Treatments

Overview by SeverityCopy Link!

Updated Date: December 4, 2020
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Medication Interactions with COVID-19 Treatments

Clinical Severity

Treatment

COVID-19 without hypoxemia

AND

Without risk factors

1. Symptomatic Treatment

COVID-19 without hypoxemia or radiographic evidence of disease

BUT

With risk factors: Age >60, cardiovascular disease, hypertension, diabetes, COPD, cancer, immunosuppressive medications, detectable HIV viral load or CD4 <200, TB, pregnancy, malnutrition (BMI <18 in adults, yellow MUAC for children < 5 years old)

1. Symptomatic Treatment

2. Antibodies or Plasma if indicated and available

3. Closer Monitoring and advance to other therapies (see below) if clinical condition worsens

COVID-19 diagnosis with hypoxemia

1. Symptomatic Treatment

2. Corticosteroids

3. Consider Remdesivir (if available and recommended by your institution)

4. Consider availability of clinical trials

COVID-19 with critical illness or ARDS

1. Symptomatic Treatment

2. Empiric antibiotics initially (commonly Ceftriaxone and Azithromycin or Doxycycline for community acquired pneumonia), with adjustment at 24-48 hours based on workup (see Bacterial Infections)

3. Corticosteroids

4. Consider availability of clinical trials

Note: Remdesivir is NOT recommended if requiring intubation

CorticosteroidsCopy Link!

Updated Date: January 13, 2020
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RecommendationsCopy Link!

  1. Low-dose systemic corticosteroids are recommended for COVID-19 positive patients who require supplemental oxygen or are critically ill
  2. Clinical considerations in patients when initiating steroids:
  1. Monitor glucose, WBC, mental status, blood pressure, risk of myopathy (especially in those who are paralyzed for > 48 hours)
  2. Assess for risk of Strongyloides and test and/or empirically treat as needed.
  3. If patient has other risk factors requiring initiation of stress ulcer prophylaxis, initiate famotidine or a proton pump inhibitoras indicated
  4. Contraindications:
  1. Hypersensitivity to steroids
  2. Relative contraindication: invasive fungal infection

EvidenceCopy Link!

  1. The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial found that dexamethasone dosed at 6 mg daily for up to 10 days (n=2104) had lower rates of 28-day mortality compared to usual care (n=4321) (22.9% vs. 25.7%; age-adjusted RR 0.83, 95% CI 0.75-0.93, p<0.001). Dexamethasone reduced deaths in mechanically ventilated patients (29.3% vs. 41.4%, RR 0.64, 95% CI 0.51-0.81) and patients receiving supplemental oxygen (23.3% vs. 26.2%, RR 0.82, 95% CI 0.72-0.94), but not among patients who did not require respiratory support (17.8% vs. 14%, RR 1.19, 95% CI 0.91-1.55) (Horby et al).
  2. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis of 7 randomized trials in which 647 of 1703 COVID-19 patients died (38%). 28-day all-cause mortality was lower among patients who received corticosteroids compared with those who received usual care or placebo (odds ratio 0.66, 95% CI 0.53-0.82, p<0.001). Of note, this meta-analysis included the RECOVERY trial results (Sterne et al).
  3. Additional data on corticosteroids for COVID-19 is evolving
  1. Additional randomized controlled trials: Jeronimo et al; Angus et al; Dequin et al; Tomazini et al.
  2. Non-randomized cohorts: Fadel et al; Fernández-Cruz et al; Keller et al; Wu et al; Nelson et al; Lu et al; Wang et al; Bani-Sadr et al; Sanz-Herrero; Yuan et al.
  3. Additional meta-analyses: Yang et al.
  4. Previous studies have shown negative effects of corticosteroids on similar viruses, albeit without the hyperinflammatory response frequently seen in COVID-19. There is no clinical evidence of net benefit from steroids in SARS-CoV, MERS-CoV or influenza infection. Observational data show increased mortality, more secondary infections, impaired viral clearance and more adverse effects in survivors (e.g., psychosis, diabetes, avascular necrosis) with steroid use at varying doses compared to usual care (Lee et al; Stockman et al; Lansbury et al; Arabi et al).
  1. The WHO makes a strong recommendation for corticosteroids in patients with severe and critical COVID-19 and a conditional recommendation not to use corticosteroids in patients with nonsevere COVID-19 (WHO COVID-19 Living Guidance, September 2020). The National Institutes of Health, Infectious Diseases Society of America, and American Thoracic Society all suggest the use of steroids in patients requiring supplemental oxygen or on mechanical ventilation (NIH Treatment Guidelines, December 2020; IDSA Treatment Guidelines, September 2020; ATS COVID-19 Updated Guidance, July 2020). The Society for Critical Care Medicine has made a weak recommendation for the use of steroids in COVID positive ARDS, but their guidance has not been updated since March prior to RCT data becoming available (SCCM COVID-19 Guidelines, March 2020)

DosingCopy Link!

Dosing regimens to consider include:

Corticosteroid

Dose

Duration

Dexamethasone (preferred if available)

6mg IV or PO daily

10 days

Hydrocortisone

50mg IV Q8h

10 days

Methylprednisolone

15mg IV BID

10 days

Prednisone/prednisolone

40mg PO daily

10 days

  1. If also treating shock, hydrocortisone 50mg IV Q6h is recommended until improvement in shock, followed by consideration of steroid dosing as above to complete 10 days of total treatment. Indications for steroids in shock include:
  1. Any shock in a patient with chronic steroid use >10mg prednisone daily
  2. Multipressor (>2 pressor) shock without history of chronic steroid use
  1. Some patients with adrenal suppression may need higher doses of supplemental corticosteroids

AntiviralsCopy Link!

RemdesivirCopy Link!

Updated Date: November 24, 2020
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RecommendationsCopy Link!

  1. Recommendations on Remdesivir are currently different depending on the institution. Remdesivir, if available, is recommended by BWH for hospitalized patients with COVID-19 disease and hypoxia (requiring supplemental oxygen or SpO2 <95% on room air), but not yet requiring intubation. The National Institutes of Health (NIH) and Infectious Diseases Society of America (IDSA) also recommend the use of remdesivir in the above population. However the World Health Organization (WHO) no longer recommends remdesivir for COVID-19 patients based on the results of their published meta-analysis, which included the WHO SOLIDARITY trial results (NIH Treatment Guidelines, December 2020; IDSA Treatment Guidelines, November 2020; Pan et al; Rochwerg et al).

PharmacologyCopy Link!

Remdesivir is a nucleotide prodrug metabolized to an analog of adenosine triphosphate, which inhibits viral RNA-dependent RNA polymerase, causing premature termination of RNA transcription

EvidenceCopy Link!

  1. Results of the adaptive NIAID trial (ACTT-1) evaluated 1062 patients with COVID-19 in a randomized, placebo-controlled trial. The median time to recovery in the remdesivir group (n=541) was 10 days (95% CI 9-11) vs. 15 days (95% CI 13-18) in the placebo group (n=521) (recovery rate ratio 1.29, 95% CI 1.12-1.49, p<0.001). The mortality rate was 6.7% with remdesivir compared to 11.9% with placebo by day 14 (HR 0.7, 95% CI 0.47-1.04) and 11.4% with remdesivir compared to 15.2% with placebo by day 29 (HR 0.73, 95% CI 0.52-1.03). Serious adverse events were reported in 24.6% of remdesivir patients and 31.6% of placebo patients (Beigel et al).
  2. The WHO-initiated SOLIDARITY trial was randomized across 30 countries and >11,000 hospitalized COVID-19 patients comparing 5 potential COVID-19 treatment regimens (remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, and combination lopinavir/r with interferon) against placebo. In the remdesivir portion of the trial, remdesivir (n=2743) did not lead to a significant difference in 28-day mortality compared to placebo (n=2708), 11.0% (301 deaths) vs. 11.2% (303 deaths) respectively (RR=0.95, 95% CI 0.81-1.11, p=0.50) (Pan et al).
  3. A randomized open-label phase 3 trial assessed outcomes with remdesivir for 5 days (n=199), 10 days (n=197), or standard of care (n=200) for patients with moderate COVID-19 disease (oxygen saturations >94%). On day 11, patients in the 5-day remdesivir arm had a higher odds of better clinical status distribution than those receiving standard of care (OR 1.65, 95% CI 1.09-2.48; p=0.02). The clinical status distribution on day 11 between the 10-day remdesivir and standard of care arms was not significantly different (p=0.18) (Spinner et al).
  4. A randomized, open-label phase 3 trial assessed treatment outcomes with remdesivir for 5- or 10-day courses in hospitalized COVID-19 patients with severe disease (oxygen saturations ≤94%). By day 14, a clinical improvement of ≥2 points on an ordinal scale occurred in 64% of patients in the 5-day group (n=200) and 54% of patients in the 10-day group (n=197). Without a placebo control, it is unclear if remdesivir altered the natural progression of disease. It does however seem remdesivir for 5 days could be considered as effective as a 10-day course. The most common adverse events noted in both groups were nausea, worsening respiratory failure, elevated LFTs, and constipation (Goldman et al).
  5. A randomized, double-blind, placebo-controlled trial evaluated remdesivir IV for 10 days versus placebo in adults with confirmed severe COVID-19 in 10 hospitals in Wuhan, China. In the intention-to-treat population of 237 participants (41% women, median age 65), remdesivir resulted in no significant difference in time to clinical improvement versus placebo (hazard ratio 1.23, 95% CI 0.87-1.75). Remdesivir was discontinued due to adverse events in 12% of patients versus 5% of patients in the placebo group. The trial was stopped early after only enrolling 52% of the target sample size due to decreasing incidence of COVID-19 in Wuhan. The authors estimated this yielded 58% power to detect a hazard ratio of 1.4 or higher. As the trial was underpowered, its findings are inconclusive (Wang et al).
  6. A number of case reports and series have been published on remdesivir use (Holshue et al; Grein et al; Antinori et al; Pasquini et al; Olender et al; Kalligeros et al).

DosingCopy Link!

  1. 200 mg IV loading dose, followed by 100 mg IV daily for 4-9 days for a total 5 to 10-day duration The package insert notes an infusion time of 30-120 minutes. If the patient is able to tolerate it, shorter infusion times (30-60 minutes) are preferred as remdesivir's active metabolite (GS-443902) is active intracellularly and achieves higher intracellular AUCs if infused over 30 minutes compared to 120 minutes (Humeniuk et al).
  1. 5-day duration is preferred in the majority of patients

Monitoring and ToxicityCopy Link!

  1. Elevated transaminases (AST, ALT), acute kidney injury, phlebitis, constipation, headache, and nausea
  2. Remdesivir is co-formulated with sulfobutyl ether β-cyclodextrin (SBECD), so there is a theoretical risk of accumulation in renal failure promoting further renal injury, similar to intravenous voriconazole. If remdesivir is being considered in patients with renal impairment, the expected benefits of treatment should outweigh the potential risks prior to initiation (Adamsick et al). If remdesivir is used in renal impairment (eGFR <30 mL/min), the powder formulation is preferred as it has less SBECD content/vial than the liquid formulation (3 grams vs. 6 grams of SBECD)

Other AntiviralsCopy Link!

FavipiravirCopy Link!

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Not recommended for routine use

See BWH Summary

Umifenovir (Arbidol)Copy Link!

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Not recommended for routine use

See BWH Summary

Lopinavir/RitonavirCopy Link!

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Not recommended for routine use outside of clinical trials

For patients on Antiretrovirals for HIV, we do not recommend changing existing ART regimens for the purposes of prophylaxis or treatment of COVID-19

See BWH Summary

InterferonsCopy Link!

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Not recommended for routine use

See BWH summary

AntibodiesCopy Link!

Convalescent PlasmaCopy Link!

Updated Date: November 15, 2020
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RecommendationsCopy Link!

  1. The FDA has issued an Emergency Use Authorization (EUA) for convalescent plasma for the treatment of hospitalized COVID-19 patients.
  2. Despite the EUA, convalescent plasma is not routinely recommended for COVID-19 patients given the lack of conclusive evidence. This stance is also supported by both the National Institutes of Health Guidelines and Infectious Diseases Society of America Guidelines.
  3. Because of the feasibility of local production, convalescent plasma may be a particularly appealing therapeutic option in low and middle-income countries. However, given the unproven benefits and potential risks, the International Society of Blood Transfusion recommends that convalescent plasma use be limited to the context of clinical research studies.

PathophysiologyCopy Link!

  1. Convalescent plasma originates from patients who have previously recovered from a viral infection and are now able to donate their immunoglobulin-containing blood
  2. The presumed mechanism of action is that antibodies present in convalescent plasma may suppress viremia

EvidenceCopy Link!

  1. The first multicenter randomized clinical trial was published on June 3, 2020, in which 103 COVID-19 patients were randomized to receive convalescent plasma (n=52) or standard of care (n=51). In this open label trial, clinical improvement occurred within 28 days in 51.9% of the convalescent plasma patients compared to 43.1% of the standard of care patients (HR 1.4, 95% CI 0.79-2.49). There was also no significant difference in mortality between groups, with 15.7% mortality in the convalescent plasma group compared to 24% with standard of care (OR 0.65, 95% CI 0.29-1.46). The findings of this study are limited however due to early termination of the trial. To provide 80% power, 200 patients were required in the analysis, but only half of that number were enrolled. Further studies are still warranted (Li et al).
  2. In a 160-patient, randomized, double-blind, placebo-controlled trial among older patients (≥65 years with comorbidities or ≥75 years without comorbidities), early receipt of high-titer convalescent plasma (<72 hours of symptoms) reduced the incidence of severe COVID-19 (RR 0.52, 95% CI 0.29-0.94) (Libster et al).
  3. The Mayo Clinic has published on their expanded access program, which to-date has analyzed 20,000 hospitalized COVID-19 patients who received convalescent plasma. In the cohort, the risk of serious adverse events was low and the seven-day mortality rate was 8.6% (8.2-9.0%). Noted side effects included cardiac events (0.37%), sustained hypotension (0.27%), thrombotic/thromboembolic complications (0.16%), transfusion-associated circulatory overload (TACO) (0.18%), transfusion-related acute lung injury (TRALI) (0.1%), and allergic transfusion reactions (0.13%), (Joyner et al; previous report with 5,000 patients: Joyner et al).
  4. Numerous smaller case series have been published to-date without reaching definitive conclusions on the use of convalescent plasma in COVID-19 (Shen et al; Duan et al; Zhang et al; Salazar et al).
  1. It’s important to note that the above case series do not prove efficacy of convalescent plasma, as the patients displayed relatively the same clinical course as many COVID-19 patients who do not receive the treatment

DosingCopy Link!

  1. Optimal therapeutic dosing is not yet known. Most ongoing studies are assessing an infusion of 1-2 units (200-500 mL) once

Monitoring and ToxicityCopy Link!

  1. Plasma transfusions in general are safe and well-tolerated in most patients. Potential side effects however include:
  1. Mild fever
  2. Allergic reactions, including serum sickness on rare occasions
  3. Transfusion-associated circulatory overload (TAC)
  4. Transfusion-related acute lung injury (TRALI) (Gajic et al)
  5. Potential risk of another infectious disease from donor, although risk is incredibly low with modern blood bank techniques
  1. There is a theoretical concern that convalescent plasma may lower a patient’s INR if on warfarin, similar to (but to a lesser degree than) fresh frozen plasma.

Monoclonal AntibodiesCopy Link!

Updated Date: January 13, 2020
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RecommendationsCopy Link!

  1. There is not enough data to support the use of monoclonal antibodies in the inpatient setting.
  2. The United States Food and Drug Administration (FDA) has issued emergency use authorizations (EUA) for two investigational monoclonal antibody therapies, bamlanivimab and casirivimab-imdevimab, for the treatment of outpatients with mild to moderate COVID-19 disease who are at high risk for progressing to severe COVID-19 and/or hospitalization. More information on the EUAs can be found here for bamlanivimab and here for casirivimab-imdevimab.
  3. There is still limited evidence for the use of monoclonal antibodies in COVID-19. Both the National Institutes of Health and Infectious Diseases Society of America recommend against their routine use outside of the context of a clinical trial (NIH Treatment Guidelines, December 2020; IDSA Treatment Guidelines, November 2020)

PharmacologyCopy Link!

  1. Bamlanivimab (LY-CoV555) is a recombinant neutralizing human IgG1κ monoclonal antibody to the spike protein of SARS-CoV-2, blocking viral entry into host cells
  2. Casirivimab-imdevimab (REGN10933-REGN10987) are two recombinant human monoclonal antibodies to the spike protein of SARS-CoV-2 (IgG1κ and IgG1λ, respectively), blocking viral entry into host cells

EvidenceCopy Link!

Outpatient

  1. BLAZE-1 was a phase 2 randomized trial that compared bamlanivimab at 3 different dosages (700 mg, 2800 mg, or 7000 mg) to placebo in 452 outpatients with COVID-19 and at least one symptom. In an interim analysis, patients who received the 2800 mg dose (n=107) had a statistically significantly lower viral load at day 11 compared to placebo (n=143), -4.00 vs. -3.47 respectively, difference -0.53 (95% CI -0.98 to -0.08). This difference was not seen with the 700 mg dose (n=101, difference -0.20, 95% CI -0.66 to 0.25) or 7000 mg dose (n=101, difference 0.09, 95% -0.37 to 0.55). When the three dosages were pooled together, there were numerically less medically attended visits within 28 days in the bamlanivimab arms (1.6%) compared to the placebo arm (6.3%). Bamlanivimab was relatively well-tolerated in all three treatment groups (Chen et al)
  2. A phase 1-3 trial randomized COVID-19 outpatients to casirivimab-imdevimab at 2 different dosages (1,200/1,200 mg or 4,000/4,000 mg) or placebo (1:1:1). The published data reported on 275 patients (Weinreich et al), but outcomes of 799 patients were reported out in the EUA provider fact sheet. The primary endpoint was the time-weighted average change from baseline in viral load from day 1 to day 7. The casirivimab-imdevimab pooled data resulted in -0.36 log10 copies/mL compared to placebo (p<0.0001). The largest reductions in viral load occurred in patients with high initial viral loads or who were seronegative at baseline. There were also numerically less medically attended visits within 28 days in the casirivimab-imdevimab arms (2%) compared to the placebo arm (4%). The median time to symptom improvement was 5 days for the casirivimab-imdevimab arms compared to 6 days for the placebo arm. Casirivimab-imdevimab was relatively well-tolerated in both dosing arms (unpublished report, casirivimab-imdevimab healthcare provider fact sheet)

Inpatient

  1. A randomized placebo-controlled trial assessed the use of bamlanivimab 7000 mg in the inpatient setting in combination with usual care (which included remdesivir, supplemental oxygen, and/or steroids). The trial was stopped early due to futility after randomizing 314 patients. The odds ratio of being in a more favorable category of a 7-category ordinal scale for pulmonary function on day 5 for patients treated with bamlanivimab compared to placebo was 0.85 (95% CI 0.56-1.29, p=0.45) (ACTIV-3/TICO LY-CoV555 Study Group)

DosingCopy Link!

  1. Bamlanivimab 700 mg IV once over 60 minutes administered as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset While the 2800-mg dose was the only dose to show a significant reduction in viral load at day 11 in BLAZE-1, the FDA’s EUA authorized the 700-mg dose for use due to issues with limited drug supply
  2. Casirivimab 1200 mg and imdevimab 1200 mg IV once over at least 60 minutes as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset

Monitoring and ToxicityCopy Link!

  1. Patients must be monitored during administration and for at least 60 minutes following the infusion of bamlanivimab to assess for signs of hypersensitivity
  2. Though data thus far is limited, the most common adverse events reported in BLAZE-1 were nausea, diarrhea, dizziness, headache, pruritus, and vomiting

Symptomatic TreatmentsCopy Link!

CoughCopy Link!

Updated Date: December 7, 2020

Non-Pharmacologic Therapy

  1. Drink plenty of fluids, preferably warm if possible
  2. A teaspoon of honey may help ease coughing symptoms
  3. Cough drops or hard candy may also be used

Pharmacologic Therapy

  1. Wet cough, difficulty clearing thick sputum: cough expectorant such as guaifenesin
  2. Dry cough: cough suppressant such as dextromethorphan

DyspneaCopy Link!

Updated Date: December 7, 2020

Dyspnea is a common physical symptom of severe COVID-19. Dyspnea may be severe. Dyspnea from COVID-19 should first be treated with oxygen and/or medications as discussed in other sections. Other underlying causes (such as severe anemia, pleural effusion, pneumothorax, or acidemia) should be ruled out and/or treated.

Non-Opioid ManagementCopy Link!

  1. Non-Pharmacologic Therapy for Dyspnea
  1. Positioning: sitting patient up in bed, if possible.
  1. Pharmacologic Therapy
  1. NSAIDs and/or acetaminophen may be used.
  2. Lorazepam can be used to ease the anxiety associated with dyspnea, but would avoid in patients who have had a previous paradoxical reaction (i.e. worsened agitation).

Opioid ManagementCopy Link!

Tool: Partners In Health Decision Tree for Opioid Treatment of Severe Dyspnea

Opioids are effective for relief of dyspnea that does not respond to treatment of underlying causes (e.g. severe anemia, severe anemia, pleural effusion, pneumothorax, or acidemia). Opioid therapy is an important component of the Essential Package for Palliative Care, which can be accessed here

  1. Candidates for Opioid Treatment of Dyspnea
  1. Opioids should be used to treat dyspnea in patients for whom survival is unlikely and treatment is focused solely on comfort and control of symptoms.
  2. Other patients with significant refractory dyspnea despite maximal treatment but expected to survive can receive opioids to treat dyspnea, although this should be done carefully in order to minimize the side effect of respiratory suppression.
  1. General Principles:
  1. Always use as needed (PRN) boluses to address acute, uncontrolled symptoms. PRN bolus dosing should be 10-20% of the 24-hour opioid dose
  1. For Opioid Naive Patients:

Normal GFR

Abnormal GFR (<50)

(Not absolute contraindication to morphine, but caution should be taken due to drug stacking)

No COPD

  • Morphine 5-10mg PO q3h PRN (use the 20mg/ml concentrate)

  • Morphine 2-4mg IV q2h PRN
  • Hydromorphone 1-2mg PO q3h PRN

  • Hydromorphone 0.1-0.2mg IV q2h PRN

COPD

  • Morphine 2-5mg PO q4h PRN (use the 20 mg/ml concentrate)

  • Morphine 1-2 mg IV q2h PRN
  • Hydromorphone 2-4mg PO q4h PRN

  • Hydromorphone 0.2-0.4mg IV q2h PRN

  1. If frequent doses are needed, schedule an effective morphine dose Q4H and add a rescue dose as needed at 10% of the total daily dose
  2. If patient is not well-managed with the above, add opioid infusion:
  1. Consider drip If > 3 bolus doses in 8 hours
  2. Calculate initial dose with total mg used/8 hours
  1. e.g. 1+2+2+2= 7 mg; begin drip at 7mg/8 hr = 1 mg/h
  2. Depending on symptoms and goals of care, consider reducing hourly rate by 30-50%. If patient is at end of life, would use 100% of hourly rate.
  1. Continue PRN dosing at current dose (if effective) or titrate as per above
  1. For Opioid tolerant patients:
  1. If able to take PO:
  1. Continue current long-acting doses if renal and hepatic function tolerate
  2. Continue current oral PRN dose if effective q4h prn
  1. If ineffective, increase dose by 50% and order range of up to 3 x basal dose
  1. e.g. 5 mg PO MS q3h prn; increase to 7.5 mg; 7.5-22 mg PO q3h PRN
  1. If unable to take PO, severe or rapidly escalating symptoms:
  1. Convert as-needed PO doses to IV pushes as needed
  1. Use the IV Conversion chart (see chart below)
  2. Decrease PRN dose by ⅓ for incomplete cross-tolerance when switching between opioid classes
  1. e.g. to convert 20 mg of oxycodone to IV hydromorphone: 20 mg oxy = 1.5 mg IV hydromorphone; 1.5 mg x ⅔ =1 mg IV
  1. Convert PO long-acting/ sustained release opioids to an infusion:
  1. Calculate 24-hour dose of PO sustained release (SR) morphine
  1. Divide by 3 for the total 24h mg IV (Morphine PO/IV = 3:1)
  1. Divide the 24h mg IV total by 24h for the hourly drip rate (mg)
  1. e.g. 30 mg SR PO morphine q8 hr= 90 mg PO in 24 h; 90 mg /3 = 30 mg IV dose; 30 mg / 24 h ~1 mg/hr IV morphine infusion
  1. Continue PRN dosing. PRN dose should be 100-200% of opioid drip rate
  1. e.g. 1 mg/hr IV morphine infusion; PRN dose is 1-2 mg IV q2h

Abbreviated Opioid Equianalgesic Table (for complete table and an example conversion see DFCI Pink Book)

Drug

PO/PR (mg)

Subcut/IV (mg)

Morphine

30

10

Oxycodone

20

n/a

Hydromorphone

7.5

1.5

Fentanyl

(See table below for transdermal conversions)

n/a

0.1 (100 mcg)

PainCopy Link!

Pharmacologic:Copy Link!

Opioid management of pain should be managed similarly to Opioid Management for Dyspnea.

AnxietyCopy Link!

Updated Date: December 7, 2020
Literature Review (Anxiety & Depression):
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NonpharmacologicCopy Link!

Feelings of uncertainty and fear can fuel anxiety

  1. Important to first acknowledge and normalize distress reactions
  2. Correct misinformation. Provide accurate information (regarding patient’s current medical condition and next steps, regarding hospital protocols and measures being taken for safety)
  3. Offer counseling (Spiritual, Psychocological, Social Work)
  4. Offer mindfulness strategies
  5. Strategies for reducing distress
  1. Restful sleep, eating regular meals, exercising
  2. Talking to loved ones (by telephone or video chat)
  3. Diaphragmatic breathing (breathing to inflate the abdomen)
  4. Muscle relaxation

PharmacologicCopy Link!

  1. Continue home psychotropic medication regimen if possible
  2. For patients with evidence of delirium
  1. Quetiapine 12.5-25mg TID PRN or Haloperidol 1-2.5 mg orally or IV Q4H as needed (can also be scheduled Q6 – 8 H)
  1. For patients without evidence of delirium
  1. Quetiapine 12.5-25mg TID PRN
  2. Lorazepam 0.5-2 mg PO/SL TID PRN; 0.5-2 mg IV TID PRN or Diazepam 2.5-5mg every 6 to 24 hours
  1. For patients with risk of respiratory depression or history of respiratory illness
  1. Buspirone 5-15mg PO TID
  1. For moderate or severe anxiety in a patient expected to survive, start fluoxetine 20mg orally daily. Increase dose as needed every 7 days to achieve good effect, maximum 80mg per day. Other selective serotonin uptake inhibitors (SSRIs) that can be used instead of fluoxetine include sertraline and citalopram. Beware of QTc prolongation with some SSRIs.

Anxiety Related to Dyspnea or End of LifeCopy Link!

  1. Benzodiazepines (if patient is not delirious; can use in either intubated or non-intubated pts — use with caution in older patients)
  1. Lorazepam (longer half-life) 0.5-2 mg PO/SL q4-6h PRN; 0.5-2 mg IV q2h PRN
  2. Midazolam (shorter half-life) 0.2-0.5 mg IV slowly q 15 min PRN or 0.1-0.3 mg/hr IV infusion
  3. Diazepam 2.5-5mg every 6 to 24 hours
  1. SSRI/SNRI: Continue home dose if possible. If NPO, replace with prn benzodiazepine

Respiratory SecretionsCopy Link!

Updated Date: December 7, 2020
Literature Review (Airway Clearance):
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Literature Review (Dornase):
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  1. Patients can develop thick secretions from Covid-19 itself or secondary bacterial pneumonia
  2. Nebulized treatments may help with airway secretion management, but published evidence is not available
  3. Options include:
  1. Normal (0.9%) saline nebulizer BID
  2. N-acetylcysteine (“Mucomyst”) nebulizer BID or TID
  1. N-acetylcysteine can cause bronchoconstriction
  2. Pre-treat with albuterol 2.5mg just prior to delivery
  1. Nebulized hypertonic (3-7%) saline once daily
  1. Hypertonic saline can cause bronchoconstriction
  2. If using, start with 3% saline to assess response and bronchoconstriction.
  3. Pre-treat with albuterol 2.5mg just prior to delivery
  1. Dornase alfa 2.5mg nebulizer once daily
  2. Dornase can cause bronchoconstriction, mucosal bleeding, and can clog the HEPA filter, requiring intermittent replacement by RT
  3. Avoid in the setting of bloody secretions
  4. Pre-treat with albuterol 2.5mg just prior to delivery
  5. It would be reasonable to consider other agents, including N-acetylcysteine, first given the need to change HEPA filters. In addition, a RCT for dornase nebulizer versus saline will begin shortly at BWH. However, if persistent secretions, it is reasonable to try dornase nebulizer
  1. Although avoided if possible since it is an aerosol generating procedure, bronchoscopy for pulmonary toilet can be performed if needed on COVID-19 confirmed or PUI patients.

Secretions at the End of LifeCopy Link!

Pharmacologic management (not to be used with secretions with significant mucus). Avoid using > 2 of these at the same time; if more than one is required, monitor for development of anticholinergic crisis

  1. Glycopyrrolate 0.2 – 0.4mg IV q2hrs prn secretions, rattling sound
  2. Hyoscyamine sulfate 0.125-0.25mg PO q4hrs prn secretions, rattling sound
  3. Scopolamine 1.5mg TD q72hrs if patient not awake and no apparent delirium or history of delirium. Note that the patch will take ~ 12 hours to take effect
  4. Hyoscine butylbromide (alternative formulation of scopolamine) 20mg orally/IV/SC Q6H PRN or scheduled.

Nausea and VomitingCopy Link!

Updated Date: December 7, 2020

  1. Consider reversible etiologies such as gastritis, constipation, anxiety.
  2. Match treatment to etiology of nausea:
  1. Chemoreceptor Trigger Zone (blood brain barrier breakdown)
  1. haloperidol, metoclopramide, ondansetron, olanzapine, aprepitant
  1. Gastrointestinal:
  1. ondansetron, metoclopramide, dexamethasone (if malignant obstruction)
  1. CNS cortical centers:
  1. lorazepam for anticipatory nausea, dexamethasone (tumor burden causing ICP)
  1. Vestibular:
  1. meclizine, scopolamine, diphenhydramine
  1. Additional information can be found at the DFCI Green Book (page 11 for more dosing recommendations):
  1. Ondansetron 8-24mg/day IV/PO (usually on a q6h PRN schedule, max single dose 16mg) *causes constipation* Beware QTc prolongation.
  2. Haloperidol 0.5-2 mg IV/PO q 4-8 hours *extra-pyramidal effects unlikely at these low doses*
  3. Metoclopramide 10-40 mg IV/PO TID-QID *pro-motility*
  4. Olanzapine 2.5-10 mg PO/dissolvable daily *off label, effective for concurrent anxiety, will not exacerbate constipation*
  5. Prochlorperazine 10 mg PO TID-QID (max 40 mg/day) 25 mg PR BID *very sedating, overlaps with haloperidol, metoclopramide, perphenazine*
  6. Meclizine 25-50 mg PO daily

DeliriumCopy Link!

Updated Date: December 20, 2020
Literature Review:
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  1. Non-pharmacologic:
  1. Frequent reorientation when appropriate
  2. Early mobilization (getting out of bed)
  3. Promotion of sleep-wake cycles via use of room lighting and stimulation and quiet location
  4. Timely removal of unnecessary restraints, catheters, lines, and other devices
  5. Ensuring use of glasses/hearing aids once patient is sufficiently alert
  6. Reverse contributing medical conditions as able
  7. Consult psychiatry services if available

  1. Pharmacologic
  1. Avoid delirium-causing medications (anticholinergics, benzodiazepines, opioids) whenever possible
  2. Treat comorbid symptoms and underlying medical illness
  3. For agitation/aggression:
  1. Antipsychotics
  1. Haloperidol: Mild agitation: 0.5-1.0 milligrams intravenously, or 1- 2 milligrams by mouth every 6 hours and 1-2 milligrams every 2 hours as needed; Moderate agitation: 2-4 milligrams intravenously; Severe agitation: 4-10 milligrams; Maximum dose: 20 milligrams / 24 hours
  2. If unresponsive to treatment, olanzapine (Zyprexa), 2.5 to 5 milligrams (by mouth, sublingual, or intravenously) every 12 hours. Based on onset (6h), PO/SL olanzapine should not be used PRN for agitated delirium Maximum dose: 30 milligrams / 24 hours. **do not combine with benzodiazepines given by other routes, due to increased risk of respiratory depression**
  3. If haloperidol/olanzapine not effective or contraindicated, can try:
  1. Quetiapine (Seroquel) 12.5-50 milligrams every night at bedtime, can increase to every 6-12 hours. Titrate up to effect by 50 mg – 100 mg/day. Max dose: 600-800 mg/day
  2. Aripiprazole (Abilify) 5 milligrams by mouth daily; maximum dose 30 milligrams daily
  1. Alpha 2 Agonists - helpful for patients for ventilator weaning; also good option if prolonged QTc
  1. Dexmedetomidine (Precedex) intravenously - easy to adjust dosing given short half-life
  2. Consider use of clonidine 0.1 milligrams twice daily (can uptitrate) - available as a transdermal patch as well.
  1. Mood Stabilizers
  1. Valproic Acid (good option if prolonged QTc): Start at 125-250 milligrams intravenously every 8 hours three times daily, however, COVID patients are seeming to need escalations in doses (up to anti-manic dosing of 15-25 milligrams/kilogram) in combination with antipsychotics (such as haloperidol or olanzapine, as above).
  1. Others
  1. For regulation of sleep/wake cycle: Mirtazapine (Remeron): 7.5 milligrams (can increase, but it is more sedating at lower doses)
  1. Considerations for Geriatrics Patients
  1. High risk for delirium given restrictive visitor policy, disorienting effect of PPE use by staff, difficulty hearing/identifying caregivers through masks
  2. Avoid delirium-causing medications such as anticholinergics and benzodiazepines (See here for a comprehensive Beers Criteria List)
  3. If acutely agitated, not redirectable by non-pharmacologic means, trial 12.5 milligrams trazodone x 1 as needed, repeat dose at 30 min if no effect
  4. Use antipsychotics (such as haloperidol, olanzapine, quetiapine) as last resort only, and only if QTc is < 500. Dose reductions should be used (suggestions: Haloperidol, Mild agitation 0.25 -0.5 mg IV or 1 to 2 mg PO q6h and 1 mg q2h PRN; Moderate agitation: 1-2 mg IV; Severe agitation: 2 mg IV Maximum dose: 20 mg / 24 hours)

AnticoagulationCopy Link!

Prophylactic DosingCopy Link!

Updated Date: December 19, 2020
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For Patients Who are Not Critically IllCopy Link!

  1. For outpatients, we do not recommend prophylaxis
  2. For non-critically ill inpatients, VTE rates appear to be similar to general ward patients amongst those receiving standard prophylactic anticoagulation.
  1. Standard dosing: For inpatients, we recommend standard dosing (American Society of Hematology)
Standard Dosing VTE ProphylaxisCopy Link!

VTE Dosing Weight Adjustment

CrCl ≥ 30mL/min

CrCl < 30mL/min

(or enoxaparin unavailable)

Standard

Enoxaparin 40mg daily

Heparin 5000 units Q8H

Obese (≥120kg or BMI ≥ 35)

Enoxaparin 40mg BID or 0.5mg/kg Daily

(max dose 100mg daily)

Heparin 7500 units Q8H

Low Body Weight (< 50kg*)

Enoxaparin 30mg daily

Heparin 5000 units BID-TID

*LBW does not have a universal definition for LMWH dosing, we define it differently in the non-ICU (<50kg) and ICU (<60kg) populations to help achieve our targeted anticoagulant effect, though this remains an active area of research

For Critically Ill PatientsCopy Link!

  1. Experts are divided as to whether standard, intermediate, or full dose anticoagulation provides the optimal balance of benefit of anticoagulation with risk of bleeding for COVID patients (Bikdeli et al). One study reported improved survival with therapeutic anticoagulation, but was severely limited by confounding (Paranjpe et al). A propensity score-matched analysis suggested there was no survival benefit of therapeutic anticoagulation (Tremblay et al). A small study of 49 ICU patients in Belgium suggests intermediate dose prophylaxis is associated with an odds ratio of 0.13 for pulmonary embolism (Taccone et al). Multiple ongoing studies are evaluating the optimal dosing strategy. We recommend either standard dosing or intermediate dosing.
  1. Standard dosing: As of October, 2020 the American Society of Hematology recommends standard dosing. UCSF also uses standard dosing.
  2. Intermediate dosing: Given the elevated VTE risk relative to baseline in its COVID ICU patient population (1.5-2 fold), BWH uses intermediate dosing for critically ill patients and post-critically ill patients.
  3. Full dosing: As of December, 2020 no guidelines bodies are recommending therapeutic dosing for DVT prophylaxis in COVID19 patients.

Intermediate Dosing VTE ProphylaxisCopy Link!

  1. Inclusion (BWH recommendations):
  1. COVID-19 confirmed and PUI patients with critical illness at any point during hospitalization
  2. Platelets >25,000
  1. Exclusion:
  1. If Platelets <25,000 or bleeding, hold prophylaxis and start thromboembolic deterrent stockings and sequential compression devices

VTE Dosing Weight Adjustment

CrCl ≥ 30mL/min

CrCl < 30mL/min

(or enoxaparin unavailable)

Standard

Enoxaparin 40mg BID

Heparin 7,500 units Q8H

Obese (≥120kg or BMI ≥ 35)

Enoxaparin 0.5mg/kg BID

(max dose 100mg BID)

Heparin 10,000units Q8H

Low Body Weight (< 60kg)*

Enoxaparin 30mg BID

Heparin 7,500 units Q8H

*LBW does not have a universal definition for LMWH dosing, we define it differently in the non-ICU (<50kg) and ICU (<60kg) populations to help achieve our targeted anticoagulant effect, though this remains an active area of research

Therapeutic DosingCopy Link!

Updated Date: September 5, 2020
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  1. Recommendations for therapeutic anticoagulation of patients with known DVT or PE remain the same as prior to COVID-19.
  1. While some institutions are considering full dose anticoagulation in severe COVID-19 disease without known VTE, our interpretation of the data is that the risks outweigh the benefits at this time, unless documented DVT or PE. Preliminary data from Wuhan suggest that prophylactic LMWH or heparin may be of benefit in those patients with severe COVID-19 and D-dimer levels > 6 times the upper limit of normal (Tang et al).
  2. A propensity score-matched cohort study of 3,772 participants compared COVID-19 patients receiving anticoagulation/antithrombotic therapy prior to diagnosis to patients without prior anticoagulation/antithrombotic therapy. No statistically significant difference in survival or time to mechanical ventilation was observed (Tremblay et al.)
  1. If the patient is on direct oral anticoagulants (DOACs) or Warfarin for Afib or VTE, assess on an individual basis whether to switch to a parenteral anticoagulant with a shorter half-life (LMWH or heparin) based on clinical status.
  1. Consider the same clinical criteria used for non-COVID-19 patients. For example:
  1. Consider LMWH or heparin in COVID-19 patients with AKI, procedures that require time off therapeutic anticoagulation or clinical instability (e.g., patients requiring critical care).
  2. Continue home anticoagulation regimen in clinically stable COVID-19 patients without other contra-indications, with close monitoring of factors that could influence pharmacokinetics (e.g., antibiotics that could increase the effect of Warfarin; renal function for DOACs).
  1. DOACs can be continued in patients on steroids and remdesivir. The benefits likely outweigh the risk of potential interactions between medications (e.g., by the induction of CYP3A4 or the multidrug efflux pump P-glycoprotein by dexamethasone).
  1. Speculative use of therapeutic anticoagulation or tissue plasminogen activator (TPA)
  1. While therapeutic anticoagulation has been used empirically in some severe COVID-19 patients in Wuhan given the possible microthrombi in pulmonary vasculature, our interpretation of the data is that the risks outweigh the benefits at this time, unless documented DVT or PE (Hardaway et al).
  1. Similarly, TPA has been proposed as a possible therapeutic. We recommend against TPA for ARDS

AspirinCopy Link!

Updated Date: December 7, 2020

Aspirin can continue to be used in patients in whom it is indicated (i.e. cardiovascular disease prevention), but at this point in time, there is not enough evidence to support its use strictly for COVID-19 prevention and/or treatment

  • A small retrospective study showed a possible improvement with aspirin started before or early during admission. This has yet to change clinical practice (Chow et al).

AntibioticsCopy Link!

Choice of AntibioticsCopy Link!

A discussion of the risks/benefits of empiric antibiosis and suggested initial regimens is found under Bacterial Infections, whether or not to give empiric antibiosis, and choice of agent. A common initial regimen for community acquired pneumonia is ceftriaxone and azithromycin or doxycycline.

Treatments for Comorbid DiseasesCopy Link!

RAAS InhibitorsCopy Link!

Angiotensin Converting Enzyme Inhibitors (ACEi) and Angiotensin II Receptor Blockers (ARB)

Examples: Lisinopril, Enalapril, and Captopril
Updated Date: May 10, 2020
Literature Review:
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RecommendationsCopy Link!

  1. For outpatients, ACEi/ARBs should not be discontinued
  2. For inpatients, ACEi/ARBs should not be discontinued unless otherwise indicated (e.g., acute kidney injury, hypotension, shock)

Pathophysiology and EvidenceCopy Link!

  1. SARS-CoV-2, the virus that causes COVID-19, enters via the same cell-entry receptor as SARS-CoV, namely angiotensin-converting enzyme II (ACE2) (Paules et al). SARS-CoV-2 is thought to have a higher affinity for ACE2 than SARS-CoV.
  2. ACE2 is expressed in the heart, lungs, vasculature, and kidneys. ACE-inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) in animal models increase the expression of ACE2 (Zheng et al), though this has not been confirmed in human studies. This has led to the hypothesis that ACEi and ARBs might worsen myocarditis or precipitate ACS. It has also been hypothesized that the upregulation of ACE2 is therapeutic in COVID-19 and that ARBs might be protective during infection (Gurwitz).
  3. The evidence that currently exists favors continuing these medications unless otherwise indicated to stop them because their abrupt discontinuation, particularly in those who have heart failure or have had a myocardial infarction, may lead to clinical instability and adverse outcomes (Vaduganathan et al). The American College of Cardiology, American Heart Association and Heart Failure Society of America joint statement recommends against discontinuing ACEi and ARBs in patients with COVID-19 (Bozkurt et al, HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19, 2020)

StatinsCopy Link!

Examples: Simvastatin, Rosuvastatin, Pravastatin
Updated Date: December 7, 2020

  1. Statins can continue to be used in patients in whom they are indicated, but at this point in time, there is not enough evidence to support their use strictly for COVID-19 prevention and/or treatment

Calcium Channel BlockersCopy Link!

Examples: Amlodipine, Nifedipine, Diltiazem, Verapamil

Updated Date: January 7, 2021

  1. Calcium channel blockers can continue to be used in patients in whom they are indicated, but there is not enough evidence to support their use for COVID-19 prevention and/or treatment

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)Copy Link!

Updated Date: May 10, 2020
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RecommendationsCopy Link!

  1. Concern has been raised that NSAIDs may worsen COVID-19 disease. This has not been proven clinically to-date, so we cannot make a recommendation for or against their use at this time

PharmacologyCopy Link!

  1. SARS-CoV-2 binds to cells via ACE2. ACE2 is upregulated by ibuprofen in animal models, and this might contribute to increased pathology (see “Angiotensin Converting Enzyme Inhibitors (ACE-I) and Angiotensin II Receptor Blockers (ARB)” section of this chapter).

EvidenceCopy Link!

  1. Reports from France indicate possible increase in mortality with ibuprofen in COVID-19 infection, but these reports have not been corroborated (Fang et al; Day). WHO clarified on March 20, 2020 that it does not recommend avoiding NSAIDs as initially stated March 18th (WHO, COVID-19 Interim guidance, March 2020)

BronchodilatorsCopy Link!

Updated Date: December 7, 2020
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Bronchodilators are not indicated for COVID alone in the absence of other indications, such as asthma or COPD. Some patients may have bronchoconstrictive responses to infection and so they may help some patients, but should not be used as a default treatment for all patients. When using, try to use meter-dose inhalers (MDIs) with a spacer instead of nebulizers where possible to decrease aerosols

NebulizersCopy Link!

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Nebulizers should be used very sparingly as they pose a risk to staff due to aerosolized virus. An inhaler with a spacer will provide similar benefit in most patients. Limit nebulizers to patients with severe wheezing who do not respond to inhalers. Any nebulizers should be done on airborne precautions (e.g. N95 mask use for all staff and private room for the patient, with negative pressure if possible). Airborne precautions should be continued for at least 1-3 hours after the treatment finishes.

Tool: Instructions on How to Make a Spacer With a Water Bottle: WHO-ICRC Basic Emergency Care Course (p.158)

Meter-Dose InhalersCopy Link!

Meter-Dose Inhalers (MDIs) can still be used and normal, and should be used with a spacer for efficacy.

Tool: For simple instructions on how to make a spacer with a water bottle, see page 158 of the WHO-ICRC basic Emergency Care Course.

Inhaled CorticosteroidsCopy Link!

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This section is in process

Blood ProductsCopy Link!

Updated Date: May 1, 2020
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  1. In general, treat bleeding rather than numbers.
  2. We recommend a restrictive transfusion strategy (Hct > 21, Hgb > 7). Randomized controlled trials of ICU patients have shown that a conservative transfusion strategy (Hgb > 7) is associated with less pulmonary edema, fewer cardiac events and no evidence of harm compared to a liberal transfusion strategy (Hébert et al; Holst et al; Gajic et al).
  3. If hemodynamically stable, transfuse 1 unit at a time and reassess needs.
  1. A conservative approach to transfusions is encouraged given risks associated with blood product transfusions, limited supply (blood drives are limited by social distancing), and volume overload being of particular concern in COVID patients.
  1. Fresh frozen plasma (FFP) or 4 factor-PCC (lower volume) should be given for active bleeding in the setting of known or suspected coagulation abnormalities.
  2. For warfarin reversal, use 4 factor-PCC given longer effect and lower volume.
  1. If PCC is unavailable, FFP and vitamin K (10mg IV administered over 60 minutes) should be given
  2. If FFP is unavailable, vitamin K should still be given, although it can take hours to have an effect
  1. Massive transfusion protocol, as a very limited resource, will need to be activated only by a senior clinician.
  2. Tranexamic acid: only for ongoing oozing/bleeding with over DIC and hyperfibrinolysis.
  3. Procedures: If the patient is at high bleeding risk, the most experienced operator should perform the procedure to minimize complications.
  1. We recommend avoiding subclavian lines when placing central venous catheters in coagulopathic patients.

Patient

DVT ppx

Transfusion Thresholds

Transfuse 1 unit at a time

RBC

Platelets

Cryo

FFP

No bleeding,

Plts > 30k

LMWH daily or

SC UFH TID

Hgb < 7, If ACS,** Hgb > 10

n/a

Fibrinogen < 100

INR > 10

No bleeding, but patient requires anticoagulation

Heparin gtt

PTT goal depends on indication

Hgb < 7, If ACS,** Hgb > 10

Plts < 30k

Fibrinogen < 100

INR > 10

No bleeding,

Plts < 30k

SCDs*

Hold pharmacologic

Hgb < 7, If ACS,** Hgb > 10

Plts < 10k

Fibrinogen < 100

INR > 10

Minor Procedures

(a-lines, CVCs)

Continue pharmacologic ppx in most patients

SCDs* if not using pharmacologic

Hgb < 7, If ACS,** Hgb > 10

Plts < 10k

Fibrinogen < 100

INR > 3

Mild Bleeding or Rigors (increases risk of ICH in thrombocytopenia)

Continue pharmacologic ppx in most patients

SCDs* if not using pharmacologic

Hgb < 7, If ACS,** Hgb > 10

Plts < 20k

Fibrinogen < 100

INR > 3

Intracranial Hemorrhage

+ SCDs*

Hold pharmacologic if able

Hgb < 7, If ACS,** Hgb > 10

Plts < 75k

Fibrinogen < 100

INR > 1.7

Serious Bleeding#, Trauma or Major Procedure

(includes LP)

+ SCDs*

Hold pharmacologic if able

Transfuse for active bleeding

Plts < 50k or higher

Fibrinogen < 100

INR > 2

(INR > 1.4 for LP)

* SCDs = sequential compression devices = “pneumoboots”

** ACS = Acute Coronary Syndrome

# Intracranial hemorrhage and massive bleeding are not included here.

ImmunosuppressantsCopy Link!

This section is in process

ImmunomodulatorsCopy Link!

HydroxychloroquineCopy Link!

Updated Date: November 15, 2020
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RecommendationsCopy Link!

  1. Hydroxychloroquine and chloroquine are not recommended in the treatment of COVID-19 outside of clinical trials
  2. Despite an initial EUA, the FDA concluded that it is unlikely that chloroquine or hydroxychloroquine will be effective in treating COVID-19 and that the benefits do not outweigh the risks for use in COVID-19, thereby revoking EUA 039 originally authorized on March 28, 2020 (FDA EUA Revocation Letter June 15, 2020). The World Health Organization, National Institutes of Health and Infectious Diseases Society of America also recommend against its use (WHO Treatment Guidelines, May 2020; NIH Treatment Guidelines, October 2020; IDSA Treatment Guidelines, August 2020)

PharmacologyCopy Link!

Hydroxychloroquine (HCQ) is an anti-malarial 4-aminoquinoline shown to have in vitro activity against diverse RNA viruses, including SARS-CoV-1 (Touret et al).

EvidenceCopy Link!

  1. The first randomized control trial for COVID-19 post-exposure prophylaxis was published on June 3, 2020. Asymptomatic patients who had household or occupational exposures to others with COVID-19 for more than 10 minutes within 4 days of exposure were randomized to receive either placebo (n=407) or hydroxychloroquine 800 mg once, 600 mg in 6-8 hours, then 600 mg daily for 4 additional days (n=414). The incidence of new illness compatible with COVID-19 was 11.8% in the hydroxychloroquine arm and 14.3% in the placebo arm (absolute difference -2.4%, 95% CI -7 to 2.2%, p=0.35). Side effects were more common in the hydroxychloroquine arm (40.1% vs. 16.8%), but no serious adverse reactions were reported (Boulware et al)
  2. The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial in the United Kingdom has enrolled over 11,500 patients to-date into multiple treatment arms, two of which are hydroxychloroquine and standard of care. While it hasn’t yet been published, the hydroxychloroquine arm of the study ceased enrollment on June 4, 2020 due to lack of benefit. The independent Data Monitoring Committee found that the hydroxychloroquine arm (n=1542) had similar outcomes in terms of 28-day mortality compared to the standard of care arm (n=3132) (25.7% vs. 23.5%, HR 1.11, 95% CI 0.98-1.26, p=0.10) (RECOVERY statement June 5, 2020)
  3. The WHO-initiated SOLIDARITY trial was randomized across 30 countries and >11,000 hospitalized COVID-19 patients comparing 5 potential COVID-19 treatment regimens (remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, and combination lopinavir/r with interferon) against placebo. In the hydroxychloroquine portion of the trial, hydroxychloroquine (n=947) did not lead to a significant difference in 28-day mortality compared to placebo (n=906), 11.0% (104 deaths) vs. 9.3% (84 deaths) respectively (RR=1.19, 95% CI 0.89-1.59, p=0.23) (Pan et al)
  4. The NIH’s ORCHID trial has also stopped enrolling patients after the data and safety monitoring board (DSMB) determined that while hydroxychloroquine did not cause additional harm, it also was very unlikely to provide benefit to hospitalized patients with COVID-19 (NIH press release June 20, 2020)
  5. A number of other studies have also shown no positive impact with the addition of hydroxychloroquine in COVID-19 patients (Tang et al; Geleris et al; Mahevas et al; Borba et al; Magagnoli et al).

Anti-IL-6 Agents (e.g. Tocilizumab)Copy Link!

The routine use of anti-IL-6 agents (Tocilizumab, Sarilumab, Siltuximab) is not recommended outside the context of a clinical trial

Tool: See BWH Summary
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Anti-IL-1 Agents (e.g. Anakinra)Copy Link!

The routine use of anti-IL-1 agents (e.g. Anakinra, Canakinumab, Rilonacept) is not recommended outside the context of a clinical trial

Tool: See BWH summary

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Other Miscellaneous AgentsCopy Link!

AzithromycinCopy Link!

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There is not sufficient supporting evidence to use azithromycin for COVID-19 disease outside of clinical trials, unless concomitant community-acquired pneumonia is suspected and atypical coverage is needed. Numerous studies have raised concerns about the deleterious effects of hydroxychloroquine and azithromycin combination therapy (Mercuro et al; Bessière et al; Chorin et al)

For more information on the pharmacology and evidence, please see BWH’s protocols

Antihelminths (Ivermectin)Copy Link!

Updated Date: January 2, 2021

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RecommendationsCopy Link!

  1. A small number of low-quality studies have published data on the use of ivermectin as a therapy for COVID-19. At this time, it is not possible to make any conclusions regarding the efficacy of ivermectin therapy for the treatment of COVID-19. We do not recommend ivermectin use for the treatment of COVID-19 at this time. The United States FDA has issued a warning against using ivermectin intended for animals for the treatment of COVID-19
  2. Patients should be assessed for risk of concurrent Strongyloides Infection. Ivermectin may be indicated for empiric treatment of strongyloides in patients with COVID-19 to prevent complications from corticosteroid therapy.

PharmacologyCopy Link!

  1. The antiviral activity of ivermectin is not entirely clear, but it is postulated that ivermectin may inhibit importin ɑ/β1 receptor, which transmits viral proteins into the host cell nucleus (Caly et al).

EvidenceCopy Link!

  1. In vitro, Caly and colleagues infected cells with SARS-CoV-2 and exposed them to 5 μM of ivermectin over 72 hours. At 24 hours, there was a 93% reduction in viral RNA and at 48 hours, the effect increased to loss of essentially all viral material (~5000-fold decrease). The ivermectin concentration resulting in 50% inhibition (IC50) was estimated to be ~2 μM (Caly et al).
  1. Multiple subsequent studies have shown that ivermectin dosing would need to be much higher than the current maximum approved dosing in order to reach the needed concentration in vivo (Schmith et al; Jermain et al; Momekov et al).
  2. Two letters to the editor have also challenged the initial in vitro study (Bray et al).
  1. A small randomized control trial compared ivermectin 12 mg daily for 5 days (n=22) or ivermectin 12 mg x1 and doxycycline daily for 5 days (n=23) against placebo (n=23). Ivermectin monotherapy showed a reduction in time for viral clearance with a mean duration 9.7 days vs. 12.7 days for placebo (p=0.02), but ivermectin + doxycycline did not show a reduction (11.5 days). Of note, the drug manufacturer sponsored this study. Further studies are required and conclusions can't be made from this study (Ahmed et al).
  2. A small prospective controlled (non-randomized) trial compared 2 to 3 doses of ivermectin in combination with 5 to 10 days of doxycycline (n=70) with standard care (n=70). Ivermectin/doxycycline therapy was associated with reduced time to recovery of 10.6 days compared to 17.9 days for placebo (p<0.0001). These results are not peer-reviewed and further studies are needed in order to make any conclusions regarding ivermectin therapy and COVID-19 (Hashim et al).
  3. A retrospective cohort reviewed the impact of ivermectin use in 280 COVID-19 patients in four Florida hospitals. Mortality was less in patients who received ivermectin (n=173, 15% mortality) compared to those who received standard of care (n=107, 25.2% mortality). After adjusting, the mortality difference between groups remained significant (aOR 0.27, 95% CI 0.09-0.80, p=0.03). These findings however require randomized controlled trials for confirmation (Rajter et al).
  4. Additional case series have been published on the use of ivermectin in COVID-19 (Camprubi et al).

DosingCopy Link!

  1. The dose needed to obtain therapeutics concentrations is likely not feasible (see Evidence above). For parasitic diseases, ivermectin dosing ranges from 150 to 400 μg/kg. Published reports thus far have utilized doses of 200 μg/kg once or 12 mg once daily for 5 days
  2. Nausea and vomiting, rash, CNS effects (dizziness, drowsiness, ataxia), itching, eosinophilia, tachycardia, hypersensitivity reactions. Toxicities with higher-than-approved doses are not yet fully understood (Navarro et al)

NitazoxanideCopy Link!

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Nitazoxanide should not be used outside of clinical trials as overall clinical evidence is lacking and optimal dosing is not known

For more information on the pharmacology and evidence, please see BWH’s protocols

FamotidineCopy Link!

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This section is in process

Vitamins & MineralsCopy Link!

ZincCopy Link!

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We do not recommend routine use of zinc for the treatment or prevention of COVID-19, except as part of a clinical trial. For more information on the pharmacology and evidence, please see BWH’s Protocols

Vitamin CCopy Link!

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While this idea has been popular on social media, there is currently no evidence to support low- or high-dose vitamin C in COVID-19 patients. For more information on the pharmacology and evidence, please see BWH’s Protocols

Vitamin DCopy Link!

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This section is in process

Clinical TrialsCopy Link!

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This section is in process

Plasma ExchangeCopy Link!

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This section is in process