severe infection (e.g., known tuberculosis, invasive fungal infection, HBV, HCV, HIV).
- Substantial immune dysfunction (e.g., AIDS, TNF inhibitors, chemotherapy).
- Absolute neutrophil count <500 cells/mm3.
- (Lymphopenia is sometimes considered a contraindication, but studies have shown that the administration of baricitinib to COVID patients actually improves their lymphopenia.)(32592703, 32809969)
- GFR >30 ml/min: 4 mg/day.
- GFR 15-30 ml/min: 2 mg/day.
- Tablets can be crushed and administered via gastric tube.(34480861)
- Continue for up to 14 days (discontinue sooner if the patient is discharged from the hospital).(33306283, 34480861)
- Tofacitinib is a JAK-inhibitor, similar to baricitinib. It has a slightly different affinity to various JAK-inhibitors, so it's efficacy in COVID could be different.
- The STOP-COVID multicenter RCT found that tofacitinib reduced the composite endpoint of respiratory failure or death (with respiratory failure defined as requiring high-flow nasal cannula, noninvasive ventilation, or invasive ventilation)(p = 0.37, fragility index of one).(34133856)
- Currently, evidence supporting tofacitinib is less robust than that supporting baricitinib (specifically, baricitinib has been shown to reduce mortality whereas tofacitinib hasn't). Therefore, baricitinib may be the currently preferred agent. However, tofacitinib could remain useful in some situations:
- Shortage of baricitinib.
- Renal failure (unlike baricitinib, tofacitinib is mostly metabolized by the liver so it may be used in the context of more severe renal failure).
- Indications may be similar to those for baricitinib (i.e., patients hospitalized for management of COVID pneumonia).
- Hepatic impairment (defined as Child-Pugh Class C cirrhosis 🧮).
- Active severe infection (e.g., known tuberculosis, invasive fungal infection, HBV, HCV, HIV).
- Substantial immune dysfunction (e.g., AIDS, TNF inhibitors, chemotherapy).
- Absolute neutrophil count <500 cells/mm3.
- Absolute lymphocyte count <500 cells/mm3.
- Coadministration with a potent CYP3A4 inducer (e.g., rifampin).
- 10 mg BID if normal hepatic & renal function and no interacting medications.
- Indications to reduce the dose to 5 mg BID include:(34133856)
- Coadministration with a medication that is a strong inhibitor of CYP3A4, or coadministration with a medication that is a moderate CYP3A4 inhibitor and a strong CYP2C19 inhibitor. Such medications include fluconazole, itraconazole, ritonavir, lopinavir, and clarithromycin.
- Moderate or severe renal impairment (GFR <50 ml/min or hemodialysis).
- Moderate hepatic impairment.
- Continue for up to 14 days (discontinue sooner if the patient is discharged from the hospital).
why remdesivir doesn't work
- By the time most patients are admitted to the hospital, their viral levels are already falling briskly. Consequently, there is probably no role for any antiviral therapy at this point in the illness.
- Two RCTs have demonstrated that remdesivir has no effect on viral titers among hospitalized patients. An antiviral therapy which doesn't affect viral levels is unlikely to be beneficial.(34534511, 32423584)
clinical evidence that remdesivir doesn't work
- Numerous RCTs show that remdesivir doesn't affect mortality.(33264556)
- Remdesivir didn't affect the risk of intubation or the number of ventilator-free days within the SOLIDARITY or DISCOVERY trials.(34534511, 33264556)
- 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, remdesivir actually tended to increase the hospital length of stay in the SOLIDARITY and DISCOVERY trials. This is likely because SOLIDARITY and DISCOVERY were open-label trials (which better reflect the clinical reality of this situation). Open-label use of remdesivir 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.🌊 (33264556)
- Currently, despite five RCTs, there is no evidence of any reproducible or clinically meaningful benefit from remdesivir.
safety & side effects
- Known side effects include:
- Infusion-related reactions (hypotension, diaphoresis).
- Renal failure.
- 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 most studies of remdesivir (including ACTT-1), women of childbearing age were required to use contraception for a month after exposure to remdesivir.
bottom line on remdesivir?
- The World Health Organization currently does not recommend the use of remdesivir.(32887691) Many guidelines in the United States continue to recommend remdesivir, but hopefully these will be updated on the basis of the SOLIDARITY and DISCOVERY trials.
- ⚠️ Remdesivir should be used only within the context of a randomized controlled trial.(34534513)
- 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.🛑
questions & discussion
questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- 🎥 = Link to supplemental media.
- 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]
- 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]
- 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]
- 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]
- 32423584 Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y, Luo G, Wang K, Lu Y, Li H, Wang S, Ruan S, Yang C, Mei C, Wang Y, Ding D, Wu F, Tang X, Ye X, Ye Y, Liu B, Yang J, Yin W, Wang A, Fan G, Zhou F, Liu Z, Gu X, Xu J, Shang L, Zhang Y, Cao L, Guo T, Wan Y, Qin H, Jiang Y, Jaki T, Hayden FG, Horby PW, Cao B, Wang C. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 May 16;395(10236):1569-1578. doi: 10.1016/S0140-6736(20)31022-9 [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]
- 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]
- 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]
- 34133856 Guimarães PO, Quirk D, Furtado RH, Maia LN, Saraiva JF, Antunes MO, Kalil Filho R, Junior VM, Soeiro AM, Tognon AP, Veiga VC, Martins PA, Moia DDF, Sampaio BS, Assis SRL, Soares RVP, Piano LPA, Castilho K, Momesso RGRAP, Monfardini F, Guimarães HP, Ponce de Leon D, Dulcine M, Pinheiro MRT, Gunay LM, Deuring JJ, Rizzo LV, Koncz T, Berwanger O; STOP-COVID Trial Investigators. Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021 Jul 29;385(5):406-415. doi: 10.1056/NEJMoa2101643 [PubMed]
- 34480861 Marconi VC, Ramanan AV, de Bono S, Kartman CE, Krishnan V, Liao R, Piruzeli MLB, Goldman JD, Alatorre-Alexander J, de Cassia Pellegrini R, Estrada V, Som M, Cardoso A, Chakladar S, Crowe B, Reis P, Zhang X, Adams DH, Ely EW; COV-BARRIER Study Group. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021 Aug 31:S2213-2600(21)00331-3. doi: 10.1016/S2213-2600(21)00331-3 [PubMed]
- 34534511 Ader F, Bouscambert-Duchamp M, Hites M, Peiffer-Smadja N, Poissy J, Belhadi D, Diallo A, Lê MP, Peytavin G, Staub T, Greil R, Guedj J, Paiva JA, Costagliola D, Yazdanpanah Y, Burdet C, Mentré F; DisCoVeRy Study Group. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial. Lancet Infect Dis. 2021 Sep 14:S1473-3099(21)00485-0. doi: 10.1016/S1473-3099(21)00485-0 [PubMed]
- 34534513 Gyselinck I, Janssens W. Remdesivir, on the road to DisCoVeRy. Lancet Infect Dis. 2021 Sep 14:S1473-3099(21)00559-4. doi: 10.1016/S1473-3099(21)00559-4 [PubMed]