COVID-19

Analgosedation Options

Intermittent IV Bolus

Continuous Infusions

Other things to consider:

Fentanyl patches

Oral immediate release tab formulations (oxy, morphine, hydromorphone) down OG/NG tube 

Oral liquid formulations (oxy, morphine, hydromorphone) down OG/NG tube

Pooling small propofol vials (20ml) into empty IV bags when 100ml propofol vials run short

Using small propofol vials (20ml) to prime lines vs using the large bottles (lines changed q12H) to save content in 100ml bottles

Phenobarbital

• Bolus dose: 15 – 20 mg/kg IV
• Infusion: 0.5 – 1 mg/kg/hr
• Pros: provides deep level of sedation, provides anticonvulsant effects
• Cons: Some dosage forms contain propylene glycol and may cause propylene glycol toxicity, increased LFT’s, rare incidence of SJS, long acting (difficult to titrate, may accumulate with prolonged use and increase time to awakening)

Remifentanil 

• Continuous infusion: 0.1 to 1 mcg/kg/h
• Pros: easy to titrate (short half-life)
• Cons: May cause hypotension and bradycardia

Remdesivir (GS5734): 

• MOA: RNA dependent RNA pol inhibitor
• Level of Evidence:
  • Preliminary results from a multinational ACTT-1 RCT on 1059 patients has showed a statistically significant median recovery time of 11 days for Remdesivir arm vs 15 days for placebo arm. Estimates of mortality by 14 days were not statistically significant (7.1% for the Remdesivir group vs 11.9% for the placebo group).
  • RCT of 237 in China showed no benefit on clinical improvement in patients who received Remdesivir compared to placebo. One month mortality was reported as 13.9% in the Remdesivir arm vs 12.8% in the control arm. Remdesivir was discontinued due to adverse events in 12% of patients in the Remdesivir arm vs 5% in the placebo arm.
  • A Gilead-funded open-label RCT on 357 patients did not show improvement in clinical outcomes in patients with a longer trial of Remdesivir (5 days vs 10 days). Participants didn't require mechanical ventilation. Study found no statistically significant difference between the two groups, as measured by a 7 point ordinal scale.
  • NIH closed recruitment for ACTT-1 trial. Next trial ACTT-2 will evaluate safety and efficacy of Remdesivir +/-Baricitinib.
• Access:
  • FDA approved emergency use authorization for Remdesivir in severe disease in children and adults. No longer available through compassionate use, except for pregnant women or children. 
  • USA clinical trials: NCT04280705 (ACTT-1), NCT04401579 (ACTT-2), NCT04292730 (moderate disease), NCT04292899 (severe disease).
• Recommended Use:
  • Consider enrolling in clinical trial for moderate or severe disease
  • Under FDA's emergency use authorization, Remdesivir may be used only to treat adults, peds (>/= 3.5Kg) and pregnant woman with suspected or confirmed COVID-19 AND SpO2<94 on RA, requiring supplemental oxygen, mechanical ventilation or ECMO.
  • Do not use in renal impairment (<eGFR<30ml/min)
  • Consider limiting course to 5 days in non-mechanically ventilated patients if in short supply
• Dosing: LD 200mg IV x1d, then 100mg IV QD x4-9days
• Toxicities: Nausea, vomiting, ALT elevations, constipation, phlebitis, risk of accumulation in renal failure that can lead to renal injury (Remdesivir Fact Sheet)

Chloroquine/Hydroxychloroquine (Plaquenil):

• MOA: Prevents endosome-mediated viral entry and viral release. Also has anti-inflammatory properties but mechanism is not fully understood yet.
• Level of Evidence: Multiple combinations in clinical trials.  
  • Open label RCT of 150 patients with mild to moderate disease in China showed no benefit in clinical presentation from HCQ + SOC vs SOC alone. AE were more common in HCQ vs SOC (30% vs 9%).
  • In a double-blind RCT, HCQ used as postexposure prophylaxis showed no benefit compared to placebo. In the study, asymptomatic patients with high-risk Covid-19 exposure within the last 4 days were given hydroxychloroquine (N = 414) or placebo (N = 407). There was no significant difference between the groups in terms of developing Covid-19 (HCQ= 11.8% vs. Placebo = 14.3%); However, side-effects were significantly more common in the HCQ group (40.1% vs. 16.8%).
  • Observational study of HCQ in 1376 consecutive hospitalized patients with COVID-19 in NY showed no significant association between HCQ and the risk of intubation or death. Study findings cannot be used to rule out benefit or harm due to observational design.
  • Retrospective study of 1438 hospitalized in NY showed that patients receiving HCQ + AZI were more likely to suffer from cardiac arrest than patients receiving neither. Also, there was no in-hospital mortality benefit associated with HCQ, AZI or both.
  • RECOVERY trial preliminary data showed that there was no significant benefit on 28-day mortality in HCQ vs placebo arm, 25.7% HCQ (N=1542) vs 23.5% placebo (N=3132). Investigators decided to stop recruiting hospitalized patients for HCQ arm of the trial.
• Recommended Use:
  • FDA recommends against HCQ/CQ use except in a clinical trial 
  • FDA recommends against the use of high-dose chloroquine (600 mg, BID, for 10 days) for treating COVID-19
  • Calculate risk score for QTc prolongation.
  • Discontinue all other QT-prolonging drugs if possible. Obtain baseline EKG before first dose. Continue telemetry monitoring.
  • Do not start if QTc>500ms (or 550ms with pacing or BBB)
  • Do not use as post-exposure prophylaxis
• Access: Consider use within clinical trials only if possible.
• Dosing: 400mg PO BID x 1d, then 200mg BID (or TID) x 4-9days
• Toxicities: QTc prolongation, GI symptoms, bone marrow suppression

Lopinavir/Ritonavir (Kaletra): 

• MOA: Protease inhibitor/CYP3A4 inhibitor
• Level of evidence: Multiple trials are ongoing involving Kaletra in comparison or in combination with other treatments such as Arbidol, IFN-b (MIRACLE trial) and hydroxychloroquine.
  • Open-label Randomized trial of 127 patients showed that early Kaletra, Ribavirin +/-IFN beta treatment shortened time of viral shedding in patients with mild to moderate disease (7 days for combination  vs 12 days for Kaletra alone).
  • First RCT showed no benefit of monotherapy vs standard of care; however, there was some improvement noted in those receiving the drug early. 
  • In the USA, clinical trials include NCT04372628 (outpatient setting), and NCT04328012 (hospitalized patients).
• Access: Consult ID team at your institution for off-label use. Enroll in trials if possible.
• Recommended Use: 
  • NIH experts panel strongly recommended against the use of Kaletra or other HIV protease inhibitors, except in the setting of clinical trials.
  • NCID Singapore suggests use as first-line for high-risk, on-severe patients with <7 days of symptom onset; may be combined with interferon-Beta.
  • If used, the patient's HIV status should be known 
• Dosing: 400/100mg BID x10-14days
• Toxicities: GI intolerance, QTc prolongation, ALT elevations, Drug-Drug Interactions (ie Apixaban, Tacrolimus, Amiodarone)

Favipiravir (Avigan): 

• MOA: RNA-dependent RNA pol inhibitor: broad spectrum antiviral in vitro. 
• Level of Evidence: Multiple trials are ongoing involving Favipiravir alone or in combination with Hydroxychloroquine, Tocilizumab, Kaletra and Darunavir/ritonavir. 
  • In vitro proof of antiviral activity against influenza and multiple RNA viruses. 
  • A small non-randomized open label study with historical controls (Kaletra + IFN alpha) showed Favipiravir + IFN alpha had earlier time to viral clearance than control arm (4 days vs 11 days). 
• Access: FDA approved only for clinical trials in the USA at this time. Clinical trials in the USA: NCT04346628 (mild disease), and NCT04358549 (hospitalized patients).
• Recommended Use: Limited use in the USA at this time. No recommendations can be made at this time.
• Dosing:  Study doses are 1800mg BID x1d, then 1000mg BID x9-14days (or 800mg BID for mild disease or Child Pugh A Liver impairment)
• Toxicities: Elevated uric acid, concerns for teratogenicity and embryotoxicity

Sources: 

Beigel, John H., et al. “Remdesivir for the Treatment of Covid-19 — Preliminary Report.” Remdesivir for the Treatment of Covid-19 — Preliminary Report, 22 May 2020, doi:10.1056/NEJMoa2007764. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2007764

Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. The New England Journal of Medicine. 2020Jun3.

Cao B, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. Available from: DOI: 10.1056/NEJMoa2001282

Caridi-Scheible M. Clinical and team management in the COVID-ICU: Successful strategies from the first week. Lecture presented at; 2020; Emory Critical Care Center, Atlanta, GA

CDC. COVID-19 Treatment Guidelines. 2020April21. Available from: https://covid19treatmentguidelines.nih.gov/introduction/

COVID-19 Protocols. Brigham and Women\'s Hospital COVID-19 Clinical Guidelines. Available from: https://covidprotocols.org/

Gautret P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020Mar20. Available from https://doi.org/10.1016/j.ijantimicag.2020.105949

Goldman JD, Lye DC, Hui DS, Marks KM, Bruno R, Montejano R, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. New England Journal of Medicine. 2020.

Hernandez AV, Roman YM, Pasupuleti V, Barboza JJ, White CM. Hydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19: A Living Systematic Review. Annals of Internal Medicine. 2020 May 27.

Interactions with Experimental COVID-19 Therapies. University of Liverpool. Available from: https://liverpool-covid19.s3.eu-west-2.amazonaws.com/landing-page/Covid_InteractionSummary_Web_2020_Mar12.pdf

Magagnoli J, et al. Outcomes of Hydroxychloroquine usage in United States veterans hospitalized with Covid-19. 2020April21. Available from: https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v

Mehra, Mandeep R, et al. Hydroxychloroquine or Chloroquine with or without a Macrolide for Treatment of COVID-19: A Multinational Registry Analysis. The Lancet , 20 May 2020, doi:DOI: 10.1016/S0140-6736(20)31180-6. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext

National Institute of Allergy and Infectious Diseases. Available from: https://www.niaid.nih.gov/

NIH U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/

Sheahan TP, et al. Comparative Therapeutic Efficacy of Remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nature Communications. Available from: https://doi.org/10.1038/s41467-019-13940-6

Silva MG, et al. Effects of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. Available from: https://jamanetwork-com.proxygw.wrlc.org/journals/jamanetworkopen/fullarticle/2765499

RECOVERY (Randomised Evaluation of COVID-19 Therapy). No clinical benefit from use of HCQ in hospitalised patients with COVID-19. 2020June5. Available from: https://www.recoverytrial.net/

Use of Remdesivir in COVID-19. Available from: https://rdvcu.gilead.com/

Vasoo S. National COVID-19 Clinical Rounds: Critical Care, Lifesaving Treatment and Clinical Operations. Lecture presented at; 2020; National Centre for Infectious Disease. 

Tocilizumab (Actemra): 

• MOA: Anti IL-6 receptor monoclonal antibody, mitigates inflammatory response
• Level of Evidence:
  • Preliminary data from a prospective, single-armed study of 63 patients estimated that early tociluzumab therapy is associated with a two-fold increase of survival (HR 2.2 95% CI: 1.3-6.7, p<0.05)
  • Systematic chart review of 29 severely ill patients with COVID-19 noted significantly reduced levels of CRP compared to baseline after initiation with Tocilizumab, suggesting reduction of hyperinflammatory state
  • Case series of 20 severe and critical patients showed improvement in fever and oxygen requirements after Tocilizumab administration
  • Multiple trials of monotherapy or combination treatments underway.
• Recommended Use: Per NCID Singapore, in severe disease, especially cytokine release storm. Treatment guided by IL-6 levels.
• Access: Consult ID team at your institution for off-label use. Enroll in trials if possible.
• Dosing: 4-8mg/kg IV x1 (<800mg). If no response, dose may be repeated 12hrs later.
• Toxicities: ALT elevations, black box warning for serious infections (ie opportunistic infections, reactivation of latent TB and HBV)

Sarilumab (Kevzara): 

• MOA: Anti IL-6 receptor monoclonal antibody, mitigates inflammatory response
• Level of Evidence: Off-label, investigational use. Multiple trials of monotherapy treatments underway.  
• Recommended Use: In severe disease, especially cytokine release storm. Treatment guided by IL-6 levels.
• Access: Consult ID team at your institution for off-label use. Enroll in trials if possible. Enroll in trials if possible. USA clinical trials: NCT04315298 (hospitalized patients), and NCT04359901 (moderate disease).
• Dosing: One study use dose of 200mg SC x 1
• Toxicities: Transamitis, neutropenia, infusion reactions, URI, UTI, black box warning for serious infections (ie opportunistic infections, reactivation of latent TB and HBV)

Siltuximab:

• MOA: Anti IL-6 monoclonal antibody
• Level of evidence: Off-label, investigational use. Compassionate use in a case series of 21 patients in Italy who received Siltuximab showed that 7 improved CPAP/NIV requirements while 9 remained stable, and 5 worsened (1 death). No clinical conclusions about efficacy and safety can be made at this point. Few trials of monotherapy treatments underway. 
• Recommended Use: In severe disease only, especially cytokine release storm. Treatment guided by IL-6 levels.
• Access: Consult ID team at your institution for off-label use. No clinical trials have started in the USA yet.
• Dosing: 11mg/kg IV x1
• Toxicities: Edema, URI, pruritus, skin rash, hyperuricemia, thrombocytopenia, hypotension

Canakinumab:

• MOA: Anti IL-1 beta monoclonal antibody
• Level of evidence: Investigational use only. There is a theoretical potential utility of IL-1 blockage for cytokine storm. A reanalysis of a phase III randomized trial in severe sepsis suggested that a subset of severe sepsis patients were responsive to IL-1 blockade treatment. Few trials of monotherapy treatments underway. 
• Recommended Use: In severe disease only, especially cytokine release storm. 
• Access: Consult ID team at your institution for off-label use. Clinical trials in the USA: NCT04362813 (CK Release Syndrome), and NCT04365153 (proof of concept). 
• Dosing: 4mg/kg (max 300mg) SC x1 OR 450mg for body weight 40-60 kg, 600 mg for 60-80 kg or 750 mg for >80 kg in 250 mL of 5% dextrose infused IV over 2 hours
• Toxicities: Infections, GI intolerance, injection site reactions, cytopenia, transaminitis

Leronlimab (PRO140): 

• MOA: Anti-CCR5 IgG4 monoclonal antibody
• Level of Evidence: Two clinical trials for mild/moderate and severe disease are currently recruiting patients. No clinical trial results have been released.  
• Recommended Use: Only in severely ill patients
• Access: Consult ID team at your institution for off-label use. Enroll in trials if possible. USA clinical trials: NCT04343651 (mild/moderate disease), and NCT04347239 (severe disease) 
• Dosing: 700mg SC q1wk x 2wks
• Toxicities: Local injection reaction

Convalescent Serum: 

• MOA: Using passive antibody transfer from recovered patients is currently being explored as a treatment and prophylactic method. 
• Level of Evidence:
  • In a Chinese multicenter RCT on 103 patients, those with severe COVID-19 (i.e. ARDS, hypoxemia) experienced significant clinical benefit after a trial of convalescent plasma with standard therapy vs standard therapy alone (91.3% vs 68.2%). Patients with life-threatening COVID-19 (i.e. shock, organ failure) did not experience significant clinical benefit. The study’s primary outcome was improvement within 28 days, defined as either live discharge or decrease in 2 points of a 6 point disease severity scale.
  • No clinical trial data has been gathered yet, but results of a pilot study and a Case series study in China showed positive results.
  • Case series of 5 critically ill (COVID-19 and ARDS) patients who received convalescent plasma in addition to antiviral regimens improved clinical status post-transfusion. Given limited clinical data, no recommendation can be made at this point.
• Access: FDA authorized the use of convalescent plasma through eIND (emergency IND) and expanded access for patients with serious or life-threatening infections. 
  • Providers can request single-patient use through eIND application. Physicians should complete Form FDA 3926 and submit form to CBER_eIND_Covid-19@FDA.HHS.gov. FDA will respond within 4 hours. More info found here.
  • Expanded access for patients who are unable to participate in RCTs. This allows acute care facilities to participate in an investigational expanded access under an IND that is already in place. Mayo Clinic is leading the effort for expanded access. Workflow for physicians on how to enroll patients in Mayo Clinic expanded access can be found here.
  • Clinical trials: Physicians interested in initiating a clinical trial should submit traditional IND to FDA. The office of Blood Research and Review is reviewing requests expeditiously. More info about IND application (21 CFR 312) here.
• Recommended Use: Only for serious severely ill patients. Early administration seems to be more effective.
• Dosing: Varies. Studies have used from 200-400ml plasma infusions.
• Toxicities: Well-tolerated; however, plasma transfusion reactions (mild fever, allergic reactions, TALI) can happen

Sources:

Antwi?Amoabeng D, Kanji Z, Ford B, Beutler BD, Riddle MS, Siddiqui F. Clinical Outcomes in COVID?19 Patients Treated with Tocilizumab: An Individual Patient Data Systematic Review. Journal of Medical Virology. 2020 May 21.

Biologics Evaluation and Research. Investigational COVID-19 Convalescent Plasma-Emergency INDs. U.S. FDA. Available from: https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma

COVID-19 Protocols. Brigham and Women's Hospital COVID-19 Clinical Guidelines. Available from: https://covidprotocols.org/

Duan K, et al. The feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study. MedRxiv. Available from: https://www.medrxiv.org/content/10.1101/2020.03.16.20036145v1

Expanded Access to Convalescent Plasma for the Treatment of Patients With COVID-19. Mayo Clinic. Available from: https://www.uscovidplasma.org/

Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19. Jama. 2020 Jun 3.

NIH U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/

Sciascia S, Aprà F, Baffa A, Baldovino S, Boaro D, Boero R, Bonora S, Calcagno A, Cecchi I, Cinnirella G, Converso M. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in severe patients with COVID-19. Clin Exp Rheumatol. 2020 May 1;38:00-.

Shen C et al. Treatment of Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020. Available from: https://jamanetwork.com/journals/jama/fullarticle/2763983

Slater H. Phase II Trial of Leronlimab for COVID-19 Enrolls First Patients. Cancer Network. 2020. Available from: https://www.cancernetwork.com/news/phase-ii-trial-leronlimab-covid-19-enrolls-first-patients

Xu X, et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. ChinaXiv. Available from: https://www.ser.es/wp-content/uploads/2020/03/TCZ-and-COVID-19.pdf

COVID Clinical Trials Database

Convalescent Plasma

Tocilizumab

Remdesivir:

Bronchodilators: 

• Nebulization should be avoided especially in areas outside airborne isolation due to the risk of viral aerosolization. 
• Inhalers should be administered using MDI and spacers.

ACE Inhibitors/ARBs: 

• No clinical evidence that these agents may help or worsen COVID-19 . 
• ACE inhibitors/ARBs should not be discontinued in COVID-19 patients. 
• Only consider discontinuation if acute kidney injury, hypotension or other contraindications develop. 

NSAIDs: 

• FDA, WHO and EMA stated that NO clinical data at this point suggests increased risk in patients with COVID-19 using NSAIDs. 
• Acetaminophen is preferred for fever in COVID-19 (except normal contraindication eg poor liver function).

Sources:

EMA gives advice on the use of NSAID for COVID-19. 2020Mar18. Available from: https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19

FDA advises patients on use of non-steroidal anti-inflammatory drugs (NSAIDs) for COVID-19. 2020Mar19. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-patients-use-non-steroidal-anti-inflammatory-drugs-nsaids-covid-19

JHMI Clinical Guidance for Available Pharmacologic Therapies for COVID-19. 2020Apr7. Available from: https://www.hopkinsguides.com/hopkins/ub?cmd=repview&type=479-1130&name=5_538747_PDF

Lee N, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. 2004Dec31. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15494274

Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19 [Internet]. RECOVERY Trial. 2020 [cited 2020Jun21]. Available from: https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19

MGH COVID-19 Treatment Guidance. 2020Apr14. Available from: https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf

Stockman L, et al. SARS: systematic review of treatment effects. 2006Sep3. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16968120

Wax R, et al. Practical recommendations for critical care and anesthesiology teams caring for novel coronavirus (2019-nCoV) patients. 2020Feb7. Available from: https://link.springer.com/content/pdf/10.1007/s12630-020-01591-x.pdf

Wu C, et al. Risk Factors Associated With ARDS and Death in Patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China. 2020Mar13. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32167524

Zhenwei Y, et al. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. 2020Mar31. Available from: https://www.journalofinfection.com/article/S0163-4453(20)30191-2/pdf