Clinical Presentation and course of illness B. Principles ... · It behooves us to establish evidence-based clinical protocols to pro-actively plan the management of these patients

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

Last Updated: 8/4/20

HMH Critical Care Council COVID-19 Guidelines

Many COVID-19 patients will require critical care. Based on the China experience1-3, 15.7

percent of admitted patients were critically ill on admission or became critically ill during

hospitalization. Critically ill COVID-19 patients have a high mortality rate. Data reported from

China found that 61.5% of critically ill patients with COVID-19 had died by day 28 of ICU

admission. 1

It behooves us to establish evidence-based clinical protocols to pro-actively plan the

management of these patients and anticipate high volumes of critically ill patients.

A. Clinical Presentation and course of illness

1. Fever – among 1,099 hospitalized COVID 19 patients, fever was present 44% at hospital

admission. 89% developed fever during admission

2. Cough- 46-82%

3. Myalgia or fatigue 11-52%

4. Shortness of breath 3-31%

5. ARDS developed in 17–29% of hospitalized patients, and secondary infection developed in

10%

6. Approximately 20-30% of hospitalized patients with COVID-19 and pneumonia have

required intensive care for respiratory support.

B. Principles of Infection Control

1. PUI and Presumed cases should be under airborne, and contact isolation.

i. Refer to maestro link Link to HMH Recommendations for Isolation Rooms: https://hmhmaestro.org/wp-content/uploads/COVID-Room-Placement-03-15-0-v1.0.pdf

Diagnostic Workup

Suggested Laboratory for Critically Ill Patients

Day 1 CBC with differential

CMP

Lactic acid

CPK

CRP

IL-6

LDH

Ferritin

ABG

Urinalysis

Blood/urine cultures

Day 2 until symptom resolution CBC

CMP

Lactic acid

LDH

CRP

IL-6

Ferritin

ABG

Prognostic indicators (negative): Lymphopenia and Leukopenia

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

Last Updated: 8/4/20

Diagnose and treat all other conditions. Consider full differential diagnosis until COVID-19

diagnosis is established and continue to consider possible coinfections.

Continuous monitoring with telemetry and pulse oximetry

C. Pulmonary Tx:

Combine aggressive tx while minimizing aerosolization of respiratory secretions

o Bronchodilators prn: Avoid Nebulized medications. Prefer MDI in non-ventilated patients. To

conserve supply, reserve for patients with active wheezing. If giving to a patient on a

ventilator, a one way valve must be utilized for nebulized treatments via the vent circuit to

avoid aerosolization into the surrounding environment

1. Early ambulation if possible

2. Conservative fluid management

3. O2 supplementation

a. Nasal cannula and facemask O2 as needed

b. Increase FiO2 as needed and favor 100% non-rebreather over Hi-Flow.

c. Hi-Flow can be used but use with caution given potential concerns for aerosolization of

the virus. Recommend placing a surgical mask on patient over Hi Flow to minimize

aerosolization.

4. Avoid BiPAP/CPAP. Associated with high treatment failure rates and increased risk of

aerosolization of the virus

a. If BiPAP/CPAP used, must use filter on expiratory limb.

b. High flow O2 with proning appears to be effective.

5. Consider proning in non-intubated patients with severe hypoxemia https://hmhmaestro.org/wp-content/uploads/Guideline-for-Proning-the-NonIntubated-Adult-Patient.pdf

6. Intubation - The decision to intubate a patient is a clinical one to be made by the treating

physician. Many COVID patients seem to tolerate hypoxemia very well. However, severe

hypoxemia should be avoided and carries a significant risk for cardiac arrest. If a patient needs

to be intubated, severe hypoxemia can also prevent adequate pre-oxygenation making the

procedure more dangerous and less controlled. Would suggest considering intubation if the

Oxygen saturation is less than 88% while receiving 100% FiO2.

7. Intubation procedure

a. Standard: RSI, without BVM, one pass.

b. Pre-oxygenate with 100% FiO2 for 3-5 minutes

c. Avoid BVM. If BVM needed to oxygenate, must use BVM filter attachment.

d. Favor use of video-laryngoscopy

e. Controlled suctioning.

8. If intubated, follow ARDSNET protocol to ventilate with low tidal volumes and appropriate PEEP, however the protocol must be adjusted if using prone positioning.

Key points are:

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

Last Updated: 8/4/20

o This COVID ARDS patient population has been found to have a dramatic positive response to prone positioning, with significant improvements in PO2.

o Upon supination, however, the response is often quickly reversed

o Consider early use of prone positioning

o Adjustments of PEEP should only be made while in supine position to prevent severe hypoxemic events upon changing from prone to supine.

Link to Policy: “Prone Positioning for Acute Respiratory Distress Syndrome (ARDS) P-15” [PolicyStat ID: 4406686]

Please refer to Epic order set: “Novel Corona Virus -19 Prone Position Order Set For Critically ill Patients.”

9. ECMO Transfers –

a. HUMC and Jersey Shore provide ECMO services. In order to minimize transport time,

contact the center closest to your hospital.

1. ECMO referrals to HUMC are made through the transfer center – 855-367-4862

(855-FOR-HUMC)

2. ECMO referrals to JSUMC should be made through Dr. Eric Costanzo 732-757-2560

b. Hackensack and Jersey Shore ECMO teams should communicate daily to assess their

resources

c. If one site is unavailable the request will be forwarded to the other site.

d. Patients with refractory hypoxemia despite lung protective ventilation and prone

positioning who are otherwise appropriate candidates should be considered for

transfer.

e. Patients must be transferred with their ventilator from any in network facility.

f. The transfer request will be reviewed by cardiothoracic surgery, Cardiothoracic

intensivists and the Medical intensivist.

g. The likelihood to benefit from the intervention will be the final determination.

10. Sedatives and Paralytics. There is a shortage of many of these drugs, and each hospital should

develop a plan to use alternative medications based no availability.

https://hmhmaestro.org/wp-content/uploads/COVID-19-MEDICATION-SHORTAGE-

MANAGEMENT-STRATEGIES.pdf

11. Tracheostomy

Avoid tracheostomy in COVID-19 positive or suspected patients during periods of respiratory/cardiac instability or heightened ventilator dependence.

Tracheostomy can be considered in patients with stable pulmonary/cardiac status but should generally not take place sooner than 3 weeks from intubation.

When possible, consideration should be given to performing tracheostomies at the bedside. See link to network policy.

D. Pulmonary vasodilators- Nitric Oxide and Frolan should be considered for use as “salvage

therapy”.

E. Viral myocarditis

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Last Updated: 8/4/20

a. Responsible for 7% of COVID-19 deaths and contributes to death in 33% of mortalities b. Decompensation has been reported with elevated troponins after pulmonary status

appears to have improved

c. Clinical signs i. Symptoms: chest pain, severe orthopnea, hypotension, or signs of poor perfusion, end organ damage, or circulatory collapse/cardiogenic shock

ii. New onset arrhythmia (frequent PVCs, a-fib, a-flutter, bradycardia, heart block, non-sustained VT, V-Tach, V-fib)

iii. Echo findings: 1. LVEF decreases to < 50% if baseline LVEF was normal, or decreases more than 10% from baseline if baseline was abnormal

2. Severe decrease in single or biventricular function from baseline, or any LVEF <= 25%

3. Pericardial effusion with tamponade

Treatment i. Stat EKG, ECHO, CMP, CBC, troponins, BNP, ABG, CXR

ii. Stat Cardiology consult and Critical Care consult 1. Consider in patients with Cardiogenic Shock:

a. Shock Team consultation

b. Circulatory support (eg. ECMO) iii. Correct electrolytes

iv. Treat arrhythmia 1. If indicated:

a. Amiodarone bolus and infusion per protocol

b. If patient hypotensive with SBP < 90 - Forego bolus and utilize infusion only

v. Surveillance - Due to the high mortality rate and risk of sudden circulatory collapse, recommend proactive testing

1. Non-critical care patients: continuous telemetry monitoring, daily Troponin, BNP q3d, and limited echo q3d for function and effusion

2. Critical care patients: continuous telemetry monitoring, daily Troponin, BNP q3d, and a daily limited echo for function and effusion

3. If any patient develops frequent PVCs, arrhythmia, hypotension, or signs of circulatory collapse, STAT Echo will be performed

E. Nutrition Support Recommendations

Timing

Initiate enteral support within 24 to 36 hours of admission.

Hold in those with high pressure respiratory support and/or increasing pressor requirements, need for multiple agents, MAP trends consistently <60, rising lactate trends, combined with enteral feeding intolerance (EFI): Ileus, abdominal distention, vomiting.

Consider parenteral nutrition (PN) in those patients who meet criteria for moderate or severe malnutrition meeting < 50% nutritional needs > 10 to 14 days. PN subverts concern for ischemic bowel, reduces droplet transmission and enteral related procedures/maintenance.

Delivery

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

Last Updated: 8/4/20

Cluster enteral care such as bolus times and water flushes when in room for other care.

Initiate feeding with high protein (>20%), polymeric, isosmotic formula (PROMOTE). Advance to fiber containing formula (JEVITY) once stable with bowel regularity. Anecdotal reports see increased success and nutrient delivery using Peptamen 1.5 or similar product (calorically dense, hydrolyzed whey protein, improved gastric emptying).

24 hour continuous infusion preferred (as feeding pump availability permits).

Low dose, hypocaloric/trophic advancing to at least 70-80% caloric goal over 1st week. 1. 15-20 kcal/kg actual weight (10/kg obesity/morbid obesity). 2. >1.2 g protein/kg protein, actual weight (caution excessive dosing in obesity).

Bolus administration when indicated: Peptamen 1.5, 125 mL (Prone) / 250 mL (Supine) 3-4 times daily or when nurse in room for other care.

Evaluate indication for prokinetic agents with bowel dysmotility.

Monitoring

Formula and volume goal adjustments per fevers, dehydration, hypernatremia, AKI, steroid induced hyperglycemia, pressor/sedation/paralytic requirements, GI dysmotility.

EFI: abdominal pain, nausea, diarrhea, distention, increased gastric outputs >250 mL q6h.

Consideration for non-intubated, hypoxic patient with or without need for prone therapy

Encourage smaller meals, nutrient dense snacks and calorically dense oral nutrition supplements when patient is supine (Ensure Plus, Ensure Enlive, Nepro for >350-420 calories, > 13 to 20 g protein per 240 mL serving).

Hold trays or downgrade to NPO if patient displays increased work of breathing with oral intake and/or requires increased oxygen requirements.

Reference

Nutrition Therapy in the Patient with COVID-19 Disease Requiring ICU Care https://www.nutritioncare.org/uploadedFiles/Documents/Guidelines_and_Clinical_Resources/Nutrition%20Therapy%20COVID-19_SCCM-ASPEN.pdf

F. Palliative Care Considerations:

a.Consider placing Palliative Care consult in EPIC for goals of care discussion and/or symptoms related to end of life care (EOLC). If implementing EOLC, use EOLC order set in EPIC and consider compassionate extubation or ventilator de-escalation. [Note: With Ventilator de-escalation, endotracheal tube will remain in place and ventilator circuit will remain intact until the patient has died. This may reduce risk of exposure of Covid-19 to visitors and bedside staff]

b. For clinical guidance: management of symptoms commonly encountered in patients with serious illness and COVID-19: https://hmhmaestro.org/wp-content/uploads/symptom-management-guidelines.pdf

c. For clinical guidance: difficult conversations during the COVID-19 era https://hmhmaestro.org/wp-content/uploads/Difficult-Conversations-Guidance-04-27-20.pdf

Ventilator De-Escalation Recommendations https://hmhmaestro.org/wp-content/uploads/Palliative-Care-Considerations-Critical-Care-.pdf

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

Last Updated: 8/4/20

G. Treatment Recommendations

General Treatment Guidance

There is currently no evidence from RCTs to recommend any specific treatment for patients with suspected or confirmed COVID-19 infection. Treatment should be considered in symptomatic patients requiring hospitalization based on a careful assessment of risk factors. The majority of treatment is supportive care with prevention of spread of the disease.

The decision to initiate treatment outside of a clinical trial should be based on a risk assessment including clinical status, co-morbid conditions, acuity of illness, and concomitant medications

EMPIRIC ANTIBIOTICS

Due to the difficulty in differentiating bacterial vs viral pneumonia at the time of presentation, it may be appropriate to initiate an empiric antimicrobial regimen based on the clinical diagnosis (CAP, HCAP, or septic shock). Due to the low incidence of bacterial co-infection, consider discontinuation of antibiotics upon return of a positive COVID-19 PCR. If targeting CAP organisms:

Mild to moderate pneumonia: Ceftriaxone 1 gram IV q24h plus doxycycline 100 mg PO BID for 5-7 d

Severe pneumonia (critically ill): Ceftriaxone 2 gram IV q24h plus azithromycin 500mg IV daily for 5-7 d

ANTICOAGULATION

The underlying coagulopathy associated with COVID-19 remains to be full elucidated, patients admitted to the hospital with the disease appear to hypercoagulable. Additionally, some patients with severe disease may progress to disseminated intravascular coagulation (DIC) with fulminant activation of coagulation, microvascular thrombosis and consumption of coagulation factors.

VTE prophylaxis in hospitalized patient

VTE prophylaxis is indicated for all patients with COVID-19 infection unless a contraindication is present (active bleeding or platelet count < 25 x 103 /L or fibrinogen < 0.5 g/L)

Low molecular weight heparin is preferred over unfractionated heparin if CrCl > 30 mL/min to minimize entry into patient room

For patients with ESRD or AKI requiring renal replacement therapy, prophylaxis with unfractionated heparin is preferred

Sequential compression devices are recommended if pharmacological prophylaxis is contraindicated

1. Prophylactic Dosing Recommendations (NON-Critically Ill Patients)

Medication Recommended

Dosing Obesity*

(>100 kg or BMI >40 kg/m2) CrCl < 30 mL/min

Enoxaparin 40 mg SQ daily 40 mg SQ twice daily 30 mg SQ daily

Unfractionated heparin

5000 units SQ q8h 7500 units SQ q8h No adjustment

2. Prophylactic Dosing Recommendations for Critically-Ill Patients at High Thrombotic Risk

Medication Recommended

Dosing Obesity*

(>100 kg or BMI >40 kg/m2) CrCl < 30 mL/min

Enoxaparin 40 mg SQ q12h 0.5 mg/kg SQ q12h 40 mg SQ daily

Unfractionated heparin

7500 units SQ q8h Utilize enoxaparin No adjustment

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

Last Updated: 8/4/20

Increased prophylactic doses in critically ill patients have been suggested by some clinicians due to an increased perceived thrombotic risk despite standard dose prophylaxis. In a recently published study of 184 critically ill COVID patients, despite receiving standard pharmacologic prophylaxis, 31 experienced thrombotic events (25 PEs, 3 other venous thrombotic events, 3 arterial thrombotic events)

* Obesity may be overrepresented in the COVID-19 population (https://doi.org/10.1101/2020.03.30.20047415).

While increasing prophylactic dosing in obese patients remains controversial due to conflicting data, given the high prevalence of large body habitus in this disease and the observation that VTE risk may be increased, the suggested dosing is above.

Diagnosis of VTE and Therapeutic Anticoagulation

What is the role of biomarkers such as D-dimer in diagnosis of VTE and use of therapeutic anticoagulation? o Elevated D-dimer levels are a common finding in patients with COVID-19, and do not currently

warrant routine investigation for acute VTE in absence of clinical manifestations or other supporting information

o D-dimer has low specificity and it is important to determine if there are other causes of high D-dimer levels, such as pregnancy, inflammation, malignancy, trauma, liver disease, secondary infection, myocardial infarction, renal failure, or coagulopathy.

o Current guidance (ASH, ACC, NIH) recommends against using biomarker thresholds, such as elevated D-dimer, as the sole reason to trigger escalations in anticoagulant dosing outside the setting of a clinical trial, despite it being a marker of poor prognosis. However, acutely worsening clinical status in conjunction with laboratory value changes, such as rising D-dimer, should necessitate further thromboembolic workup or empiric treatment.

Confirmed VTE o Initiate therapeutic anticoagulation. o Low molecular weight heparin is preferred in patients with low bleeding risk, normal renal

function (CrCl >30mL/min), and who are clinically stable

Suspected VTE o Diagnostic imaging should be performed as soon as possible to confirm the presence or

absence of thrombosis If a CT-scan of the chest with IV contrast cannot be performed (i.e. renal impairment) then

an echocardiogram should be considered to assess for signs of potentially worsening right ventricular dysfunction and in rare circumstances a clot in transit

Venous dopplers of the legs may be useful to detect DVTs as well o If there is a high clinical suspicion for thrombosis, it is reasonable to start empiric therapeutic

anticoagulation prior to performing imaging studies to confirm diagnosis If there is no VTE detected, then de-escalation to prophylactic dose anticoagulation may

be reasonable If there is no possibility of performing imaging studies to diagnose DVT/PE, it may

reasonable to initiate empiric therapeutic anticoagulation in the following scenarios: Intubated patients who develop sudden clinical and laboratory findings highly consistent with PE (acute worsening of oxygenation, low blood pressure, tachycardia), especially when CXR and/or markers of inflammation are stable or improving.

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

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Patients with physical findings consistent with thrombosis, such as superficial thrombophlebitis, peripheral ischemia or cyanosis, thrombosis of dialysis filters, tubing or catheters, or retiform purpura (branching lesions caused by thrombosis in the dermal and subcutaneous vasculature).

Patients with respiratory failure, particularly when D-dimer and/or fibrinogen levels are very high, in whom PE or microvascular thrombosis is highly suspected and other causes are not identified (e.g., ARDS from COVID-19, fluid overload).

POST DISCHARGE ANTICOAGULATION

Post Discharge treatment for new or established thrombotic disease: ● DOACs should be considered as first-line therapy in appropriate patients, to minimize the need

for frequent laboratory monitoring and clinic visits. LMWH may be considered in select cases (e.g.

DOAC is not approved by insurance), however the need for subcutaneous injections may limit its

feasibility for long term use. In general, warfarin should be avoided to limit contact of patients

with healthcare services required for INR monitoring.

● In patients with VTE receiving hemodialysis, apixaban may be a reasonable option. In several

retrospective studies, apixaban was shown to be effective without conferring an increased risk of

bleeding in this patient population.

● Contraindications to DOACs include mechanical heart valves, valvular AF, pregnancy or

breastfeeding, APLS, and co-administration of medications including strong CYP3A and P-

glycoprotein inhibitors (-azole medications, HIV protease inhibitors [dependent on DOAC, may

just require dose reduction], CYP3A4 inducers (antiepileptics), St. John’s Wort, rifampin, etc.

● Current guidelines recommend patients with provoked PE/DVT be treated for a duration of 3

months.

Post-discharge thromboprophylaxis in the absence of confirmed thrombotic disease:

● The incidence of VTE post-discharge in COVID-19 patients is unknown, however these patients

appear to be at higher risk than the general population. Consideration to continue post-discharge

prophylaxis should be given to patients who are deemed high-risk. High-risk groups in the non-

COVID-19 context that have previously been considered for extended thromboprophylaxis after

hospital discharge include reduced mobility, advanced age, comorbidities such as active cancer,

and elevated D-dimers. D-dimer should be one of the factors considered for initiating post-

discharge thromboprophylaxis, but decisions should not be made based on this value alone.

● Extended prophylaxis using a regimen of rivaroxaban 10 mg daily (or apixaban 2.5 mg Q12H for

patients with CrCl <30mL/min) may reduce the risk of VTE, at the cost of an increase in bleeding

events, including major bleeding. The rationale for recommending apixaban in the setting of renal

impairment is due to an increased risk of bleeding observed with rivaroxaban 10 mg daily in this

patient population.

● In patients that don’t meet criteria for high thrombotic risk based on above or have unacceptable

bleeding risk, low dose aspirin can be considered as an alternative antithrombotic agent.

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

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● The recommended duration of prophylaxis with these agents is unclear, but should be at least 7

days but not exceed 30 days.

Should empiric therapeutic anticoagulation be continued post-discharge in patients without a diagnosis of VTE due to inability to undergo diagnostic imaging?

There is insufficient evidence at this time to recommend therapeutic anticoagulation post-discharge in patients without confirmed VTE.

For patients in whom therapeutic anticoagulation is discontinued at discharge, please refer to the previous section, ‘Post-discharge thromboprophylaxis in the absence of confirmed thrombotic disease’ for further recommendations.

If therapeutic anticoagulation is continued due to high suspicion or high risk of PE/DVT, repeat imaging (CT chest or duplex ultrasound of the lower extremities) should be performed within 30 days, once the patient is considered negative for COVID-19.

STATINS

Patients on guideline-directed statin therapy should be continued

Patients who are not on statins but have a guideline indication for a statin (e.g. history of MI, CAD, etc), if no contraindication, consider starting: o Atorvastatin 40 mg daily or rosuvastatin 20 mg daily (high-intensity statins) o When major drug-drug interactions with atorvastatin or rosuvastatin are expected, pravastatin

80 mg daily should be considered

Currently there is no outcome data that supports the use of statins in patients with COVID-19 infection outside of guideline indications

Caution: elevated liver enzymes may preclude inclusion in clinical trial (avoid statins if AST/ALT >3x upper limit of normal)

Rationale: o Cardiovascular disease and diabetes are major risk factors for COVID-19 disease severity and

mortality. The case-fatality rates with COVID-19 infection are 10.8% in patients with established CVD and 7.3% with diabetes

o Statins may also help promote antiviral innate immune response

STEROIDS

Recommended Criteria for Use:

Dexamethasone 6mg IV/PO Daily for up to 10 days in patients with COVID-19 who are on mechanical ventilation or who require supplemental oxygen

Treatment with dexamethasone should be avoided in patieents with COVID-19 who do not require supplemental oxygen.

Rationale for Corticosteroids: Based upon the preliminary, unpublished results of the RECOVERY trialconducted by the Ntaional Health Service in the United Kingdom, the NIH and ISDA have recommended the use of corticosteroids for the treatment of patients with clinically-suspected or confirmed COVID-19 in their recent guidelines. The use of dexamethasone(DM) 6mg IV/PO for 10 days or until discharge (whichever comes first) in hospitalized patients that required supplemental oxygen or mechanical ventilation resulte in significantly reduced 28 day mortality when compared to the standard of care(SOC) (21.6% DM vs 24.6% SOC, p<0.001). The outcomes were more favorable based on increasedseverity of illness at randomization.

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

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IL-6 ANTAGONIST

Based on site availability, please consider enrollment into an IL-6 antagonist clinical trial prior to evaluation for off-label use of tocilizumab

The following criteria have been revised to identify patients that may benefit from IL-6 inhibition with tocilizumab based on preliminary observational data: Patient must meet the following criteria: 1. Acute Respiratory Distress Syndrome on mechanical ventilation or worsening oxygenation (despite

corticosteroids) with high oxygen requirements (80-100%) on High Flow Nasal Cannula or 15 L Non-Rebreather Mask

2. Course of illness is greater than 7 days from onset of symptoms 3. Informed Consent documented in the medical record

Exclusion for tocilizumab:

Known active tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections

Presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) less than 2000 mm3, AST/ALT greater than 5 x upper limit of normal, platelets < 50,000

Presence of multi-organ system failure in a critically ill patient Adult Dosing Regimen: 4 mg/kg – 8 mg/kg IV over 30 minutes x 1 dose (Max Dose 800 MG)

COVID-19 INVESTIGATIONAL CLINICAL TRIALS: Wherever possible, preference should be given to enrolling patients in clinical trials All requests for consideration of patients for clinical trials, including for convalescent serum trials, should be submitted via one of two pathways: 1. Via the Epic order "Referral to COVID Research" OR 2. Via the Research Trial enrollment line: 551-996-2994 Please note that the research teams may communicate with you via Epic In-Basket messaging. Please be sure to watch your In-Baskets for these messages. Please include your best callback number so the research team can reach you with any questions or discussion.

Remdesivir (Investigational) Nucleotide prodrug that broad spectrum antiviral activity against members of the filoviruses (e.g, Ebola), Marburg virus [MARV]), SARS-CoV, MERS-CoV) and RSV **Preferred therapy for patients hospitalized due to COVID-19 based on enrollment to clinical trial or compassionate use IND Adult dosing: (see drug panel in EPIC) 200 mg IV load, then 100 mg IV q 24 h for 5 – 10 days (depending on trial or IND)

*On 3/22/20, Gilead revised the criteria for inclusion for IND (see below). An Expanded Access program is available on the individual campuses across HMH network Inclusion Criteria Compassionate Use:

Pregnancy

Patients < 18 years of age with severe disease

Exclusion Criteria Compassionate Use:

Multi-organ failure

Vasopressor requirement

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ALT > 5x ULN

CrCl < 30 mL/min or dialysis

Sarilumab or Tociluzimab (Investigational) Human IgG1 anti-IL-6 receptor α (anti-IL-6Rα) monoclonal antibody that binds selectively to both membrane-bound and soluble IL-6R

Sarulimab: 2:1 randomization 400 mg IV ONCE or SOC

Tocilizumab 2:1 randomization 8 mg/kg IV ONCE vs placebo (may repeat one dose in 8-12 h)

Inclusion: Hospitalized adults with evidence of pneumonia by chest radiograph and requiring supplemental oxygen by nasal cannula or other route with confirmed COVID-19

Convalescent plasma (open-label)

All requests for convalescent serum infusion will be handled via the internal HUMC convalescent plasma trial. This plasma is of very high quality with confirmed high antibody titers. Because we have access here at HUMC to the high-titer convalescent plasma under the HUMC protocol, HUMC will not utilize the Mayo website/route.

Please include the below information in the comments section of the Referral to COVID Research order: - ABO group - Date of admission - Date of intubation (if applicable) - Your best contact number

Convalescent plasma (expanded access program through Mayo Clinic IRB)

Click the link for the patient enrollment form: https://redcap2.mayo.edu/redcap/surveys/?s=R3DHR7X8N4

Information, protocol, consent forms and site registration, enrollment and followup forms are available at www.USCOVIDplasma.org.

Inclusion Criteria: 1. >18 years 2. Lab confirmed SARS-CoV-2 3. Admitted to acute care facility for

COVID-19 complications 4. Severe or life threatening COVID-19, or

high risk of progression to severe or life threatening

5. Informed consent by patient or healthcare proxy

Severe COVID-19 defined as >1 of following:

Dyspnea

Respiratory rate > 30/min

Blood O2 sat < 93%

PaO2/FiO2 ratio <300

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

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Lung infiltrates >50% within 24-48 hr Life threatening COVID-19 defined as >1 of the following:

Respiratory failure

Septic shock

Multiple organ dysfunction or failure

Dantrolene (Ryanodex®) vs SOC (open-label) Day 1 &2: Dantrolene 1/mg/kg IVP q12h f/b Day 3-14: Dantrolene 2 mg/kg IVP q12h

Inclusion: 1:1 randomization

Hospitalized adults with COVID-19 severity score 3-5 according to WHO Ordinal Scale of Severity

Onset of symptoms within 7 days prior to screenLab

Confirmed SARS-CoV-2 infection within 48 hours prior to screening

Febrile temperature (>99 oF oral)documented within 24 hours of consent

TREATMENTS THAT ARE NOT RECOMMENDED AT THIS TIME

Hydroxychloroquine: There is insufficient clinical data to support the role of hydroxychloroquine in treatment of COVID-19. The evidence that has been accrued thus far does not suggest a clear benefit, and may be suggestive of potential harm in both hospitalized patients and outpatients.

NEW RECOMMENDATION: The routine use of hydroxychloroquine for the treatment of COVID-19

CANNOT be recommended at this time. The results of ongoing clinical trials will further define a role, if any, before the decision is made to prescribe hydroxychloroquine to a hospitalized patient.

Azithromycin in combination with hydroxychloroquine has received much attention in the recent media. The release of unpublished reports and public opinion has significantly influenced the demand for this regimen. The data continues to be too limited to make a recommendation for this combination for the treatment of COVID-19 when evaluated in the context of a risk vs potential benefit scenario. Due to the lack of documented clinical outcomes and the risk of potential harm (e.g. additive QTc prolongation), at this time it is not recommended to use azithromycin as monotherapy or to it in combination with hydroxychloroquine for treatment of COVID-19. We will continue to evaluate new information as it becomes available

Lopinavir-ritonavir (Kaletra®) is no longer recommended for the treatment of COVID-19 based on a recently published clinical trial conducted in China (3/18/2020 NEJM) demonstrating no benefit over the standard of care in 199 patients infected with SARS CoV-2

Vitamin C: Currently, there is no published literature demonstrating a clinical benefit to advocate for the use of vitamin C against SARS CoV2. The interest for use with COVID-19 comes from a suggested benefit in other viral infections based on the premise that vitamin C serum levels are reduced in the setting of acute infectious diseases and that there may be some immunomodulating effects that would be beneficial with viral infections. In repeated meta-analyses, vitamin C has not demonstrated a reduction in the incidence of the common cold. A reduction in the duration of colds was demonstrated in some trials, however could not be replicated in subsequent trials. Despite the biological plausibility that vitamin C may be beneficial for the treatment of viral infections, there is

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

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limited evidence to support a recommendation at this time. We will continue to evaluate new information as it becomes available

Other therapies: Therapies with insufficient evidence for treatment of COVID-19: oseltamivir, baloxavir, interferon, ribavirin, IVIG, zinc. As evidence emerges, status will be updated.

H. Blood Cultures

Due to the low incidence of bacterial co-infection in patients presenting with COVID-19 infection,

the following strategy is recommended to avert unnecessary testing and further focus antimicrobial

treatment.

Recommendations are broken into 3 categories:

1. High Suspicion COVID-19 infection Blood cultures are NOT recommended

2. Low Suspicion COVID-19 infection COVID-19 in the differential as a rule out

Draw 1 set of blood cultures

3. Presentation consistent with:

Critical illness

Immunosuppression

High Suspicion due to signs/symptoms consistent with bacterial infection

Draw 2 sets of blood cultures

I. Criteria for Initiating Hydroxychloroquine and Cardiac Monitoring Parameters

1. Criteria for Hydroxychloroquine use

High-Suspicion of COVID-19 (Pending test result)

Positive COVID-19

Patients must meet the following criteria: 1. Hospitalized adults (≥ 18 yr of age)*

AND 2. Not requiring mechanical ventilation at

time of evaluation** AND

3. Clinical presentation consistent with COVID-19 as listed below

Characteristics of COVID-19:

Persistent fevers, cough, myalgia or fatigue, shortness of breath, dyspnea

Lymphopenia, thrombocytopenia, and leukopenia

Elevated alanine aminotransferase and aspartate aminotransferase levels,

Patients must meet the following criteria: 1. Hospitalized adults (≥ 18 yr of age)*

AND 2. Not requiring mechanical ventilation at time

of evaluation**

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

Last Updated: 8/4/20

lactate dehydrogenase, prolonged prothrombin time

Chest radiographs characterized by bilateral patchy infiltrates or chest CT scans demonstrate ground-glass infiltrates

* Patients in the Emergency Department may be initiated if pending hospital admission

** Patients requiring mechanical ventilation early in the course of the disease (e.g. before day 8 of illness) may be considered for treatment

after discussion with the covering infectious diseases consultant

2. Cardiac Monitoring Parameters for Hydroxychloroquine

QTc Monitoring

Obtain baseline 12-lead EKG with calculation of QTc.

Avoid use in patients with QTc >=500 msec (narrow QRS < 120msec) or QTc >= 550 msec (wide

QRS >=120msec); cardiology consultation and follow-up is advised if potential therapy benefit is

high.

Caution with use of concomitant QT-prolonging medications

Place high-risk patients (risk score >7) on continuous telemetry (see below)

Obtain repeat QTc measurement by EKG or telemetry at 48 hours and at 96 hours

Discontinue the medication if there is QTc prolongation > 50 msec from baseline. If

prolongation is detected by telemetry strips, validate with 12-lead EKG prior to discontinuation.

Patients already on telemetry during treatment with HCQ may have their telemetry

discontinued 24 hours after stopping the medication.

If there is polymorphic ventricular tachycardia or torsades de pointes, discontinue the QT-

prolonging medication immediately and consult cardiology.

Calculation of Risk Score for QTc Interval Prolongation

Risk Factors Points Risk Score Category

Risk Score

Age >68 years 1 Low <7

Female sex 1 Moderate 7-10

Loop diuretic 1 High >11

Serum K+ <3.5 mEq/L 2

Admission/baseline QTc >450 ms 2

Acute myocardial infarction 2

+>2 QTc-prolonging drugs 3

Sepsis 3

Heart failure 3

One QTc-prolonging drug 3

Maximum Risk Score 21

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

Last Updated: 8/4/20

J. Post-Exposure Prophylaxis

Currently there are no recommendations for post-exposure prophylaxis with medications

Links:

Gilead – Remdesivir request https://rdvcu.gilead.com/

HMH Maestro Clinical Alerts https://hmhmaestro.org/clinical_alerts/covid19/

Prone Positioning policy found in Policy Stat https://pstat-live-

media.s3.amazonaws.com/pdf_cache/policy/4406686/a41203d1-3780-4002-88f4-

616dbf332c85/Prone%20Positioning%20for%20Acute%20Respiratory%20Distress%20Syndrome

%20-ARDS-%20P-15.pdf

ARDSNET protocol found in Policy Stat https://pstat-live-

media.s3.amazonaws.com/pdf_cache/policy/5281168/3cf2696f-6458-4a1c-9d6e-

01552347cd30/ARDSNET%20Ventilator%20Protocol.pdf

HMH COVID-19 Home Page: https://hmhmaestro.org/covid-19-action-center/

Link to HMH Emergency Medicine Care Pathway: https://hmhmaestro.org/wp-

content/uploads/HMH-COVID-ED-care-pathway-1.7_3-16-20_9pm-1.pdf

Link to COVID Intubation Box and Cardiac Arrest Guideline: https://hmhmaestro.org/wp-

content/uploads/COVID-Intubation-box-and-Cardiac-Arrest-Medication-Updated-3.27.20.pdf

Link to HMH Cardiovascular Care Guidelines: https://hmhmaestro.org/wp-

content/uploads/COVID19-Cardiovascular-Care-guidelines-v1.2-3-30-20-1200h.pdf

Link to HMH Dialysis recommendations: https://hmhmaestro.org/wp-

content/uploads/2020-03-12-COVID-Considerations-for-Dialysis-Patients-DRAFT.pdf

Link to HMH Obstetrical Recommendation: https://hmhmaestro.org/wp-

content/uploads/2020-03-15-COVID-Considerations-for-Obstetrical-Patients-DRAFT-v-

2.1.docx

Link to HMH Newborn Management Recommendation: https://hmhmaestro.org/wp-

content/uploads/2020-03-19-Newborn-Management-Draft-v-2.9.pdf

Seton Hall Library Resources Page:

https://library.shu.edu/COVID19_elective/resources

University of Liverpool COVID-19 Drug Interactions: http://www.covid19-

druginteractions.org/

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

Last Updated: 8/4/20

VI. REFERENCES 1. Wei-jie Guan, Zheng-yi Ni, Yu Hu, et al. Clinical Characteristics of Coronavirus Disease 2019 in China.

NEJM February 28, 2020 DOI: 10.1056

2. CDC. Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease

(COVID-19). https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-

patients.html. Accessed 3/12/2020.

3. Yang X, Yu Y, Xu J, Shu H, Xia J, et al. Clinical course and outcomes of critically ill patients with SARS-

CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet

Respir Med. 2020.

4. Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. [The Epidemiological

Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19) in China]. Zhonghua

Liu Xing Bing Xue Za Zhi. 2020;41(2):145–151

5. Wang, M, Ruiyuan C, Leike Z et al. Remdesivir and chloroquine effectively inhibit the recently

emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020 30;269-271.

6. Yao X, Fei Y, Miao Z, et al. In vitro antiviral activity and projection of optimized dosing design of

hydroxychloroquine for the treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-

CoV-2). Clin Infect Dis 2020; https://doi-org.proxy.lib.umich.edu/10.1093/cid/ciaa237

7. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in

treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020 Feb 19 [Epub

ahead of print]; doi:10.5582/bst.2020.01047.

8. Colson P, Rolain JM, Lagier JC et al. Chloroquine and hydroxychloroquine as available weapons to

fight COVID-19. Int J of Antimicrob Agents (2020);

https://doi.org/10.1016/j.ijantimicag.2020.105932

9. Chu CM et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical

findings. Thorax 2004; 59: 252–56

10. Ying-Hui Jin. Cai L, Cheng ZS, Cheng H, et al. rapid advice guidelines for the diagnosis and treatment

of 2019 novel coronavirus (2019-n-CoV) infected pneumonia standard version. Military Medical

Research 2020;7(4):1-23

11. Cao,B, Wang,D, Wen,W et al. A trial of lopinavir-ritonavir in adults hospitalized with Severe Covid-

19. N Engl J Med 2020; Mar 18 (epub ahead of print) DOI: 10.1056/NEJMoa2001282

12. Mehta P, McAuley DF, Brown M, et al. COVID-19: Consider cytokine storm syndromes and

immunosuppression. Lancet 2020 https://doi.org/10.1016/S0140-6736(20)30628-0.

13. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill

ICU patients with COVID-19. Thrombosis Research. 2020.

14. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and Thrombotic or Thromboembolic Disease:

Implications for Prevention, Antithrombotic Therapy, and Follow-up. Journal of the American

College of Cardiology. 2020:27284.

15. Reed D, Palkimas S, Hockman R, Safety and effectiveness of apixaban compared to warfarin in

dialysis patients. Res Pract Thromb Haemost. 2018;2:291–298.

QUESTIONS CONCERNS CONTACT DR ROBERT BAYLY 732-379-0832

Last Updated: 8/4/20

16. Siontis KC, Zhang X, Eckard A, et al. Outcomes Associated With Apixaban Use in Patients With End-

Stage Kidney Disease and Atrial Fibrillation in the United States. Circulation. 2018;138(15):1519-

1529.

17. Weitz JI, Raskob GE, Spyropoulos AC et al, Thromboprophylaxis with Rivaroxaban in Acutely Ill

Medical Patients with Renal Impairment: Insights from the MAGELLAN and MARINER Trials,

Thrombosis and Haemostasis, 2020; 120(03): 515-524.

18. Cohen AT, Spiro TE, Büller HR et al. MAGELLAN Investigators. Rivaroxaban for Thromboprophylaxis

in Acutely Ill Medical Patients. N Engl J Med 2013; 368: 513-23.

19. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in

acutely ill medical patients. N Engl J Med 2016; 375: 534-44.

20. Spyropoulos AC, Ageno W, Albers GW, et al. Rivaroxaban for Thromboprophylaxis after

Hospitalization for Medical Illness. New England Journal of Medicine. 2018;379(12):1118-1127.

21. COVID-19 and VTE/Anticoagulation: Frequently Asked Questions.

https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation Accessed 4/20/2020

22. Xu X, Han M, Li T, et al Effect treatment of severe COVID-19 patients with tocilizumab. China Xiv

2020.

23. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Du C, Zhang Y, Song J, Wang S, Chao Y,

Yang Z, Xu J, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y. Risk Factors Associated

With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019

Pneumonia in Wuhan, China. JAMA Intern Med 2020;13.

24. Shang L, Zhao J, Hu Y, Du R, Cao B. On the use of corticosteroids for 2019-nCoV pneumonia: Lancet.

2020 Feb 29;395(10225):683-684. doi: 10.1016/S0140-6736(20)30361-5. Epub 2020 Feb 12.

25. Alhazzani W, Moller MH, Arabi YM, et al Surviving sepsis campaign: guidelines on the management

of critically ill adults with coronavirus disease 2019 (COVID-19).

.