Updated: 5/4/2020

Review of Therapies for COVID-19 and Consolidated Clinical Trial Results

Is COVID-19 the end of evidence-based medicine?

While practitioners have a healthy skepticism about new FDA approved entities, this reasoning has apparently been set aside in the face of this pandemic. It

appears that any potential treatment is fair game, and clinicians are willing to try almost anything.

“We cannot just do nothing for these patients.” As much as the “don’t just stand there, do something” feeling is real, it is also likely dangerous to our

patients. The prevailing evidence in critical care suggests that “doing less is more” as the more we try to interfere or disrupt the pathways of critical illness,

the worse the patient outcomes.” Todd Rice & David Janz https://www.atsjournals.org/doi/pdf/10.1513/AnnalsATS.202004-325IP

COVID-19 – A reminder to reason. Another thoughtful commentary on the tendency to rely on anecdote during a crisis, with the wish to accomplish

“something” and the tendency to “anchor”- closing the decision-making process prematurely, before exploring reasonable alternative. The authors suggest

increased clinical equipoise and skepticism, and above all, doing the basics that are known to improve outcome. Ivry Zagury-Orly and Richard M Schwartzstein.

https://www.nejm.org/doi/full/10.1056/NEJMp2009405?query=RP

Most information is adult-focused, but pediatric guidelines are now available (see #16 below).

With that caveat, the following is a compilation of items from a variety of different sources. The items have been referenced as available, but inclusion is NOT

AN ENDORSEMENT FOR USE. Clinicians need to evaluate the source literature, consider adverse effect profile and drug interaction potential, and ideally enroll

patients in a clinical trial when possible. Comments are the opinion of the author (Judith Jacobi, PharmD, MCCM, FCCP, BCCCP, Critical Care Pharmacist).

Disclaimer: Author has used multiple sources to maintain this list, but does not claim that it is complete with the constant influx of information, the reader

should evaluate other sources, as suggested

Updates are noted, as applicable.

Medication Guidance Updated 4/22/2020

1) Link to ASHP COVID-19 Medication Website and evidence table https://www.ashp.org/COVID-19 Link updated 4/21/2020

2) Review article on emerging pharmacotherapy https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.2398

3) Additional Medication Considerations (see table below)- Unusual effects and supportive therapies

4) IDSA Guidelines recommend that unproven therapies only be used in the context of a clinical trial https://www.idsociety.org/practice-guideline/covid-

19-guideline-treatment-and-management/

5) NIH Treatment Guidelines published. Does not recommend and pre-exposure prophylaxis, post-exposure prophylaxis, and states that no drug is

proven safe and effective for treatment, so insufficient data for or against any therapy. Multiprofessional panel, included several pharmacists.

https://covid19treatmentguidelines.nih.gov/ Updated 4/22/2020

6) Role of the clinical pharmacist https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/jac5.1231

a. Consider writing name and role on face shield so you can be identified easily as the pharmacist

b. Some hospitals attach their photo to the outside of gown so patients can see a “face”

Updated: 5/4/2020

7) Many papers are coming from pre-print servers such as Medrxiv.org Caution: Preprints are preliminary reports of work that have not been certified by

peer review. They should not be relied on to guide clinical practice or health-related behavior and should not be reported in news media as

established information.

8) Research Guidance: FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency.

https://www.fda.gov/media/136238/download

9) Research Inventory: searchable database at https://icite.od.nih.gov/covid19/search/

10) Research Reviews: The Publons site has a listing of COVID-19 research (almost 5000) with a listing of what has been peer reviewed, reviewer scores,

and Altmetric scores, sorted by date at https://publons.com/publon/covid-19/?sort_by=date. The listing is searchable. They are asking Publons

members to add their reviews, using their special guidelines. Epocrates has a list of trial updates

https://www.epocrates.com/e/guideline/03_19?cid=false&t=tab1&p=page2

11) The need for standard IV concentrations to be define and clearly communicated, along with consistent dosing units was emphasized by ISMP with an

error report at https://ismp.org/acute-care/special-edition-medication-safety-alert-april-16-2020/covid-19 They suggest the ASHP Standardize 4

Safety (S4S) list at https://www.ashp.org/-/media/assets/pharmacy-practice/s4s/docs/s4s-proposed-standard-concentrations-adult-continuous-

infusions.ashx

12) Extension tubing use: Updated 4/8/2020

a. Do not use for insulin- will lose a lot of drug through adsorption to plastic

b. Use microbore tubing to minimize volume – measure the volume that is actually required, depending on the number of extension sets that

are linked.

c. Use a tube (like a pool noodle sliced open) to keep the tubing off the floor or other intervention like taping to floor to reduce tripping hazard

and inadvertent disconnection.

d. Use an adhesive device (like used for foley catheter tubing) to keep tubing on a wall (see photos)

e. photo courtesy of Angela D. Crain, APN, MS, CCNS

f. Some hospitals have determined that they will not use extension tubing routinely, since 2-3 sets for each fluid is a lot and unlikely to sustain

that (supply chain)

Updated: 5/4/2020

g. Consider moving head of bed closer to the door to minimize tubing length- some have used multiple sets in series- can be as much as 26 ml-

will cause a delay in time between pump program change and effect at patient (e.g. BP change with vasopressor)

i. Phenylephrine syringe protocol for IV push administration (e.g. 50-100 mCg doses) at bedside would facilitate rapid effect.

h. ISMP has resources at https://ismp.org/covid-19-resources

i. Guidance re pumps outside room :

https://ismp.org/acute-care/special-edition-medication-safety-alert-april-3-2020/covid-19

j. ECRI tested rates of 5-300 ml/hr with 5 common pumps and found these to be acceptable rates.

k. Label tubing inside and outside the room

l. Use barcode scanner through a glass door or window to preserve this safety system

m. Use a single extension tubing in the room connected to a splitter that is outside the room (chicken foot or stopcocks) and only infuse

compatible medications

i. Central line preferred over other lines

ii. Follow central line insertion and maintenance bundles to reduce CLABSI risk

n. If a bag is empty, hang a saline IVPB and set VTBI to 30 ml to complete the flush of that medication and alert you when that has been

completed

i. Use dextrose for solutions like amiodarone or trimethoprim/sulfa due to compatibility limitation.

13) Medical calculators and drug interaction resources Updated 4/20/2020

a. MD Calc: phone app and website https://www.mdcalc.com/covid-19 Calculate HScore for hemophagocytic syndrome

i. https://mailchi.mp/mdcalc/bcrss-italys-pathway-for-covid-inpatients?e=797133dcf3 has treatment algorithm from Italy that is

associated with lab and radiology results

b. Calculate by QxMD: free site, calculate likelihood of intubation based on oxygenation and respiratory rate:

https://qxmd.com/calculate/calculator_724/rox-index-to-predict-risk-of-intubation

c. QTc prolongation risk at crediblemeds.org

d. Tisdale Risk Score for arrhythmia with prolonged QTc https://www.pharmacyjoe.com/tisdale-risk-score-calculator/

i. Suggested to be effective at identifying low risk for patients with QTc prolongation, and less effective for moderate to high risk

identification at Su K, McGLoin R, Gellatly RM. Pharmacotherapy doi.org.10.1002/phar.2400

14) Monitoring: (aggregated from multiple protocols)

a. Baseline testing: ECG, CXR, CBC with diff, LFT, CPK, Lactate, Procalcitonin, Troponin, Inflammatory biomarkers (CRP/Ferritin, LDH, D-Dimer, IL-

6,)

i. Also suggested: Respiratory viral panel, Influenza A/B, HBV serology, HCV Ab, HIV Ab/Ag

ii. Turn continuous QT monitoring on if bedside monitors have that feature and using QTc prolonging agents

b. Repeat inflammatory markers: (other labs per usual protocols)

i. Daily (D-Dimer, ferritin, CRP, ESR, LDH, troponin), CPK (esp. on propofol) (also triglyceride if on propofol- use other agent if > 1000,

add other sedatives to reduce propofol dose if value is rising > 500)

ii. If clinically indicated (worsening inflammatory syndrome): Lactate, IL-6, procalcitonin, LFT

c. Analysis of lab parameters that are potentially predictive of more severe disease published

d. Repeat: ECG (esp. if using QTc prolonging agents) every 2-3 days

Updated: 5/4/2020

e. Consider using patient’s home continuous glucose monitor (CGM) for appropriate patients able to participate in care. (see DKA discussion in

table below)

i. Verification of glucose with hospital point-of-care meter is advised prior to insulin dosing.

15) Pre-emptive therapy: There is no emergency in a pandemic- take care of yourself first- if you get sick, you might save this patient, but your family and

others will suffer later Updated 4/23/2020

a. Intubate early if not maintaining pO2 on > 6L NC- delayed intubation being discussed extensively

i. Better to do it before they crash

ii. Patients do crash when intubated- may be dehydrated (fever) or at limit of compensation

1. Consider epinephrine IV push- have it ready at intubation (diluted epi: use 1mg of 1:10,000 = 100 mCg and further dilute

with 9 ml NaCl = 10 mCg/ml, dose is 2-10 mCg over 1 minute- titrate small doses to effect. Convert to infusion if persistent.

iii. APRV as a mode for patients- keeps them awake and may help resolve significant shunting.(may not be tolerated with prior COPD or

asthma)

iv. Self-proning has been shown beneficial to improve oxygenation in in 74% of non-intubated patients with hypoxia despite oxygen

therapy (pilot study N=50) The patients who failed and required intubation, about half did so within 1 hour, the rest between 1-24hr.

Of the patients who improved with proning, 13.5% were intubated in the next 1-3 days.

https://onlinelibrary.wiley.com/doi/abs/10.1111/acem.13994

b. Sites rethinking avoidance of non-invasive ventilation, if a filter can go on exhalation valve. This may be used more for patients with hypoxia

by without significant desaturation or tachypnea.

c. Central line and arterial line

i. Likely needed for medication administration and arterial line for labs and BP and cardiac monitoring

16) Therapy Guidelines and Resources Updated 5/1/2020

a. ICU therapy review published 4/6/2020 (note some statements have been contradicted by newer data)

https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(20)30161-2.pdf

b. Emory protocols available on-line https://www.emoryhealthcare.org/covid/medical-professionals.html

i. Information for non-ICU professionals here and at other sites such as SCCM

c. SCCM COVID-19 resources https://www.sccm.org/Disaster

i. Rapid Resource Center https://www.sccm.org/COVID19RapidResources/Home

ii. Education (esp. for non critical-care personnel)

iii. Journal articles from SCCM publications and other journals

iv. COVID-19 registry

v. Discussion group

vi. Mechanical ventilation strategies

d. Alberta Health Services, Canada- excellent examples of procedures and educational signs

https://www.albertahealthservices.ca/assets/info/ppih/if-ppih-covid-19-care-adult-critically-ill.pdf

Updated: 5/4/2020

e. UpToDate has FREE protocols, procedures and resources at https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-critical-

care-issues#H4049006309 and http://healthclarity.wolterskluwer.com/coronavirus-resources.html

f. Australian Guidelines with very well displayed decision trees. Only using antivirals in the context of clinical trials. Updated 4/22/2020

https://covid19evidence.net.au/#decision-flowcharts

g. Univ of MN and Fairview Hospital have an evidence-based medicine website https://covidebm.umn.edu/

h. Pediatric therapy guidelines from a multicenter group from the Pediatric Infectious Diseases Society. See paper for terminology definitions.

Since children have less severe illness treatment, the decision to use an antiviral should be individualized, and preferably only considered for

patients with more severe illness within a clinical trial. Data on impact of co-morbidities is discussed. If an antiviral is considered, the panel

suggests remdesivir due to its biologic plausibility and few adverse effects. HCQ could be considered (without azithro) if unable to use

remdesivir. https://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa045/5823622

i. NIH Treatment Guidelines published. Does not recommend and pre-exposure prophylaxis, post-exposure prophylaxis, and states that no drug

is proven safe and effective for treatment, so insufficient data for or against any therapy and suggests that use be limited to a clinical trial.

Multiprofessional panel, included several pharmacists. Also discussed critical care and concomitant therapy.

https://covid19treatmentguidelines.nih.gov/ Updated 4/22/2020

j. ASHP and ASA Statement on Minimizing Medication Waste addresses use and reuse with proper disinfection, medication storage, and

beyond-use dating (BUD). https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/Joint-ASHP-ASA-

Statement-on-Minimizing-Medication-Waste.ashx?utm_source=SM042320&utm_medium=TW&utm_campaign=asajoint

k. Cleveland Clinic Curbside Consults cover a variety of COVID topics. https://www.ccjm.org/content/covid-19-curbside-consults

l. Evergreen Health in Washington State, has compiled their “Lessons Learned” from COVID-19. This comprehensive document covers

diagnosis through therapy and discharge. Pandemic planning, resources, supply chain, and many other topics are discussed.

https://www.evergreenhealth.com/covid-19-lessons

17) Cardiac Arrest Guidelines Updated 4/14/2020

a. AHA Interim guidance for Basic and Advanced Life Support in Adults, Children and Neonates with COVID-19 at Edelson DP, et al.

10.1161/CirculationAHA.120.047463

i. Updated algorithms provided

b. See Appendix 4

18) Care consolidation bundle (compiled by Laura Zane, PharmD and others)

a. Group medication administration times and lab schedule to limit RN entry into the room- use ‘scheduled’ sigs when possible b. Ready-to-use dosage forms whenever possible- meds cannot come back out of the room.

i. Label every syringe if someone else drew it up outside the room 1. Turn on label capability of automated dispensing cabinets if available

ii. Use standard medication safety tools (bar code scanners)- not a time to risk medication errors c. Use fluid boluses and monitor impact on CVP and stroke volume (SV) or stroke volume variation (SVV). Can also use passive leg raise

i. Do not volume overload- right heart failure is common ii. Concentrate infusions as much as possible

Updated: 5/4/2020

d. Consider compounding larger bags to avoid having to change bags as frequently- especially for medication that may require constant administration (drip rates are high, PCA for pain, etc)

e. Ensuring appropriate DVT prophylaxis (these patients may be higher risk)- use criteria for high risk patients see thrombosis section in table 1 for more discussion.

f. IV to oral conversions when possible g. Review inhaled medications. Consider change from nebulization to (MDI) inhalers for COVID (+) patients that are NOT on ventilation. If

vented or non-COVID, make attempt to use nebs preferentially to preserve MDI’s h. De-escalate broad spectrum antibiotics if procalcitonin remains low –but be vigilant for late/superinfection i. Critical care patients (Apply the above principles and recommendations listed below):

i. Recommend daily TG monitoring for propofol patients (some institutions are allowing TG up to 1000) Consider alternate sedative if >500; consider.

j. Continue to monitor for tube administration with all critical care patients- review medications that are long acting, not to be crushed, or bio/chemo hazard. Determine what can be held during hospitalization and what would need an alternative enteral or IV substitution. Review home medication list

k. CRRT: consider dosing strategies to limit administrations (q8h extended infusion zosyn vs q6h) l. If on paralytic: check for need to continue at 24h and 48h. Most cases should stop at 48h. If drip is extended past 48h, contact provider to

clarify (due to clinical data and shortages); consider intermittent dosing (cisatracurium or rocuronium) in some cases. i. Provide eye protection with ophthalmic ointment every 4 hours or eye bubble humidification devices. Update 4/9/20

m. Limit or find alternative to insulin infusion if ordered. Limiting frequent BG checks will preserve PPE and/or need to enter room. i. NPH every 8 hours is more- nimble for dose modification than a daily basal insulin ii. A low dose continuous infusion can be supplemented by bolus doses

n. Continue usual critical care safety bundles- central line bundle, VAP bundle, oral care, early mobilization i. Profound muscle weakness has been reported, even without steroid or NMBA usage

19) Sedation tips and tricks (See Appendix 3 for algorithm from Prime HC, developed by Andrew Mina) Update 5/1/2020

a. ASHP has provided a resource for drug shortages : https://www.ashp.org/-/media/assets/pharmacy-practice/resource-

centers/Coronavirus/docs/Tiered-medication-considerations-for-mechanically-ventilated-patients_ASHP-

Resource.ashx?la=en&hash=EABD527AEFAEF42F96C88A5F014A5D60B5D0EE23&utm_source=daily%20briefing&utm_medium=email

b. If you increase intubation 1 x rocuronium dose to 1.5 mg/kg be aware that NMB will outlast most sedatives and you should be prepared to re-

dose if you started with etomidate, ketamine, or fentanyl/midazolam. (worth remembering with any dose of NMBA)

c. Propofol transfer to larger bags- suggested use of specific plastic and BUD of 6 hours (see appendix)

i. New FDA guidance at https://www.fda.gov/media/137224/download suggests at 12-hour BUD for repacked propofol, that different

products not be combined, except in circumstances listed in the guidance, and specific labeling is provided. This is for the period of

the COVID emergency only. Updated 4/27/2020

d. High dose clonidine to reduce dexmedetomidine doses, as previously suggested (in patients where a lighter level of sedation is tolerated)

Terry K, et al. Sage Open Medicine DOI: 10.1177/2050312115621767, Gagnon DJ, et al. Pharmacotherapy 2015;35(3):251–259) doi:

10.1002/phar.1559,

e. Compound larger bags (keep standard concentration per pump library if burning through a lot of bags) or maximal concentration as

programmed in pumps, or PCA device with undiluted drug.

f. Don’t forget about the usual VAP prevention Bundle, including daily wake-ups when possible.

Updated: 5/4/2020

g. Ketamine may be an alternative (1-30 mcg/kg/min; consider start at 10mcg/kg/min)- patients on ketamine may not look “sedated” as it is a

dissociative agent- don’t try to put them in a coma by increasing dose (increased adverse effects with increasing dose. Updated 4/8/2020

i. Hypertension and tachycardia may be due to ketamine, think before you start an antihypertensive- may be better to reduce the

dose

ii. Optimal dosing has not been identified: Typical regimens start ~ 0.5 mg/kg/hr, titrate by 0.25 mg/kg/hr every 30-60 minutes, up to

maximum ~2.5-3 mg/kg/hr, but doses as high as 4 mg/kg/hr have been reported.

1. Agitation (?confusion/hallucination/delirium?) seems more common with higher doses (> 2 mg/kg/hr) so further dose

increase for agitation after initial response may worsen the situation

2. BIS values may increase on ketamine, so this monitoring mode is unlikely to be helpful

3. Note units, some sites use mcg/kg/min

iii. It has been suggested (but not tested) to apply a fixed dose ketamine infusion 0.1 mg/kg/hr and then titrate an opioid or other

sedative as needed to keep the patient calm and comfortable. Interesting approach that is worth considering.

h. Fentanyl patches to reduce or avoid IV infusion- absorption may increase with fever

i. High-dose fentanyl increases risk of serotonin syndrome among patients on SSRI, SNRI, but high doses may be a risk without concurrent

therapies.

i. Consider hydromorphone infusion- reported successful transition using fentanyl 100 mCg to hydromorphone 1 mg conversion.

Kovacevic MP, et al. J Pharm Pract https://journals.sagepub.com/doi/abs/10.1177/0897190018786832. Titrate hydromorphone to

desired analgesia or RAAS.

j. For significant IV shortages with analgesics/sedatives, see next items or algorithm in Appendix 3 for alternatives.

k. Phenobarbital (po, IV) to decrease sedation needs- very long acting- give a front load and back off- not great data – status epilepticus dosing

is 10-20 mg/kg IV over 10-15 minutes (max 60 mg/min) at the high end, sedation dose is a maximum of 400mg per day (usual 30-120mg per

day)

l. Remifentanil: studied Breen D, et al. Critical Care 2005, 9:R200-R210 (DOI 10.1186/cc3495) 0.1 to 0.15 mCg/kg/min and titrated to response

also Mohrien KM, et al review reported that 0.1-0.2 mCg/kg/min, titrate in increments of 0.025 mCg /kg/min every 5 min; doses up to 0.75

mCg /kg/min have been used, CCNQ 2014; 37:137-151 (it is gone as soon as you stop it, so be aware of rapid elimination. Monitor for

tolerance development) Review by Tan JA, Ho KM. Anaesthesia 2009 doi:10.1111/j.1365-2044.2009.06129.x reported doses in mCg/kg/hr

with reports of 6 -60 mCg/kg/hr (but most less than 20 mCg/kg/hr)

i. Sufentanil: 10 times more potent than fentanyl: Drug interactions and serotonin syndrome risk should be assessed.

ii. Memis D, et al. Crit Care 2003, 7:R123-R128 (DOI 10.1186/cc2365 used 1 mCg/kg IV push then ~ 20-30 mCg/hr (titrated to BIS) also

mention doses of 0.44 – 1 mCg/kg/hr, used by other authors.

iii. Another report by Costa G, et al. https://ccforum.biomedcentral.com/articles/10.1186/cc3199 used 0.003 ± 0.001 mCg/kg/min

(range 0.0009 – 0.01 mCg/kg/min) in a small number of patients.to achieve Ramsay score goal.

iv. An individual hospital protocol reported at 0.05 mCg/kg/hr titrate by 0.03 mCg/kg/hr hourly for pain score > 4, maximum 1.5

mCg/kg/hr (Natividad Medical Center, Salinas, CA)

m. Sufentanil SL tablets (Dsuvia) could be an option for selected patients, but frequency of dosing and inability to titrate would be a

disadvantage.

Updated: 5/4/2020

n. Pentobarbital infusion when all else fails- I have used dose of 10 mg/kg over 1 hour followed by 2-3 mg/kg/hr x 5 hr then maintenance doses

of 0.05 – 2 mg/kg/hr for sedation when nothing else works. Monitor for hypotension and if continued for more than 3-5 days, it will induce its

own metabolism and that of other drugs. Doses of 10-15 mg/kg followed by 0.05 – 4 mg/kg/hr have been used for super-refractory seizures.

Pugin D, et al. 2014 May 21. doi: 10.1186/cc13883. A review by Shorvon S, Ferlisi M. in Brain Brain, Volume 134, Issue 10, October 2011,

Pages 2802–2818, https://doi.org/10.1093/brain/awr215 listed a bolus of 2-3 mg/kg then 3-5 mg/kg/hr and noted reports of bolus doses 1-

19 mg/kg and infusion 0.5-20 mg/kg/hr (high serum concentrations will cause cardiac collapse, immune suppression, severe ileus).

o. Gabapentin and pregabalin have some opioid-sparing effects for peri-operative use, but effectiveness to reduce opioid infusion (sedation)

requirements are likely to be modest at best.

p. Diazepam has been used for ICU sedation with a regimen of 10mg Q 6hr or less via the enteral route with opioids and supplemented by PRN

benzo doses IV as needed. Diazepam dose/frequency adjusted to maintain sedation target. Gessin G, et al. Diazepam as a component of g0al-

directed sedation in critically ill trauma patients. J Crit Care 2011; 26:122-126.

20) Neuromuscular Blockade (Updated 4/21/2020) see appendix 2 for titration examples

a. Succinylcholine is an alternative for intubation in ED and OR. Avoid using if history of malignant hyperthermia, skeletal muscle myopathies,

following acute care of critically ill patient to reduce risk of significant hyperkalemia.

b. See SCCM Guideline https://journals.lww.com/ccmjournal/pages/articleviewer.aspx?year=2016&issue=11000&article=00016&type=Fulltext

c. Ensure adequate sedation (infusion) prior to NMBA initiation and by assessing prior to intermittent NMBA dosing.

i. For continuous NMBA, the best tool is to turn off the infusion Q 12-24 hr to assess pain, sedation, and need for ongoing paralysis

ii. While Bispectral Index and similar tools may be used, the endpoint is not well defined and impact on outcome has not been defined.

1. I propose that on a BIS monitor, a very slight response to stimulation suggests deeper sedation, and a large change (> 20??)

represent slighter sedation, but this has not been studied. This is without regard to the resting value.

d. Supply-sparing strategy is intermittent IV push doses for ventilator dyssynchrony/overbreathing/elevated plateau pressure. If frequent doses

are needed, use lowest effective infusion. If no significant effect from 1-2 doses, suggest abandoning this treatment.

e. ARDS dosing was cisatracurium at 37.5 mg/hr in clinical trials x 48hr without train of 4 monitoring (TOF) but this was convenience dosing to

eliminate the need for monitoring in a clinical trial setting.

f. Flannery suggests titrated dosing to reduce drug use in this commentary Flannery A, Moss M. Crit Care Med 2020;48:588-590.

https://journals.lww.com/ccmjournal/Citation/2020/04000/Rescue_Neuromuscular_Blockade_in_Acute_Respiratory.18.aspx

i. A nurse titrated study reported cisatracurium 14 ± 4 mg/hr targeting 0/4 TOF and others have used clinical assessment

ii. Atracurium infusion rate was reduced Q 12hr until patient movement and then increased to a slightly higher dose to maintain that

effect (ventilator synchrony)

1. Titrate the infusion off at this timepoint, if tolerated

g. Rocuronium and vecuronium will accumulate, as will pancuronium, with infusion or frequent doses in the absence of muscle movement.

i. Accumulation risk higher with renal or hepatic dysfunction

h. Pancuronium is longer-acting and may be helpful, if available.

i. Tachycardia, histamine release may occur

Educational Resources

Updated: 5/4/2020

21) Chest has prepared a brief COVID-19 summary document that may be suitable for provider and patient education at https://www.chestnet.org/-/media/chesnetorg/Guidelines-and-Resources/Documents/COVID19_Clinical_Summary_2020.ashx?la=en&hash=FF5DD6DC02F6341CB6222FFF6750399794E1C888

22) Post-ICU Syndrome Education- provide this information to patients and families as they improve. https://doi.org/10.1164/rccm.2018P15 23) Delirium-related Distress and Recovery Challenges for survivors of COVID-19 at https://redcap.uits.iu.edu/surveys/?s=F3CWY9JF33 24) Mechanical ventilation educational resources for those clinicians not usually in the ICU. https://www.atsjournals.org/doi/abs/10.34197/ats-

scholar.2020-0039IN

Updated: 5/4/2020

Additional Medication Considerations in COVID-19 Unusual Effects and Supportive Therapies

(see tips above, also) Unusual Effects

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

Ascorbic Acid and Glucose Meter Inaccuracy Updated 4/21/2020

High doses will interfere with meters using a glucose oxidase or glucose dehydrogenase methodology- false high values (Roche, Abbott, ReliOn, Bayer, others)

Send samples to lab to verify relationship between meter and lab methodology or use Nova Stat-strip

Bacterial and Fungal Infection Updated 5/4/2020

Literature review from UK on co-infection rates with SARS-1 and COVID-19. Included 18 fill-text reports. Co-infection was uncommon at hospital admission- only 8% of COVID-19 patients. The wide use of antimicrobials at admission presents an important stewardship opportunity. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa530/5828058#.Xq1QMMOm53k.twitter

Not clear if rates are low, or if literature is incomplete.

De-escalate antimicrobial therapy quickly if use don admission, esp if procalcitonin remains low.

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

Cardiac Arrest Care Guidelines Adult and Pediatrics Updated 4/10/20

See Appendix 4

General principles in COVID-19 patients published by AHA at https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.047463 Algorithms reflect updates: Reduce exposure of providers: Don PPE, limit personnel, use mechanical compression device, early intubation and ventilation with a ventilator. Use HEPA filter on ambu-bags. Consider passive ventilation. Consider appropriateness of starting and continuing resuscitation

Delirium Updated 4/29/2020

Rates of delirium have been reported to be quite high with moderate to deep sedation regimens. Anecdotal reports of successfully maintaining patients on light sedation despite proning or other treatments are appearing. Suggest only adding moderate to deep sedation if the patient demonstrates the need for this therapy (ventilator asynchrony, tachypnea, breath stacking) Delirium review within the context of COVID illustrates risk factors and measures to reduce delirium, including the well-established ABCDE bundle. The pathophysiology of delirium in this setting is also reviewed. https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-02882-x

There are no proven treatments to prevent or treat delirium.

DKA.HHS Hyperglycemia in DM1 and DM2 patients along with insulin resistance

SGLT-2 Inhibitors can cause euglycemic DKA- be suspicious if metabolic acidosis is worse than

ADA suggests checking ketones if glucose

Pancreatic inflammation (SARS-CoV binding to ACE2 receptors in pancreas) may explain the significant hyperglycemia in DM2 patients (prior to addition of steroids), This was observed in SARS-1, also. Hypertriglyceridemia is also part of metabolic dysregulation and inflammation. https://www.nature.com/articles/s41574-020-0353-9.pdf?origin=ppub

Insulin infusion until anion gap has closed High doses have been reported

Some sites check glucose Q 3hr on insulin infusion, although more often is safer. Set glucose target to 140-180 mg/dL. As inflammation abates, anticipate a significant

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

Update 4/27/2020

lactate suggests. Stop these agents. Do not restrict fluid in the setting of DKA

> 240 mg/dL

Suggest treating according to established DKA protocols and then ensuring continued use of basal insulin. FDA has provided guidance for use of home continuous glucose monitors like Dexcom G6 and Abbott FreeStyle Libre for non-critical patients. Verify glucose with hospital meter prior to insulin dosing. Use home CGM primarily as an alert mechanism, not for insulin dosing. Should have a mechanism to document the trigger for insulin doses in the EMR. https://www.fda.gov/medical-devices/blood-glucose-monitoring-devices/faqs-home-use-blood-glucose-meters-utilized-within-hospitals-during-covid-19-pandemic An ADA webinar suggested patients bring their own glucose monitors and monitoring supplies to the hospital and that they be allowed to self-monitor . UK Guidance document (multiply glucose in IU x ~18 for conversion to mg/dL) https://www.diabetes.org.uk/resources-s3/public/2020-04/COvID_Front_Door_v1.0.pdf ADA Webinar discussed CGM use, link with obesity, challenges when converting degludec to glargine (half-life 25 vs 12 hr, respectively), matching CST doses and insulin, glucose targets, etc. https://professional.diabetes.org/content-page/american-diabetes-association-town-hall-covid-19-inpatient-care-people-diabetes An international consensus on DM in COVID suggests liberal use of IV insulin in severely ill patients to avoid variable absorption from SQ and goal glucose 72-180 mg/dL (higher min. if frail) with time in range > 70%. Also continue DPP-4 agents and home insulin continued, other oral agents stopped.

Continued basal insulin with a lower dose of infusion has been used. Most oral agents should be stopped until the patient is stable

reduction in insulin requirements. SGLT-2 inhibitors will cause persistent glucosuria for days, provide glucose infusion to avoid hypoglycemia if not being fed.

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

https://www.thelancet.com/action/showPdf?pii=S2213-8587%2820%2930152-2

HELLP Syndrome or preeclampsia Updated 4/17/2020

Montefiore Medical Center explained OB protocol – they now test all women admitted to OB unit and have found many COVID + patients and concerned that COVID symptoms may overlap with HELLP Syndrome (platelet count would be essential) or preeclampsia

Discussed on the CMS call 4/17/2020

Hemophagocytic Lymphohistiocytosis (sHLH) or Cytokine Storm Updated 4/27/2020

Fever, cytopenia, ferritin, TG, fibrinogen, AST, organomegaly

HScore suggested to predict secondary HLH see MDCalc app or website https://www.mdcalc.com/covid-19 Support for the HScore in a letter https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2930628-0 Assumption that COVID-19 is associated with sHLH has been questioned and may miss other important causes https://www.medpagetoday.com/infectiousdisease/covid19/86021?xid=nl_mpt_blog2020-04-20&eun=g359746d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=ItsAcademic_042020&utm_term=NL_Gen_Int_Its_Academic_Active A review of HLH treatments (Non COVID) and discussion of the disease is available at https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-02878-7

Consider using the HScore as criteria for IL-6 inhibitor therapy

Interleukin-6 Dysregulation Updated 4/28/2020

Role of this mediator reviewed in a Non-peer reviewed pre-print paper with comments on potential role for tocilizumab. IL-6 levels 3-fold higher in patients with complicated disease and higher risk of death. https://www.medrxiv.org/content/10.1101/2020.03.30.20048058v1.full.pdf Trigger suggested as 5 x ULN of IL-6 level with persistent fever/hypotension or HScore, although some sites are not relying on IL-6 value but are using clinical criteria

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

Sepsis researchers presented a different interpretation of the pathophysiology of COVID and states it reflects immunosuppression and vascular disease and is not consistent with ARDS or cytokine-release syndromes. https://www.readcube.com/articles/10.1007/s00134-020-06059-6

MDI Use for multiple patients Albuterol Updated 4/10/2020

See ISMP article and protocol from Spectrum HC in MI. Need strict disinfection protocol and patient-specific spacer. https://ismp.org/resources/revisiting-need-mdi-common-canister-protocols-during-covid-19-pandemic

Prolonged QTc With Chloroquine Updated 4/27/2020

Chloroquine (CQ) and Azithromycin And high-doe chloroquine

New report from Brazil compared 2 doses CQ- all already on Azithromycin 500mg/day x 5 plus ceftriaxone Pts > 75 yoa all in high dose group Goal N=440, stopped at 81 for adverse effects AE: 25% QTc . 550 msec, rhabdo, Ventricular tachycardia and death No apparent benefit in mortality (at day 6) vs. local “historical” controls- described as similar patients file:///C:/Users/jjmow/Downloads/borba_2020_oi_200372.pdf Suggestions to minimize arrhythmia risk are • ECG/QT interval monitoring- stop if QTc > 500 msec

• Withhold agents with baseline QTc ≥ 500 msec, or known congenital long QT syndrome

• Correct K to > 4 mEq/L and Mg to > 2 mg/dL

• Avoid other QTc prolonging agents

https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.120.047521 Review https://doi.org/10.1002/phar.2387

High 600mg Chloroquine base BID x 10 days (goal) Low 450mg x 2 then 450mg daily x 4 for total 2.7gm base.

Do not use high dose chloroquine with azithromycin The Chinese guideline used chloroquine phosphate 500mg BID x 10 days for total 10gm of the salt- = 6gm of chloroquine base. The Brazil high dose was 2 x the Chinese regimen using 600mg BASE BID x 10 days for total 12gm. https://pubmed.ncbi.nlm.nih.gov/32164085/ Program bedside monitors to display QTc QTc prolongation risk summarized at crediblemeds.org

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

Reduce dose in renal insuff Clcr < 10ml/min

Prolonged QTc with Hydroxychloroquine (HCQ) Updated 5/4/2020

HCQ with azithromycin

Non-peer reviewed preprint: Systemic Review of risk for QTc prolongation for HCQ alone and in combination with other agents in rheumatoid arthritis patients (not COVID). No comment on efficacy. Cardiac AE greatest in women, median age 56y, primarily conduction delay. Azithro addition to HCQ increased 30-day mortality risk HR= 2.19 [1.22-3.94] vs HCQ with sulfasalazine, HR also increased for chest pain and heart failure. https://www.medrxiv.org/content/10.1101/2020.04.08.20054551v1.full.pdf A pharmacist has reviewed kinetics and considerations for HCQ plus azith effectiveness and safety. https://www.mediterranee-infection.com/wp-content/uploads/2020/04/azithroquine_manuscript-soumis.pdf See chloroquine section above for arrhythmia risk reduction strategies. Mercuro studied 90 hospitalized pts on HCQ ± Azithro. Obesity, DM, hypertension common comorbidities. Azithro contributed more to QTc prolongation (23 msec [IQR 10-40 msec]) vs. HCQ alone (5.5 [-15.5-34.5 msec]). With HCQ 19% with QTc > 500 msec, 3% change of >60 msec. HCQ + Azith 21% with QTc > 500 msec and 13% change of >60 msec. Prolonged QTc mor elikely with concurrent loop diuretics (adj OR 3.38, 95% CI 1.03-11) or baseline QTC > 450 msec OR 7.11. 10 patients stopped for HCQ adverse events. https://jamanetwork.com/journals/jamacardiology/fullarticle/2765631

Not a COVID population QTc prolongation risk summarized at crediblemeds.org Increased risk QTc prolongation with loop diuretics

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

Prolonged QTc with Hydroxychloroquine (HCQ)

Another report of QTc prolongation and 1 TdP with HCQ and Azithro. N=251 with ECG tracing review. 16% with QTC > 500 msec, N=7 with early termination of therapy. https://www.medrxiv.org/content/10.1101/2020.04.27.20074583v1.full.pdf

HCQ 400mg BID x 2 doses then 200mg BID x 4 days + Azith 500mg/day x 5 days

Renal Replacement Therapy – CRRT alternatives Updated 4/20/2020

SLED PI RRT And Drug Dosing

Sites considering prolonged HD (8hr) or intermittent CRRT (12hr at 45 ml/kg/hr) https://www.nxstage.com/hcp/therapies/pirrt/ https://viewer.mediafly.com/nx0428_share#/document/641640cd243b4466b8f37efdcd389664product304309?page=7&parentSlug=641640cd243b4466b8f37efdcd389664product211428 Hoff Ann Pharmacotherapy 2020 ;54. update antibiotic dosing IHD, P-IRRT, CRRT https://journals.sagepub.com/doi/abs/10.1177/1060028019865873?journalCode=aopd Pistolesi V et al. AAC 2019 Aug;63(8). https://aac.asm.org/content/aac/early/2019/05/15/AAC.00583-19.full.pdf Sethi Antibiotic dosing in SLED https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088477/ Brown Drug Dosing in SLED review 2020 file:///C:/Users/jjmow/Downloads/pharmacy-08-00033-v2.pdf See UptoDate for review by Bruce Mueller Gharibian KN et al. Clin Neph 2016 Jul;86(7):43-50. Lewis SJ et al. J Clin Pharmacol 2016 Feb 26. doi: 10.1002/jcph.727. Lewis SJ et al. Renal Replacement Therapy 2016 2:45.

See also references such as LexiComp

Stroke See also Thrombosis

Report of 5 patients < 50yoa with stroke also dx. With COVID. Rate unusual compared with historical rates. https://www.nejm.org/doi/full/10.1056/NEJMc2009787?query=featured_home

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

Updated 4/29/2020

Emergency guidance on stroke therapy were issued by AHA/ASA and encourages adherence to standard stroke treatment guidelines where possible. Telestroke consults can facilitate assessment and appropriate transfer. https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.120.030023

Thrombosis See also Stroke Updated 5/1/2020

Anticoagulation

May be higher risk if D-dimer > 2000 > 3x ULN

VTE prophylaxis for high risk population- use once daily regimen when possible to minimize room entry and PPE use. Oral DOAC use has been suggested for VTE treatment to decrease frequency of PPE use. ISTH Guidance suggests all patients get LMWH for VTE ppx. (unless active bleed or platelet < 25,000). Baseline PT, D-dimer, serum fibrinogen, & platelet count Updated 4/9/20 https://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14810 Duke suggests systemic anticoagulation with D-dimer > 1500 ng/ml (> 3 x upper limit of normal) and fibrinogen > 800 mg/ml. Suggest heparin infusion for anti-inflammatory effect. But need to assess for elevated baseline PTT (antiphospholipid cases NEJM) and antithrombin III deficiency if unresponsive. Am Soc Hematology Q&A: microvascular thrombosis and DIC: Monitor for DIC, and worsened parameters may suggest need for more aggressive care. Avoid blood products unless bleeding (see site for treatment) Do not suggest therapeutic anticoagulation unless VTE is documented. https://www.hematology.org/covid-19/covid-19-and-coagulopathy https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation

LMWH for prophylaxis Therapeutic anticoagulation not indicated unless VTE is documented. Do not transfuse in DIC unless actively bleeding

Purpura fulminans reported in China, high rate of catheter and CVVH thrombosis, VTE/PE everywhere. Score degree of DIC using ISTH (see MdCalc) or SIC score http://dx.doi.org/10.1136/bmjopen-2017-017046 Consider anti-Xa monitoring of LMWH if used with diminished renal function or apparent treatment failure. Maintain a high index of suspicion to thrombosis and image promptly.

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

A Chinese report showed association between anticoagulation (mostly VTE prophylaxis doses) use and lower mortality in patients with severe sepsis-induced coagulopathy, but is a selected population, so bias highly likely. No mortality benefit overall. https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14817 4/10/20 Report from the Netherlands at Noted that they are now using higher doses of LMWH for VTE prevention because of 31% cumulative incidence of thrombosis apparently after censoring population for discharge and death- proper handing is likely to reduce this % to less than 20%). However, inadequate data provided to establish actual numbers. Confirmed VTE in 27%, arterial thrombosis= ischemic stroke 3.7%. PE listed N=25 of 31 with confirmed thrombotic complications. Reported N=25 with PE as 81% of those with confirmed thrombosis (? N= 50, but value not reported) No D-Dimer values reported. No routine VTE screening. Final paper posted by publisher https://www.thrombosisresearch.com/article/S0049-3848(20)30120-1/pdf International consensus report and literature review suggestions (see paper for complete listing):

• Moderate or severe COVID without DIC: risk stratify for VTE prophylaxis (ppx), give appropriate anticoagulant(AC) for ppx, no routine VTE screening despite D—dimer elevation.

• Mod/sev with DIC: ppx AC, but no therapeutic AC or intermediate AC=(enoxaparin 1mg/kg/day, 40mg BID, or UFH with PTT 50-57 sec), Chronic AC – weight risk to benefit, consider less intense dosing, continue DAPT if platelet > 50,000, consider single agent if < 25,000. At discharge, consider AC ppx for 45 days, with ambulation/activity.

• See paper for comments with other diseases ACS, other thrombosis

• See paper for decision trees regarding VTE ppx and warfarin management

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

See Appendix 5 for a summary of potential drug interactions between COVID therapies and antiplatelet agents. Journal pre-proof paper now published https://www.sciencedirect.com/science/article/pii/S0735109720350087 Cleveland Clinic Protocol suggests 3 categories of patients with D-dimer > 3,000 ng/ml as marker for high intensity prophylaxis (enoxaparin 40mg Q 12hr, higher doses in obese) unless CLcr <10), and confirmed VTE as trigger for therapeutic heparin. All others get standard VTE ppx. https://www.ccjm.org/content/covid-19-curbside-consults#Mucha_Coagulopathy A case series from Italy reports thrombosis complications and suggests more liberal use of vein screening for VTE. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175449/ A French report on PE incidence suggested D-dimer >2660 mCg/ml was 100% sensitive for PE and 67% specific based on 106 patients with CTA and 30% with PE. Treatment is not discussed. https://pubs.rsna.org/doi/pdf/10.1148/radiol.2020201561 Cleveland Clinic Dosing Guidelines suggest higher doses for prophylaxis in obese with acceptable renal function. https://www.ccjm.org/content/covid-19-curbside-consults Anticoagulation Forum resources https://acforum-excellence.org/Resource-Center/index.php#resultsplacemain French report of VTE events N=150 prospective series in ICU for ARDS, Imaging done for suspicion of thrombotic event. 42.7% relevant VTE events: PE 25% of those imaged for respiratory decline or rising D-dimer, median 5.5 days

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

See Appendix 7

after ICU admit. 4 of 15 having head CT/MRI with stroke (bleed and ischemic), CRRT occlusion in 97% of those on that therapy (heparin or citrate used). ECMO N=12 and 3 centrifugal pump occlusions. Arterial events (limb, mesenteric N=6). Lupus anticoagulant positive in 88%- other lab patterns reported, but no specifics on anticoagulant ppx or therapy used. https://www.esicm.org/wp-content/uploads/2020/04/863_author_proof.pdf ISTH Webinar recorded 4/27/20 https://academy.isth.org/isth/2020/covid-19/293464/doctor.jerrold.h.levy.and.doctor.nicole.p.juffermans.html?f=menu%3D8%2Ac_id%3D293464%2Afeatured%3D16772 PERT Webinar recorded 4/6/20 https://pertconsortium.org/webinar/webinar-covid-10-and-pulmonary-embolism-perspectives-from-china-and-the-united-states/ A proposed algorithm for anticoagulation in COVID-19 patients suggests treatment based on risk of thromboembolism and by location ICU vs non-ICU. Low risk pts ppx. is stratified by D-dimer levels. This is a corrected proof https://academic.oup.com/ehjcvp/advance-article/doi/10.1093/ehjcvp/pvaa036/5827239#.XqsYG5sAFxp.twitter

Thrombolysis Updated 4/27/2020

Alteplase As salvage therapy severe ARDS (P/F < 50 & pCO2 > 60 despite

Proposed Alteplase for extreme ARDS suggested in extreme situation where ECMO is not an option. No data on patient use. Must weigh bleeding risk. (Moore HB, et al. J Trauma Acute Care Surg DOI: 10.1097/TA. 0000000000002694https://journals.lww.com/jtrauma/pag

Alteplase: proposed 25mg over 2 hours then 0.04 mg/hr (do not

Updated: 5/4/2020

Effect Drug(s) Associated data

Trials or Clinical Experience Dosage Comments

prone/max ventilation

es/articleviewer.aspx?year=9000&issue=00000&article=97967&type=Citation 4/10/20: 3 cases who received alteplase reported by Wang J, et al. 25mg x 1 over 2 hr then 25 mg over 22 hr followed by heparin infusion produced transient improvement in oxygenation. 1 died, no mention of outcome in the other 2 patients. https://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14828 A trial is designed to give 10mg IV push then 40mg over 2 hours followed by heparin infusion. Part 2 of the trial would give a higher dose if the 50mg regimen is tolerated. https://clinicaltrials.gov/ct2/show/NCT04357730?term=tpa&cond=COVID-19&draw=2&rank=1

exceed 0.9 mg/kg total)

Ventilator Associated Pneumonia (VAP) Updated 4/28/2020

Nurses who are not used to caring for ventilated patients may not be following the bundle VAP prevention strategies (oral care, frequent suctioning) – higher VAP rates seen anecdotally

Updated: 5/4/2020

Therapies not in ASHP Table (when first written 4/10/2020), see also epocrates resources for clinical trial updates Updated 5/4/2020

https://www.epocrates.com/e/guideline/03_19?cid=false&t=tab1&p=page2

A review of 10 medications that may have activity against SARS-CoV-2 and the mechanisms involved has been published in Nature. It is very comprehensive in

describing down viral metabolic mechanisms. However, theory does not translate into therapy readily, as the timeline of viral infection may be important to

consider relative to achievable drug therapy, along with potential toxicity of the agent at needed doses. For example, while tacrolimus and mycophenolic acid

are listed, the outcome of COVID-19 in transplant patients has not been encouraging- not clear if that is related to co-morbidities or a difference between

acute and chronic use. Clinical trials with some of the agents may be proposed, ongoing or mostly abandoned (chloroquine).

https://www.nature.com/articles/s41586-020-2286-9_reference.pdf

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

Acetazolamide, Nifedipine and Phosphodiesterase Inhibitors-5 Updated 4/14/2020

Similarity of some CVOID patients to high-altitude pulmonary edema

Idea suggested, but no data provided. No clinical trials reported in clinicaltrials.gov Pulmonary vasodilation could worsen intrapulmonary shunting. Acetazolamide could worsen metabolic acidosis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096066/#!po=50.0000

Alteplase Inhaled Updated 4/27/2020 See thrombosis section above for systemic tx

Reduce clotting in the airways and alveolar small vessels

Reports of patients with hemorrhagic secretions and possible bits of lung tissue via ETT make this a dubious therapy but is apparently being researched. A clinical compassionate use trial is enrolling patients and is now listed on ClinicalTrials.gov. rt-PA 10mg in 5ml diluent via mech vent or NIVV every 6 hours x 66 hr vs. standard care https://clinicaltrials.gov/ct2/show/NCT04356833?term=tpa&cond=COVID-19&draw=2&rank=2 https://www.bidmc.org/about-bidmc/news/2020/04/covid-19-anti-clotting-medication l

Not recommended

Angiotensin II Updated 4/27/2020

Treat hypotension

La Jolla has made Drug available in Europe and the UK for clinical use in refractory vasodilatory shock. Not clear if it has any effect on ACE2 levels in humans (Angiotensin II is proinflammatory but may increase ACE2 levels and reduce viral uptake) Theoretical role in prevention and treatment is discussed in this editorial- suggests exogenous Ang-2 as competitor for COVID binding. https://ccforum.biomedcentral.com/track/pdf/10.1186/s13054-020-02862-1 A single case report of a patient who took lisinopril at home was exquisitely sensitive to ANG-2 during COVID-19 treatment led to speculation that it had a role earlier than the 3rd vasopressor. There have been prior reports of patients with Ang-2 sensitivity, especially with ARDS, so likely

Maximize VTE prophylaxis

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

premature to speculate on a specific role in COVID therapy. https://journal.chestnet.org/article/S0012-3692(20)30747-9/pdf Ham Sensitivity to angiotensin II… Ann Intensive Care doi.org/10.1186/s13613-019-0536-5

Anticoagulation

See thrombosis section in table above

Baricitinbib +/- ritonavir Updated 4/14/2020

In vitro inhibition of viral uptake

Proposed mechanism: https://www.thelancet.com/article/S1473-3099(20)30132-8/fulltext Stebbing J, et al. Lancet Inf Dis 2020;20:400-402 Open-label clinical trial https://www.clinicaltrials.gov/ct2/show/NCT04320277 Adaptive trial of baricitinib 2mg x 1 for COVID treatment to assess safety. Open label, single arm, compared with similar patients. Is underway https://clinicaltrials.gov/ct2/show/NCT04340232?term=covid&cond=baricitinib&draw=2&rank=2

B: 4mg/day oral with Ritonavir 600mg BID x 2 weeks

BCG Updated 4/27/2020

There is no evidence that BCG protects against COVID. But 6 trials evaluating BCG vaccine listed in ClinicalTrials.gov. Most are placebo controlled and being used to study COVID prevention in healthcare workers. 1 is looking at Tb testing in all COVID patients to evaluate if a positive test is associated with a difference in outcome.

Chloroquine See QTc prolongation discussion in table above

Colchicine Updated 4/27/2020

Anti-inflammatory

Colchicine is being studied vs. usual care in 8 trials listed in ClinicalTrials.gov. A pilot at Maimonides is testing moderately ill patients on O2 with an endpoint of % that escalate to need more than 8 L/min using a high dose vs. SOC.( 1.2mg x 1 then 0.6 mg BID x 14 days) A multicenter trial (COLCORONA) of non-hospitalized COVID patients is testing 0.5mg BID x 3 days then daily x 27 days with an endpoint of death or hospitalization.

Wide range of doses

COVID-related GI side effects likely to limit the population

Corticosteroids (CTS) Initiation and prolonged therapy Updated 5/1/2020

Anti-inflammatory

While routine steroid use is not recommended for viral pneumonia by WHO, there has been benefit demonstrated in ARDS- SUGGESTED for use in severe ARDS P/F < 200 within 14 days of onset. Methylprednisolone 1 mg/kg/day (up to day 7) or 2 mg/kg/day (late after day 6 on onset) followed by weaning over 13 days. https://journals.lww.com/ccmjournal/Fulltext/2017/12000/Guidelines_for_the_Diagnosis_and_Management_of.16.aspx Dexamethasone 20mg daily x 5 days,+ 10 mg daily x 5 days (stopped earlier if extubated) for patients with ARDS and persistent P/F < 200 x 24hr had more ventilator-free days and lower mortality than control group. Study was stopped early for slow enrollment, but most common reason to not enroll was MD bias that the patient needed steroids- so patients enrolled who were

See Appendix 6

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

not expected to benefit. https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(19)30417-5.pdf A review for SCCM has challenged the WHO recommendation against CTS and states “there is no

justification to categorically deny the use of CST in severe life-threatening cytokine storm: assoc. with COVID-19 in

hospitals not involved in a RCT.” Large studies in H1N1 and SARS-1 lend support for their use. Theoretical mechanisms discussed. Common drug/regimens listed. See Appendix 6. https://journals.lww.com/ccejournal/pages/articleviewer.aspx?year=2020&issue=04000&article=00018&type=Fulltext NIH Guideline insufficient data for or against use for ARDS https://covid19treatmentguidelines.nih.gov/ Retrospective cohort N=115 consecutive pts with COVID-19 and hospitalized who were treated with CTS based on MD discretion (N= 73)- given to 52% noncritical and 76% critical pts. Treated pts were sicker, more comorbidity, worse labs and had more adverse outcomes, however multivariate analysis did not show a significant difference in either ICU admission or mortality. Authors concluded no demonstrated benefit of CTS, but likely too small to find anything that contributes to our knowledge. Pre-print, not peer reviewed. https://www.medrxiv.org/content/10.1101/2020.04.21.20066258v1.full.pdf

Cytokine Adsorption Extracorporeal Updated 4/27/2020

Reduce cytokine storm

Marker Therapeutic D2000 Adsorption Cartridge has Emergency Use Authorization (EUA) with apheresis https://www.terumobct.com/Pages/News/Press%20Releases/Terumo-BCT-and-Marker-Therapeutics-received-the-first-device-FDA-Emergency-Use-Authorization-(EUA)-to-treat-acute-respirato.aspx General information at https://dpheiosaq45d3.cloudfront.net/wp-content/uploads/2020/04/ards-whitepaper.pdf https://www.markerhealth.com/ Fact sheet for providers https://www.fda.gov/media/136836/download Fact sheet for patients: https://www.fda.gov/media/136835/download CytoSorb also has EUA for COVID with extracorporeal circulation (CRRT). Manufacturer site has detailed info on potential use, a webinar, and other resources. https://cytosorb-therapy.com/en/covid-19/ CytoSorb studied in sepsis and associated with lower mortality https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2588-1 However, Cytosorb also was not beneficial in another trial of sepsis with respiratory failure despite removing IL-6.

Removes drugs from circulation

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

A clinical trial is registered for the Toraymyxin cartridge for hemoperfusion at https://clinicaltrials.gov/ct2/show/NCT04352985?term=toraymyxin&cond=COVID-19&draw=2&rank=1 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187015 Drug removal beneficial in overdose but may be detrimental in COVID patients as it removes hydrophobic agents. No data with remdesivir, possible removal of HCQ/azith https://www.fda.gov/media/136866/download A review on use of this technology reported removal of vancomycin, aminoglycosides, digoxin, theophylline, phenobarbital, phenytoin, carbamazepine, valproic acid, tacrolimus, cyclosporine. https://www.karger.com/Article/FullText/500013 See also https://cytosorb-therapy.com/wp-content/uploads/2018/02/2017_Koertge_Poster_ESAO.pdf Use has been reported without CRRT doi.org/10.1016/j.jcrc.2018.11.003

ECMO Updated 4/28/2020

Improve oxygenation

ECMO has been very difficult in COVID due to the thrombotic state and multiple organ failure. ELSO has a variety of resources and presentations on their blog at https://elso.blog/2020/04/22/ecmo-in-covid-19-what-have-we-learned-so-far/ Experience from U of Pittsburgh reported from first 10 patients, protocols not discussed https://onlinelibrary.wiley.com/doi/epdf/10.1111/jocs.14583

Emapalumab Updated 4/14/2020

Anti interferon-ɣ Ab

Part of 3 arm study vs. anakinra 400mg/day x 15 days vs standard care. Trial described. https://clinicaltrials.gov/ct2/show/NCT04324021?term=covid&cond=emapalumab&draw=2&rank=1

6 mg/kg Q 3 days x 5

Epoprostenol (epo) (inhaled) or iNOS for ARDS Updated 4/23/2020

Reduce pulmonary hypertension and improve oxygenation

Inhaled vasodilators affect vessels associated with well-ventilated alveoli. They may improve oxygenation, but not shown to improve outcome in ARDS. At Mass General Hospital, they prefer inhaled nitric oxide (iNO) is a rapid-acting vasodilator , may increase risk of AKI, may cause methemoglobinemia. See their website of more rationale https://advances.massgeneral.org/research-and-innovation/article.aspx?id=1152 Use of inhaled epoprostenol was listed as having been used in a small COVID case series. No mention on outcome. file:///C:/Users/jjmow/Downloads/jama_arentz_2020_ld_200020%20(2).pdf A protocol should be in place for patient and ventilator management, & weaning. Veletri has been used as well as Flolan. https://www.universityhealthsystem.com/~/media/files/clinical-pathways/inhaled-epoprostenol-guideline-1114.pdf?la=en

See ASHP Table

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

https://www.utmb.edu/policies_and_procedures/Non-IHOP/Respiratory/Respiratory_Care_Services/07.03.60%20Inhaled%20Epoprostenol.pdf Systematic review of inhaled prostaglandins for ARDS (non-COVID) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451707/pdf/chest_147_6_1510.pdf A retrospective report in ARDS (non COVID) suggested comparable effect on oxygenation and ventilation when comparing fixed-dose epo inhaled vs. iNO. https://journals.sagepub.com/doi/10.1177/0885066620906800 NIH Guideline recommends a trial of inhaled pulmonary vasodilator as a rescue therapy, but if no rapid improvement in oxygenation, it should be tapered off. https://www.covid19treatmentguidelines.nih.gov/critical-care/oxygenation-and-ventilation/ Numerous companies now supply devices for iNO administration, and many are part of clinical trials for COVID patients NIH Guidelines recommend against the routine use of inhaled NO

Famotidine Updated 5/1/2020

Theoretically binds to a coronavirus enzyme called papainlike protease which is used for replication Use instead of PPI or no heartburn med associated with better outcome in China (unpublished)

Reportedly studying 120mg IVPB in 100ml over 1 hr Q 8hr (per CBS tv coverage) for COVID therapy. This trial does not appear in ClinicalTrials.gov, so cannot verify the dose. Reportedly doing a placebo-controlled RCT. https://www.sciencemag.org/news/2020/04/new-york-clinical-trial-quietly-tests-heartburn-remedy-against-coronavirus# As of 5/1 it is now in clinicalTrials.gove and is an active intervention in a 3-arm trial. Comparing HCQ + famotidine to HCQ +placebo vs. historical control not treated with HCQ or famotidine. Target N=1170, primary outcome is mortality. Pts excluded if Clcr < 50 ml/min or other criteria specific to HCQ. Including adults with pulm infiltrates, or hypoxia, or on mechanical vent. And radiographic confirmed COVID and randomized within 24hr of hospital admission. A positive SARS-CoV-2 test is not required. https://clinicaltrials.gov/ct2/show/NCT04370262?term=famotidine&cond=COVID&draw=2&rank=1

Cannot validate dose being studied

High dose increases risk of neurologic adverse effects.

Heparin via nebulization Updated 5//4/2020

Eliminate fibrin-mediated acute lung injury and

Study protocol in pre-print, not peer reviewed. Proposing to study in Australia nebulized heparin using an Aerogen vibrating mesh membrane system 25,000 unit/5ml Q 6h x 10 days while on mechanical ventilation. Criteria for adults, within 48hr of intubation, P/F < 300 , outcome is time to separation from mechanical ventilation to day 28, as well as safety and measures of clinical improvement. NO DATA- is a proposed trial only.

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

inhibit SARS-CoV-2 virus

https://www.medrxiv.org/content/10.1101/2020.04.28.20082552v1.full.pdf

HIV Protease Inhibitors

See ASHP COVID resources

Hydroxychloroquine (HCQ) ± Azithromycin (Azith) Hydroxychloroquine (HCQ) See ASHP for more information See QTc prolongation in adverse event table, above Updated 5/4/2020

In vitro appears to reduce viral load

AE: hypoglycemia, even in absence of other hypoglycemic medications, seizures, rash. Monitor CBC, LFT’s, QTc Chen, doi.org/10.1101/2020.03.22.20040758 pre-publication study of 62 pts with mild illness (P/F > 300) in China N=31 on HCQ 400mg/day vs. standard care (lots of other stuff), 1-day faster fever reduction and pneumonia was reported as better on day 5, but blinding not discussed. High likelihood of bias. https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3.full.pdf Chen, pilot study of HCQ N=30, RCT vs. standard care. HCG 400mg/day, endpoint at day 7 = viral clearance- no difference between groups in that or fever resolution. DOI: 10.3785/j.issn.1008-9292.2020.03.03 Molina Pre-print report: N=11 patients with fever/on nasal oxygen treated with HCQ 600 mg/day x 10 days and azithromycin 500mg/day x 5 days. No benefit- 1 died, 2 to ICU, 1 prolonged QTc, no evidence viral clearance at day 5-6. https://www.sciencedirect.com/science/article/pii/S0399077X20300858?via%3Dihub Tang Randomized, open-label trial of HCQ 1200mg daily x 3 then 800mg daily x 2-3 weeks (high dose) compared with standard care, total N=150 with mild/moderate disease (fever/cough, LDH ~ 200 U/L, CRP ~ 10 mg/L)), treated late (day 16-17 after disease onset) showed no difference in viral clearance by 28 days, no difference in rate of improvement, higher rate of any adverse event (30% vs 9%, p=0.001) mostly diarrhea and non-serious events. Not blinded, no placebo control, stopped early, pre-publication, not peer reviewed. Reported post-hoc benefit when adjusting for other antivirals. https://www.medrxiv.org/content/10.1101/2020.04.10.20060558v1 Mahevas French retrospective report of 181 patients with pneumonia on at least 2L/min oxygen. N=84 received HCQ 600mg/day and 97 did not. Reported comparable severity of illness (CRP > 40 mg/L in 86%). No difference in DAY 7 outcomes: rate of ICU transfer, mortality, or ARDS development. May be inadequate duration of follow-up. 9.5% of HCQ patients had treatment stopped for ECG changes. A pre-print document, not peer reviewed. Did not state if data analyst was blinded to treatment group. https://www.medrxiv.org/content/10.1101/2020.04.10.20060699v1

Suggest keeping K > 4 mmol/L and Mg > 2 mEq/L Use oral K when possible

Int Soc Antimicrob Chemother has apologized for publishing a poorly reviewed paper but has not withdrawn the Gautret paper that suggested a benefit of HCQ/Azith DOI : 10.1016/j.ijantimicag.2020.105949 from publication

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

Hydroxychloroquine (HCQ)

Esper A telemedicine team assessed SARS-CoV symptoms and prescribed HCQ (800mg x 1 then 400mg daily x 6) and Azith (500mg daily x 5) for N=636 consecutive pts who were not in immediate need of hospitalization. All followed via telemedicine daily x 5 then BID until 14th day of symptoms. Of these N=412 started tx and N=224 refused tx and served as the control group. Hospitalization was 1.9% with tx and 5.4% in control (NNT=28). Treatment prior to day 7 of symptoms led to hospitalization in 1.7 and 3.2%, respectively (NNT =23). Authors concluded that tx reduced need for hospitalization. Control group may be self-selection bias for lower severity of illness, providers were not blinded to treatment when deciding who to refer for hospitalization, and chest CT of those treated was slightly worse, although not all received a CT (61% tx, 24% control). https://pgibertie.files.wordpress.com/2020/04/2020.04.15-journal-manuscript-final.pdf Magagnoli Retrospective data from VA Health N=97 HCQ, N=113 HCQ/Azith, N=158 no HCQ. Found no benefit of benefit of HCQ ± Azith in reducing mechanical ventilation and HCQ was associated with higher mortality. There was no protocol for use of COVID therapies in place, and no control – resulted in significant baseline differences. In labs and vital signs. Pre-print, not peer reviewed. https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1 NIH Guideline insufficient data for or against use, use only within a clinical trial, https://covid19treatmentguidelines.nih.gov/ Million reports again on Southern France experience- N=1061 March 3-31. Most with low severity of illness, treated with at least 3 days of HCQ 200mg TID/Azith 500mg x 1 then 250mg/day x4 and followed for ≥ 9 days. Excluded long QTc and G6PD deficiency. Endpoints = GO (good outcome), PO (poor outcome = ICU transfer or in hospital ≥ 10 days, death), PVO (poor viral outcome= still shedding at day 10). These was ~20% of positive cases and the majority of those with eligible data. 95% had low NEWS score for severity. Outcome 91.7% with GO, 4.3% with PO and 4.4% with PVO (was overlap with PO patients). Poor outcome associated with age, beta-blockers, ARB, and high-med NEWS score. Authors compared results with another population of patients. Also did HCQ serum levels and reported median 0.21 [0.00-1.01] mCg/ml. 11.4% had undetectable levels on day 2.It is unknown what concentration is needed for this virus. Not sure what to make of 98.7% cure rate in population with low severity of illness. Overall a much better paper from this group, but unable to assess role of treatment without a control population. https://www.mediterranee-infection.com/early-treatment-of-1061-covid-19-patients-with-hydroxychloroquine-and-azithromycin-marseille-france/

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

Meyerowitz, et al. A review of datasets using HCQ was compiled and published along with a discussion of mechanism and immune effects. Authors conclude it should only be used in a RCT. https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202000919 Abu Dhabi report that associates HCQ use with slower viral clearance using repeated nasopharygeal swabs in 34 patients with mild-moderate disease – 62% on HCQ and rest as control. Not a RCT, so despite attempt to adjust for confounders, this likely represents treatment bias. Pre-print paper, not peer reviewed https://www.medrxiv.org/content/10.1101/2020.04.27.20082180v1 Another retrospective observational trial from China N=568 critically ill (on mech vent with P/F <300) with COVID (Feb 1 to Apr 8) on a variety of agents and 48 also received HCQ. Mortality lower in HCQ 18.8% vs. 45.8% SOC, with no difference in LOS, despite later start of treatment in HCQ arm. There was a huge variety of other meds (antiviral, IgG, immunoenhancer (not named) and interferon was given only to non-HCQ group) used in both groups. Adjusted mortality remained lower in HCQ group. Not clear why so few patients were treated with HCQ at this hospital. Likely treatment bias or some other confounder influencing results. Pre-print, not peer reviewed https://www.medrxiv.org/content/10.1101/2020.04.27.20073379v1.full.pdf

200mg BID x 7-10 days

Hydroxychloroquine (HCQ) Pharmacokinetics

A study by Perinel reported HCQ blood levels for N=13 on 200mg 3 x daily, median 83kg (63-117) median Clc 80 ml/min (CKD-EPI_ (12-118)- but one was on CRRT Plan for concentration monitoring/frequency was not reported. Goal range blood level= 1-2 mCg/ml achieved in mean 2.7 days (1-4.5) in all but 3 patients- they were not described. The origin of this goal range is not known, and it has not been tested prospectively in vivo for efficacy. Dose reduced in 4 and 2 stopped for QTc prolongation. Authors propose LD; 800mg x 1 then 200mg BID x 7 days based on some kinetic simulations from non COVID patients. Missing info: site of administration (gastric or jejunal, concurrent enteral feeds, concurrent drug therapy, protein binding and albumin conc. Not reported, actual kinetic data from these patients such as Vd, half-life). https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa394/5816960 Prior report projected the HCQ dose for COVID from in vitro antiviral data had suggested a LD 400mg then 200mg BID x 4 days. They modeled based on simulated Chinese patients. They predicted lung:plasma ratio 400:1. SARS-CoV2 EC50 established in vitro for lung tissue concentration goal 0.72 microM at 48hr and was associated with a blood level of > 0.5 mCg/ml in simulated dosing of 800mg + 400mg day 1 then 400mg daily https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa237/5801998

A conc. 0.36 mCg/ml was reported to decrease viral load by 50% in cell culture.

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

U of MN study: Dose for prophylaxis (ppx) evaluated to achieve the EC50 0.72 microM (in the blood) (based on in vitro data) in 50%of patients- and also evaluate a target 1.44 microM. Model suggests for pre-exposure ppx a LD: 800mg then 400mg 2-3 x per week. Post-exposure ppx: a LD: 800mg, then 600mg in 6 hr and 600mg daily x 4 days. Their graphic suggests that this higher dose would maintain a concentration above 1.5 microM = 0.5 mCg/ml. Authors noted that the common dose of 400mg daily x 5 days would be inadequate to achieve EC50 in 50% of their modeled patients. https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.1874

U of MN Blood level target is well below the goal conc. 1-2 mCg/ml by Perinel for COVID treatment.

Ibrutinib Updated 4/23/2020

BTK-inhibitor impacts TLR-mediated signaling and reduces cytokine expression

Letter to editor describes 6 patients who receive it chronically who developed COVID. 5 were on 420mg/day and had mild cases. 1 was on 140mg/day due to arthralgias. This patient had a worsening clinical course and received multiple potential therapies. The ibrutinib dose was initially reduced to 140mg/day while hospitalized and later increased to 420mg/day on day 11/12 after oxygenation worsened. The higher dose was associated with improved oxygenation and reduced cytokine levels. Authors suggest that the dose of this agent not be reduced with COVID and that this agent be considered for future evaluation. https://ashpublications.org/blood/article/doi/10.1182/blood.2020006288/454437/The-BTK-inhibitor-ibrutinib-may-protect-against?searchresult=1

Hypothesis generating only.

Ivermectin Updated 4/23/2020

Has rapid antiviral activity against SARS-CoV-2 virus in vitro, no human data. https://reader.elsevier.com/reader/sd/pii/S0166354220302011?token=5FCDDB13A9C6DB62DF43C688DB41F1F425556281EF59FD2D80ABA5911E1BEA9514B4E89828B95A2FD582C7F3E76AE0EA Caly L, et al. Antiviral Research, https://doi.org/10.1016/j.antiviral.2020.104787. A pharmacokinetic analysis suggests that the levels used in vitro are not attainable in humans without excessive toxicity. https://www.medrxiv.org/content/10.1101/2020.04.11.20061804v1.full.pdf Reportedly being used in FL with HCQ, azithromycin and zinc with “best results” early in the course of treatment. In lay press only. U of Baghdad to study HCQ and Ivermectin 12mg weekly- placebo-controlled RCT planned, not yet enrolling patients as of 4/14/2020 https://clinicaltrials.gov/ct2/show/NCT04343092?cond=ivermectin&draw=3&rank=20 A multinational registry has reported on N=704 patients who received ivermectin (iver) versus matched controls using automated transfer of real-world data (N=68,230 in the database). Average dose 150mCg/kg (no SD reported). In the text, it was described that of those who required mech vent (3.1% iver vs 9.7% control), mortality was 7.3% vs 21.3% and overall mortality 1.4 vs 8.5%, respectively. However, the tables and figures appear to indicate vastly different values- e.g. overall mortality iver < 0.5% vs between 1-1.5% control and the table 1.8% vs. 10.2%,

150 mCg/kg

FDA warns against use of animal drugs for humans Data and results are very inconsistent in this paper, and conclusion may be inaccurate.

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

respectively. Since this is a multinational study, the decision to intubate may have varied and influenced patient outcome, although data came from comparable regions of the world. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3580524

Ketamine max concentration Updated 4/16/2020

Sedation of difficult patients

Patients on ketamine may not look “sedated” as it is a dissociative agent- don’t try to put them in a coma by increasing dose (increased adverse effects with increasing dose) Hypertension may be due to ketamine, think before you start an antihypertensive- may be better to reduce the dose. See additional comments in the sedation section. Concentration of 10mg/ml reported with BUD of 48hr by U of Rochester

1-30 mCg/kg/min can start at 10 mCg/kg/min

Lopinavir-ritonavir ± Arbidol Updated 5/4/2020

N=73 hospitalized patients in China, retrospective review LR vs LR+A. No difference in cure rate or other outcome measures, including viral clearance. Groups similar but described as “ordinary” or “heavy” clinical classification (not defined). Pts do not appear to have been very ill otherwise. Small number prevents any conclusion about either regimen. Pre-print, not peer reviewed. https://www.medrxiv.org/content/10.1101/2020.04.25.20079079v1.full.pdf

Melatonin Updated 5/4/2020

Indirect anti-inflammatory, anti-oxidation, immune enhancing

Theoretical benefit suggested https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102583/pdf/main.pdf No data to support its use. Anecdotal use of very high doses (80mg daily) https://news4sanantonio.com/news/local/area-doctor-sees-success-in-experimental-covid-19-treatment-using-melatonin 1 trial listed for prophylaxis of 2mg vs placebo nightly as prophylaxis in healthcare workers. In La Paz. https://clinicaltrials.gov/ct2/show/NCT04353128?term=melatonin&cond=COVID-19&draw=2&rank=1 Melatonin for sleep promotion has been suggested but data for sleep promotion is not encouraging in a 2013 meta-analysis (7 min reduced latency, 8 min enhanced sleep time) unless natural melatonin is lacking or when trying to sleep at a different time than normal for diurnal variation. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063773

Start low dose and increase as needed for sleep. COVID dose is not known

Low risk, but effect is theoretical only.

Neumifil Updated 5/1/2020

Blocks spike protein from binding to ACE2

Compound prevented cells from being infected by SARS-CoV-2. Creators envision a preventative nasal spray but have not started clinical trials. https://www.newsweek.com/experimental-coronavirus-drug-neumifil-shows-promise-lab-scientists-hope-rapidly-start-1501101

Nutrition Updated 4/9/2020

Minimize protein wasting and physical deterioration

ASPEN/SCCM guidelines at Early (within 12 hr intubation) gastric continuous enteral nutrition to provide 15-20 kcal/kg (Actual wt) and 1.2-2 mg/kg protein using standard polymeric isosmotic formula (≥ 20% protein) Also addressed assessment, documentation, monitoring, use of PN (avoid soybean lipids), prone

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

position, and ECMO. https://www.sccm.org/getattachment/Disaster/Nutrition-Therapy-COVID-19-SCCM-ASPEN.pdf?lang=en-US

Plasma Exchange Update 4/17/2020

Remove cytokines

Theoretical benefit suggested for patients with cytokine storm Keith P, et al. Crit Care https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-2836-4 but no benefit in earlier trials of sepsis https://www.researchsquare.com/article/rs-16022/v1 Case series published but all received multiple other therapies, and no control patients N=5. doi:10.1001/jama.2020.4783 N=10 doi:10.1073/pnas.2004168117 N=1 https://www.sciencedirect.com/science/article/pii/S092485792030131X?via%3Dihub

RAAS Impact: Angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB) Update 5/1/2020

Maximize angiotensin binding of virus to limit cell penetration

Complex interplay between antihypertensive drugs and impact on RAAS. Organizations suggest continuing antihypertensive agents. No evidence for/against use of these agents as therapies. https://www.nejm.org/doi/full/10.1056/NEJMsr2005760 https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30153-3/fulltext https://els-jbs-prod-cdn.jbs.elsevierhealth.com/pb/assets/raw/Health%20Advance/journals/jmcp/jmcp_ft95_3_5-1585588116123.pdf China retrospective report showed association of inpatient ACE-I/ARB use with a lower risk of all-cause mortality in chronic hypertension patients. N=1128 (188 with and 940 without-but on other antihypertensives). Data adjusted for uneven variables propensity testing & sensitivity testing done. Supports continued use of ACE-I/ARB when possible, although does not address a new start of these agents. https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.120.317134 UK cohort database study N=205 patients hospitalized (single-center) with COVID on ACE-I/ARB at least 7-days prior to or during admission, associated with lower risk of disease progression = ICU admission, or death in 7days with adjustments for comorbidities and baseline imbalances. Pre-print study, not peer reviewed. Does not suggest addition of ACE-I/ARB, and other variables not explained. Not clear how many inpatients actually received ACE-I/ARB. https://www.medrxiv.org/content/10.1101/2020.04.07.20056788v1.full.pdf Report from China indicated no difference in outcome of 1178 patients with COVID based on prior use of ACE-I or ARB, using endpoints of severity of illness and survival in hospital. file:///C:/Users/jjmow/Downloads/jamacardiology_li_2020_br_200006.pdf A large case control study from China, using case cohort N=610 with COVID-19 (lab confirmed) and N=48,667 population-based controls tested medications vs. outcome. Data from 14 hospitals with shared HER. Higher BMI, DM, and CVAD are independent risks for COVID-19. With hypertension, taking CCB increased risk OR 1.67 (95% CI 1.2-2.9) vs ARB lower risk OR 0.24 (95%

NIH recommends continuing home therapy but recommends against new use just for COVID treatment unless in a clinical trial

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

ARB/ACE-I

CI 0.17-0.34), ACE-I OR 0.65 (95%CI 0.26-1.57- NSS). Use of corticosteroids assoc. with critical COVID OR 7.56 (95%CI 1.17-48.93). Likely, not enough on ACE-I to assess impact, but no obvious relationship with outcome. Does not address the role of these agents in treatment of COVID. Pre-print, not peer reviewed. https://www.medrxiv.org/content/10.1101/2020.04.24.20077875v1.full.pdf Meta-analysis of effect of ACE-I/ARB on death and severity of illness, included small trials and 5 trials were evaluated including 308 treated vs 1172 not treated patients. Suggested reduced risk of severe disease OR 0.56 (95% CI 0.34-1.89(and odds of death OR 0.38 (0.19-0.74). Pre-print, not peer reviewed. https://www.medrxiv.org/content/10.1101/2020.04.23.20076661v1.full.pdf Large database (Surgical Outcomes Collaborative Registry- International with auto data extraction) report N=8910 patients with COVID-19 who had been discharged or died in hospital (5.8%). Factors associated with death (multivariate analysis) were age > 65, comorbidities as previously reported. ACE-I or ARB use not associated with a higher risk of in-hospital death, female sex, ACE-I and statins were assoc. with improved chance of survival to discharge. Oddly, no data on CCB. https://www.nejm.org/doi/full/10.1056/NEJMoa2007621?query=RP NYU database of all those tested for COVID-19 (N=12,594), drilled down to hypertensive by hx N=4357 (35%) and 59.1% tested COVID +, the rest were tested but negative. Slightly higher likelihood of ICU admission/severe disease with prior CCB use but lower with ACE-I, ARB, Beta-blocker or thiazide vs. matched controls. https://www.nejm.org/doi/full/10.1056/NEJMoa2008975?query=RP Italian database report N=6272 with COVID-19 matched to N=30,759 in health database. More COVID pts on antihypertensives. No association between ACE-I/ARB and risk of infection. https://www.nejm.org/doi/full/10.1056/NEJMoa2006923?query=RP

Concurs with prior recommendation to continue CV therapies.

Remdesivir Clinical Trials Update 5/4/2020

Antiviral efficacy vs. SARS-CoV-2 in vitro and animal models. Reduced viral load and clinical symptoms in animal models using early treatment.

Compassionate use experience was reported in a series of 61 patients (data from 8 not analyzed) and suggested that 84% had improved at day 28, but without a control population from the same sites, it is impossible to interpret this data. More seriously ill patients (on vent) or > 70yoa did not have the same likelihood of improvement. Serious adverse events were reported in 12% of patients, but without control, unable to separate disease from drug-related events. nejm.org/doi/full/10.1056/NEJMoa2007016 Gilead updated this list to demonstrate that trials in China had been stopped (not Gilead sponsored) reportedly for lack of patient enrollment. Active clinical trials include those with both moderate and severe disease. https://www.gilead.com/purpose/advancing-global-health/covid-19/remdesivir-clinical-trials

See ASHP Table for more information

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

A rhesus macaques (animal) study of SARS-CoV-2 (causes a transient lower resp tract infection). Treated 12-hours post inoculation with 10mg/kg IV over 5 minutes x 1 then 5mg/kg IV daily vs placebo control (vehicle). Serial swabs for viral load, blinded CXR, BAL, and blinded necropsy at day 7. Rem treated had lower clinical severity scores, less pulmonary involvement, reduced viral replication in lower but not upper resp tract. Less viral RNA in lung specimens after autopsy and no virus was isolated from lungs of treated animals. Less visible pneumonia in lung tissue specimen. Pre-print, not peer reviewed. https://www.biorxiv.org/content/10.1101/2020.04.15.043166v1.full.pdf Leaked data of a ongoing clinical trials was reported by Pharmacy Practice News. Interim data is often incorrect in a clinical trial, so it is premature and inappropriate to make treatment decisions based on this information. They also provide an analysis of the compassionate use study reported above from NEJM. https://www.pharmacypracticenews.com/Covid-19/Article/04-20/Early-Data-on-Remdesivir-for-COVID-19-Cause-Guarded-Optimism/58063?utm_source=Social&utm_medium=twitter&utm_campaign=0422remdesivir NIH Guideline insufficient data for or against use, use only within a clinical trial, https://covid19treatmentguidelines.nih.gov/ Results from China were inadvertently leaked by WHO and then withdrawn Suggested no benefit in an RCT mortality 13.9% vs control 12.8%. Stated no virological or clinical benefit. Trial was stopped early. https://www.statnews.com/2020/04/23/data-on-gileads-remdesivir-released-by-accident-show-no-benefit-for-coronavirus-patients/ Results published in Lancet a few days later. RCT, remdesivir 200mg IV x 1 then 100mg/day x 10 days for treatment of N=237 pts with O2 saturation < 94% on room air, PNA on CXR, with clinical improvement (hospital discharge or at least 2-point improvement in a 6-point scale) as endpoint. Block randomization planned based on level of respiratory support- population appeared balanced at baseline. Other therapies were permitted. Pts were within 12 days of symptom onset. Target enrollment not met (goal N=325), due to reduced patient hospitalization. Treatment not started until median symptom day 10 (IQR 9-12). 66% also on corticosteroids. Followed to day 28. No significant difference in time to clinical improvement (ITT) median 21 days (IQR 13-28 vs placebo 23 days (IQR 15-28), HR 1.23 [95% CI 0.87-1.75]. Was a trend to improvement with earlier therapy initiation. Mortality similar. Adverse events (AE) similar, but more remdesivir pts stopped treatment for AE (12% vs 5%). No difference in rate of viral load decline (Nasal PCR and lower resp). Study stopped early likely reduced power to show effect, and late treatment may reduce likelihood of benefit. Many secondary endpoints, unlikely to reflect any real difference

No reduction in viral shedding in monkeys Will be important to see if difference in treatment onset vs. US trial

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

statistically, but suggested small reduction in time to improvement 21 vs 23 days if therapy started earlier. https://marlin-prod.literatumonline.com/pb-assets/Lancet/pdfs/S0140673620310229.pdf Letter to NIAID from Gilead stated that DSMB reviewed data and is continuing the RCT for planned follow-up, due to apparent response to remdesivir (200mg IV x 1 then 100mg daily x 10 days) that is better than placebo at interim analysis on 4/27/20 (time to recovery 31% faster, p<0.001) median recovery 11 vs 15 days, respectively, with a trend for survival benefit. The trial closed to new enrollment on 4/19/20. Patients were on O2 but mechanical ventilation was not required (moderate illness= hospitalized ± on oxygen). N=1063 patients included. Daily assessment in hospital and after discharge to day 29. ClinicalTrials.gov stated primary outcome is time to recovery by day 29 [Recovery defined as hospitalized, not on O2, no longer requires ongoing medical care, not hospitalized with limits on activity or requiring home O2, or not hospitalized, no limitations], with secondary outcome to be improvement in an 8-point ordinal severity scale, laboratory marker change, grade ¾ adverse events, serious AE, duration of hospitalization or new NIVV, or new O2, or new ventilator or ECMO. The ordinal scale will also be used to measure time to improvement of 1 item on the scale, also NEWS change. No data has been published, so this is not even a pre-publication paper yet. https://clinicaltrials.gov/ct2/show/NCT04280705?term=remdesivir&cond=COVID-19&draw=2&rank=8 https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19 EUA granted for COVID-19 in adults and children hospitalized with severe disease 5/1/20, Gilead reportedly donating drug

Trial methods changed prior to data analysis- initial plan to assess mortality was changed to assessing time to recovery. Goal was to void missing treatment effect by picking a single timepoint for assessment..

Sarilmab Updated 4/28/2020

Reduce cytokine storm

Primary endpoint met (lowering CRP) with sarilumab 200mg or 400mg IV vs. placebo. However, no clinical benefit overall N=457 (28% severe = on O2, 49% critical= on vent/HFO/in ICU, 23% MSOF). Had a 7-point outcome scale. Trend to benefit, so ongoing with 400mg IV and critical group. https://investor.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-provide-update-us-phase-23-adaptive

Ongoing with 400mg per day

Siltuximab Reduce cytokine storm

Pre-peer review pre-print case series N=21 with severe P/F median 127 on NIV or CPAP, treated with 11 mg/kg/day over 1 hour, may repeat x 1. CRP and IL-6 elevated at baseline and fell with treatment. Respiratory status: 33% improved, 43% “stabilized” and 24% worsened and required mechanical ventilation. No control group. https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v2.full.pdf

Recombitant Soluble ACE2

Overwhelm binding sites of SARS-CoV-2

Pre-publication report discusses theoretical role and status of in vitro trials Monteil V, et al. CellPress DOI: 10.1016/j.cell.2020.04.004

Not available

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

to prevent cellular uptake

Describes a spike protein plug to bind SARS-CoV-2 virus and prevent cell entry. https://www.biorxiv.org/content/10.1101/2020.04.29.067728v1.full.pdf

Would need to be administered very early

Statins Update 5/1/2020

Upregulate the activity of ACE2 and may reduce endothelial dysfunction.

Continue home statin therapy, but may be prudent to monitor CPK, especially with high-dose or prolonged propofol use (propofol-related infusion syndrome). Rhabdomyolysis has been reported with COVID-19, frequency/etiology unknown. Statins were used with ARB’s during Ebola treatment, and open label use suggested benefit. Reviewed at https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.2397 NIH Guidelines recommend continuation of home therapy and against the addition specifically for COVID therapy Large database (Surgical Outcomes Collaborative Registry- International with auto data extraction) report N=8910 patients with COVID-19 who had been discharged or died in hospital (5.8%). Factors associated with death (multivariate analysis) were age > 65, comorbidities as previously reported. ACE-I or ARB use not associated with a higher risk of in-hospital death, female sex, ACE-I and statins were assoc. with improved chance of survival to discharge. https://www.nejm.org/doi/full/10.1056/NEJMoa2007621?query=RP

Tocilizumab Updated 5/1/2020

Reduce cytokine storm

Role of this mediator reviewed in a Non-peer reviewed pre-print paper with comments on potential role for tocilizumab. IL-6 levels 3-fold higher in patients with complicated disease and higher risk of death. https://www.medrxiv.org/content/10.1101/2020.03.30.20048058v1.full.pdf Case series N=30 treated with tocilizumab (<80 yoa, rapidly deteriorating (O2 increase > 3 L/min in 12 hr), pneumonia, high CRP, and over 5 days of disease duration, reduced need for mechanical ventilation OR 0.42 {0.2-0.89} and a no impact on adjusted mortality. Early treatment associated with avoidance of ICU transfer. Not peer reviewed. https://www.medrxiv.org/content/10.1101/2020.04.20.20061861v1.full.pdf Press report benefit in the CORIMUNO-TOCI open label randomized trial in France in N=129 (target N=228) hospitalized with PNA but not in ICU. N=65 tocilizumab vs 64 SOC. Less need for new ventilation or death at day 14 with tocilizumab. https://www.aphp.fr/contenu/tocilizumab-improves-significantly-clinical-outcomes-patients-moderate-or-severe-covid-19. Shortage strategy is to limit dose to 400mg

8 mg/kg, repeat x 1 at MD discretion 8mg/kg day1, repeat day 3 if no response.

Many studies gave the drug IV, although in the US it is approved for SQ administration. LexiComp suggests a 60 minute infusion after diluted solution (IV form product) is allowed to

Updated: 5/4/2020

Drug(s) Rationale Trials or Clinical Experience Dosage Comments

reach room temp Some hospitals require chemo RN to administer it.

Valproic Acid Updated 5/4/2020

Attenuate expression of pro-inflammatory cytokines

Protocol proposed to study valproic acid 20mg/kg/day and escalate to 60 mg/kg/day to achieve conc 50-100 mCg/ml. Given IVPB over 1 hr in 3 equal doses per dayOutcome is reduction in case fatality rate at least 50% with 10 days treatment and safety monitoring- LFT, platelets, pancreatitis. Propose to study severely ill (not defined) pts on mech vent of any duration with COVID of any duration and hospitalization of any duration. Pre-print, not peer reviewed. https://www.medrxiv.org/content/10.1101/2020.04.26.20079988v1.full.pdf.

Unclear study methodology and patient selection. Not recommended

Zinc Update 4/11/2020

Boost immune system

Has been studied in common colds and a Cochrane review suggested it inhibited viral replication. It is best when used very early in the course of a common cold. It was reported to inhibit SARS-CoV replication in cell culture PLoS Pathogens 6(11):e1001176 DOI: 10.1371/journal.ppat.1001176 Using zinc lozenges has not been studied in COVID-19, but likely low risk Zinc sulfate may bind to hydroxychloroquine when administered simultaneously- suggested to avoid concurrent administration via a feeding tube. Zinc sulfate low bioavailability, and dose is not known. Prophylaxis study (dose not specified) and treatment study using Zinc gluconate and ascorbic acid 800mg/day in divided doses is listed in clinicaltrials.gov for patients being tested for COVID. https://clinicaltrials.gov/ct2/show/NCT04342728?term=covid&cond=zinc&draw=2&rank=3 Australian research using IV Zinc mentioned in the press, dose not known

Zinc sulfate 50 mg at bedtime

BAL = bronchoalveolar lavage NIVV= noninvasive ventilation NEWS= National Early Warning Score CXR= chest x-ray EUA = Emergency Use Authorization PNA = pneumonia HFO = high flow oxygen PPX = prophylaxis MSOF = multiple system organ failure SOC = standard of care Footnote:

Updated: 5/4/2020

Appendix 1:

Baxter bags for propofol: What we do know: written by Vivian Lee on ASHP Connect

"Typical" IV bags are unlikely an option for pooling - they are likely to be made of PVC +/- plasticized by DEHP. Propofol is incompatible with these materials.

(Specifically, propofol adsorbs to PVC and leaches DEHP from DEHP-plasticized PVC).

• Propofol is best stored in glass containers. There is data to support polyolefins containers as well, waiting for details of an internal study from Fresenius Kabi Germany

• FYI, polyolefins is a family of plastics that includes polypropylene and polyethylene. If you see either or both cited as the material of your bag, you're good

• From the moment the propofol bottle is punctured and hung, the bottle and tubing need to be changed at 12 hours; I think there are 2 reasons to this: o Oxygen immediately enters the vial and causes oxidative degradation. During manufacturing nitrogen is injected into the vial headspace to

prevent oxidation o With most tubing being made of PVC, this prevents prolonged contact between propofol and the tubing

• From the moment the propofol is transferred from the bottle "to another container", the drug may only be used for 6 hours o I think this is a conservative manufacturer statement to guarantee minimal drug adsorption to the new container in case it is not glass or

polyolefin-based o There is also comment about earlier degradation when the propofol is preserved with sodium metabisulfite (more likely to be the case with

generic formulations) than with EDTA (more likely with brand product Diprivan®)

The above is based on Trissel’s, product monographs from Aspen and Fresenius Kabi and other online research. I am still waiting for further info from them

that rationalizes use of the 6 hour BUD. From how I understand it, the safest way to pool propofol if you must do it now, is to source a polyolefin-based bag

and apply a 6ihour BUD from the moment propofol is pooled into it. For instance, Baxter Canada has provided me info that their VIAFLO and INTRAVIA bags are

made of polyolefins. You may be able to source others of this material made in U.S. She prefers the INTRAVIA bag with TOTM-plasticized PVC ports.

Continue to change IV tubing every 12 hours.

See also FDA Guidance on repackaging during COVID-19 emergency https://www.fda.gov/media/137224/download

Updated: 5/4/2020

Appendix 2 Sample NMBA dosing information

NMBA Protocol: loading dose and infusion, with assessment every 1-2 hours for achievement of clinical goal, bolus for movement, coughing, vent dyssynchrony (defined as patients respiratory rate more than 1 breath above set rate by Katie Madding, PharmD, BCPS, BCCCP, Miami Valley Hospital, Dayton, OH), unable to reduce plateau pressure. If more than 1 bolus needed, increase infusion dose by 10%. If no bolus needed, attempt to reduce dose every 12 hours (vecuronium and rocuronium will accumulate, so lower doses are likely to be acceptable)

a. TOF is not the titration endpoint but may be used to determine the lowest possible dose: Dose to maintain the clinical effect with the highest

possible TOF.

i. Monitor TOF every 1-2 hours while titrating infusion, then every 4-12 hours during maintenance.

ii. Goal TOF is generally ≥ 2/4.

iii. Follow an established protocol for technique and site of testing if you do TOF measurement

b. Intermittent dose NMBA with rocuronium or vecuronium would target patient movement, dyssynchrony with ventilator, cough, etc.

i. May reduce duration of NMBA but also require more trips into a room

ii. Rocuronium 0.5 mg/kg IV push every 1 hour PRN movement or TOF > 2/4 (higher doses may give a longer duration) Consider

rounding to nearest whole vial to minimize waste.

iii.

Cisatracurium Nomogram: CISatracurium 100 mg per 100 mL 0.9% NaCl IV; Initiate infusion of 3 mcg/kg/min. May titrate by 1 mcg/kg/min per Train-of-Four

(TOF) assessment. May bolus 20 mg via pump PRN for significant muscle movement. Adjust dose per nomogram

If TOF is: Action: Recheck TOF in

0 of 4 Decrease dose by 25% (dose x 0.75) 1 hour

1 of 4 Goal; no change. If 2 consecutive TOF results of either 1 or 2 out of 4 then

change TOF assessment to Q 12 hours 4 hours

2 of 4 Goal; no change. If 2 consecutive TOF results of either 1 or 2 out of 4 then

change TOF assessment to Q 12 hours 4 hours

3 of 4 May increase dose by 25% (dose x 1.25) if not at clinical goal 2 hours

4 of 4 May bolus 0.15 mg/kg and increase dose by 25% (dose x1.25) if not at clinical

goal 2 hours

Rocuronium Nomogram: 200 mg per 100 mL Dextrose 5% in Water IV; Initiate infusion of 5 mcg/kg/min. May titrate by 0.5 mcg/kg/min per Train-of-Four

(TOF) assessment. May bolus 50 mg via pump PRN for significant muscle movement. Maximum dose: 12 mCg/kg/min and adjust dose per TOF

If no movement visible, check TOF every 6 hours

If TOF 0 of 4, hold drip and recheck TOF every 30 minutes until movement or 2 of 4.

If TOF is 1 of 4, reduce dose by 0.5 mcg/kg/min

If TOF is 2 or 3 of 4 continue current rate

If TOF is 4 of 4 OR movement is visible AND not at clinical goal, increase by 0.5 mcg/kg/min Q 30 minutes

Call MD if not able to achieve clinical goal

Updated: 5/4/2020

a. There is no data that the use of a physio-neurologic monitor (e.g. BIS, ____) is associated with an improved assessment of sedative

requirements during NMBA, but may be used if available. A defined numeric goal is not known, but a blunted response to stimulation

(minimal increase in value) is associated with deep sedation.

ANOTHER CISATRACURIUM PROTOCOL (Dr. Madding, PharmD, Miami Valley Hospital, Dayton, OH) Bolus Cisatracurium 0.2 mg/kg/dose, BOLUS FROM INFUSION ONCE AND Cisatracurium 200 mg/200 mL infusion, 0.5 – 10 mcg/kg/min Titrate to vent synchrony as described below or* TOF 2 0f 4 if ordered. Infusion admin instructions: Ensure patient is sedated to RASS -4 or -5 before initiating therapy. Start infusion at 3 mcg/kg/min (based on IBW). If patient respiratory rate is ≥ 2 breaths per minute above set rate on ventilator within 15 minutes, increase rate by up to 1 mcg/kg/min. May increase rate as rapidly as one time every 15 minutes to achieve goal of 0-1 breaths per minute above set rate. If patient has not breathed above the vent in 4 hours, decrease infusion rate by up to 1 mcg/kg/min. Maximum rate 10 mcg/kg/min. Contact provider if 10 mcg/kg/min is reached and ordered titration goal is not achieved. Wean: discontinue infusion (no weaning required). OTHER PROTOCOLS

https://www.uwhealth.org/cckm/cpg/medications/name-97559-en.html

Updated: 5/4/2020

https://sites.utexas.edu/pharmacotherapy-rounds/files/2019/10/Small-Res-Rounds-Handout-Final-Oct-2019-without-pic.pdf

Updated: 5/4/2020

Appendix 3: Sedation Algorithms

Agent MOA Dosing Onset Duration Prolonged with organ

dysfunction? Advantages Disadvantages

Analgesics

Fentanyl

Opioid See flowsheet

below

15 sec

30 min-1 hour (prolonged

with continuous

infusion - 2-4 hours)

Hepatic - Easily titratable - Rapid onset of

action

- Parent compound accumulates due to lipophilicity

- Short duration of action limits is use for intermittent pushes

Hydromorphone 5-10 min 3-5 hours Hepatic

Morphine 5-10 min 3-5 hours Hepatic, renal

- Hypotension may occur from histamine release

- Metabolites accumulate in renal failure

Sedatives

Propofol

GABAA receptor agonist and NMDA receptor antagonist

5-50 mcg/kg/min (bolus not recommended outside of RSI)

< 1 minute

40 min – 7 hours (with accumulation)

No - Rapid onset and

offset

- Tubing and bottle must be changed every 12 hours

- Lipid formulation carries risk for infection and hypertriglyceridemia

- Hypotension - Propofol-related infusion

syndrome (PRIS) with prolonged use

Dexmedetomidine Alpha-2 adrenergic agonist

0.2-1.5 mcg/kg/hr (bolus not recommended)

15-20 min

1-2 hours

Hepatic (not studied in CrCl <30 mL/min

- Can be used to wean to extubation

- Has opioid-sparing properties

- Bradycardia - Hypotension - Should not be used for

deep sedation (e.g. paralysis)

- Concern for rebound hypertension and tachycardia with prolonged use

Updated: 5/4/2020

Midazolam GABAA receptor agonist

1-10 mg/hr 2-5 min

1-2 hours (prolonged with continued exposure and continuous infusions)

Liver, renal

- Shorter duration of action makes it the most ideal benzodiazepine for continuous infusion titrations, in most cases

- Parent compound accumulates due to lipophilicity

- Active metabolites accumulate in renal failure (not dialyzable)

Lorazepam GABAA receptor agonist

1-10 mg/hr 5-20 min 12-24 hours No

- Long duration of action is advantageous for intermittent bolus therapy

- Propylene glycol-induced acidosis and renal failure with higher dose infusions

Ketamine NMDA receptor antagonist

0.1-0.5 mg/kg bolus 0.5-6.5 mcg/kg/min

<1 minute

1-2 hours Hepatic, renal - Analgesic

properties

- Hypersalivation - Tachyarrhythmias and

hypertension - Emergence reaction

(delirium, hallucinations)

Phenobarbital Barbiturate

30-120 mg/day in 2 to 3 divided doses (maximum: 400 mg/day)

5 minutes

6-12 hours (prolonged with repeat exposure)

Hepatic, renal - Synergistic effect

when used with benzodiazepines

- Active metabolites accumulate

- Propylene glycol-induced acidosis and renal failure with higher dose infusions

- Limited data and experience for ICU-related sedation

Updated: 5/4/2020

Algorithm 1 – IV Analgesia

All patients receiving continuous analgesia and/or sedation should receive daily SATs/SBTs per institution-specific policies.

Assess patient for pain (Wong-Baker,

CPOT ≥3, BPS >3)

Positive for

pain

Negative for

pain

Hydromorphone 0.5 mg q30min PRN

OR Morphine 2 mg q30min PRN

Assess for need for sedation

Fentanyl infusion

If requiring >2 doses in

any 2-hour period

If fentanyl not available

Refractory agitation

Hydromorphone or morphine infusion (hydromorphone

preferred in renal dysfunction)

Assess for need for sedation

Updated: 5/4/2020

Algorithm 2 – IV Sedation

Paralyzed

Once pain has been controlled or ruled out as a cause of agitation, move to algorithm 2

for sedative management. The following recommendations are in order of preference

and are subject to availability.

All patients receiving continuous analgesia and/or sedation should receive daily

SATs/SBTs per institution-specific policies.

For all patients with RASS >0 or SAS >4 and QTc <500, add

quetiapine 50 mg q12h (titrate up as tolerated)

Not paralyzed

Midazolam infusion Lorazepam 4 mg IV push q20min PRN

If requiring >3 doses in

any 1-hour period

Propofol infusion (preferred) Check baseline TG and q48h If TG ≥300 or propofol dose ≥40 mcg/kg/min, re-check

q24h DC therapy if TG ≥500

Midazolam 2 mg q15 min PRN + Midazolam infusion, in

comments: Titrate midazolam infusion

up by 1 mg/hr if 3 pushes of midazolam in 1 hour is needed for refractory

agitation

Phenobarbital 130 mg x1 to reduce

midazolam infusion dose Redose only if infusion doses begin to rise

Updated: 5/4/2020

In the case of a severe IV sedation shortage, algorithm 3 is to be implemented.

If propofol

unavailable

or patient

refractory

If propofol and

midazolam unavailable

Ketamine 0.1 mg/kg bolus followed by 1 mcg/kg/min, titrate by 0.5 mcg/kg/min

q30min

Phenobarbital 65 mg x1 followed by

30 mg q4h PRN RASS >0 (maximum 400 mg/day)

Dexmedetomidine should be

reserved for patients with

agitation to avoid intubation or

weaning mechanical ventilation in

patients cannot tolerate being of

sedation. If propofol, midazolam,

and ketamine unavailable

If doses of

midazolam

>5 mg/hr and

patient is not

currently a

candidate for

extubation

Updated: 5/4/2020

Algorithm 3 – PO Analgesia & Sedation Protocol

Paralyzed

For all patients with RASS >0 or SAS >4 and QTc <500, add

quetiapine 50 mg q12h (titrate up as tolerated)

Not paralyzed

Persistent

agitation

despite

adequate pain

control

Oxycodone 5 mg PO q6h (up to 10 mg PO q6h)

+ Lorazepam 6 mg PO q4h (up

to 10 mg PO q4h)

Titrate up until RASS -4 to -5 prior to paralysis

Lorazepam 4 mg PO q4h around the clock (up to 10 mg PO q4h)

If patient RASS >-4 on

lorazepam 10 mg PO q4h

Add: Phenobarbital 65 mg PO q12h

(titrate to maximum of 400 mg PO/day)

If patient RASS >-4 on

lorazepam 10 mg PO q4h

Add: Phenobarbital 65

mg PO q12h (titrate to

maximum of 400 mg PO/day)

Positive for pain Negative for pain

Assess pain scale (Wong-

Baker, CPOT, or BPS)

Oxycodone 5 mg PO q6h + 5 mg PO q4h PRN (increase standing dose by 5 mg if 4 PRN doses required in a 24-

hour period)

Updated: 5/4/2020

Appendix 4. Code Blue Updated 4/10/2020

Updated: 5/4/2020

Appendix 5. Drug Interactions between antiplatelet or anticoagulant agents and investigational COVID-19 therapies.

http://www.onlinejacc.org/content/early/2020/04/15/j.jacc.2020.04.031

Updated: 5/4/2020

Appendix 6. Potential corticosteroid regimens.

https://journals.lww.com/ccejournal/pages/articleviewer.aspx?year=2020&issue=04000&article=00018&type=Fulltext

Updated: 5/4/2020

Appendix 7. Proposed anticoagulation prophylaxis and treatment. European Society of Cardiology

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BglghkgBZQMEAS4wEQQMvAWZOJQQ1qYEtfsHAgEQgIICQ8ldIqqqgfxK2Q6fqSVYDWvCY7DgK06mFPg0QBdmtV1rUAsN6JnaCYqDCEJahfZ0JWTmFnC_dfRqquL75-

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