COVID-19

Updated: 2020-Mar-31

Outpatient Management

In-Hospital (Non-ICU) Management

ICU Management

Therapies

Organ Involvement & Special Conditions

Discharge Planning

Goals of Care & Ethics

Personal Protective Equipment

Background & Research

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1
 COVID-19 | Outpatient

Outpatient Management

Outpatient Management

Pets

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 COVID-19 | Inpatient

In-Hospital (Non-ICU) Management

Orders | Admission and Daily Trends

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 COVID-19

ICU Management

Orders | Admission and Daily Trends

ICU Bundle

Mechanical Ventilation

Non-Invasive Positive Pressure Ventilation (NIPPV)

Proning

ECMO

Emergency Protocol | Bi-level to Ventilator

Shock: Septic, Cardiogenic, Cytokine Storm

Undifferentiated Shock in COVID-19

Septic Shock and Secondary Infections

Cardiogenic Shock

Cytokine Activation Syndrome

Pharmacology

Pressors and Inotropes

Sedation

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 COVID-19

Therapies

Antibiotic Stewardship

Metered-dose inhalers (MDIs) vs nebulizers

Airway Clearance

Inhaled Pulmonary Vasodilators

Corticosteroids

Blood Products

Experimental Therapies and Clinical Trials

Remdesiver

Hydroxychloroquine and Chloroquine

Lopinavir / Ritonavir

Anti-IL6 Agents (Tocilizumab, Siltuximab)

ACE-I and ARBs

NSAIDs

Statins

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 COVID-19

Cardiac Complications

Acute Cardiac Injury

Cardiovascular Testing

Arrhythmias

Acute Coronary Syndromes

Pericarditis and Myocarditis

Renal Manifestations

Acute Kidney Injury (AKI)

Liver Manifestations

Liver Disease

Thrombotic and Coagulation Manifestations

Thrombotic Disease

Disseminated Intravascular Coagulation (DIC)

Oncology Considerations

Oncology Considerations

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 COVID-19

Discharge Planning

Discharge | For Patients

Discharge | For Providers

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 COVID-19 | Goals of Care & Ethics

Goals of Care & Ethics

Palliative Resources

VitalTalk Playbook

Addressing Advance Care Planning

CPR | Talking about it with patients (MGH)

Rationing Resources

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 COVID-19 | Personal Protective Equipment

Personal Protective Equipment

Airborne vs Droplet | What’s the difference?

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 COVID-19

Background

Clinical Snapshot

Clinical Course

Epidemiology

Timeline of Events

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 COVID-19 | Outpatient

What to do if you are sick:

When to Seek Medical Attention:

- If you develop emergency warning signs for COVID-19 get medical attention immediately.
- Emergency warning signs include*:
- Trouble breathing
- Persistent pain or pressure in the chest
- New confusion or inability to arouse
- Bluish lips or face

Call 911 if you have a medical emergency:

- If you have a medical emergency and need to call 911, notify the operator that you have or think you might have, COVID-19.
- If possible, put on a facemask before medical help arrives.

How to discontinue home isolation:

- People with COVID-19 who have stayed home (home isolated) can stop home isolation under the following conditions:
- If you will not have a test to determine if you are still contagious, you can leave home after these three things have happened: 1) You have had no fever for at least 72 hours
(that is three full days of no fever without the use medicine that reduces fevers) 2)AND other symptoms have improved (for example, when your cough or shortness of breath
have improved) 3) AND
at least 7 days have passed since your symptoms first appeared
- If you will be tested to determine if you are still contagious, you can leave home after these three things have happened: 1) You no longer have a fever (without the use
medicine that reduces fevers) 2) AND other symptoms have improved (for example, when your cough or shortness of breath have improved), 3) AND you received two
negative tests in a row, 24 hours apart. Your doctor will follow CDC guidelines.

Stay home except to get medical care:

- Most people with COVID-19 have mild illness and are able to recover at home without medical care.
- Do not leave your home, except to get medical care.
- Do not visit public areas.
- Stay in touch with your doctor.
- Call before you get medical care.
- Be sure to get care if you have trouble breathing, or have any other emergency warning signs, or if you think it is an emergency.
- Avoid using public transportation, ride-sharing, or taxis.

Separate yourself from other people in your home, this is known as home isolation
- Stay away from others: As much as possible, you stay away from others.
- You should stay in a specific “sick room” if possible, and away from other people in your home.
- Use a separate bathroom, if available.

Call ahead before visiting your doctor

- Many medical visits for routine care are being postponed or done by phone or telemedicine.
- If you have a medical appointment that cannot be postponed, call your doctor’s office, and tell them you have or may have COVID-19. This will help the office protect
themselves and other patients.

If you are sick wear a facemask in the following situations, if available.

- You should wear a facemask, if available, when you are around other people (including before you enter a healthcare provider’s office).
- If the person who is sick is not able to wear a facemask (for example, because it causes trouble breathing), then as their caregiver, you should wear a facemask when in the
same room with them.
- Visitors, other than caregivers, are not recommended.
- Note: During a public health emergency, facemasks may be reserved for healthcare workers.
- You may need to improvise a facemask using a scarf or bandana

Cover your coughs and sneezes

- Cover: Cover your mouth and nose with a tissue when you cough or sneeze.
- Dispose: Throw used tissues in a lined trash can.
- Wash hands: Immediately wash your hands with soap and water for at least 20 seconds. If soap and water are not available, clean your hands with an alcohol-based hand
sanitizer that contains at least 60% alcohol.

Clean your hands often

- Wash hands: Wash your hands often with soap and water for at least 20 seconds. This is especially important after blowing your nose, coughing, or sneezing; going to the
bathroom; and before eating or preparing food.
- Hand sanitizer: If soap and water are not available, use an alcohol-based hand sanitizer with at least 60% alcohol, covering all surfaces of your hands and rubbing them
together until they feel dry.
- Soap and water: Soap and water are the best option, especially if hands are visibly dirty.
- Avoid touching: Avoid touching your eyes, nose, and mouth with unwashed hands.

Avoid sharing personal household items

- Do not share: Do not share dishes, drinking glasses, cups, eating utensils, towels, or bedding with other people in your home.
- Wash thoroughly after use: After using these items, wash them thoroughly with soap and water or put in the dishwasher.

Clean all “high-touch” surfaces everyday

- Clean high-touch surfaces in your isolation area (“sick room” and bathroom) every day; let a caregiver clean and disinfect high-touch surfaces in other areas of the home.
- Clean and disinfect: Routinely clean high-touch surfaces in your “sick room” and bathroom.
- Let someone else clean and disinfect surfaces in common areas, but not your bedroom and bathroom.
- If a caregiver or other person needs to clean and disinfect a sick person’s bedroom or bathroom, they should do so on an as-needed basis.
- The caregiver/other person should wear a mask and wait as long as possible after the sick person has used the bathroom.
- High-touch surfaces include phones, remote controls, counters, tabletops, doorknobs, bathroom fixtures, toilets, keyboards, tablets, and bedside tables.
- Clean and disinfect areas that may have blood, stool, or body fluids on them.
- Household cleaners and disinfectants: Clean the area or item with soap and water or another detergent if it is dirty. Then, use a household disinfectant.
- Be sure to follow the instructions on the label to ensure safe and effective use of the product.
- Many products recommend keeping the surface wet for several minutes to ensure germs are killed.
- Many also recommend precautions such as wearing gloves and making sure you have good ventilation during use of the product.

Monitor your symptoms

- Common symptoms of COVID-19 include fever and cough.
- Trouble breathing is a more serious symptom that means you should get medical attention.
- If you are having trouble breathing, seek medical attention, but call first.
- Call your doctor or emergency room before going in and tell them your symptoms. They will tell you what to do.
- Wear a facemask: If available, put on a facemask before you enter the building.
- If you can’t put on a facemask, cover your coughs and sneezes.
- Try to stay at least 6 feet away from other people.
- This will help protect the people in the office or waiting room.
- Follow care instructions from your healthcare provider and local health department: Your local health authorities may give instructions on checking your symptoms and
reporting information.

Updated: 2020-04-02
Return to Index Source: CDC: What To Do if You Are Sick 11
 COVID-19 | Outpatient | Pets

COVID-19 and Animals

Can I get COVID-19 from my pets or other animals:

- There is no reason at this time to think that any animals, including pets, in the United States
might be a source of infection with this new coronavirus that causes COVID-19.
- To date, CDC has not received any reports of pets or other animals becoming sick with COVID-19
in the United States.
- Pets have other types of coronaviruses that can make them sick, like canine and feline
coronaviruses. These other coronaviruses cannot infect people and are not related to the
current COVID-19 outbreak.
- However, since animals can spread other diseases to people, it’s always a good idea to practice
healthy habits around pets and other animals, such as washing your hands and maintaining
good hygiene.
- For more information on the many benefits of pet ownership, as well as staying safe and
healthy around animals including pets, livestock, and wildlife, visit CDC’s Healthy Pets, Healthy
People website.

Do I need to get my pet tested for COVID-19:

- No. At this time, routine testing of animals for COVID-19 is not recommended.

Can animals carry the virus that causes COVID-19 on their skin or fur:
- At this time, there is no evidence that the virus that causes COVID-19 can spread to people from
the skin or fur of pets.
- Talk to your veterinarian about the best ways to care for your pet.

Should I avoid contact with pets or other animals if I am sick with COVID-19:
- You should restrict contact with pets and other animals while you are sick with COVID-19, just
like you would around other people.
- Although there have not been reports of pets or other animals becoming sick with COVID-19, it
is still recommended that people sick with COVID-19 limit contact with animals until more
information is known about the new coronavirus.
- When possible, have another member of your household care for your animals while you are
sick. If you are sick with COVID-19, avoid contact with your pet, including petting, snuggling,
being kissed or licked, and sharing food.
- If you must care for your pet or be around animals while you are sick, wash your hands before
and after you interact with pets.

Are pets from a shelter safe to adopt:

- There is no reason to think that any animals, including shelter pets, in the United States might
be a source of COVID-19.

What about imported animals or animal products:

- CDC does not have any evidence to suggest that imported animals or animal products pose a
risk for spreading COVID-19 in the United States.
- This is a rapidly evolving situation and information will be updated as it becomes available. The
U.S. Centers for Disease Control and Prevention (CDC), the U. S. Department of Agriculture
(USDA), and the U.S. Fish and Wildlife Service (FWS) play distinct but complementary roles in
regulating the importation of live animals and animal products into the United States.
- CDC regulates animals and animal products that pose a threat to human health, USDA
regulatesexternal icon animals and animal products that pose a threat to agriculture; and FWS
regulatesexternal icon importation of endangered species and wildlife that can harm the health
and welfare of humans, the interests of agriculture, horticulture, or forestry, and the welfare
and survival of wildlife resources.

Updated: 2020-04-02
Return to Index Source: CDC: COVID-19 and Animals 12
 COVID-19 | Outpatient

Testing
Outpatient Positive COVID test: NORTH SHORE
❑ Please notify Infection Control at x4744 if your patient has known outpatient positive COVID test
result so the patient can be appropriately cohorted and repeat testing can be avoided.

Updated: 2020-03-25
Return to Index Source: No formal source 13
 COVID-19 | Non-ICU Management

Orders | On Admission
❑ CBC with differential
❑ BMP
❑ LFTs
❑ LDH,
❑ CRP
❑ D-dimer
❑ Troponin / CPK
❑ PTT / INR
❑ Procalcitonin
❑ Baseline EKG

Orders | Daily
For stable floor patients, consider every other day
❑ CBC with differential
❑ BMP

Every other day:

❑ LFTs
❑ LDH
❑ CRP
❑ D-dimer
❑ Troponin / CPK (if in ICU)
❑ Triglycerides (if on propofol)

If clinical worsening, add:

❑ PTT / INR
❑ Procalcitonin
❑ Ferritin, Fibrinogen
❑ EKG

Expert opinion does NOT recommend routine pro-BNP

Imaging
❑ CXR (portable) is sufficient in most cases.
- Avoid routine daily CXR (unlikely to change management, evaluate case-by-case)
- Chest imaging variable; bilateral patchy opacities most common

❑ CT Chest often will not change treatment

- Obtain only if necessary (risk of transmission, time associated with transport /
decontamination of equipment)

❑ Point of Care Ultrasound of the lungs can be used but by experienced providers only

❑ Obtain additional studies only if necessary

❑ Avoid routine TTEs

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 14
 COVID-19 | Non-ICU Management

Orders | On Admission
❑ CBC with differential
❑ CMP / Mg / Phos
❑ LDH,
❑ CRP, ESR
❑ D-dimer
❑ Ferritin
❑ Lactate
❑ T-Cell subset
❑ CKs
❑ ABG with lactate
❑ G6PD
❑ PTT / INR
❑ Procalcitonin
❑ Baseline EKG

Orders | Daily
❑ CBC with differential
❑ CMP / Mg / Phos
❑ CRP
❑ ABG with lactate
❑ EKG daily while on Chloroquine (which prolongs QTc)

Clinical Practice
Blood Cultures:
❑ Refrain from ordering routine blood cultures in COVID positive patients with persistent fevers
unless you suspect a secondary nosocomial process. It is expected that these patients will be
febrile for days due to the virus.

Antibiotics:
❑ We can likely discontinue antibiotics in COVID patients once the diagnosis is confirmed in most
cases. Like with anything else, we have limited resources and it is important to be good
stewards of antibiotic use.

Continuous Pulse Ox:

❑ Discontinue continuous pulse ox order in Sunrise if not needed.
- We should ingrain this practice into our daily workflow as not all COVID units can
accommodate continue pulse ox monitoring.

Consults and Imaging:

❑ We should made every effort to limit consults and ordering tests(i.e. imaging) in COVID positive
patients to mitigate the risk of exposure.

RVP Testing:
- Be aware that the traditional RVP test will no longer be processed and will be cancelled if the
patient is being ruled out for COVID-19.

Updated: 2020-03-26
Return to Index Source: No formal source 15
 COVID-19 | Non-ICU Management

Testing | Initial
If you suspect a new COVID case on a non-COVID unit, the following steps should be taken:
❑ Notify infection control at x4744.
❑ The patient should be swabbed on the non-COVID unit.
- The patient will remain on the non-COVID unit until further instruction from Infection Control
is provided.

Testing | Repeat
Review the attached algorithm to be used as a guide on who should be retested when the initial test
result is negative.

ED Patients (who are admitted): NORTH SHORE

❑ The decision to retest when the initial COVID test returns negative will be made by the HIC
based on the clinical characteristics with the support of the algorithm.
❑ The HIC should then contact Logistics at x2495
❑ If a retest will be performed, the patient will be admitted to a COVID unit pending the result of
the second test.

Floor Patients: NORTH SHORE

❑ The decision can be made by the hospitalist in conjunction with the COVID ID unit
advisor/consultant or infection prevention.
❑ The ID attending will then communicate this information back to Infection Control.

Updated: 2020-03-25
Return to Index Source: No formal source 16
 COVID-19 | Non-ICU Management

Management | Medical
Management is largely supportive
❑ Fluid management should be conservative due to risk of hypoxia/CHF
❑ Antiviral and immune-modulating therapies are investigational
❑ See section on experimental therapy

MOLST
Advanced Care Planning (Early)
❑ In conscious patients, review or sign Health Care Proxy form
❑ Discuss and document goals of care on admission
❑ Educate patient and family on disease course
❑ Focus on desired quality of life and tolerance for ICU measures)

Respiratory Support
See separate section on respiratory support

Supplemental Oxygen:
❑ Humidified nasal cannula (NC) 1 to 8 LPM for target SpO2 92-96%
- If a patient requires > 8 LPM NC:
- Initiate dry Venturi mask (non-humidified to reduce aerosolization risk)

❑ Start Venturi mask at 9 LPM and FiO2 28%

- Up-titrate FiO2 to goal SpO2 of 92-96% (not exceeding FiO2 35%)
- If FiO2 > 35% then increase flow to 12 LPM
- Notify ICU triage pager

❑ Avoid high-flow nasal cannula (HFNC) and non-invasive positive pressure ventilation (NIPPV;
i.e. CPAP/BiPAP) for ARDS.
- If a patient is DNR/DNI or otherwise is not eligible for intubation:
- Current policy advises avoiding HFNC or NIPPV in DNI/DNR patients. However, neither HFNC
nor NIPPV is prohibited and case-by-case exceptions could apply.
- This is an evolving area without definitive evidence or uniform policy that underwent multi-
disciplinary discussion.

Early intubation:
❑ We recommend early consultation with anesthesia for possible intubation in the setting of
rapidly progressive hypoxia.
- Case reports from China suggest high failure rates for non-invasive ventilation, including high-
flow nasal oxygen (Zuo et al, Chin Med Sci J, 2020)
❑ For patients maintained on Venturi mask, once FiO2=60% and SpO2 < 92%, call for intubation if
patient is a candidate for mechanical ventilation
- Many centers suggest Rapid Sequence Intubation when fully paralyzed, without ambu-bag
(which generates aerosols) and highly experienced operators (e.g., anesthesia attending).
- Consider additional indications for intubation (tachypnea, work of breathing)

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 17
 COVID-19 | ICU Management

Orders | On Admission
❑ CBC with differential
❑ BMP
❑ LFTs
❑ LDH,
❑ CRP
❑ D-dimer
❑ Troponin / CPK
❑ PTT / INR
❑ Procalcitonin
❑ Baseline EKG

Orders | Daily
For stable floor patients, consider every other day
❑ CBC with differential
❑ BMP

Every other day:

❑ LFTs
❑ LDH
❑ CRP
❑ D-dimer
❑ Troponin / CPK (if in ICU)
❑ Triglycerides (if on propofol)

If clinical worsening, add:

❑ PTT / INR
❑ Procalcitonin
❑ Ferritin, Fibrinogen
❑ EKG

Expert opinion does NOT recommend routine pro-BNP

Imaging
❑ CXR (portable) is sufficient in most cases.
- Avoid routine daily CXR (unlikely to change management, evaluate case-by-case)
- Chest imaging variable; bilateral patchy opacities most common

❑ CT Chest often will not change treatment

- Obtain only if necessary (risk of transmission, time associated with transport /
decontamination of equipment)

❑ Point of Care Ultrasound of the lungs can be used but by experienced providers only

❑ Obtain additional studies only if necessary

❑ Avoid routine TTEs

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 18
 COVID-19 | ICU Management

Orders | On Admission
❑ CBC with differential The following COVID Order Sets are now
❑ CMP / Mg / Phos available in Sunrise:
❑ LDH,
❑ CRP, ESR ❑ ED COVID-19
- Stop ordering ESR, it is backing up the lab. ❑ COVID-19 Management:
❑ D-dimer - to be used for admitting non-ICU pts
❑ Ferritin ❑ COVID-19 ICU Management
❑ Lactate ❑ COVID-19 Immunology Supplemental
❑ T-Cell subset Labs
❑ CKs
❑ ABG with lactate
❑ G6PD
❑ PTT / INR
❑ Procalcitonin
❑ Baseline EKG

Orders | Daily
❑ CBC with differential
❑ CMP / Mg / Phos
❑ CRP
❑ ABG with lactate
❑ EKG daily while on Chloroquine (which prolongs QTc)

Clinical Practice
Blood Cultures:
❑ Refrain from ordering routine blood cultures in COVID positive patients with persistent fevers
unless you suspect a secondary nosocomial process. It is expected that these patients will be
febrile for days due to the virus.

Antibiotics:
❑ We can likely discontinue antibiotics in COVID patients once the diagnosis is confirmed in most
cases. Like with anything else, we have limited resources and it is important to be good
stewards of antibiotic use.

Continuous Pulse Ox:

❑ Discontinue continuous pulse ox order in Sunrise if not needed.
- We should ingrain this practice into our daily workflow as not all COVID units can
accommodate continue pulse ox monitoring.

Consults and Imaging:

❑ We should made every effort to limit consults and ordering tests(i.e. imaging) in COVID positive
patients to mitigate the risk of exposure.

RVP Testing:
- Be aware that the traditional RVP test will no longer be processed and will be cancelled if the
patient is being ruled out for COVID-19.

Updated: 2020-03-31
Return to Index Source: No formal source 19
 COVID-19 | ICU Management

“ICU Bundle”
Rationale: Use of a daily checklist ensures that routine quality measures are in place for each patient.
Review Bundle Checklist at the end of each patient’s presentation, every day. Each section should be
performed unless there is a contraindication or barrier to implementation. If a contraindication is
present, discuss how barriers may be overcome.

Ventilator
SAT and SBT (perform concurrently if able):
❑ Spontaneous Awakening Trial (SAT): Turn off sedation
❑ Spontaneous Breathing Trial (SBT): Place patient on Pressure Support 5/5
Contraindications to SAT/SBT include: FiO2 > 50%, PEEP > 8, O2 sat < 90%, pH < 7.30, SBP < 90 or
MAP < 60, Paralysis, intracranial pressure >15, concern for significant bleeding
If ARDS:
❑ Goal Vt 4-6 cc/kg of ideal body weight (calculated by height), plateau pressure < 30
❑ Head of bed at >30 degrees
❑ Oral care is ordered

Sedation / Delirium
❑ Ask: Is patient delirious (CAM+)?
❑ Review med list for any deliriogenic medications and discontinue/change where possible
❑ Define RASS goal
❑ Record QTc daily, consider changing medications if QTc > 500

Restraints
❑ Ask: Are restraints needed?
❑ Sign necessary restraint orders
❑ Discuss barriers to removing restraint orders

Mobility
❑ Consult PT for early mobility
❑ Contraindications include: deep sedation, paralysis

Tubes / Lines / Drains

❑ List all tubes / lines / drains and discuss if any can be removed or should be changed

Patient / Family Communication

❑ Discuss if patient has healthcare making capacity - if not, activate healthcare proxy
❑ Update families by phone
❑ Suggest RN update at least daily
❑ MD update Q3 days, with any significant clinical change, or per family request

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 20
 COVID-19 | ICU Management

“ICU Bundle” | Continued

Rationale: Use of a daily checklist ensures that routine quality measures are in place for each patient.
Review Bundle Checklist at the end of each patient’s presentation, every day. Each section should be
performed unless there is a contraindication or barrier to implementation. If a contraindication is
present, discuss how barriers may be overcome.

GI / Nutrition
❑ Famotidine 20mg IV BID in intubated patients;
❑ Pantoprazole 20-40mg IV daily if history of GERD or GI bleed
❑ Review nutrition, consult nutrition if not already done.
- While awaiting nutrition input, start enteral nutrition:
- In most patients, Osmolite 1.5 @10mL/hr, advance by 20mL Q6h to goal 50mL/hr
- If renal failure and high K or phos: Nepro @ 10mL/hr, advance by 10mL Q6h to goal 40mL/hr
❑ MVI with minerals daily
❑ thiamine 100mg daily x3 days
❑ folate 1mg daily x 3 days
❑ Ask: Is bowel regimen adequate? Make changes if necessary.
❑ Review glucose range over past 48h and insulin regimen, adjust regimen if needed.
❑ Goal glucose range is 70-180

Disposition
❑ Discuss anticipated dispo, barriers to dispo

MOLST
Code Status
❑ Review current code status, discuss if goals of care are realistic with prognosis - if not, discuss
with patient / family

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 21
 COVID-19 | Mechanical Ventilation

Initial Settings
❑ Mode:
= Volume Control (AC/VC)

❑ Tidal Volume (Vt):

= 6 ml/kg (based on ideal body weight [IBW] (from ARDSnet)
- IBW men (kg)= 50 + 2.3 (height in inches – 60)
- IBW women (kg)= 45.5 + 2.3 (height in inches – 60)

❑ Respiratory Rate (RR):

= 16-24, higher if acidosis present

❑ PEEP:
= based on BMI:
- BMI < 35: PEEP 10
- BMI 35 to 50: PEEP 12
- BMI > 50: PEEP 15

❑ FiO2:
= 100% on intubation then rapidly wean to SpO2 92-96%
- (Barrot et al, N Engl J Med, 2020)

Orders:
❑ Obtain STAT portable CXR to confirm endotracheal tube location:
❑ Order and page radiology at time of intubation
- Prioritize CXR and vent titration over procedures (such as CVC placement) if possible.
❑ ABG (preferred) or a VBG within 30 minutes of intubation
- Adjust ventilation and oxygenation as needed

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 22
 COVID-19 | Mechanical Ventilation

Updated: 2020-03-25
Return to Index Source: NSUH Rapid Critical Care Management Primer 23
 COVID-19 | Mechanical Ventilation

Updated: 2020-03-25
Return to Index Source: NSUH Rapid Critical Care Management Primer 24
 COVID-19 | Mechanical Ventilation

Updated: 2020-03-25
Return to Index Source: NSUH Rapid Critical Care Management Primer 25
 COVID-19 | Mechanical Ventilation

Updated: 2020-03-25
Return to Index Source: NSUH Rapid Critical Care Management Primer 26
 COVID-19 | Mechanical Ventilation

Mechanical Ventilation | Lung Protection

What is the standard approach to ARDS that might be applicable to COVID-19 patients?
- With reference to ARMA, FACTT, LOVS, EXPRESS, ALVEOLI, ART and PROSEVA
- Since everything we are seeing about these patients indicates that they are similar to normal ARDS patients,
if somewhat milder than might have been expected, we can have great confidence in applying the evidence-
based supportive care approach that has been developed by ARDSnet/PETAL and others over the last 50
years of ARDS research.
- This is one reason why there is such a high degree of similarity between the various treatment
guidelines for ICU care of COVID-19 patients that are now publicly available such our own, those
published by the Brigham and Women’s Hospital and those published last week by the Society of
Critical Care Medicine.
- All of the guidelines, including the MGH ones, amount to reiteration of standard evidenced-based
critical care.
- The papers mentioned above constitute the core of the evidence base for the critical care of ARDS.
- All the available guidelines urge low tidal volume ventilation (as outlined in the classic ARMA trail),
conservative fluid management (as outlined in the FACTT trial) , judicious use of PEEP in the event
of poor mechanics or poor oxygenation and prone ventilation for those failing to respond
(associated with a substantial mortality benefit in PROSEVA) and judicious use of PEEP in the event
of poor mechanics or poor oxygenation.
- There are two places where the MGH guidelines diverge more significantly from those put out by the SCCM.
- These are in the use of HFNC and/or NIPPV and the use of high PEEP.
- The MGH guidelines discourage the use of HFNC and/or NIPPV in COVID-19 patients and the SCCM
guidelines suggest their use in order to forestall intubation.
- The SCCM guidelines suggest the use of high PEEP and/or recruitment maneuvers and the MGH
guidelines de-emphasize recruitment maneuvers and high PEEP, while acknowledging that select
patients may benefit.
- The issue of NIPPV and HFNC is a significant one and will be dealt with at length in a subsequent
FLARE email. Tonight’s email deals extensively with the issue of PEEP and the appropriate way to
set it in ARDS in general and COVID-19 associated respiratory failure in particular.
- We provide summaries of the three major, early trials of high PEEP approaches EXPRESS, ALVEOLI and LOVS.
- These three trials have in common that they showed no mortality benefit to high PEEP and/or
recruitment strategies.
- This was surprising, because the physiologic rationale for PEEP and recruitment maneuvers is clear
– in ARDS the critical opening pressure of some lung units is increased, leading to those units being
under ventilated at normal airway pressures and, to the extent that they are still perfused,
increased shunt and arterial hypoxemia.
- These units may, in fact, require quite elevated trans-pulmonary pressures.
- Fortunately, the lung pressure-volume is characterized by substantial hysteresis so that the
pressure required to keep a lung unit open may be substantially less than that needed to open it.
- These observations seem to constitute a compelling rationale for a high-driving pressure
recruitment maneuver followed by relatively high PEEP and this approach came to be known as
the open lung approach.
- Despite the discouraging clinical results, subsequent meta-analysis suggested that there did exist a
subset of patients who benefit from an open lung approach.
- This was the background to the ART trail published in 2017 which tested a formal
recruitment maneuver followed by physiologically titrated PEEP based on the best tidal
compliance.
- This trial generated great interest as in showed an increase in mortality in the treatment
arm.
- Three randomized trials with no benefit and one that suggested harm constitute an
impressive argument against an open lung approach.
- Nevertheless, there are problems with ART. If the contention was that only a subset of patients
benefit from PEEP, it was somewhat unsatisfying that ART made no attempt to identify this
subgroup.
- In fact, the difference in driving pressure between the two arms of ART was only 2cm
H2O which indicates not much recruitment occurred, perhaps because the patients
where not enriched with the subgroup purported to benefit.
- A fair summary of this literature is that the clinical evidence for high PEEP and
recruitment for every patient is poor.
- However, it is still likely true that if driving pressure does not increase (or goes down)
as PEEP increases then recruitment is occurring and this is likely to be beneficial.
- This summary forms the basis of the recommendations in our guidelines for use of the
ARDSnet low PEEP table if patients are not meeting targets on initial settings and for
careful individual PEEP titration if expert personal are available (to monitor driving
pressure during the titration and determine if patients are truly recruitable).

Updated: 2020-03-23
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 COVID-19 | Mechanical Ventilation

PEEP | High vs Low in ARDS

National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. "Higher versus lower positive
end-expiratory pressures in patients with the acute respiratory distress syndrome." New England
Journal of Medicine 351.4 (2004): 327-336.

ALVEOLI
- Higher versus lower positive end-expiratory pressures in patients with the acute respiratory
distress syndrome. N Engl J Med. 2004;351(4):327-36.

Background:
- High PEEP vs. low PEEP: high PEEP may improve O2, reduce VILI, but can worsen circulatory
depression or overdistention

Methods:
- n = 549 ALI/ARDS pts (P:F ratio<300 + bilateral infiltrates, enrolled within 36 hrs of onset),
randomized to low/high PEEP on MV (on 6cc/kg Vt, and Pplat <30cm), according to tables of
PEEP/FiO2, below:
- NOTE: 171 pts were enrolled initially and split between low vs. high PEEP groups, but then it
was found that the difference in mean PEEP between the high/low PEEP groups was too small;
the remaining 378 patients were randomized between a low and a new higher PEEP protocol.

Results:
- LOW PEEP group: Mean PEEP 8.3+/- 3.2cm H2O
- HIGH PEEP group: Mean PEEP 13.2 +/-3.5 cmH2O
- Primary Outcome (Low vs. High), in-hospital mortality: 24.9% vs. 27.5% (p = 0.48, 95% CI for
difference -10% to +4.7%).
- Secondary Outcome, # of days with unassisted breathing out of 28 days (Low vs. High): 14.5+/-
10.4 vs. 13.8+/-10.6 (p = 0.50).

Conclusion: Clinical outcomes are similar between high/low PEEP groups.

Probabilities of Survival and of Discharge Home While Breathing without Assistance, from the Day of
Randomization (Day 0) to Day 60 among Patients with Acute Lung Injury and ARDS, According to
Whether Patients Received Lower or Higher Levels of PEEP

Updated: 2020-03-23
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 COVID-19 | Mechanical Ventilation

PEEP | High vs Moderate in ARDS

Mercat, Alain, et al. "Positive end-expiratory pressure setting in adults with acute lung injury and acute
respiratory distress syndrome: a randomized controlled trial." Jama 299.6 (2008): 646-655.

EXPRESS
- ALVEOLI was followed by two trials, EXPRESS and LOVS, studying the impact of alveolar
recruitment via recruitment maneuvers.

Question:
- Is a strategy that tries to increase recruitment via the highest possible PEEP (up to maximal
plateau pressure) better than a moderate PEEP level (both with low tidal volumes)?
- That is, is it more important to increase alveolar recruitment or to minimize alveolar distention?

Methods:
- n = 767 ALI patients at 37 centers in France (2002-2005); randomized to receive either PEEP up
to plateau pressure of 28-30 cm H2O (“increase recruitment strategy”) or PEEP 5-9cm H2O
(“minimal distention strategy”)

Results:
- LOW PEEP/minimal distention group: Mean PEEP
- HIGH PEEP/alveolar recruitment group: Mean PEEP
- Primary outcome:
- 28 d. mortality (low PEEP vs. high PEEP): 31.2% vs. 27.8% (p = 0.31; RR 1.12 95% CI:
1.12, 0.90-1.40)
- Secondary outcomes:
- 60d. hospital mortality: 39.0% vs. 35.4% (p = 0.30; RR 1.10, 95% CI 0.92-1.32)
- Vent free days: 3 (IQR 0-17) vs 7 (IQR 0-19), (p = 0.04)
- Organ-failure-free days at 27 days: 2 (IQR 0-16) vs. 6 (IQR 0-18) (p = 0.04)

Conclusions:
- Compared to a moderate PEEP strategy, using a strategy to increase recruitment by maximizing
PEEP up to an acceptable plateau pressure did NOT reduce mortality, but it did increase # of
vent-free days and organ-failure-free days.
- *Other noted side effects of high recruitment strategy: improved lung function (compliance,
oxygenation, less adjunctive therapies), and more fluids required to support hemodynamics. No
difference in PTX, vasopressor therapy, extubation failure

Error bars indicate 95%

confidence intervals. A total of
382 were assigned to the minimal
distension strategy and 385 to the
increased recruitment strategy.
Day 28 mortality according to the
quartile of the ratio of partial
pressure of arterial oxygen over
fraction of inspired oxygen
(PaO2:FIO2) before randomization.
The interaction between the
study group and the
PaO2:FIO2 quartile at baseline was
not significant (P = .40).

Updated: 2020-03-23
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 COVID-19 | Mechanical Ventilation

PEEP | High vs Moderate in ARDS

Mercat, Alain, et al. "Positive end-expiratory pressure setting in adults with acute lung injury and acute
respiratory distress syndrome: a randomized controlled trial." Jama 299.6 (2008): 646-655.

LOVS
- Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-
expiratory pressure for acute lung injury and acute respiratory distress syndrome

Objective:
- To compare an established low-tidal-volume ventilation strategy with an experimental strategy
based on the original ‘open-lung approach,’ combining low tidal volume, lung recruitment
maneuvers, and high positive-end–expiratory pressure

Methods:
- RCT, years 2000-2006, 30 ICUs in Canada, Australia, and Saudi Arabia.
- Patients: 983 patients with acute lung injury/ARDS and P:F <250.
- Exclusion criteria: Inability to wean from experimental strategies such as nitric oxide, severe
chronic respiratory disease, >48 hours of eligibility, and a few others.
- Experimental strategy:
- Tidal volume target 6 mL/kg, Pplat<40, recruitment maneuvers, higher PEEP levels
(“lung open ventilation strategy”).
- Patients started with a recruitment maneuver, which included a 40-second breath-hold
at 40 cm H2O airway pressure, on FIO2 of 1.0.
- An additional recruitment maneuver followed each disconnect from the ventilator, up
to 4 times daily.
- Control strategy:
- Tidal volume target 6 mL/kg, Pplat<30, conventional PEEP levels. Recruitment
maneuvers were not permitted.

Results:
- Mean PEEP was ~15 in experimental group and ~10 in control group during the first 72h
(P<0.001).
- All-cause hospital mortality occurred in ~36% in experimental group and ~40% in control group
(RR 0.90, 95% CI 0.77-1.05, P=0.19).
- There was no significant difference in barotrauma rates.
- The experimental group had significantly lower rates of prespecified secondary outcomes,
including refractory hypoxemia, death with refractory hypoxemia, and use of rescue therapies;
the point estimate of the risk ratio for each of these was ~0.5-0.6.

Conclusions:
- The study did not demonstrate that the “lung open ventilation strategy” results in significantly
lower all-cause mortality compared with the established approach at the time.
- However, the “lung open ventilation strategy” improved secondary outcomes related to
hypoxemia and rescue therapies, and there was no significant difference in barotrauma.

Takeaway message:
- Higher PEEP and recruitment maneuvers do not reduce all-cause mortality in ALI/ARDS, but
they appear to reduce the risk of refractory hypoxemia and need for rescue therapies, and they
do not appear to cause significant harm for most patients.
- Implications for clinical care:
- There may be a subgroup of patients who benefit from higher PEEP (lung recruitment
in those with more edema and collapse of dependent regions) and another subgroup
who do not benefit or are harmed by higher PEEP (overdistention).
- Thus, in the absence of barotrauma, it is reasonable to try higher PEEP and recruitment
maneuvers while monitoring Pplat, airway driving pressure (Pplat – PEEP), O2
saturation, and hemodynamics. Note that few patients in this study were proned

Updated: 2020-03-23
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 COVID-19 | Mechanical Ventilation

PEEP | High vs Moderate in ARDS

Mercat, Alain, et al. "Positive end-expiratory pressure setting in adults with acute lung injury and acute
respiratory distress syndrome: a randomized controlled trial." Jama 299.6 (2008): 646-655.

LOVS
- Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-
expiratory pressure for acute lung injury and acute respiratory distress syndrome

Strengths of the study:

- Good adherence to protocols; complete follow-up; multicountry.

Limitations of the study:

- Unable to differentiate between effects of higher PEEP, higher Pplat, or recruitment maneuvers;
some baseline differences between groups.

Details of interest:
- Among the motivations for a “lung open ventilation strategy”: trying to prevent atelectrauma
(repetitive alveolar collapse with shearing), and potential oxygen toxicity from high FIO2.
- In this study, the most common causes of lung injury were sepsis (47%), pneumonia (45%), and
gastric aspiration (19%)
- ~44% of patients in both groups were treated with neuromuscular blockade.
- The protocol adherence appeared to have been generally successful: the experimental group
had significantly higher PEEP, higher Pplat, lower FIO2, and higher P:F ratios on days 1, 3, and 7,
compared to the control group.
- Patients in the experimental group were, on average, 2.4 years younger than those in the
control group.
- When adjusted for some baseline variables, including age and APACHE II score, the RR of all-
cause hospital mortality in the experimental group was 0.97 (95% CI 0.84-1.12, P=0.74)
compared to the control group.
- Rescue therapies included inhaled nitric oxide, prone ventilation, high-frequency oscillation,
high-frequency jet ventilation, and ECMO.
- In the experimental group, 22% of patients developed a complication associated with a
recruitment maneuver. These included hypotension, hypoxemia, and arrhythmia.

Updated: 2020-03-23
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 COVID-19 | NIPPV

NIPPV
MGH guidelines advise against the use of NIPPV and HFNC, but other centers are using these
modalities. Why the difference?
- Our reasoning is two-fold:
- To the extent that these patients have ARDS, NIPPV and HFNC present a serious risk of
propagating lung injury.
- Our usual understanding of the pathophysiology of VILI does not distinguish
between spontaneous large tidal volumes and mechanically ventilated large
tidal volumes.
- High trans-pulmonary pressure is to be avoided in ARDS. Full stop.
- Thus, early intubation with lung protective ventilation is to be preferred in the
guidelines over HFNC/NIPPV.
- The recent letter in the NEJM pointing to moderately long persistence of aerosolized
virus does highlight the potential risk to staff with aerosol generating procedures
including HFNC and NIPPV.
- Granted they used a lot of HFNC in China, but with somewhat different PPE
practices. Use in Italy and at other centers here has been only with limitation
of flow and patients wearing masks over the cannula in the case of HFNC and
helmet ventilation in the case of NIPPV.
- The helmet set up is not widely available here.

Updated: 2020-03-24
Return to Index Source: MGH Fast Literature Assessment and Review – Dr. Corey Hardin 32
 COVID-19 | Bi-level to Vent

Bi-level to Ventilator
The following is a protocol to turn the more common bi-level positive airway pressure (BiPAP)
machine into a functional invasive mechanical ventilator, through a 3D printed adaptor they also
designed to aid in the conversion.

- BiPAP is one type of PAP, or positive airway pressure, non-invasive machine that is commonly
used to maintain a consistent breathing pattern at night or during symptom flare-ups in people
with sleep apnea, congestive heart failure or chronic obstructive pulmonary disease (COPD), a
chronic inflammatory lung disease.
- As the health systems nationwide brace themselves for a potential increase in COVID-19
patients and New York Governor Andrew Cuomo calls for an increased supply of ventilators for
hospitals statewide, a team led by Hugh Cassiere, MD, medical director for respiratory therapy
services at North Shore University Hospital (NSUH) and Stanley John, NSUH’s director of
respiratory therapy, developed a method to convert the non-invasive Philips Respironics V60
BiPAP machine into a pressure controlled ventilator for both patients with and without COVID-
19 induced lung disease.
- Learn more here

Click here to view video tutorial

Updated: 2020-03-28
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 COVID-19 | Bi-level to Vent

Bi-level to Ventilator
Emergency protocol for using Philips Respironics V60 ventilator with pressure control ventilation
(PCV) option as a pressure-controlled ventilator using a conventional bipap circuit

You may use the conventional exhalation valve and/or circuit sold by Philips Respironics

❑ Turn on machine and hit the menu tab.

-Please ensure the patient is not connected to the V60 machine
❑ Under the menu tab select the option for Mask/port
❑ Select →ET/trach option (extreme left)
❑ Hit Accept

Updated: 2020-03-28
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 COVID-19 | Bi-level to Vent

Bi-level to Ventilator
Then chose type of exhalation port
❑ Select →Other
❑ Hit accept

Updated: 2020-03-28
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 COVID-19 | Bi-level to Vent

Bi-level to Ventilator
Perform exhalation port test
❑ Keep circuit open
❑ The machine will detect the open circuit and ask you to occlude the outlet port that connects
to the patient end of the circuit

Updated: 2020-03-28
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 COVID-19 | Bi-level to Vent

Bi-level to Ventilator
Now occlude the outlet keeping the exhalation valve port open
❑ Hit start test
❑ Test takes 4-5 seconds when you see the green bar the test was completed successfully or
thatyou passed the test

Updated: 2020-03-28
Return to Index Source: Hugh Cassiere, MD, Stanley John RT, Todd Goldstein, PhD 37
 COVID-19 | Bi-level to Vent

Bi-level to Ventilator
❑ Select mode- Batch PCV

Updated: 2020-03-28
Return to Index Source: Hugh Cassiere, MD, Stanley John RT, Todd Goldstein, PhD 38
 COVID-19 | Bi-level to Vent

Bi-level to Ventilator
❑ Place patient on the appropriate pressure settings parameters prior to activating mode as
follows:
❑ The EPAP will be the same as the PEEP
❑ For IPAP use the plateau pressure measured on the conventional ventilator as a
baseline
❑ The Fi02 would be the same
❑ The ramp should be turned off
❑ The rise time can be adjusted based on patients demand. We recommend a rise time
of 3

❑ Now activate the batch change by hitting select (Active Batch Change)

Updated: 2020-03-28
Return to Index Source: Hugh Cassiere, MD, Stanley John RT, Todd Goldstein, PhD 39
 COVID-19 | Bi-level to Vent

Bi-level to Ventilator
❑ Add 2 HEPA filter, one immediately connected to the V60 main gas port outlet and the second
HEPA gets connected to the exhalation valve port closer to the ET/Trach

❑ Add 2 HEPA filter, one immediately connected to the V60 main gas port outlet and the second
HEPA gets connected to the exhalation valve port closer to the ET/Trach

- We recommend that the HEPA filter on the exhalation valve port be connected to a blind
reservoir
- *In order to connect to an ETT tube you need to use the Philips Respironics conventional
exhalation valve and/or circuit kit.
- **In situations where the manufacturer’s connection is unavailable, Northwell Health has
successfully replicated and tested a 3D printed solution that is autoclavable and reusable.

Authored by Hugh Cassiere, MD, Stanley John RT, Todd Goldstein, PhD

Updated: 2020-03-28
Return to Index Source: Hugh Cassiere, MD, Stanley John RT, Todd Goldstein, PhD 40
 COVID-19 | Mechanical Ventilation

Targeted Sedation for Ventilator Synchrony

RASS
❑ Initial target: -2 to -3 (see table below):
- Maintain deep sedation immediately post-intubation while paralyzed (assume 60 minutes for
Rocuronium, 10 minutes for succinylcholine)

Preferred initial sedation regimen:

❑ Fentanyl/Hydromorphone (boluses +/- infusion) + Propofol:
- Target analgosedation and optimize analgesia first while decreasing sedative requirements

❑ Measure triglycerides and lipase every third day on propofol or earlier if other reasons for
hypertriglyceridemia

Adjunct agent:
❑ Midazolam
❑ Use dexmedetomidine only when nearing extubation

Target ventilator synchrony:

- Ventilator-induced lung injury (VILI) is common in patients who are not synchronous with the
ventilator and can cause significant lasting damage
- Once at target RASS after paralytics have worn off, assess patient synchrony with the ventilator (e.g.
signs of breath-stacking, double triggering, other ventilator alarms)
- Titrate sedatives/analgesics to ventilator synchrony allowing for deeper RASS
- If patient remains dyssynchronous despite deep sedation (RASS -5), initiate continuous paralytics
(ensure BIS 40 to 60 prior to initiating and during paralysis)

Updated: 2020-03-23
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 COVID-19 | Mechanical Ventilation

Ventilation Management
Follow ARDSnet ventilation where possible:

❑ Tidal volumes
- Should be 4-6 cc/kg using IBW to minimize volumes (and thus ventilator injury)
- Minute ventilation (respiratory rate x tidal volume) typically drives pH and PC02:

❑ Titrate ventilatory parameters to pH, not PCO2

- To achieve low tidal volumes, we tolerate hypercapnia (functionally no limitation unless clinical
sequelae) and acidemia (pH > 7.2)
- Because tidal volumes are low, the respiratory rate often has to be high to accommodate;
- Typical RR is 20-35 breaths/minute
- pH goal is normally 7.25-7.45:

❑ If pH > 7.45 → ↓ RR
❑ If pH 7.15-7.30 → ↑ RR until pH > 7.30, or PaCO2 < 25 (max RR= 35 breaths/minute)
❑ If pH < 7.15 → ↑ RR to 35 breaths/minute
❑ If pH still < 7.15 → perform the following:
- Tidal volume may be ↑ by 1 mL/kg until pH > 7.15
- - - Until plateau pressure reaches 30 cm H2O or tidal volume reaches 8 cc/kg
- Deep sedation advancing to RASS -5 if needed
- If no improvement, initiate continuous paralysis
- If still no improvement, initiate prone ventilation
- - -This may improve V/Q matching and better ventilation

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 42
 COVID-19 | Oxygenation Management

Oxygenation Management
Minimizing oxygen toxicity:
- PEEP and Fi02 drive oxygenation
- The goal is to deliver a partial pressure of oxygen to perfuse tissues (PaO2 > 75, Sp02 >92%)
while limiting lung injury from high distending pressures (Ppl < 30) and hyperoxia (FiO2 < 75,
SpO2 < 96%).
- Lower limit goals for PaO2 / SpO2 are widely debated (and discussed in Rationale);
- PaO2 > 55 and SpO2 >88% are also commonly used at BWH.

PEEP management:
If patient is hypoxic on Vt = 6 ml/kg and ideal PEEP from PV tool (or PEEP determination from ARDSnet
table for non-Hamilton G5 ventilators), perform the following:
❑ Deep sedation, advancing to RASS -5 if needed; if no improvement then:
❑ Initiate continuous paralysis (cisatracurium bolus 0.2mg/kg followed by infusion at 0-5
mcg/kg/min titrated to patient-ventilator synchrony); if no improvement then:
❑ Initiate prone ventilation (see below);
- High consideration for use early in severe ARDS (<36 hours from ARDS onset, start discussion
of proning when P:F < 150, prone within 12 hours of FiO2 > 75%)

Checking plateau pressure:

❑ Check plateau pressure with every change in tidal volume, PEEP, or clinical deterioration
(worsening oxygenation) but not as part of routine practice
- If PPl is > 30 cm H20, → ↓ VT by 1 ml/kg (minimum 4 mL/kg)
- If Ppl is < 25 H20 and VT < 6 mL/kg, → ↑ VT by 1 mL/kg until Ppl > 25 cm H2O or TV= 6 mL/kg
- If Ppl is < 30 cm H20 and patient is breath stacking or dyssynchronous, then ↑ V T in mL/kg
increments to 7 mL/kg or 8 mL/kg so long as plateau pressure is < 30 cm H20

Adjusting Fi02:
❑ Adjust Fi02 after optimizing PEEP
- Goal FiO2 < 75%;
- If FiO2 > 75% → patient requires ventilator optimization
- It is reasonable to put a desaturating patient temporarily on 100% Fi02, but remember to wean
oxygen as rapidly as possible

Rationale:
- Avoiding hyperoxia: Extensive mammalian animal data demonstrates that hyperoxic injury
occurs at an FiO2 ≥ 75% (at sea level) with the rate of injury increasing as FiO2 exceeds that
threshold.
- In multiple mammalian models, an FiO2 of 100% for 48 to 72 hours is associated with nearly
100% mortality rate.
- In lung injury models, the time to death is markedly attenuated.
- In an effort to reduce the potential for hyperoxic injury, the threshold of FiO2 ≥ 75% triggers
progressive intervention throughout this protocol: increased sedation, paralysis, proning and
ECMO consultation.
- For a review of hyperoxic acute lung injury, see Kallet and Matthay, Respir Care, 2013.

Setting the lower oxygen limits:

- There is debate on the proper PaO2 goal, and our rationale relies on evidence for lack of benefit
from conservative PaO2 goals in clinical trials (i.e., PaO2 > 55) and past association between
lower PaO2 and cognitive impairment, although the evidence is certainly not definitive (mean
PaO2 71 [IQR 67-80] for cognitively impaired survivors versus mean PaO2 86 [IQR, 70-98] in non-
impaired survivors of ARDS (Mikkelsen et al, Am J Respir Crit Care Med, 2012).
- In the LOCO2 multi-center, randomized clinical trial, patients with ARDS were randomized to
their PaO2 55-70, SpO2 88-92%; or PaO2 90-105, SpO2 >95%); the trial was stopped after
enrollment of 205 patients due to futility and safety concerns (44% mortality in conservative
oxygen group versus 30%; (Barrot et al, New Eng J Med, 2020).

Updated: 2020-03-23
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 COVID-19 | Proning

Proning
Prone early:
- We recommend early proning in severe ARDS without vasodilator trial (a departure from our
typical practice for ARDS not due to COVID-19): < 36 hours from ARDS onset, start discussion of
prone when P:F < 150, prone within 12 hours of FiO2 > 75% (Guérin et al, N Engl J Med, 2013).

Eligibility criteria for proning:

Eligibility may vary depending on resources and staffing. Currently we recommend:
❑ Age < 75
❑ No high grade shock
- Either single agent norepinephrine 20 mcg/min or norepinephrine < 15 mcg/min and
vasopressin
❑ Not on CRRT or at risk of impending renal failure
- Due to difficulties in maintaining dialysis access while proned
❑ The only absolute contraindications to proned ventilation
- Spinal cord injury and open chest
- BMI and patient size are NOT contraindications

Managing a proned patient:

❑ Maintain deep sedation with target RASS -4 to -5 while proned.
❑ 1 hour post-initiation of prone ventilation:
- Adjust oxygen parameters: re-assess lung mechanics (plateau pressure and P-V tool to
determine optimal PEEP) and adjust PEEP and titrate FiO2
- Assess tidal volume and adjust ventilation parameters
- If Vt < 6 ml/kg, may increase to maximum limit of 8 ml/kg while Ppl < 30 (preferred maximum
is 6 ml/kg)
❑ If patient demonstrates improvement on proning then recommend:
- Discontinuing of continuous neuromuscular blockade and re-assess ventilator dyssynchrony;
re-institute if dyssynchronous
- Return to supine ventilation when following criteria are met:
• Ppl < 25
• FiO2 < 50%
• pH > 7.3
• P:F > 200
❑ Repositioning and skin care while proned:
- Currently we recommend continuing proning as per the MICU proning protocol.
- This may change in the future depending on availability of PPE and staffing.

Escalation if still hypoxic:

❑ If hypoxia (PaO2 < 55 with FiO2 > 75%) persists after proning; then initiate continuous inhaled
epoprostenol (see “COVID-19 Therapies and Clinical Trials” chapter)
❑ If FiO2 > 75% despite above, recommend consultation with ECMO team (see “ECMO
consultation” section of this chapter)

Updated: 2020-03-23
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 COVID-19 | Proning

Escalation of treatment to Acute Lung Injury Center http://b.link/ECMO or 718.413.1745 (LIJ MICU
attending) or 1833-NYCECMO.

Updated: 2020-03-25
Return to Index Source: NSUH Rapid Critical Care Management Primer 45
 COVID-19 | Proning

Proning | Background
There is widespread consensus on the benefit of prone positioning in the treatment of intubated
patients with severe ARDS (Beitler et al., 2014; Fan et al., 2017; Guérin et al., 2013).
- In the setting of severe SARS-CoV-2 infection, some centers have also considered the use of
prone positioning in the management of spontaneously breathing patients without invasive
mechanical ventilation.
- In this FLARE, we discuss the physiologic rationale for prone positioning in ARDS and review the
limited reports to date on “proning” non-intubated patients in the setting of COVID-19.

Before delving into the physiology, we want to emphasize that management of ARDS in COVID-19
should prioritize lung-protective ventilation.
- Clinical trials and subsequent meta-analyses have only established the therapeutic benefit of
prone positioning in the context of low tidal volume mechanical ventilation (Beitler et al., 2014;
Guérin et al., 2013).
- Thus, we do not suggest prone positioning in a non-intubated patient with ARDS if intubation
appears otherwise indicated at that time (i.e. we do not recommend it as an alternative or
rescue therapy to avoid intubation).
- Prone positioning could be considered if intubation is not feasible, is discordant with a patient’s
goals and values, or is otherwise not indicated.

Proning | Physiologic Benefits

Distribution of transpulmonary pressures, recruitment and V/Q matching

A brief aside for non-pulmonary/critical care readers:

- Transpulmonary pressure (PTP) is the pressure distending the lung, and is defined as: PTP =
pressure at the airway opening - pleural pressure.
- When monitoring mechanical ventilation in the ICU, we typically approximate PTP with the
pressure at the airway opening (as displayed on the ventilator).
- However, as the equation above indicates, there are two components to the true
distending pressure: (1) the pressure measured at the airway opening, and (2) the
pleural pressure.
- To understand the important role of the pleural pressure, consider a trumpet player
who generates an enormous alveolar pressure to force exhalation while playing a loud
note.
- Her lungs nevertheless do not experience an enormous distending pressure
(transpulmonary pressure) and burst. Why not? Because the high pressure inside the
alveolus is balanced by an opposing pleural pressure, elevated due to the contraction
of her abdominal and chest wall muscles.

Updated: 2020-03-29
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 COVID-19 | Proning

Proning | Physiologic Benefits

Pleural pressure is not homogeneous across the lung surface.
- It is less negative in the dependent portion of the lung than in the non-dependent portion.
- This gradient results, in part, from dependent portions of the lung supporting the
weight of the lung above.
- As a result, in the supine position, transpulmonary pressure is greater in the ventral
(non-dependent) lung than in the dorsal (dependent) lung.
- In ARDS, this difference is intensified by the increased weight of edematous, injured
tissue and consequent dorsal alveolar collapse (derecruitment).
- At the same time, the aerated ventral lung preferentially receives greater airflow and is
at risk for overdistension (Figure 1).

The problem of derecruitment is exacerbated in the supine position by the weight of the
mediastinal contents resting on the lung, whereas in the prone position the mediastinum is
supported by the sternum. Finally, the lung is not symmetric along the dorsal-ventral axis -- there is
a greater mass of tissue in the dorsal lung than the ventral lung. Therefore there is a greater
amount of dependent lung in the supine position compared to the prone position. Thus proning
results in dorsal recruitment, leading to a net increase in recruited lung and a decrease in
overdistended lung. The anatomic asymmetry also results in improved V/Q matching in the prone
position. Given that there are more alveoli and vessels in the dorsal lung, and therefore more blood
flow to dorsal lung regardless of patient position, recruiting that region will result in a net decrease
in shunt (perfusion without ventilation) (Bellani et al., 2009; Nyrén et al., 1999).

Finally, the distribution of stresses within lung tissue is more homogenous in the prone position.
This is expected to mitigate the propagation of lung injury that is often associated with
heterogeneous inflation of the injured lung (Liu et al., 1990).

Updated: 2020-03-29
Return to Index Source: MGH Fast Literature Assessment and Review - Dr. Jason Maley. 47
 COVID-19 | Proning

Proning | Right Ventricular Function

- If prone positioning is successful in lung recruitment, the resultant increases in aeration and
oxygen tension should mitigate hypoxemic vasoconstriction.
- When these changes occur in the dorsal regions of the lung, which receive the majority
of non-gravity dependent blood flow, pulmonary vascular resistance (and thus RV
afterload) decrease (Jozwiak et al., 2013).
- Thus, prone position may improve RV function.

Non-intubated Patients in the Setting of COVID-19

- The above physiologic rationale for prone positioning emphasizes the benefit of recruitment of
dorsal lung regions and redistribution of transpulmonary forces.
- These changes may be expected to also occur in the proned non-intubated patient
(especially if NIPPV is provided) though we lack direct clinical evidence to better inform
this approach.
- Of note, low tidal volumes cannot be guaranteed in the spontaneously breathing, non-
sedated patient, which may potentially lead to injurious inflation patterns due to
increased transpulmonary pressures (Yoshia et al., 2017).

- Two descriptive reports suggest that non-intubated prone positioning was pursued for the
treatment of ARDS in the setting of COVID-19 in China.
- In these reports, patients were prone for ~2 hour periods, with multiple sessions each
day, either receiving HFNC or NIPPV (Ding et al., 2020; Sun et al., 2020).
- Anecdotes from colleagues across the United States suggest the successful use of this
approach as well.

Conclusion
- Intubation and lung-protective ventilation remain the cornerstone of ARDS management,
including the management of COVID-19-associated ARDS.
- If intubation is not feasible or is discordant with a patient’s goals and preferences (e.g.
DNI), prone positioning in the non-intubated patient is likely safe and may be effective
based on the above physiologic rationale.
- We recommend assessment of changes in oxygenation after prone positioning to
assess the efficacy and close monitoring as would be performed in an intubated
patient.

Updated: 2020-03-29
Return to Index Source: MGH Fast Literature Assessment and Review - Dr. Jason Maley. 48
 COVID-19 | ECMO

ECMO
Refractory Hypoxemia:
- If despite PEEP optimization, paralysis, prone ventilation, optimizing volume status, pulmonary
vasodilators (when available) the patient meets the following criteria, then consider ECMO
consult

❑ Ppl > 30
❑ FiO2 > 75%
❑ P:F < 80

Candidacy:
- Final ECMO guidelines for COVID-19 patients remain under development.
- Examples of common considerations include:

❑ Patient age < 65

❑ Mechanical ventilation duration < 7 days
❑ BMI < 35 and patient body weight < 150 kg
❑ CrCl > 30
❑ No multiorgan failure or high grade shock (can be on single pressor; norepinephrine < 15
mcg/min)
❑ No active solid or liquid malignancy
❑ Absolute neutrophil count > 500
❑ Platelets > 50,000
❑ Able to tolerate anticoagulation on initiation (no active hemorrhage)
❑ No evidence of irreversible neurological injury
❑ Able to perform ADLs at baseline prior to illness

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 49
 COVID-19 | ECMO

Updated: 2020-03-23
Return to Index Source: MGH ECMO Protocol during COVID19 Pandemic 50
 COVID-19 | Antibiotic Stewardship

Antibiotic Stewardship
Antibiotic choice:
Antibiotics should reflect IDSA guidelines, presumed source, and MDRO risk. For a presumed
pulmonary source:

- Without risk factors for MRSA or Pseudomonas (i.e. living in community, no prior MDROs):
❑ Ceftriaxone + Azithromycin

- With risk factors for MRSA or Pseudomonas (i.e. chronic hospitalization, prior MDR infections):
❑ Vancomycin + Cefepime, and consider Ciprofloxacin if high concern for Pseudomonas

Formulation:
- Give oral antibiotics (Azithromycin, Levofloxacin, Ciprofloxacin) when possible to reduce volume
load, unless concerns for poor oral absorption

Coinfection:
- If concurrent influenza give Oseltamivir
- Given lymphopenia consider Pneumocystis and treat accordingly

Discontinuation:
- Antibiotics should be discontinued as soon as possible (within 48h) if:
❑ Clinical status is not deteriorating,
❑ Cultures do not reveal pathogens at 48h
❑ Procalcitonin and WBC are relatively stable from 0 to 48h
❑ Clinical judgement should prevail over any specific lab value

Rationale:
- Clinical reports indicate that rates of bacterial superinfection of COVID19 are low (10-20%), but
when present increase mortality risk.
- Anecdotal reports suggest less MRSA superinfection than with influenza.
- Unnecessary antibiotics carry risks of fluid overload and drug-resistance, as well as the
possibility that antibiotics may become a limited resource. (Zhou et al, Lancet, 2020; Yang et al,
Lancet Respir Med, 2020; Lippi and Plebani, Clinica Chimica Acta, 2020; WHO, COVID-19
Guidelines, 2020)

Updated: 2020-03-23
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 COVID-19 | MDIs

Metered-dose inhalers (MDIs) vs. nebulizers

Non-intubated patients:
- For COVID-19 Confirmed or PUI, use MDI (inhalers), NOT nebulizers, due to the increased
aerosol risk.
- Because MDI supply is limited, only prescribe when needed.
- For non-COVID-19 Confirmed or PUI patient, use nebulizers even if on droplet precautions (e.g.,
influenza) because MDI supply is limited.
- After a patient is COVID-neg (and no longer on COVID precautions per infection control): After
the patient’s current MDI runs out, switch to neb.

Intubated patients:
- The ventilator circuit is a closed system so nebulizers can be used when required (e.g., DuoNeb
standing and albuterol PRN).

Rationale:
- Nebulization may aerosolize viral particles and contribute to disease transmission.
- COVID-19 clinical reports do not indicate wheeze as a common symptom, and not all patients
require bronchodilators (Zhou et al, Lancet, 2020; Yang et al, Lancet Repir Med, 2020; Guan et
al, N Engl J Med, 2020; WHO, COVID-19 Guidelines, 2020)

Updated: 2020-03-23
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 COVID-19 | Airway Clearance

Airway Clearance
Management principles:
- Reports from Wuhan and Italy indicate that some patients develop very thick secretions causing
dangerous mucus plugging.
- However, nebulizers and airway clearance techniques may aerosolize secretions
- Airway clearance should be used only in selected ventilated patients (closed circuit) with
extremely thick secretions to avoid mucus plugging that would require bronchoscopy

For thinning secretions:

- Anecdotal reports suggest Dornase alfa may be particularly effective in thinning secretions in
COVID-19 patients. However, data for Dornase alfa in non-CF patients is poor.
- For now we recommend:
❑ Dornase alfa 2.5mg nebulizer once daily
- Can cause bronchoconstriction and mucosal bleeding
❑ Pre-treat with albuterol 2.5mg, just prior to delivery
- Avoid in setting of bloody secretions
- Alternative:
❑ Nebulized hypertonic (3-7%) saline once daily
- Side effects can include bronchoconstriction
- Start with 3% to assess response and bronchoconstriction
❑ Pre-treat with albuterol 2.5mg just prior to delivery
- Avoid N-acetylcysteine due to frequent dosing requirements

Airway clearance:
❑ Continue chest PT vests if patient uses at home (e.g., CF patients) with appropriate
isolation precautions.
- Bronchiectasis patients may be considered on a case-by-case basis
❑ Avoid oscillating positive expiratory pressure devices (Aerobika or Acapella) and cough
assist (MIE)

Updated: 2020-03-23
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 COVID-19 | Inhaled Pulmonary Vasodilators

Inhaled Pulmonary Vasodilators

Indications for use:
- Inhaled vasodilators should NOT be routinely used except in two circumstances:
- As a rescue strategy in already prone ventilated patients
- There is no evidence of survival benefit of inhaled vasodilators in ARDS, and
there are risks of viral aerosolization when connecting the device (Fuller et al.,
Chest, 2015; Gebistorf et al., Cochrane Database Syst Rev, 2016; Afshari et al,
Cochrane Database Syst Rev, 2017)
- To reduce RV afterload in hemodynamically significant RV failure in consultation with
cardiology

Instructions for use:

- If inhaled vasodilators are used, they should reevaluated at 4 hours
❑ Inhaled Epoprostenol:
❑ Start continuous nebulization at 0.05mcg/kg/min based on IBW
- If no improvement in P/F ratio in 2 hours, wean off by decreasing 0.01mcg/kg/min
every hour
❑ Inhaled Nitric Oxide (iNO):
- Strong consideration in refractory ARDS that does not respond to inhaled
epoprostenol.
- Limited in vitro data notes that iNO at high doses inhibits replication of SARS-CoV, but
this has not been studied in vivo. (Akerstrom et al., J Virol, 2005; Gebistorf et al.,
Cochrane Database Syst Rev, 2016)
- iNO may be included in future trial protocols, such as early initiation in milder disease
(non-intubated).

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 54
 COVID-19 | Corticosteroids

Corticosteroids
Data on corticosteroids for COVID-19:
- Most studies show negative effects of corticosteroids on similar viruses
- There is no clinical evidence of net benefit from steroids in SARS-CoV, MERS-CoV or influenza
infection, and observational data show increased mortality, more secondary infections,
impaired viral clearance and more adverse effects in survivors (e.g. psychosis, diabetes,
avascular necrosis). (Lee et al., J Clin Virol, 2004; Stockman et al., PLoS Med, 2006; Arabi et al.,
Am J Respir Crit Care Med, 2018; WHO, COVID-19 Guidelines, 2020; Wu et al., JAMA Int Med,
2020)
- However, a new retrospective cohort (201 patients, 84 [42%] of whom developed ARDS)
demonstrated that among patients with ARDS, methylprednisolone decreased risk of death (HR,
0.38; 95% CI, 0.20-0.72) (Wu et al., JAMA Int Med, 2020)

Recommendation:
- We recommend AGAINST using steroids for COVID-19 except as part of a clinical trial
- This is in line with WHO Guidelines as of 3/13/2020

Use corticosteroids if required for other indications:

Use the lowest dose for the shortest duration:
❑ Asthma or COPD exacerbation
- 40mg prednisone PO or 30mg methylprednisolone IV, once daily x 3-5 days
❑ Shock with history of chronic steroid use > 10mg prednisone daily:
- 50mg hydrocortisone IV Q6H until improvement in shock
❑ Multipressor shock without history of chronic steroid use
- 50mg hydrocortisone IV Q6H until improvement in shock

Updated: 2020-03-23
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 COVID-19 | Corticosteroids

Corticosteroids
Why avoid steroids for ARDS in COVID-19
- Multiple studies have been done over the past few decades to determine the effect of steroids
to treat ARDS.
- The results of these trials have been both positive and negative making its use
controversial for ARDS (see table below).
- Thus, the utility of steroids for non-COVID-19 ARDS patients is unclear
- Additionally, the data from influenza and other viral illnesses suggest an increased mortality in
viral PNA and viral-mediated ARDS when steroids are used (Ni 2019, Tsai 2020).
- Therefore, there is concern that corticosteroids could be harmful in the viral syndrome
that is COVID-19 ARDS.
- It is also important to note that the LaSRS trial showed worse mortality in patients who
received steroids 14 days after the onset of ARDS (Steinberg 2006).
- As patients in the available case series on COVID-19 present to the ICU
around day 10-12, it may be prudent to avoid steroids due to this association.
- Additionally, both CDC and WHO guidelines currently do not recommend steroids.

Why are some people using them?

- The SCCM guidelines suggest as a weak recommendation amidst admittedly low-quality
evidence to use corticosteroids.
- Data for steroids include a non-peer-reviewed case series in which COVID-19 patients
with severe disease had a shorter duration of O2 use and improved radiographic
studies (Wang 2020).
- However, there is potential for confounding in this non-randomized study so we, as
well as the SCCM, are hesitant to use this data to guide clinical care.
- Additionally, there is data in community-acquired pneumonia that showed that corticosteroids
may reduce the need for mechanical ventilation, reduce mortality, and may improve
radiographic findings (Siemieniuk 2015).
- These trials were mostly in non-ICU patients and were not with viral pneumonia and
thus we do not believe can be easily applied to this COVID-19 population.

Take home points

- Therefore, with the evidence for potential harm and the lack of evidence for benefit in this
population, we do not recommend giving steroids routinely for COVID-19 ARDS.
- We caveat this recommendation with the understanding that there may be secondary
indications for steroid use (for example adrenal insufficiency, septic shock, transplant, etc.) in
which we support the use of steroids with careful weighing of the risks and benefits

Several ARDS practice-changing studies were published in the midst of all of these trials. Significant limitations include: small
sample sizes, some studies with cross-over between groups, and trials without standardized ventilator management

Updated: 2020-03-24
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 COVID-19 | Remdesivir

Remdesivir

Updated: 2020-03-23
Return to Index Source: 57
 COVID-19 | Remdesivir

Remdesivir
Background
- Nucleotide analogue that inhibits RNA dependent RNA polymerase
- Broad antiviral activity in vitro:
- SARS, MERS, hemorrhagic viruses including Ebola
- RCT ongoing at UCSF
- 10 days IV Remdesivir for hospitalized COVID-19 patients with moderate-severe disease

Updated: 2020-03-23
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 COVID-19 | Remdesivir

Remdesivir
Wang, Manli, et al. "Remdesivir and chloroquine effectively inhibit the recently emerged novel
coronavirus (2019-nCoV) in vitro." Cell research 30.3 (2020): 269-271.

- Nucleotide analogue that inhibits RNA dependent RNA polymerase

- Broad antiviral activity in vitro:
- SARS, MERS, hemorrhagic viruses including Ebola
- RCT ongoing at UCSF
- 10 days IV Remdesivir for hospitalized COVID-19 patients with moderate-severe disease

Updated: 2020-03-23
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 COVID-19 | Hydroxychloroquine

Hydroxychloroquine and Chloroquine

Pathophysiology:
Hydroxychloroquine is an anti-malarial 4-aminoquinoline shown to have in vitro (but not yet in-vivo)
activity against diverse RNA viruses including SARS-CoV-1 (Touret et al, Antivir Res, 2020).
It is thought to act through multiple mechanisms. (Devaux et al, Int J Antimicrob Agent, 2020)
- Inhibition of viral entry.
- HQ inhibits synthesis of sialic acids and interferes with protein glycosylation, which may
disrupt interactions necessary for viral attachment and entry. (Vincent et al, Virol J,
2005). (Olofsson et al, Lancet Infect Dis, 2005).
- Inhibition of viral release into the host cell.
- HQ blocks endosomal acidification, which activates endosomal proteases. These
proteases are required to initiate coronavirus/endosome fusion that releases viral
particles into the cell. (Yang ZY et al, J Virol 2004)
- Reduction of viral infectivity.
- HQ has been shown to inhibit protein glycosylation and proteolytic maturation of viral
proteins. Studies on other RNA viruses have shown a resulting accumulation of non-
infective viral particles, or an inability of viral particles to bud out of the host cell
(Savarino et al, J AIDS, 1996; Klumperman et al, J Virol, 1994)
- Immune modulation.
- HQ reduces toll-like receptors and cGAS-STING signaling. It has been shown to reduce
release of a number of pro-inflammatory cytokines from several immune cell types
(Schrezenmeier and Dorner, Nat Rev Rheum, 2020)

Data:
- An expert consensus group out of China suggests that Chloroquine improved lung imaging and
shortened disease course. (Zhonghua et al., CMAPH, 2020).
- Chloroquine will be included in the next treatment guidelines from the National Health
Commission, but the specific data on which this is based is not available yet. (Gao et al., Biosci
Trends, 2020)
- Hydroxychloroquine was found to be more potent than chloroquine in inhibiting SARS-CoV-2 in
vitro (Yao et al., Clin Infect Dis, 2020)

Recommendation:
- Strong consideration of hydroxychloroquine in patients who require supplemental oxygen who
are not candidates for other clinical trials.

Dosing (from the literature):

❑ Hydroxychloroquine:
- First day: 400mg PO BID
- Followed by 200mg q12 (q8h if concerns for absorption) for 5-10 days

❑ Chloroquine:
- Second line agent (increased toxicity compared to Hydroxychloroquine)
- 500mg Chloroquine phosphate 500mg PO BID for 10 days
- Common adverse reactions include:
▪ Prolonged QT interval and risk of Torsade de pointes
▪ Cardiomyopathy
▪ Bone marrow suppression
▪ Contraindicated in epilepsy and porphyria

Monitoring
❑ QTc monitoring
- If hydroxychloroquine is being administered with azithromycin, there should be
❑ Baseline ECG and daily ECG
❑ Discontinue all other QT prolonging agents
❑ Maintain continuous telemetry while under treatment
❑ Do not start if QTc >500 or 550 with pacing or BBB.
❑ Discontinue if there is an increase in PVCs or non-sustained PMVT.
- There is a reported risk of hydroxychloroquine induced cardiomyopathy.
- Case series and reports have found this to be a long-term (years) and dose-dependent
phenomenon.
- Given the anticipated short duration in COVID-19, it is not an expected risk. (Nord et al.,
Seminars in Arthritis and Rheumatism, 2004).
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 COVID-19 | Hydroxychloroquine

Chloroquine
Background
- Antimalarial with antiviral activity
- Interferes with viral entry
- By changing the acidification inside the cell
- Inhibits SARS-CoV-2 co-receptor
- Immune modulating activity
- Inexpensive, long track record
- Reported to improve pneumonia, viral clearance and disease course in China
- May require higher dose than for malaria: 500 mg BID
- Limited US supply

Updated: 2020-03-23
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 COVID-19 | Hydroxychloroquine

Chloroquine
Chloroquine: A Q&A with Dr. Raghu Chivukula

I. What is the deal with chloroquine?

Let’s start with a review of some virology basics. Coronaviruses are enveloped RNA viruses, meaning
they are coated in a piece of host cell membrane. There are several families of Coronaviruses which
differ in the receptors they use for host entry, but several papers in the last decade or so have
revealed an important role for endocytosis in viral entry. Through this process the entire virus
(envelope and all) is internalized, and the endocytosed virion therefore ends up inside a membrane-
bound compartment in the cell (an endosome) from which it must escape before making mischief in
the nucleus. This trafficking and escape process generally depends on acidification of the endosome
and/or fusion with acidified lysosomes.

OK. So what does this have to do with chloroquine (CQ)? CQ belongs to a class of agents known as
“cationic amphiphilic drugs” (CADs) which share some peculiar structural features - most notably an
amino group on one end. When these drugs encounter acidified compartments, their amino groups
become protonated and the molecules become trapped. The end result is that CADs accumulate to
very high concentrations in normally acidified compartments like the endosome, lysosome, and trans-
Golgi apparatus and have a variety of effects on the enzymes and macromolecules that reside there.
For example, this phenomenon is the mechanistic basis for phospholipidosis (“foamy macrophages”) in
patients treated with the cationic amphiphilic drug amiodarone. Each CAD induces unique but
overlapping changes in lysosomal and Golgi metabolism in complex ways specific to its chemical
composition. It should be noted here that the exact effects of CQ on lysosomes and endosomes
remains an area of active research.

Nevertheless, it has been reported for decades that chloroquine, amiodarone, and other CADs can
interfere with the replication of a diverse array of enveloped viruses including influenza, Ebola virus,
HIV, Dengue, Zika, and HCV in vitro. On the other hand, in vivo assays and clinical trials have been less
promising – chloroquine failed to prevent influenza infection in a clinical trial (Paton, et. al. Lancet Inf
Dis. 2011) and, if anything, increased viral load in an HIV trial (Paton, et. al. JAMA 2012). And,
concerningly, at least one group reported increased influenza replication in the presence of CQ (Wu,
et. al. J Med Vir 2015).

Updated: 2020-03-23
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 COVID-19 | Hydroxychloroquine

Chloroquine

II. Why do people think CQ/HCQ might be effective against SARS-Cov-2?

The majority of evidence supporting the use of CQ and its derivative, hydroxychloroquine (HCQ), come
from studies of the original SARS-Cov which emerged in 2002. In the ensuing years, basic virology
studies established that SARS-Cov depends on endosomal escape, that it buds from the Golgi
apparatus, and that its receptor (ACE2) is itself glycosylated in the Golgi. Thus, CQ was a rational drug
to test. Vincent and colleagues established the efficacy of CQ in inhibiting SARS-Cov replication and
provided evidence that impaired endosomal acidification as well as impaired ACE2 glycosylation might
be responsible. Similar data were reported by other groups (Keyrts, et. al. Biochem Biophys Res
Commun. 2004).

Based on these data, Wang and colleagues published two papers in Feb (Wang, et. al. Cell Research
2020) and March (Liu, et. al. Cell Discovery 2020) of this year examining the effects of CQ and HCQ
(more widely available and less toxic) on the novel SARS-Cov-2 in vitro. CQ dramatically inhibits SARS-
Cov-2 replication at low micromolar concentrations, while HCQ inhibits replication at ~10uM.
Importantly, these concentrations are at least 10-fold lower than reported cytotoxic doses – though it
is virtually certain normal cellular physiology is being perturbed to some extent.

What about clinical evidence? As of this writing (March 21), there are no rigorous clinical data
specifically demonstrating therapeutic benefit of CQ or HCQ in prevention or treatment of COVID-19
save for a “publication” (Gao, et. al. BioScience Trends 2020) which states without evidence that CQ
has proven effective in >100 patients. There are, however, >20 active clinical trials (most in China) and
it is likely that data will emerge in the coming weeks. Which brings us to ...

"Many people are saying" that HCQ and azithromycin together cure COVID-19. Is that true?
If you have been following the news, you likely saw that President Trump voiced a great deal of
enthusiasm for combination therapy with hydroxychloroquine and azithromycin (“H and A”, as he
coined). This drug combination was studied in a very small group of French patients, published a
couple of days ago (Gautret, et. al. Intl J Antimicrob Agents 2020). Let’s walk through the paper:

Study population: SARS-Cov-2 positive adults (asymptomatic and symptomatic) who expressed interest
in receiving HCQ. Controls were taken from another center or from patients who refused the drug.
Design: Patients were offered 200mg TID HCQ. Patients had NP swabs taken daily for RT-PCR of viral
load. Serum was collected for HCQ measurement. Antibiotic therapy (azithromycin) was provided
based on clinical judgement.

Inclusion/exclusion: 42 met inclusion criteria -> 6 patients lost (3 to ICU, 1 died, 1 left hospital, 1
stopped drug) -> 36 patients completed study -> 26 HCQ + 16 control. 6 of the HCQ patients also
received azithromycin based on clinical judgement “to prevent bacterial super-infection”.
Results: HCQ serum levels were 1.4±0.6 uM in the 20 patients with data available. Patients treated
with HCQ had statistically significantly higher rates of “virological cure” than those not-treated,
beginning at day 3 of treatment. The 6 patients treated with HCQ/azithromycin had “100% virological
cure” beginning at day 5.

There are several significant methodological issues with this study beyond its small size (which is
excusable). Most glaring is that qRT-PCR was only performed on half the controls, while the remainder
were assayed only as “present” versus “absent”. Second, among those patients who had qRT-PCR
performed, no QC or normalization of any kind appeared to be performed – meaning, for example, if a
swab did not really obtain cells we would not know. Third, 5 of the 6 HCQ patients not analyzed were
omitted because they had clinical deterioration; had they been included, they likely would have been
treatment failures. Fourth, the decision to administer azithromycin was entirely ad hoc, making it
highly suspect to conclude pharmacological synergy from these data. Finally, my own reanalysis of
these data (asking what the maximal observed reduction in signal was per patient) suggests treatment
effect is insignificant. Happy to share this analysis with any interested parties – they are very imperfect
given the starting material. In conclusion, I don’t find this study compelling but the question needs to
be asked in a much more rigorous fashion to know for sure.

Updated: 2020-03-23
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 COVID-19 | Hydroxychloroquine

Chloroquine
What is known about ARDS that may apply to COVID-19?
A retrospective cohort study in China recently purported that methylprednisolone may decrease the
risk of death in COVID-19-related ARDS. A Chinese hospital also announced a single-center RCT of
methylprednisolone vs placebo for adjunctive therapy of COVID-19-related severe lower respiratory
tract infection

Updated: 2020-03-23
Return to Index Source: Mass General FLARE 64
 COVID-19 | Chloroquine

Chloroquine
Wang, Manli, et al. "Remdesivir and chloroquine effectively inhibit the recently emerged novel
coronavirus (2019-nCoV) in vitro." Cell research 30.3 (2020): 269-271.

Updated: 2020-03-23
Return to Index Source: UCSF Experts on the Epidemiology, Science, & Clinical Manifestations of COVID-19, and UCSF Response65
 COVID-19 | Anti-IL6

Anti-IL6 Agents (Tocilizumab, Siltuximab)

Pathophysiology:
- IL-6 activates T cells and macrophages, among other cell types (see “Cytokine Activation
Syndrome”
- IL-6 inhibitors are approved for cytokine activation syndrome complications related to Chimeric
Antigen Receptor T cell (CAR-T) therapy (Brudno & Kochenderfer, Blood Rev, 2019; Rubin et al,
Brain, 2019)
- IL-6 levels are reported to correlate with severe COVID-19
- While patients have peripheral lymphopenia, BAL fluid is often lymphocytic, suggesting that IL-6
inhibition and prevention of T cell activation may be protective

Recommendation:
❑ We do NOT recommend routine use at this time
- There are anecdotal reports of benefit of tocilizumab in COVID19 patients but no rigorous
studies are available (Anecdotal reports from Italy; Chinese National Health Commission Clinical
Guideline, March 3, 2020.)
- Exercise caution if secondary infection is clinically suspected - including sepsis, pneumocystis
or bacterial pneumonia

Dosing regimens:
❑ Tocilizumab 4-8mg/kg (suggested dose 400mg) IV x1 (anti-IL6R mAb)
- Dose can be repeated 12h later if inadequate response to the first dose.
- Total dose should be no more than 800mg.
- Tocilizumab should not be administered more than twice.
- Common adverse effects include:
▪ Transaminitis (AST, ALT) > 22%
▪ Infusion reaction 4-20%
▪ Hypercholesterolemia 20%
▪ Upper respiratory tract infection 7%
▪ Neutropenia 2-7%
Alternative:
❑ Siltuximab 11mg/kg IV x1 (anti-IL6 mAb)
- Common adverse effects include:
▪ Edema >26%
▪ Upper respiratory infection >26%
▪ Pruritis / skin rash 28%
▪ Hyperuricemia 11%
▪ Lower respiratory tract infection 8%
▪ Thrombocytopenia 8%
▪ Hypotension 4%

Updated: 2020-03-23
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 COVID-19 | ACE-I and ARBs

ACE-I and ARBs

Pathophysiology:
- SARS-CoV-2, the virus that causes COVID-19, enters the same cell entry receptor as SARS-CoV:
angiotensin converting enzyme II (ACE2) (Paules et al, JAMA, 2020). SARS-CoV-2 is thought to
have a higher affinity to ACE2 than SARS-CoV.
- ACE2 is expressed in the heart, lungs, vasculature, and kidneys.
- ACEi and ARBs in animal models increase the expression of ACE2 (Zheng et al., Nature Reviews
Cardiology, 2020), though this has not been confirmed in human studies.
- This has led to the hypothesis that ACE-I and ARBs, might worsen myocarditis or precipitate
ACS.
- It has also been hypothesized that the upregulation of ACE2 is therapeutic in COVID-19 and that
ARBs might be protective in during infection (Gurwitz, D. Drug Dev Res, 2020).

Recommendation:
- For outpatients:
❑ We recommend against discontinuing outpatient ACEi/ARBs

- For inpatients:
❑ We against routine discontinuation of ACEi/ARBs, unless otherwise indicated (e.g.
acute kidney injury, hypotension, shock, etc).

- Rationale
- The American College of Cardiology, American Heart Association and Heart Failure
Society of America joint statement recommends against discontinuing ACE-I and ARBs
in patients with COVID-19 (Bozkurt et al., HFSA/ACC/AHA Statement Addresses
Concerns Re: Using RAAS Antagonists in COVID-19, 2020).
- This remains an area of investigation and it is unclear how these medications affect
patients with COVID-19.

Updated: 2020-03-23
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 COVID-19 | ACE-I and ARBs

ACE-2 Pathway
Background:
- Classically thought of as a pathway to modulate salt-water balance and sympathetic tone, the
RAAS pathway also includes a mechanism for vasodilation.
- This is achieved by negative regulation via ACE2, an integral membrane enzyme. As
shown in the figure below, ACE2 degrades angiotensin II into angiotensin 1-7 (Ang 1-7)
and angiotensin 1-9 (Zhang 2017).
- Ang 1-7 activates the Mas receptor, which leads to vasodilatory, antiproliferative, and
antifibrotic effects (Conti 2012, Santos 2003).
- In this way, ACE2 counterbalances the actions of ACE.

Updated: 2020-03-29
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 COVID-19 | ACE-I and ARBs

ACE-2 Tissue Distribution

- Early reports of COVID-19 manifestations in different organ systems (respiratory, cardiac, GI)
have been attributed to gene expression of ACE2 in different organs.
- However, the distribution of expression of ACE2 is uncertain. ACE2 mRNA has, in fact, been
detected in many different organs (lung, heart, GI tract), and at least one
immunohistochemistry study confirmed the presence of ACE2 in airway epithelial cells and
enterocytes (Hamming 2004).
- While this pattern may explain pulmonary and GI manifestations of SARS, ACE2 mRNA and
protein distribution in different organs (kidney, testis, endothelium) does not match the clinical
manifestation of SARS and COVID-19.
- There is clear recognition that ACE2 gene expression alone cannot predict organ susceptibility to
a viral infection.
- In fact, there are multiple published (Zou 2020, Qi 2020) and ongoing efforts (Travaglini 2020,
Zhang 2020, Zhao 2020, Lukassen 2020) to further characterize the expression of ACE2, possible
co-receptors, and associated virus-processing genes in different cell types throughout the body.

Updated: 2020-03-29
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 COVID-19 | NSAIDs

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

Recommendation:
- Consider acetaminophen instead of NSAIDs if possible; risk / benefit should be discussed with
patients and treatment team
- Reports from France indicate possible increase in mortality with ibuprofen in COVID-19
infection, but these reports have not been corroborated (Fang et al., Lancet Respir Med, 2020;
Day, BMJ, 2020)
- WHO clarified on 3/20/20 it does not recommend avoiding NSAIDs as of 3/18/20. (WHO, COVID-
19 Guidelines, 2020)

Updated: 2020-03-23
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 COVID-19 | Statins

Statins
Why consider statins in severe COVID-19 disease?
- While it is true there is no clinical evidence to date that statins are beneficial for patients with
COVID-19, there are several reasons they may be worthwhile to consider:
- Several reports so far have identified cardiovascular disease and diabetes as major risk
factors for severe COVID-19 disease and COVID-19 mortality. It follows that cardiac risk
reduction may also reduce the risk of severe COVID-19 disease.
- Myocardial injury is frequently seen in patients with severe COVID-19, and patients
with pre-existing CVD are more likely to have cardiac complications of COVID-19.
- There is theoretical evidence that statins may protect the inmate immune response in
COVID-19, namely through inhibition of the MYD88/NF-κB pathways.
- Statins may promote improved outcomes in viral pneumonia, but the evidence is mixed
and largely observational. Frost et al. (2007, large matched cohort study) found a
decreased risk of death due to COPD and influenza for patients on statins compared to
not; Vandermeer et al. (2012) and Kwong et al. (2009) found similarly for statin-users
with influenza. On the other hand, Brett et al (2011) did not find a statistically
significant association between pre-admission statin use and severity of outcome in
H1N1 patients during the 2009 pandemic.
- As discussed Sunday’s FLARE newsletter, statins may play an even more promising role
in the hyperinflammatory phenotype of ARDS, which could represent a large portion
COVID-19 ARDS patients (Calfee and Famous papers, cited below).
- Statins are generally accepted as safe, are widely available, and there is no reason to suspect
they will harm COVID-19 patients. Therefore, while they do not recommend statins purely for
respiratory failure, the MGH COVID Treatment Task Force feels that statin therapy is
reasonable among patients with an existing primary indication for statin therapy and no
contraindication.

Updated: 2020-03-24
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 COVID-19 | Blood Products

Blood Products
Recommendation:
- Restrictive transfusion strategy (Hct > 21, Hgb > 7) is recommended unless the patient is actively
bleeding or there is concern for acute coronary syndrome
- Parsimony is encouraged given limited supplies (blood drives are limited by social
distancing)
- Acute coronary syndrome: Hgb > 10
- Oncology patients: if possible, reduce threshold to Hgb >7
- All others: Hgb > 7
- Massive transfusion protocol, as a very limited resource, will need to be activated only
by the ICU attending
- Other blood products:
- Treat bleeding not numbers
- FFP or 4 factor-PCC (lower volume) for active bleeding in setting of known or suspected
coagulation abnormalities
- Warfarin reversal: use 4 factor-PCC given longer effect and lower volume
- Platelets: goal > 30K unless actively bleeding

Rationale:
- Volume overload is of particular concern in patients with COVID-19 so transfusions may be
harmful. Randomized controlled trials of ICU patients have shown that a conservative
transfusion strategy (Hgb 7) is associated with less pulmonary edema, fewer cardiac events,
fewer transfusions (likely fewer transfusion reactions) and no evidence of harm compared to a
liberal transfusion strategy.
- (Hebert et al, N Engl J Med, 1999; Holst et al, N Engl J Med, 2014; Gajic et al, Crit Care Med,
2006).

Updated: 2020-03-23
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 COVID-19 | Acute Cardiac Injury

Acute Cardiac Injury

Definition:
- Defined in studies as troponin > 99th percentile, or abnormal EKG or echocardiographic findings
(Zhou, Lancet, 2020).
- Non-specific.

Incidence:
- Incidence of 7-22% in hospitalized patients with COVID-19 in China (Ruan et al., Intensive Care
Med, 2020; Wang et al., JAMA, 2020; Chen et al., Lancet, 2020)

Prognostic implications:
- ACI is higher in non-survivors (59%, n=32) than survivors (1%, n=1) (Zhou, Lancet, 2020)
- ACI is higher in ICU patients (22%, n=22) compared to non-ICU patients (2%, n=2) (Wang, JAMA,
2020)

Time course:
- Troponin rise and acute cardiac injury tend to be late manifestations.
- Troponin increased rapidly from ~14 days from illness onset, after the onset of respiratory
failure. (Zhou et al., Lancet, 2020)
- Among non-survivors, a steady rise in troponin I levels was observed throughout the disease
course from day 4 of illness through day 22 (Zhou et al., Lancet, 2020).

Mechanism:
- The mechanism is unknown, though several have been proposed, based on very limited data
outside of case series and reports (Ruan et al., Int Care Med, 2020; Hu et al., EHJ, 2020; Zeng et
al., Preprints, 2020)
- Possible direct toxicity through viral invasion into cardiac myocytes (i.e. myocarditis).
- Acute coronary syndrome and demand ischemia
- Stress or cytokine-mediated cardiomyopathy (i.e. Takotsubo’s)

Updated: 2020-03-23
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 COVID-19 | Cardiovascular Testing

Cardiovascular Testing
Troponin:
- ICU patients: Check hsTrop daily and SCvO2 daily
- Inpatients: Check hsTrop every other day
- If hsTrop > 200 ng/L
- Obtain 12-lead ECG
- Perform point-of-care US (POCUS) if you are trained to do so
- If no new ECG or echocardiographic abnormalities, continue to monitor every
other day hsTrop

Telemetry:
- Telemetry should be used for all critically-ill patients
- At BWH, COVID-19 floor patients also have telemetry.
- For hospitals, with resource-limitations, telemetry is most important for patients who meet AHA
criteria.

ECGs:
- Daily ECGs are reasonable for individuals with severe COVID-19
- When possible, print ECGs from the in-room monitor to minimize contamination of equipment

TTE:
- Do not order routine TTEs on COVID-19 patients
- Cardiology consult or a trained provider should perform POCUS if:-
- Significant troponin elevation or decline in SCV02/ MV02
- Shock
- New heart failure (not pre-existing heart failure)
- New persistent arrhythmia
- Significant ECG changes
- If abnormalities are identified on POCUS (e.g. new reduction in LV EF<50%), a formal
TTE should be obtained and cardiology consulted
- Where possible order limited TTEs instead of full TTEs to conserve resources

Stress Testing:
- Stress testing is likely not indicated in individuals with active COVID.
- Any question of possible stress testing should be directed to cardiology

Updated: 2020-03-23
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 COVID-19 | Arrhythmias

Cardiovascular Testing
Incidence:
- Case series report the occurrence of unspecified arrhythmias in 17% of hospitalized patients
with COVID-19 (n=23 of 138), with higher rate in ICU patients (44%, n=16) compared to non-ICU
patients (7%, n=7) (Wang et al., JAMA, 2020).
- There are anecdotal reports of VT and VF as a late manifestation of COVID-19. No specific
published findings were identified.

Workup:
❑ Telemetry
❑ 12-lead EKG
❑ cardiac troponin
❑ NT-proBNP
❑ TFT
❑ SCVO2 if central line present (goal SCVO2 > 60%)
❑ POCUS to assess LV and RV function
- Obtain formal TTE if abnormalities of any of the above

Treatment:
- Atrial fibrillation/atrial flutter
❑ Beta blockade if no evidence of heart failure or shock
❑ Amiodarone if significant heart failure or borderline BPs
- There is no known increased concern for amiodarone lung toxicity
❑ If unstable, synchronized DCCV with 200 Joules biphasic

- Ventricular tachycardia (VT)

Unstable:
❑ Initiate ACLS if unstable/pulseless
-
Stable:
❑ Cardiology consult (may represent evolving myocardial involvement) if stable
❑ Amiodarone 150mg IV x 1 or lidocaine 100mg IV x 1

Updated: 2020-03-23
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 COVID-19 | Acute Coronary Syndromes

Acute Coronary Syndromes

Incidence:
- There is no current available data on the incidence of ACS in COVID.
- However, we presume that due to the presence of ACE2 receptors on the endothelium, and the
known increased risk of ACS in influenza that there is a possible increased incidence of ACS
among COVID-19 patients.
- The incidence of ACS is about 6 times as high within seven days of an influenza diagnosis than
during control interval - incidence ratio 6.05 (95% CI, 3.86 to 9.50). (Kwong et al., NEJM, 2018)

Workup:
- Elevated troponin/ECG changes alone may not be able to discriminate between:
- Coronary thrombosis
- Demand-related ischemia
- Myocarditis
- Determination of ACS will rely on all evidence available:
- Symptoms (if able to communicate)
- New dyspnea, chest pain, anginal equivalents
- Regional ECG changes
- Rate of change of Troponin changes (i.e. acute rise suggests ACS)
- Echo findings (e.g. new RWMA)
- When in doubt, request a cardiology consult

Management:
- Medical management of ACS should be coordinated with cardiology
- Treat with full dose aspirin, clopidogrel (if not bleeding), heparin, oxygen (if hypoxemic), statin,
nitrates (if hypertensive), and opioids (if persistent pain during medical management)
- Beta blockers should be used with caution given possible concomitant
myocarditis/decompensated heart failure
- If resources become constrained and door-to-balloon time is no longer adequate, cardiology
may decide to use lytic medications for COVID-19 STEMI patients in lieu of PCI

Updated: 2020-03-23
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 COVID-19 | Pericarditis and Myocarditis

Pericarditis and Myocarditis

Incidence:
- Myocarditis and pericarditis are potential manifestations of COVID-19 and source of Acute
Cardiac Injury, based on case reports/case series (Ruan et al., Intensive Care Med, 2020; Zeng et
al., Preprints, 2020; Hu et al., Eur Heart J, 2020)
- However, there is currently no evidence of proven pericarditis or myocarditis, either by biopsy
or cMRI.

Diagnosis:
- Likely no role for endomyocardial biopsy
- cMRI should be discussed on a case-by-case basis with a cardiology consult team

Management:
- Supportive for heart failure and direct viral treatments
- The use of anti-inflammatory medications such as Colchicine and Ibuprofen should also be
discussed with the cardiology consult team as this literature is evolving.

Updated: 2020-03-23
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 COVID-19 | Undifferentiated Shock

Undifferentiated Shock
Definition:
- Acute onset of new and sustained hypotension (MAP < 65 or SBP < 90) with signs of
hypoperfusion requiring IVF or vasopressors to maintain adequate blood pressure

Time course:
- Patients rarely present in shock on admission
- Natural history seems to favor the development of shock after multiple days of critical illness.

Etiology:
- The range of reasons for shock is wide and more variable than for most patients and includes:
- Cardiogenic shock
- Secondary bacterial infection
- Cytokine storm

Updated: 2020-03-23
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 COVID-19 | Undifferentiated Shock

Undifferentiated Shock
Workup for new undifferentiated shock:
- Assess for severity of end organ damage:
- UOP, Mental status, Lactate, BUN/creatinine, electrolytes, LFTs
- Obtain a FULL infectious workup, which includes all of the following:
- Labs:
❑ CBC with differential. Note that most COVID patients are lymphopenic (83%).
However, new leukocytosis can occur and left-shift can be used as a part of
clinical picture (Guan et al, N Engl J Med, 2020).
❑ Two sets of blood cultures,
❑ LFTs (for cholangitis/acalculous cholecystitis),
❑ Urinalysis (with reflex to culture),
❑ Sputum culture (if safely obtained via inline suctioning, do not perform
Bronchoscopy or sputum induction),
❑ Procalcitonin at 0 and 48h (do not withhold early antibiotics on the basis of
Procalcitonin),
❑ Urine Strep and legionella antigens
- Portable CXR (avoid CT unless absolutely necessary)
- Full skin exam
- Assess for cardiogenic shock
- Assess extremities: warm or cool on exam
- Assess patient volume status: JVP, CVP, edema, CXR
- Assess pulse pressure: If < 25% of the SBP, correlates highly with a reduction in cardiac
index to less than 2.2 with a sensitivity of 91% and a specificity of 83% (Stevenson and
Perloff, JAMA, 1989)
- Perform POCUS if trained to do so
- Labs:
❑ Obtain an SCV02 or MV02 if the patient has central access,
❑ troponin x2,
❑ NT proBNP,
❑ A1c, lipid profile, TSH
- EKG (and telemetry)
- Calculate estimated Fick Cardiac Output
- CO (Cardiac Output), L/min = VO2/ [(SaO2 - SvO2) x Hb x 13.4)],
- where VO2 = 125 mL O2/min x BSA, where BSA = [(Height, cm x
Weight, kg)/ 3,600 ]½; in patients aged ≥70, use 110 mL O2 x BSA for
VO2
- Assess for other causes of shock:
- Vasoplegia:
- Run medication list for recent cardiosuppressive medications, vasodilatory
agents, antihypertensives
- Adrenal insufficiency:
- Unless high pretest probability of adrenal insufficiency, we recommend against
routine cortisone stimulation testing
- Obstruction:
- PE (given the elevated risk of thrombosis)
- Tamponade (given elevated risk of pericarditis)
- Obstruction from PEEP
- Cytokine storm (see “Cytokine Storm” section below)
- Allergic reactions to recent medications
- Neurogenic shock is uncommon in this context
- Hypovolemia:
- Bleeding
- Insensible losses from fever
- Diarrhea/vomiting

Updated: 2020-03-23
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 COVID-19 | Undifferentiated Shock

Undifferentiated Shock

Updated: 2020-03-23
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 COVID-19 | Undifferentiated Shock

Updated: 2020-03-25
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 COVID-19 | Septic Shock

Septic Shock
Incidence:
- The reported rates of sepsis and septic shock are not reported consistently in currently available
case series
- Secondary bacterial infections are reported:
- 20% of non-survivors (Zhou et al, Lancet, 2020)
- 16% of non-survivors (Ruan et al, Intensive Care Med, 2020)
- 12-19% In H1N1 epidemic (MacIntyre et al, BMC Infect Dis, 2018)
- Concurrent Pneumocystis pneumonia has been reported in at least one case (possibly
due to lymphopenia)

Antibiosis:
- Early empiric antibiotics should be initiated within 1 hour

Conservative Fluid Management:

- Goal MAP > 65mmHg
- Start Norepinephrine while determining the etiology of undifferentiated shock
- We do not recommend conventional 30cc/kg resuscitation
- Give 250-500cc IVF and assess in 15-30 minutes for:
- Increase > 2 in CVP
- Increase in MAP or decrease in pressor requirement
- Use isotonic crystalloids; Lactated Ringer’s solution is preferred where
possible. Avoid hypotonic fluids, starches, or colloids
- Repeat 250-500cc IVF boluses; Use dynamic measures of fluid responsiveness
- Pulse Pressure Variation: can be calculated in mechanically ventilated patients
without arrhythmia; PPV >12% is sensitive and specific for volume
responsiveness
- Straight Leg Raise: raise legs to 45° w/ supine torso for at least one minute. A
change in pulse pressure of > 12% has sensitivity of 60% & specificity of 85%
for fluid responsiveness in mechanically ventilated patients; less accurate if
spontaneously breathing
- Ultrasound evaluation of IVC collapsibility should only be undertaken by
trained personnel to avoid contamination of ultrasound
- For further guidance, Conservative Fluid Management protocols are available from
from FACCT Lite trial (Grissom et al, Crit Care Med, 2015).
- Rationale:
- COVID-19 clinical reports indicate the majority of patients present with respiratory
failure without shock.
- ARDS is mediated in part by pulmonary capillary leak, and randomized controlled trials
of ARDS indicate that a conservative fluid strategy is protective in this setting (Grissom
et al, Crit Care Med, 2015; Famous et al, Am J Respir Crit Care Med, 2017; Silversides et
al, Int Care Med, 2017; WHO, COVID-19 Interim guidance, March 2020).

Pressor management
- Unless new evidence emerges, standard choices for distributive shock (i.e., norepinephrine then
vasopressin) are recommended, with high vigilance for the development of cardiogenic shock,
addressed in the next section.

Corticosteroids
- See “Systemic Corticosteroids” section within “COVID-19 Therapies and Clinical Trials” chapter.
- Stress dose hydrocortisone should still be considered in patients on > 2 pressors

Updated: 2020-03-23
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 COVID-19 | Cardiogenic Shock

Cardiogenic Shock
Incidence:
- Heart failure or cardiogenic shock was observed in 23% (n=44 of 191) of hospitalized patients in
one case series (Zhou et al, Lancet, 2020). Moreover, there were higher rates in non-survivors
(52%, n=28) compared to survivors (12%, n=16). Among 21 patients admitted to an ICU in
Washington State 33% (n=7) developed a new cardiomyopathy (Arentz et al, JAMA, 2020).
Notably, these patients tended to be older with more comorbidities and had a high mortality
(11 of the 21 died).
- Heart failure or myocardial damage contributed to death in 39% (n=29) of deaths in a series of
68 patients in Wuhan. Most (n=22 of 29) had concomitant respiratory failure (Ruan et al,
Intensive Care Med, 2020).

Diagnosis:
- Significant concern for cardiogenic shock if any of the following are present with evidence of
hypoperfusion (e.g., elevated lactate):
- Elevated NT-proBNP, or
- CvO2 < 60% (PvO2 < 35 mm Hg), or
- Echocardiogram with depressed LV and/or RV function

Time course:
- Cardiogenic shock may present late in the course of illness even after improvement of
respiratory symptoms, and manifest as a precipitous clinical deterioration in the setting of an
acute decline in LVEF (see “Acute Cardiac Injury” section in “Cardiac Complications” chapter).

Etiology:
- See “Acute Cardiac Injury” section in “Cardiac Complications” chapter.
- Mechanism is unknown, potentially direct viral toxicity, ACS, or stress cardiomyopathy.

Updated: 2020-03-23
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 COVID-19 | Cardiogenic Shock

Cardiogenic Shock
Workup:
- Rule out ACS and complete the initial work up as described in “Cardiac Complications” chapter.
- Ongoing monitoring:
- Labs:
❑ Trend troponins to peak,
❑ SCvO2 (obtained by upper body CVC) or MvO2 q8-12h or with clinical chang
❑ Lactate q4-6h,
❑ LFTs daily (for hepatic congestion)
- Daily EKGs or prn with clinical deterioration
- All cardiogenic shock cases require cardiovascular consult
- PA catheters may be placed bedside by experienced providers, with preference for use
only in mixed shock or complex cases with cardiology guidance

Medical management:
- Close collaboration with the cardiovascular consultation service is recommended
- Goals:
- Note: Achieving MAP goal is first priority, then optimize other parameters
- MAPs 65-75
- CVP 6-14,
- PCWP 12-18,
- PAD 20-25,
- SVR 800-1000,
- SCvO2 > 60%,
- CI > 2.2
- How to achieve goals:
- Continue titration of norepinephrine gtt for goal MAP 65-75
- Initiate diuretic therapy for CVP > 14, PCWP >18, PAD > 25
- Initiate inotropic support:
- Dobutamine gtt for SCvO2 < 60%, CI < 2.2 and MAP > 65.
- Start at 2mcg/kg/min.
- Up-titrate by 1-2mcg/kg/min every 30-60 minutes for goal parameters.
- Alternative strategies should be considered once dose exceeds
5mcg/kg/min.
- Maximum dose is 10mcg/kg/min.
- Ensure negative inotropes such as beta blockers, calcium channel blockers and
antihypertensives are discontinued.

Updated: 2020-03-23
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 COVID-19 | Cardiogenic Shock

Cardiogenic Shock
Candidacy for Mechanical Support
- The benefit of Mechanical Support in COVID-19 is not yet clear. In one study of patients with
severe COVID-19, five (83%) of six patients receiving ECMO died (Yang et al, Lancet Respir Med,
2020).
- There is concern that the further decrease of lymphocytes from ECMO could contribute to
higher mortality. However, this is a very small study and more information is needed.
- Patients who experience the following should prompt an immediate call to the cardiovascular
medicine consult service for consideration of mechanical support:
- Dobutamine gtt at 5mcg/kg/min (or unable to tolerate dobutamine due to
tachyarrhythmias) and SCVO2 < 60% or CI < 2.2
- Lactate > 4 after medical therapy
- The criteria for ECMO and other mechanical cardiovascular support varies among centers and
are difficult to develop under typical circumstances.
- The unclear trajectory of the COVID-19 pandemic makes these evaluations even more
difficult.
- Please refer to the separate BWH ECMO and Cardiovascular Medicine guidelines which
are in development.

The following does not reflect the recommendation of the BWH ECMO and Cardiovascular services.
However, for the purposes of general education, a hypothetical set of inclusion criteria for ECMO or
MCS could cover:
- Younger age
- Expected life expectancy >6 months pre-hospitalization
- No evidence of solid or liquid malignancy
- Able to tolerate anticoagulation
- Platelets >50,000
- Absence of severe peripheral arterial disease
- No evidence of irreversible neurological injury
- Able to perform ADLs at baseline prior to illness
- Cannot have profound respiratory failure (defined as requiring prone ventilation at time of
consult for MCS or having PaO2:FiO2 ratio < 150) (for MCS other than ECMO)

Updated: 2020-03-23
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 COVID-19 | Cytokine Activation Syndrome

Cytokine Activation Syndrome

Incidence:
- A subgroup of patients with severe COVID-19 may have cytokine storm syndrome and
secondary HLH (Mehta et al, Lancet, 2020). Patients who had cytokine storm developed rapid
progression to ARDS, shock, and multiorgan failure (Chen et al, Lancet, 2020)

Pathophysiology:
- Neutrophil activation likely contributes to the pathogenesis of cytokine storm and ARDS (Wu et
al, JAMA Intern Med, 2020). Wu et al found that COVID-19 confirmed patients with ARDS have
higher neutrophil counts, average 7.04 (95% CI: 3.98 to 10.12) vs. those without ARDS, average
3.06 (2.03 to 5.56)
- Similar patterns of cytokine storm and ARDS have been seen with SARS, MERS (Kim et al, J
Korean Med Sci, 2016)
- Other studies have suggested that increased proinflammatory cytokines in the serum are
associated with pulmonary injury in SARS, MERS, and COVID-19 (Wong et al, Clin Exp Immunol,
2004)

Workup:
- Suspect if clinical deterioration with shock and multiorgan failure
❑ CBC with diff
❑ PT/INR, PTT
❑ Fibrinogen
❑ d-dimer
❑ Ferritin
❑ liver function test,
❑ triglycerides,
❑ c-reactive protein (CRP) (Ruan et al, Intensive Care Med, 2020)
- CRP seems to correlate with disease severity and prognosis of COVID-19 (Ruan
et al, Intensive Care Med, 2020; Young et al, JAMA, 2020)
- An HScore (MDcalc online calculator) may be helpful in estimating the
probability of secondary HLH in these patients

Management:
- If high suspicion, discuss with ID about the use of IVIG, steroids, cytokine blockade, particularly
IL-6 pathway and perhaps IL-1 (see “Anti-IL6 Agents” section within “COVID-19 Therapies and
Clinical Trials” chapter).
- While steroids have been implicated with worse lung injury and outcomes, they may be
beneficial in the hyperinflammatory state.

Updated: 2020-03-23
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 COVID-19 | Thrombotic Disease

Thrombotic Disease
Incidence:
- Unclear incidence, though case reports suggest there may be increased venous
thromboembolism (VTE) in COVID-19 patients (Xie et al, Radiol Cardiothoracic Imaging, 2020)

Pathophysiology:
- The mechanism for VTE are unknown and likely multifactorial:
- Systemic inflammatory response as seen in sepsis
- Stasis/critical illness
- Possibly direct endothelial damage from viral injury/ACE2 binding
- Colleagues from Wuhan have reported finding microthrombi in pulmonary vasculature on
autopsy (Luo et al, Preprints, 2020 preprint), which could contribute to local V/Q mismatch or
hydrostatic changes causing edema. However these mechanisms remain entirely hypothetical.
- One theory:
- SARS-CoV Spike protein can be cleaved by FXa and FIIa. Cleavage of the Spike protein
activates it which promotes infectivity.
- By extension, it is hypothesized that anticoagulation might inhibit SARS-CoV-2
replication.
- There is a small case series suggesting dipyridamole may be useful, though
anticoagulation and antiplatelet agents require further investigation prior to being used
therapeutically (Liu et al, medRxiv, 2020 preprint).

Management:
- Initiate prophylactic anticoagulation therapy for all COVID-19 patients unless otherwise
contraindicated
- If CrCl > 30: Lovenox 40 mg SC daily
- If CrCl < 30 or AKI: Heparin 5000 units SC TID
- Hold if Platelets <30,000 or bleeding, start TEDs and SCDs
- If the patient is on direct oral anticoagulants (DOACs) or Warfarin for Afib or VTE, switch to full
dose anticoagulation (LMWH or UFH, as indicated based on renal function or clinical scenario).
- While therapeutic anticoagulation has been used empirically in some severe COVID-19 patients
in Wuhan given the microthrombi in pulmonary vasculature (see “Pathophysiology” above), our
interpretation of the data is that the risks outweigh the benefits at this time, unless
documented DVT or PE.

Prognosis:
- Higher D-dimer and FDP levels track with multi-organ dysfunction syndrome and poorer
prognosis (Wang et al, JAMA, 2020; Zhou et al, Lancet, 2020).

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 87
 COVID-19 | DIC

Disseminated Intravascular Coagulation (DIC)

Incidence/pathophysiology:
- Limited data: 16 of 183 hospitalized patients in Wuhan had DIC (Tang et al, J Thromb Haemost,
2020).
- Laboratory changes in coagulation parameters and FDP track with multi-organ dysfunction
(Zhou et al, Lancet, 2020).

Time course:
- Median time to onset of DIC was 4 days into hospital admission (Tang et al, J Thromb Haemost,
2020).

Workup:
- Identify and treat underlying condition
- ISTH DIC score (MDcalc online calculator)
- If score < 5, no DIC; recalculate in 1-2 days

Management:
- If bleeding, give blood products:
- For elevated PT/PTT and bleeding, use FFP or 4F-PCC (KCentra is less volume, but must
discuss dose with HAT/pharmacy)

- If not bleeding, supportive care:

- If fibrinogen < 150: FFP, cryoprecipitate or fibrinogen concentrate (RiaSTAP or Fibryga)
- RiaSTAP and Fibryga are less volume, but dose must be discussed with
HAT/pharmacy
- Transfuse platelets if < 30K

- Hold anticoagulation for active bleeding.

- Consider holding anticoagulation if patient requires blood products for supportive care,
though clinician should weigh risks and benefits.

- Start anticoagulation only if:

- Overt thromboembolism or organ failure due to clot (i.e., purpura fulminans)
- There has been no mortality benefit of therapeutic anticoagulation in DIC (Levi et al,
Blood, 2018).

Prognosis:
- DIC is associated with worse survival in COVID-19 patients.
- Out of 183 COVID-19 patients in Wuhan, 71% of non-survivors had DIC (ISTH score ≥ 5; MDcalc
online calculator) compared to 0.6% of survivors (Tang et al, J Thromb Haemost, 2020).

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 88
 ICU Pharmacology | Pressors

Agent Initial dose Maintenance dose range Max dose in refractory

Norepinephrine 8 to 12 mcg/minute 2 to 4 mcg/minute 35 to 100 mcg/minute
(noradrenaline) (0.5 to 0.75
(0.1 to 0.15 (0.025 to 0.05 mcg/kg/minute; up to
Levophed mcg/kg/minute) mcg/kg/minute) 3.3 mcg/kg/minute has
A lower initial dose of 5 been needed rarely)
mcg/minute may be
used, eg, in older adults
Epinephrine (adrenaline) 1 mcg/minute 1 to 10 mcg/minute 10 to 35 mcg/minute
(0.14 to 0.5
Adrenalin (0.014 mcg/kg/minute) (0.014 to 0.14 mcg/kg/minute)
mcg/kg/minute)
Phenylephrine 100 to 180 mcg/minute 20 to 80 mcg/minute 80 to 360 mcg/minute
until stabilized (1.1 to 6
Neo-Synephrine, (0.25 to 1.1 mcg/kg/minute);
Vazculep (alternatively, 0.5 to 2 mcg/kg/minute) Doses >6 mcg/kg/minute
mcg/kg/minute) do not increase efficacy
according to product
information in the United
States
Dopamine 2 to 5 mcg/kg/minute 5 to 20 mcg/kg/minute 20 to >50 mcg/kg/minute

Inotropin

Vasopressin (arginine- 0.03 units per minute 0.03 to 0.04 units per 0.04 to 0.07
vasopressin) minute (not titrated) units/minute;
(alternatively 0.01 to Doses >0.04
Pitressin, Vasostrict 0.03 units/minute units/minute can cause
initially) cardiac ischemia and
should be reserved for
salvage therapy
Dobutamine 0.5 to 1 mcg/kg/minute 2 to 20 mcg/kg/minute 20 to 40 mcg/kg/minute;
Doses >20
Dobutrex (alternatively, 2.5 mcg/kg/minute are not
mcg/kg/minute in more recommended in heart
severe cardiac failure and should be
decompensation) reserved for salvage
therapy
Milrinone Optional loading dose: 50 0.125 to 0.75
mcg/kg over 10 minutes mcg/kg/minute
Primacor (usually not given)

All doses shown are for intravenous (IV) administration in adult patients. The initial doses shown in this table
may differ from those recommended in immediate post-cardiac arrest management (ie, advanced cardiac
life support).

Vasopressors can cause life-threatening hypotension and hypertension, dysrhythmias, and myocardial
ischemia. They should be administered by use of an infusion pump adjusted by clinicians trained and
experienced in dose titration of intravenous vasopressors using continuous noninvasive electronic monitoring
of blood pressure, heart rate, rhythm, and function. Hypovolemia should be corrected prior to the institution
of vasopressor therapy. Reduce infusion rate gradually; avoid sudden discontinuation.

Vasopressors can cause severe local tissue ischemia; central line administration is preferred. When a patient
does not have a central venous catheter, vasopressors can be temporarily administered in a low
concentration through an appropriately positioned peripheral venous catheter (ie, in a large vein) until a
central venous catheter is inserted. The examples of concentrations shown in this table are useful for
peripheral (short-term) or central line administration. Closely monitor catheter site throughout infusion to
avoid extravasation injury. In event of extravasation, prompt local infiltration of an antidote (eg,
phentolamine) may be useful for limiting tissue ischemia. Stop infusion and refer to extravasation
management protocol.
Return to Index 89
 ICU Pharmacology | Pressors

Agent Concentration Dose Maximum

Norepinephrine 8 mg/250 ml D5W 0.01-1 mcg/kg/min 1 mcg/kg/min
(noradrenaline) (32 mc/ml) Titrate to a MAP >60
or
Levophed 16 mg/25 ml D5
(64 mcg/ml)
Epinephrine (adrenaline) 4 mg/250 ml D5W/NS 0.01-0.1 mcg/kg/min 0.1 mcg/kg/min
(16 mcg/ml)
Adrenalin

Phenylephrine 80 mg/500 ml D5W 0.4-4 mcg/kg/min 4 mcg/kg/min

(160 mcg/ml)
Neo-Synephrine, or
Vazculep 160 mg/500 ml D5W
(320 mcg/ml)
Dopamine 400 mg/250 ml D5W 1-30 mcg/kg/min 30 mcg/kg/min
(1.6 mg/ml) Titrate to a MAP > ___
Inotropin Or
800 mg /250 ml D5@
(3.2 mg/ml)
Vasopressin (arginine- 100 units/100 ml D5W 0.02-0.1 unit/min Sepsis
vasopressin) (1 unit/ml) 0.04 units/min = 2.4
ml/hr
Pitressin, Vasostrict

Dobutamine 500 mg/250 ml D5W 2.5-20 mcg/kg/min 20 mcg/kg/min

(2 mg/ml) Titrate as ordered
Dobutrex Or SVO2 or cardiac output
1,000 mg/250 ml D5@ parameters)
(4 mg/ml)
Milrinone 100 mg/100 ml NS 2-10 mg/hr Titrate to Critical Care
(1 mg/ml) Pain Observation Tool
Primacor Or (Range 0-1)
250 mg / 250 ml NS
(1 mg/ml)

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 ICU Pharmacology | Sedation

Return to Index 91
 COVID-19 | Acute Kidney Injury (AKI)

Acute Kidney Injury

Incidence:
- Incidence of AKI in COVID-19 varies widely, but estimates range from 2.1% to 29%.

Pathophysiology:
- Likely that the most common pathophysiology will be acute tubular necrosis (ATN) driven by
shock (Xianghong et al, Natl Med J China, 2020) and in some cases cytokine storm.
- Areas for future research: Some have hypothesized that there could direct cellular
injury by the virus via angiotensin converting enzyme II (ACE2). COVID-19 uses ACE2 for
cell entry. ACE2 is expressed in proximal renal tubules more than glomeruli (Fan et al,
medRxiv, 2020); but it remains likely that shock (and in some cases cytokine storm) are
the main causes of ATN.

Workup:
- Monitor Creatinine at least daily
- Studies find variable onset of AKI, from 7 days (Cheng et al, medRxiv, 2020 preprint) to 15 days
after illness onset (Zhou et al, Lancet, 2020).
- Onset of AKI more rapid and severe in patients with underlying CKD (Cheng et al, medRxiv, 2020
preprint)
- If evidence of rising BUN and/or creatinine, order urinalysis
- Patients may present with proteinuria (44%), hematuria (26.9%)

Management:
- Consult ICU nephrology early at the first sign of renal injury for all COVID-19 confirmed patients
- Do not wait until need for RRT (renal replacement therapy)/dialysis for consultation.
- At this time, all confirmed COVID-19 patients should be covered by ICU nephrology, not
general nephrology
- Managing AKI:
- Minimize nephrotoxic agents
- Give judicious fluids for suspected prerenal insults, but discuss with renal if any
ambiguity (see “Shock” chapter for conservative fluid recommendations)

Renal Replacement Therapy (RRT):

- Estimates for RRT range from 1 to 5% of hospitalized patients. Among critically ill patients, need
for CRRT ranges from 5 to 23%
- Few studies have reported outcomes of RRT. One case series reported that out of 191 patients,
10 received CRRT, and all 10 died (Zhou et al, Lancet, 2020).
- Renal will be coordinating RRT continuation and initiation
- Indications for dialysis in COVID-19 patients are the same as the indications for all
patients.
- ICU nephrology will determine the need, timing, and modality of renal replacement on a case-
by-case basis.

Prognosis:
- Increased serum creatine, BUN, AKI, proteinuria, or hematuria are each independent risk factors
for in-hospital death (Cheng et al, medRxiv, 2020 preprint)
- In two other studies, non-survivors had higher BUN and creatinine and higher rates of AKI
(Wang et al, JAMA, 2020; Yang et al, Lancet Respir Med, 2020).
- Another study found that higher BUN and creatinine are associated with progression to ARDS,
and higher BUN (though not creatinine) is associated with death (HR 1.06-1.20) (Wu et al, JAMA
Intern Med, 2020).
- In comparison, AKI was found in 6.7% of SARS patients. AKI correlated with poor prognosis and
91.7% of patients with AKI died (vs 8.8% without AKI, p < 0.0001) (Chu et al, Kidney Int, 2005).

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 92
 COVID-19 | Liver Disease

Liver Disease
Incidence:
- Up to 53% of patients had abnormal alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) (Zhang et al, Lancet Gastroenterol Hepatol, 2020).

Pathophysiology:
- Possible mechanisms of liver injury include:
- Direct viral infection of liver cells (2-10% of patients have diarrhea; COVID-19 found in
stool samples)
- Drug hepatotoxicity
- Cytokine storm
- Shock

Time course:
- In general, liver injury in mild COVID-19 disease is transient and self-resolving. However, liver
injury correlates with severity
- ALT > 40 is associated with higher odds of in-hospital death (Zhou et al, Lancet, 2020).
- AST is associated with progression to ARDS but not death; total bilirubin is associated with both
progression to ARDS and death (Wu et al, JAMA Intern Med, 2020).

Monitoring:
- Monitor LFTs every third day
- If on hepatotoxic medications, monitor more frequently in conjunction with pharmacy.
- If starting Lopinavir/Ritonavir and Chloroquine, monitor LFTs daily.
- Workup for other etiologies of liver injury with RUQUS, doppler ultrasound, hepatitis serologies,
etc., as clinically indicated.

Management:
- Consult GI/Hepatology if concern for acute liver failure (severe liver injury with elevated
bilirubin, encephalopathy, and INR >1.5).
- Run medication list for all possible offending agents and discontinue where possible.
- N-Acetyl-Cysteine is NOT RECOMMENDED at this time due to significant volume load. Chinese
studies refer to giving “liver protective drugs” in case of severe liver injury but we recommend
against this for now.
- There are no current guidelines for treatment of COVID-19 patients with underlying cirrhosis,
but societies such as AASLD are working on registries of these patients.

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 93
 COVID-19 | Liver Disease

Liver Disease
Incidence:
- Up to 53% of patients had abnormal alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) (Zhang et al, Lancet Gastroenterol Hepatol, 2020).

Pathophysiology:
- Possible mechanisms of liver injury include:
- Direct viral infection of liver cells (2-10% of patients have diarrhea; COVID-19 found in
stool samples)
- Drug hepatotoxicity
- Cytokine storm
- Shock

Time course:
- In general, liver injury in mild COVID-19 disease is transient and self-resolving. However, liver
injury correlates with severity
- ALT > 40 is associated with higher odds of in-hospital death (Zhou et al, Lancet, 2020).
- AST is associated with progression to ARDS but not death; total bilirubin is associated with both
progression to ARDS and death (Wu et al, JAMA Intern Med, 2020).

Monitoring:
- Monitor LFTs every third day
- If on hepatotoxic medications, monitor more frequently in conjunction with pharmacy.
- If starting Lopinavir/Ritonavir and Chloroquine, monitor LFTs daily.
- Workup for other etiologies of liver injury with RUQUS, doppler ultrasound, hepatitis serologies,
etc., as clinically indicated.

Management:
- Consult GI/Hepatology if concern for acute liver failure (severe liver injury with elevated
bilirubin, encephalopathy, and INR >1.5).
- Run medication list for all possible offending agents and discontinue where possible.
- N-Acetyl-Cysteine is NOT RECOMMENDED at this time due to significant volume load. Chinese
studies refer to giving “liver protective drugs” in case of severe liver injury but we recommend
against this for now.
- There are no current guidelines for treatment of COVID-19 patients with underlying cirrhosis,
but societies such as AASLD are working on registries of these patients.

Updated: 2020-03-23
Return to Index Source: BWH COVID-19 Critical Care Guidelines Work In Progress 94
 COVID-19 | Patient Info

Patient Info

Link to document
https://bit.ly/covidguide-dc

Updated: 2020-03-25
Return to Index 95
 COVID-19 | Patient Info | Tested

Patient Info | Tested

Link to document
https://bit.ly/covidguide-dc

Updated: 2020-03-25
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 COVID-19 | Patient Info | Self Quarantine

Patient Info | Self Quarantine

Link to document
https://bit.ly/covidguide-dc

Updated: 2020-03-25
Return to Index 97
 COVID-19 | Patient Info | Self Quarantine

Patient Info | Self Quarantine

Link to document
https://bit.ly/covidguide-dc

Updated: 2020-03-25
Return to Index 98
 COVID-19 | Ethics | Rationing Resources

Fairly Rationing Critical Resources

Hospitals need ways to make rational fair decisions about who gets ICU beds and ventilators if COVID-
19 patients overwhelm capacity. Douglas B. White, MD, MAS, Director of the Program on Ethics and
Decision Making in Critical Illness at the University of Pittsburgh, discusses a framework

Allocation of Scarce Critical

Care Resources During a
Public Health Emergency
Executive Summary
March 26, 2020

A Framework for Rationing

Ventilators and Critical Care
Beds During the COVID-19
Pandemic
Douglas B. White, MD, MAS1; Bernard Lo, MD2,3
March 27, 2020

Updated: 2020-03-28
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 COVID-19 | Ethics | DNR

The Importance of Addressing Advance Care Planning

and Decisions About Do-Not-Resuscitate Orders
During Novel Coronavirus 2019 (COVID-19)
J. Randall Curtis, MD, MPH1,2; Erin K. Kross, MD1,2; Renee D. Stapleton, MD, PhD3
Author Affiliations Article Information

JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4894

The novel coronavirus disease 2019 (COVID-19) pandemic is challenging health care systems worldwide and raising important
ethical issues, especially regarding the potential need for rationing health care in the context of scarce resources and crisis
capacity. Even if capacity to provide care is sufficient, one priority should be addressing goals of care in the setting of acute life-
threatening illness, especially for patients with chronic, life-limiting disease.
Clinicians should ensure patients receive the care they want, aligning the care that is delivered with patients’ values and goals.
The importance of goal-concordant care is not new or even substantially different in the context of this pandemic, but the
importance of providing goal-concordant care is now heightened in several ways. Patients most likely to develop severe illness
will be older and have greater burden of chronic illness—exactly those who may wish to forgo prolonged life support and who
may find their quality of life unacceptable after prolonged life support.1 In addition, recent reports suggest that survival may be
substantially lower when acute respiratory distress syndrome is associated with COVID-19 vs when it is associated with other
etiologies.2,3

In this context, advance care planning prior to serious acute illness and discussions about goals of care at the onset of serious
acute illness should be a high priority for 3 reasons. First, clinicians should always strive to avoid intensive life-sustaining
treatments when unwanted by patients. Second, avoiding nonbeneficial or unwanted high-intensity care becomes especially
important in times of stress on health care capacity. Third, provision of nonbeneficial or unwanted high-intensity care may put
other patients, family members, and health care workers at higher risk of transmission of severe acute respiratory syndrome
coronavirus 2. Now is the time to implement advance care planning to ensure patients do not receive care they would not want
if they become too severely ill to make their own decisions. As eloquently pointed out by an intensivist, “If you do not talk with
[your family] about this now, you may have to have a much more difficult conversation with me later.”4 Several online resources
can guide these advance care planning discussions.5-7

For patients in a community setting or living in a nursing home, clinicians should engage in discussions about goals of care now,
especially with older patients with chronic disease. During this pandemic when nonessential medical visits are currently limited,
these conversations may need to occur via telemedicine (either as a stand-alone appointment or in combination with an
appointment designated or scheduled for another purpose). This process should include primary care and specialty clinicians (eg,
cardiologists, pulmonologists, nephrologists, oncologists, and geriatricians), and patients might appreciate this opportunity to
discuss advance care planning. Depending on state regulations, patients with chronic life-limiting illness should be offered the
option to complete a physician order for life-sustaining treatments form, especially if they would not want to receive
cardiopulmonary resuscitation (CPR) or mechanical ventilation.

For hospitalized patients, one focal point for goal-concordant care is related to discussions of code status or the use of CPR and
advanced cardiac life support (ACLS). Many hospital-based clinicians overemphasize code status as the first step of a goals-of-
care discussion, but asking patients about CPR before assessing values and goals leads to ineffective code status discussions.
During this pandemic, it is equally important to understand a patient’s values and goals prior to discussing code status; however,
the importance of avoiding inappropriate CPR has increased for 2 reasons. One reason is that although unwanted or
nonbeneficial CPR under any circumstance may risk increasing psychological distress for patients’ family
members,8 inappropriate CPR during the pandemic is especially stressful and potentially dangerous for health care workers.
Another reason is that nonbeneficial or unwanted ACLS will strain available resources for personal protective equipment because
multiple health care workers are needed for effective ACLS. Therefore, the COVID-19 pandemic heightens the importance of
implementing do-not-resuscitate (DNR) orders for appropriate hospitalized patients.

The implementation of DNR orders can occur in 3 situations. First, patients or their surrogate decision makers may clearly
understand and communicate that the patient would not want CPR if the heart were to stop and may even have a physician’s
order for life-sustaining treatments form that specifies such. Second, patients or their surrogate decision makers may follow the
recommendation of a clinician to forgo CPR; this may occur through informed consent or, occasionally, informed assent (as
discussed below).9 Third, in extreme situations in which CPR cannot possibly be effective, clinicians in some health care settings
may unilaterally decide to write a DNR order.10 This latter approach is not uniformly accepted and, prior to COVID-19, it rarely
had a role. During this pandemic, however, in extreme situations such as a patient with severe underlying chronic illness and
acute cardiopulmonary failure who is getting worse despite maximal therapy, there may be a role for a unilateral DNR to reduce
the risk of medically futile CPR to patients, families, and health care workers.10

Informed assent may be a more acceptable approach to code status discussions than medical futility and may be useful for
patients in whom CPR is exceedingly unlikely to allow a successful return to a quality of life they would find
acceptable.9 The Figure provides a proposed guide for an approach to having an informed assent discussion with a patient or
family member of a patient for whom the clinician believes CPR is not indicated. The advantage of informed assent over a more
traditional informed consent approach is that the clinician does not ask the patient or designated family member to take
responsibility for the decision but rather asks the patient or family member to allow the clinician to assume responsibility. Some
family members may be willing to permit clinicians to make this decision while simultaneously being unable to accept
responsibility themselves, even if they agree, because of the psychological burden it places on them. In this setting, informed
assent may provide family members a way to agree with the clinician’s determination without assuming responsibility.
Importantly, this approach places great responsibility on clinicians to enact careful prognostication and thoughtful, respectful,
open communication with family members. This same responsibility is also present for informed consent.

Updated: 2020-03-28
Return to Index Source: Curtis JR, Kross EK, Stapleton RD. JAMA. March 27, 2020. doi:10.1001/jama.2020.4894 100
 COVID-19 | Ethics | DNR

The Importance of Addressing Advance Care Planning

and Decisions About Do-Not-Resuscitate Orders
During Novel Coronavirus 2019 (COVID-19)
J. Randall Curtis, MD, MPH1,2; Erin K. Kross, MD1,2; Renee D. Stapleton, MD, PhD3
Author Affiliations Article Information

JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4894

Updated: 2020-03-28
Return to Index Source: Curtis JR, Kross EK, Stapleton RD. JAMA. March 27, 2020. doi:10.1001/jama.2020.4894 101
 COVID-19 | Ethics | CPR

Updated: 2020-04-01
Return to Index Source: MGH Talking About CPR 102
 COVID-19 | Ethics | CPR

Updated: 2020-04-01
Return to Index Source: MGH Talking About Serious Illness 103
 COVID-19 | GAP

Geriatrics and Palliative Care (GAP) team consult service. Resources for facing the COVID 19 Pandemic.

This document provides resources for having difficult conversations with patients that are COVID 19
(+), under investigation (PUI) and/or with their decisions makers. It also provides guidance for when to
consider a Geriatrics and Palliative Care (GAP) team consult.

1) Tips for having the conversation. Please go to https://www.vitaltalk.org/guides/covid-19-

communication-skills/ or open the attached PDF that provides tips focused on communication skills to
handle different scenarios you may face when caring for COVID 19 (+) or PUI. It gives specific answers
to:
a. Screening: When someone is worried they might be infected
b. Preferencing: When someone may want to opt out hospitalization
c. Triaging: When you are deciding where a patient should go
d. Admitting: When your patient needs the hospital, or the ICU
e. Counseling: When coping needs a boost, or emotions are running high
f. Deciding: When things are not going well, goals of care, code status
g. Resourcing: When limitations force you to choose, and even ration
h. Notifying: When you are telling someone over the phone
i. Anticipating: When you are worrying about what might happen
j. Grieving: When you have lost someone.

For patients who are COVID 19 (+) or PUI and meet the below criteria, please consider consulting the
(GAP) team at any time but ideally as soon as the patient is admitted:

1) Patient > 65 years old, D Dimer > 1000, and LACE > 10

After attempting to address Advanced Care Planning the patient or the surrogate decision maker are
still looking for resuscitation and/or intubation.

2) Patient > 80 years old.

And
After attempting to address Advanced Care Planning the patient or the surrogate decision maker are
still looking for resuscitation and/or intubation.

3) Intractable symptoms (symptoms that continue to be severe even though medications have been
escalated appropriately or symptoms that require more than 4 breakthroughs in less than 24 hours)

Updated: 2020-03-25
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 COVID-19 | VitalTalk Playbook

Screening | When someone is worried they might be infected

Preferencing | When someone may want to opt out of hospitalization

Triaging | When you’re deciding where a patient should go

Admitting | When your patient needs the hospital or ICU

Counseling | When coping needs a boost, or emotions are high

Deciding | When things aren’t going well, goals of care, code status

Resourcing | When limitations fore you to choose and ration

Notifying | When you are telling someone over the phone

Anticipating | When you’re worrying about what might happen

Grieving | When you’ve lost someone

Proactive Planning in Contingency

Updated: 2020-03-28
Return to Index Source: COVID-ready communication skills: A playbook of VitalTalk Tips 105
 COVID-19 | VitalTalk Playbook

Screening | When someone is worried they might be infected

What they say What you say

Why aren’t they We don’t have enough test kits. I wish it were
testing everybody? different.
Why do the tests take The lab is doing them as fast as they
so long? can. I know it’s hard to wait.
How come the I can imagine it feels unfair. I don’t know the
basketball players got details, but what I can tell you is that was a
tested? different time. The situation is changing so fast
that what we did a week ago is not what we are
doing today.

Updated: 2020-03-28
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 COVID-19 | VitalTalk Playbook

Preferencing | When someone may want to opt out of hospitalization

What they say What you say

I am worried about this You are right to be concerned. Here’s what you
new virus. What should can do. Please limit your contact with others—
I be doing? we call it social distancing. Then you should pick
a person who knows you well enough to talk to
doctors for you if you did get really sick. That
person is your proxy. Finally, if you are the kind
of person who would say, no thanks, I don’t want
to go to the hospital and end up dying on
machines, you should tell us and your proxy.

I realize that I’m not Thank you for telling me that. What I am hearing
doing well medically is that you would rather not go to the hospital if
even without this new we suspected that you have the virus. Did I get
virus. I want to take my that right?
chances at home / in
this long term care
facility.

I don’t want to come to I respect that. Here’s what I’d like to propose.
the end of my life like a We will continue to take care of you. The best
vegetable being kept case is that you don’t get the virus. The worst
alive on a machine. [in a case is that you get the virus despite our
long term care facility precautions—and then we will keep you here
or at home] and make sure you are comfortable for as long
as you are with us.

I am this person’s proxy It is so helpful for you to speak for them, thank
/ health care agent. I you. If their medical condition did get worse, we
know their medical could arrange for hospice (or palliative care) to
condition is bad—that see them where they are. We can hope for t
they probably wouldn’t
survive the virus. Do
you have to take them
to the hospital?

Updated: 2020-03-28
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 COVID-19 | VitalTalk Playbook

Triaging | When you’re deciding where a patient should go

What they say What you say

Why shouldn’t I just go Our primary concern is your safety. We are trying
to the hospital? to organize how people come in. Please fill out
the questions online. You can help speed up the
process for yourself and everyone else.
Why are you keeping I imagine you are worried and want the best
me out of the possible care. Right now, the hospital has
hospital? become a dangerous place unless you really,
really need it. The safest thing for you is to ___.

Updated: 2020-03-28
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 COVID-19 | VitalTalk Playbook

Admitting | When your patient needs the hospital or ICU

What they say What you say

Does this mean I have We will need to test you with a nasal swab, and
COVID19? we will know the result by tomorrow. It is
normal to feel stressed when you are waiting
for results, so do things that help you keep your
balance.

How bad is this? From the information I have now and from my
exam, your situation is serious enough that you
should be in the hospital. We will know more in
the next day, and we will update you.
Is my grandfather going I imagine you are scared. Here’s what I can say:
to make it? because he is 90, and is already dealing with
other illnesses, it is quite possible that he
will not make it out of the hospital. Honestly, it
is too soon to say for certain.
Are you saying that no I know it is hard to not have visitors. The risk of
one can visit me? spreading the virus is so high that I am sorry to
say we cannot allow visitors. They will be in
more danger if they come into the hospital. I
wish things were different. You can use your
phone, although I realize that is not quite the
same.
How can you not let me The risk of spreading the virus is so high that I
in for a visit? am sorry to say we cannot allow visitors. We
can help you be in contact electronically. I wish
I could let you visit, because I know it’s
important. Sadly, it is not possible now.

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Counseling | When coping needs a boost, or emotions are high

What they say What you say

I’m scared. This is such a tough situation. I think
anyone would be scared. Could you share more
with me?
I need some hope. Tell me about the things you are hoping for? I
want to understand more.
You people are I can see why you are not happy with things. I am
incompetent! willing to do what is in my power to improve
things for you. What could I do that would help?
I want to talk to your I can see you are frustrated. I will ask my boss to
boss. come by as soon as they can. Please realize that
they are juggling many things right now.
Do I need to say my I'm hoping that's not the case. And I worry time
goodbyes? could indeed be short. What is most pressing on
your mind?

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Deciding | When things aren’t going well, goals of care, code status

What they say What you say

I want everything We are doing everything we can. This is a tough
possible. I want to live. situation. Could we step back for a moment so I
can learn more about you? What do I need to
know about you to do a better job taking care
of you?
I don’t think my Well, let’s pause and talk about what they would
spouse would have have wanted. Can you tell me what they
wanted this. considered most important in their life? What
meant the most to them, gave their life
meaning?
I don't want to end up Thank you, it is very important for me to know
being a vegetable or that. Can you say more about what you mean?
on a machine.
I am not sure what my You know, many people find themselves in the
spouse wanted—we same boat. This is a hard situation. To be honest,
never spoke about it. given their overall condition now, if we need to
put them on a breathing machine or do CPR, they
will not make it. The odds are just against us. My
recommendation is that we accept that he will
not live much longer and allow him to pass
on peacefully. I suspect that may be hard to
hear. What do you think?

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Resourcing | When limitations fore you to choose and ration

What they say What you say, and why

Why can’t my 90 year old This is an extraordinary time. We are trying to use resources in a
grandmother go to the ICU? way that is fair for everyone. Your grandmother’s situation does not
meet the criteria for the ICU today. I wish things were different. [C]

Shouldn’t I be in an intensive Your situation does not meet criteria for the ICU right now. The hospital
care unit? is using special rules about the ICU because we are trying to use our
resources in a way that is fair for everyone. If this were a year ago, we
might be making a different decision. This is an extraordinary time. I
wish I had more resources.[C]
My grandmother needs the ICU! I know this is a scary situation, and I am worried for your grandmother
Or she is going to die! myself. This virus is so deadly that even if we could transfer her to the
ICU, I am not sure she would make it. So we need to be prepared that
she could die. We will do everything we can for her.[C]

Are you just discriminating I can see how it might seem like that. No, we are not discriminating. We
against her because she is old? are using guidelines that were developed by people in this community
to prepare for an event like this. The guidelines have been developed
over the years, involving health care professionals, ethicists, and lay
people to consider all the pros and cons. I can see that you really care
about her. [C]
You’re treating us differently I can imagine that you may have had negative experiences in the past
because of the color of our skin. with health care simply because of who you are. That is not fair, and I
wish things had been different. The situation today is that our medical
resources are stretched so thin that we are using guidelines that were
developed by people in this community, including people of color, so that
we can be fair. I do not want people to be treated by the color of their
skin either. [C]
It sounds like you are rationing. What we are doing is trying to spread out our resources in the best way
possible. This is a time where I wish we had more for every single
person in this hospital. [C]
You’re playing God. You can’t do I am sorry. I did not mean to give you that feeling. Across the city, every
that. hospital is working together to try to use resources in a way that is fair
for everyone. I realize that we don’t have enough. I wish we had
more. Please understand that we are all working as hard as possible. [C]

Can’t you get 15 more Right now the hospital is operating over capacity. It is not possible for us
ventilators from somewhere to increase our capacity like that overnight. And I realize that must be
else? disappointing to hear. [C]
How can you just take them off I’m so sorry that her condition has gotten worse, even though we are
a ventilator when their life doing everything. Because we are in an extraordinary time, we are
depends on it? following special guidelines that apply to everyone here. We cannot
continue to provide critical care to patients who are not getting better.
This means that we need to accept that she will die, and that we need to
take her off the ventilator. I wish things were different. [C]

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Notifying | When you are telling someone over the phone

What they say What you say

Yes I’m his daughter. I I have something serious to talk about with you.
am 5 hours away. Are you in a place where you can talk?

What is going on? I am calling about your father. He died a short time
Has something ago. The cause was COVID19.
happened?

[Crying] I am so sorry for your loss. [Silence][If you feel you

must say something: Take your time. I am here.]

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Anticipating | When you’re worrying about what might happen

What you fear What you can do

That patient’s son is Before you go in the room, take a moment for
going to be very angry. one deep breath. What’s the anger about? Love,
responsibility, fear?
I don't know how to Remember what you can do: you can hear what
tell this adorable she’s concerned about, you can explain what’s
grandmother that I happening, you can help her prepare, you can be
can’t put her in the present. These are gifts.
ICU and that she is
going to die.
I have been working all Talk to them about what you are worried about.
day with infected You can decide together about what is best.
people and I am There are no simple answers. But worries are
worried I could be easier to bear when you share them.
passing this on to the
people who matter
most.
I am afraid of burnout, Can you look for moments every day where you
and of losing my heart. connect with someone, share something, enjoy
something? It is possible to find little pockets of
peace even in the middle of a maelstrom.
I’m worried that I will Check your own state of being, even if you only
be overwhelmed and have a moment. If one extreme is wiped out, and
that I won’t be able to the other is feeling strong, where am I
do what is really the now? Remember that whatever your own state,
best for my patients. that these feelings are inextricable to our
human condition. Can you accept them, not try
to push them away, and then decide what you
need

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Grieving | When you’ve lost someone

What I’m thinking What you can do

I should have been Notice: am I talking to myself the way I would
able to save that talk to a good friend? Could I step back and just
person. feel? Maybe it’s sadness, or frustration, or just
fatigue. Those feelings are normal. And these
times are distinctly abnormal.
OMG I cannot believe Notice: am I letting everything get to me? Is all
we don’t have the right this analyzing really about something else? Like
equipment / how how sad this is, how powerless I feel, how puny
mean that person was our efforts look? Under these conditions, such
to me / how thoughts are to be expected. But we don’t have to
everything I do seems let them suck us under. Can we notice them, and
like its blowing up feel them, maybe share them?
And then ask ourselves: can I step into a less
reactive, more balanced place even as I move
into the next thing?

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Proactive Planning in Contingency

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Proactive Planning in Rationing

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 COVID-19 | PPE | Airborne vs Droplet

< 10 um

< 5 um

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Aerodynamics of SARS-COV-2 in Wuhan Hospitals

Liu, Yuan, et al. "Aerodynamic Characteristics and RNA Concentration of SARS-CoV-2 Aerosol in Wuhan
Hospitals during COVID-19 Outbreak." bioRxiv (2020).

Takeaway:
-

Methods
- These authors looked at aerosol and surface samples from:
- The Renmin Hospital of Wuhan University (which was, and is designated for the
treatment of severe cases of COVID-19)
- Wuchang Fangcang Field Hospital (one of the first temporary hospitals which was
renovated from an indoor sports stadium) to quarantine and treat mildly symptomatic
patients
- Outdoor public areas in Wuhan
- They then measured the viral RNA concentrations in these specimens
- It is important to know that these authors did NOT look at whether these viral
specimens could infect cells; they only looked for the presence of viral RNA

Results
- Patient Area (Fangcang): Viral load was minimal (concentration - 1-9 copies m-3)
- Patient Area (Renmin): Viral load completely absent in ICUs (concentration = 0)
- Floor of ICU (Renmin): Viral load high (113 copies m-3)
- Toilet Room (Fangcang): Viral load elevated (19)

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Aerodynamics of SARS-COV-2 in Wuhan Hospitals

Liu, Yuan, et al. "Aerodynamic Characteristics and RNA Concentration of SARS-CoV-2 Aerosol in Wuhan
Hospitals during COVID-19 Outbreak." bioRxiv (2020).

Takeaway:
-

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Influenza transmission
Yan, Jing, et al. "Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a
college community." Proceedings of the National Academy of Sciences 115.5 (2018): 1081-1086.

Bottom Line:
-

Methods
- Collected exhaled breath of patients (college students) for 30 minutes while the participants
were seated with their face inside of a large open-end cone-shaped device (see below)
- The inlet cone draws in 130 liters of air per minute and allowed participants to breath,
talk, cough and sneeze naturally throughout the sample collection
- Subjects were asked to breathe normally and to recite the alphabet once at 5, 15 and
25 minutes
- They collected coarse (particles >5 um) and fine particles (<5um)
- Audible, spontaneous coughs and sneezes during breath collection were counted by
direct observation in real time and by playback of digital recording

Results
- On the left pane (coarse aerosol >5 um), on the right fine aerosol (<5 um)
- Stratified according to cough frequency
- They compared those who never coughed (red), to those who coughed seldomly
(green), to those who coughed >once per minute (purple)
- They could that virus particles contained in coarse particles were similar when comparing
frequent coughers to infrequent coughers
- They did find however that viral RNA contained in fine particles was dramatically increased in
those who coughed frequently compared to those who coughed infrequently
- This means that a person produces particles with a high viral load not when they cough,
but actually during times when they don’t cough
- These observations suggest that cough is more of an epi-phenomon (more a response to
irritation associated with high viral loads in distal airways, than a directs source of infectious
aerosols
- Several researches have recently shown that exhaled aerosols are generated from
normal healthy lungs by small airway closure and reopening
- It has been hypothesized that during respiratory infection airway closure and
reopening frequency would be increased due to inflammation, with an
increase in aerosol generation
- This suggests that individuals that are sick produce fine virus laden particles during
speaking and breathing that have a high viral load and can travel far down into the
lungs of a susceptible individual
- These are the kind of particles that are likely not filtered well by a surgical
mask

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Influenza transmission
Tang, Julian W., et al. "Qualitative real-time schlieren and shadowgraph imaging of human exhaled
airflows: an aid to aerosol infection control." PLoS One 6.6 (2011).

- Using a newly constructed airflow imaging system, airflow patterns were visualized that were
associated with common, everyday respiratory activities (e.g. breathing, talking, laughing,
whistling).
- The effectiveness of various interventions (e.g. putting hands and tissues across the
mouth and nose) to reduce the potential transmission of airborne infection, whilst
coughing and sneezing, were also investigated.
- From these qualitative schlieren and shadowgraph imaging experiments, it is clear that making
some effort to contain one's cough or sneeze puffs is worthwhile.
- Typical conversation at distance of the order of 1 m apart appears to be safe for much of the
time, but it can be seen that individuals talk in very different ways with a large variety of
airflows patterns, even when speaking the same words.
- Such variation may also occur within the same individual depending on different
situations, e.g. relaxed conversation versus a heated argument.
- Hence differences in pronunciation and elocution, as well as talking in different
languages [30], may all be significant variables affecting the generation of potentially
infectious aerosols during human speech.

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 COVID-19 | PPE

Updated: 2020-03-25
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 COVID-19 | PPE

Updated: 2020-03-29
Source: Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with
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 COVID-19 | Basics | Snapshot

Fast Facts
Clinical presentation: non-specific, flu-like illness
• Fever (44-98%)
• Cough (46-82%)
• Shortness of breath (20-64%)
• Upper respiratory symptoms, nasal / sinus congestion (5-25%)
• GI symptoms (10%; usually before respiratory symptoms)

Transmission:
• Large droplets and fomites
• Viral particles survive < 24h on cardboard, < 72h on plastic or steel (van Dorelmalen et al, New
Engl J Med, 2020)
• Aerosols (droplet nuclei, < 5 um), estimated < 4h
• Incubation period: median 4 days, common range 2-7 days, up to 24 days
• Symptomatic and asymptomatic patients can transmit the virus

Course for admitted patients:

• ~ 80% do not require critical care
• ~ 10-20% develop bacterial superinfection
• ~ 2-20% have respiratory viral co-infection (unpublished report, CA-DPH)
• ~ 20% develop ARDS
• ~ 5% develop renal injury requiring renal replacement therapy
• Elevated AST / ALT (~200s) is common; fulminant hepatitis not reported
• Cardiomyopathy in critically ill patients; some progress to cardiogenic shock late in course
(anecdotal reports)

Reasons for ICU admission:

• Hypoxemic respiratory failure is the most common indication for ICU.
• Reports of rapid progression to intubation within 12-24h
• Few patients with shock, can develop late in course
• Median time from symptom onset to ICU transfer is ~10 days

Poor prognostic indicators:

• Demographics: Age > 65, male
• Comorbidities: cardiovascular disease (includes hypertension), pulmonary disease, diabetes,
malignancy, immunosuppression
• Lab findings: severe lymphopenia, elevated troponin, elevated creatinine, elevated LDH,
elevated CRP, elevated D-dimer

Cause of death:
• ~53% respiratory failure
• ~33% concomitant respiratory and heart failure
• ~7% cardiac or heart failure alone
• Mortality rate appears to correlate with age and availability of medical resources (Ruan et al,
Intensive Care Med, 2020)

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 COVID-19 | Basics | Clinical Snapshot

Hyperlink to PDF

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 COVID-19 | Basics | Clinical Snapshot

Hyperlink to PDF

Updated: 2020-03-28
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 COVID-19 | Background

Clinical Course

Zhou, Fei, et al. "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in
Wuhan, China: a retrospective cohort study." The Lancet (2020).

Updated: 2020-03-23
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 COVID-19 | Background

Case Fatality Rate

UCSF Experts on the Epidemiology, Science, & Clinical Manifestations of COVID-19, and UCSF Response

Updated: 2020-03-23
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 COVID-19 | Epidemiology

Fast Facts

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