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Brigham and Women’s Hospital

COVID-19 Clinical Guidelines

This document is a work in progress. We have much to learn.

This is updated regularly with evolving information; do not print.

Please send suggestions: BWHCOVIDGuidelines@gmail.com

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Updated the week of March 30th includes:

  • Discharge planning
  • Changed PEEP recommendations
  • NIPPV/HFNC recommendations
  • New therapeutics
  • Cardiac arrests
  • Palliative recommendations
  • Ethical considerations

Disclaimer: This document is intended as a resource for clinicians caring for critically-ill COVID-19 patients, based on available evidence and recommendations of governing bodies. The recommendations do not replace clinical judgment or the need for individualized patient care plans. While we attempt to keep this document up-to-date, the literature on COVID-19 is rapidly evolving, and we suggest that practitioners search for the most up-to-date literature on any specific topic. These guidelines will also rapidly evolve as they are implemented into clinical practice and we receive feedback from practitioners. Finally, these guidelines were developed based on practice patterns and infrastructure at Brigham and Women’s Hospital in Boston, MA; local factors should be taken into account if utilized at other hospitals.

1: Clinical Course, Prognosis, and Epidemiology

Clinical course

Clinical presentation

  1. Non-specific, flu-like illness, with myalgias
  2. Fever (44-98%)
  3. Cough (46-82%)
  4. Shortness of breath (20-64%)
  5. Upper respiratory symptoms, nasal / sinus congestion (5-25%)
  6. Anosmia (Anecdotal reports summarized by ENT groups in USA, UK)
  7. GI symptoms (10%; can be before respiratory symptoms)

Transmission

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

Disease Course

  1. ~ 80% do not require critical care
  2. ~ 10-20% develop bacterial superinfection
  3. ~ 2-25% have respiratory viral co-infection (Qingdao, China: Xing et al, medRxiv, 2020 preprint; Stanford, CA, USA: Shah N, Medium, 2020 unpublished data)
  4. ~ 20% develop ARDS
  5. ~ 5% develop renal injury requiring renal replacement therapy
  6. Elevated AST / ALT (~200s) is common; fulminant hepatitis not reported
  7. Cardiomyopathy in critically ill patients; some progress to cardiogenic shock late in course (anecdotal reports)

Reasons for ICU admission

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

Prognosis

Poor prognostic indicators

  1. This section is in development.
  2. Demographics: Age > 65, male
  3. Comorbidities: cardiovascular disease (includes hypertension), pulmonary disease, diabetes, malignancy, immunosuppression
  4. Lab findings: severe lymphopenia, elevated troponin, elevated creatinine, elevated LDH, elevated CRP, elevated D-dimer

Cause of death

  1. ~53% respiratory failure
  2. ~33% concomitant respiratory and heart failure
  3. ~7% cardiac or heart failure alone
  4. Mortality rate correlates with age and availability of medical resources (Ruan et al, Intensive Care Med, 2020)

Epidemiology

  1. This section is in development

2: Non-ICU (ED & Inpatient Floor) Management, Triage, Transfers

Personal Protective Equipment and Infection Control

Personal Protective Equipment:

  1. Location-specific PPE guidance: There are location-specific differences (e.g., Shapiro SP-ICU versus Tower ICU COVID testing) in place, so refer to your location guidelines.
    1. Easy to read “grid” summarizing PPE here (Partners login required)
    2. Partners PPE Guidance (Partners login required)
  2. For aerosol generating procedures: Strict isolation (aerosol) PPE (including N95 masks) are needed during and for 45 mins. after aerosol generating procedures (such as nebulization, NIPPV). These procedures are preferentially done in negative airflow rooms.
  3. To donate PPE: Please use this link for donations of PPE or targeted funding for PPE

ICU Strict isolation manual:

  1. Step-by-step protocols for working in COVID-19 precaution patient rooms (e.g., transporting a patient, lab draws, micro testing like COVID-19 swab, sterile procedures like central venous catheters) are linked here.

Diagnostic Testing

COVID testing

  1. This is an area that is actively changing and varies widely by hospital, test availability, and local epidemiology. Partners criteria available here (Partners login required)

Laboratory studies and EKGs

On admission

If not obtained in ED, draw following morning

CBC with differential

BMP, Magnesium

LFTs, Troponin & CPK, NT-proBNP

LDH, CRP, D-dimer, Procalcitonin

PTT/INR, Ferritin

Baseline EKG

Extended Respiratory Viral Panel - only if would change management (high risk patients such as transplant, onc, ICU)

Daily

Can change to every other day in stable floor patients

CBC with differential

BMP, Magnesium

If ICU: Troponin & CPK, NT-proBNP, VBG / ABG PRN

Every other day

LFTs, Troponin & CPK, NT-proBNP

LDH, CRP, D-dimer, Ferritin

If on propofol: Triglycerides

Weekly - only in heme malignancy / stem cell transplant patients

Glucan, Galactomannan

+/- additional per primary oncologist

If clinical worsening

CBC with differential

BMP, Magnesium, LFTs

Troponin & CPK, NT-pro-BNP

LDH, CRP, D-dimer, Procalcitonin

PTT/INR, Fibrinogen, Ferritin

ABG preferred over VBG

Repeat EKG

Chest imaging

  1. Portable CXR is sufficient in most cases. Avoid routine daily CXR (unlikely to change management, evaluate case-by-case). Avoid CT chest unless otherwise indicated.
    1. Chest x-ray: Chest imaging variable; bilateral patchy opacities most common.
    2. CT chest: Chest CT often will not change treatment; obtain only if necessary (risk of transmission, time associated with transport / decontamination of equipment).
    3. Point of care ultrasound: Point of care ultrasound of the lungs can be used but by experienced providers only.

Other studies

  1. Avoid other studies unless really necessary due to PPE limitations and transmission risk associated with transport.
    1. Avoid routine TTEs (for cardiac studies, see: “Cardiac Complications of COVID” chapter).

Respiratory Escalation Pathway and Intubation

For persons NOT under investigation for COVID-19

  1. Nasal Cannula, venturi mask:
    1. Continue standard practices
  2. Noninvasive ventilation, high flow nasal cannula:
    1. Indications remain the same (including OSA)
    2. Because rates of asymptomatic carriage in the community are unknown, and aerosolization risk is unknown, wherever possible:
      1. Consider alternate options as available (e.g., nocturnal nasal cannula.)
      2. Use airborne precautions (Strict isolation, N95, negative pressure room)
      3. Use a closed circuit: BWH NIPPV machine with dual limb with a HEPA filter and BWH mask without anti-asphyxia valve.
      4. Ensure masks/devices fit well and there is minimal air leak
      5. Avoid use of home NIV devices (particularly if single limb with anti-asphyxia valve)
    3. Treat as though this person is a PUI (see below)
  3. Cardiac Arrest:
    1. Treat as though this person is a PUI (see below)

For Persons Under Investigation (PUI) or with confirmed COVID-19

  1. Nasal Cannula:
    1. Use humidified nasal cannula (NC) 1 to 8 LPM for target SpO2 92-96%.
    2. If a patient requires >6L, consult ICU (COVID ICU Triage, p39999) for consideration of ICU transfer. If on floor, consult anesthesia for assessment and close monitoring (COVID Anesthesia Team, p39265).
      1. This does not mean the patient necessarily needs to be intubated at this or needs immediate ICU transfer.
  1. Venturi Mask:
    1. If a patient requires > 8 LPM NC, initiate dry Venturi mask (non-humidified to reduce aerosolization risk)
      1. Start at 9 LPM and FiO2 28%
      2. Up-titrate FiO2 to goal SpO2 of 92-96% (not exceeding FiO2 35%)
        1. If FiO2 > 35% then increase flow to 12 LPM
  2. Noninvasive Ventilation and High Flow Nasal Cannula:
    1. NIPPV and HFNC should NOT be used in most circumstances, including to delay intubation
      1. For patients already on NIPPV/HFNC, transition to Venturi mask or non-rebreather mask if possible, ideally 45 minutes prior to intubation
    2. Selected exceptions are outlined in detail in the respiratory chapter of this document and include:
      1. Rapidly reversible etiologies (e.g. flash pulmonary edema)
      2. Known OSA/TBM without a good alternative
      3. Select DNI patients as a bridge to family arrival or intervention
    3. If NIPPV/HFNC is used, it must be under strict airborne precautions including a negative pressure room
  3. Early intubation:
    1. If venturi mask FiO2 = 60% or SpO2 < 92% (or for hypercapnia or work of breathing), call for intubation and pre-oxygenate with non-rebreather
      1. In ED this is the on-call provider, for Floor page COVID Anesthesia Team p39265
    2. Rapid Sequence Induction (RSI) should be performed, avoiding bagging
      1. by the most experienced airway provider
      2. using a video laryngoscope (SCCM COVID19 Guidelines) (APSF Considerations for Airway Manipulation, 3/20/2020).
      3. For more detailed instructions, see intubation chapter

Other Management Principles

Medical management:

  1. Management is largely supportive. Antiviral and immune-modulating therapies are investigational. Further details in “COVID Therapies and Clinical Trials” chapter.
    1. Fluid management should be conservative due to risk of hypoxia/CHF. Further details in fluids section.

Early Advance Care Planning:

  1. In conscious patients, review or sign Health Care Proxy form and discuss and document goals of care on admission
    1. Educate patient and family on disease course and prognosis
    2. Focus on desired quality of life and tolerance for ICU measures
    3. Early consultation of palliative care if appropriate

Triage to ICU

Consult the ICU triage team EARLY for:

  1. Provider concern
  2. Respiratory distress
    1. Need O2 > 6 LPM to maintain SpO2 > 92% or PaO2 > 65.
    2. Rapid escalation of oxygen requirement.
    3. Significant work of breathing.
  3. Hemodynamic instability after initial conservative fluid resuscitation
    1. SBP < 90, Mean arterial pressure < 65, or Heart rate > 120.
  4. Acidosis
    1. ABG with pH < 7.3 or PCO2 > 50 or above patient’s baseline.
    2. Lactate > 2.
  5. Need for intensive nursing care or frequent laboratory draws requiring arterial line.
  6. Severe comorbid illness / high risk for deterioration.

Transfer Process

See also ICU Strict Isolation Procedures Manual.

ED to Floor

  1. This section is in development

Floor / ED to ICU:

  1. ICU RN brings ICU bed to the floor for transfer (to avoid bed transfer in COVID precautions room and subsequent bed cleaning).
  2. Patient wears surgical mask, with an extra clean gown and sheet on top.
  3. Providers wear standard PPE during transport.
  4. Security facilitates the shortest and fastest transfer route, walks 6 ft away from patient and providers, not required to wear PPE
  5. Necessary tests (e.g. CT), should be obtained during transfer if possible.

ICU to floor:

  1. RN wears standard PPE
  2. Patient travels in wheelchair or stretcher
  3. Security facilitates the shortest and fastest transfer route, walks 6 ft away from patient and providers, not required to wear PPE

Floor to discharge:

  1. RN wears standard PPE
  2. Patient travels in wheelchair
  3. Security facilitates the shortest and fastest transfer route, walks 6 ft away from patient and providers, not required to wear PPE
  4. Patient is escorted directly into vehicle; contact care management if patient does not have access to a personal vehicle

Discharge Planning (Inpatient)

Discharge criteria

  1. Consider discharge for patients’ who meet the following clinical criteria:
    1. Resolution of fever >48 hours without antipyretics
    2. Improvement in illness signs and symptoms (cough, SOB, and oxygen requirement)

Discharge for patients with unstable housing or who leave Against Medical Advice (AMA)

  1. Additional resources for patients with unstable housing and requests for AMA discharge are in development.

Confirmed COVID-19 Discharge Checklist

  1. If unable to complete any components of checklist:review community resources, discuss transportation and post-acute care options with care coordination and consider ongoing hospitalization

Discharge contingencies

  • Verify and document contact number for patient and primary support person; ensure active phone service, voicemail functioning, and language preference correctly documented
  • Verify residence with private room, ability to adhere to home isolation instructions and risk of transmission to persons with immunocompromising conditions in the home
  • Confirm ability to manage ADL/iADLs with degree of support at home
  • Confirm that patient has resources/social support to receive 1-2 weeks of food and other necessary supplies while under quarantine
  • Perform DME needs assessment and consider sponsorship from hospital if item unable to be delivered or obtained by primary support person

Discharge medications/supplies

  • Provide 30-day supply of medications to cover duration of home isolation, recommend meds-to-bed delivery if available
  • Provide a surgical mask as available to infected patients who are discharging home (instructions for use in discharge instructions)

Transportation

  • Verify patient has a ride by private vehicle or arrange transportation via ambulance (infected person should wear mask in vehicle)

Discharge instructions

  • Counsel patient on voluntary isolation procedures and use standard Epic Smart Phrase SPUCOUNSELING
  • Use standard Epic Smart Phrases SPUDISCHARGECOVIDPOSITIVE or SPUDISCHARGECOVIDNEGATIVE for discharge and home isolation instructions

Ambulatory follow-up plan

  • Verify and document patient’s primary care provider
  • Provide warm handoff via phone or in-basket message to patient’s primary care provider and confirm that they are able/willing to answer questions post-discharge

Community resources

3: Respiratory Support

Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS)

Pathophysiology

  1. Histology of COVID-19 associated lung disease shows bilateral diffuse alveolar damage with cellular fibromyxoid exudates, desquamation of pneumocytes, pulmonary edema, and hyaline membrane formation.
  2. There is also some evidence of direct viral injury to lung tissue. (Xu et al, Lancet Respir Med, 2020).

Definition of Acute Respiratory Distress Syndrome (ARDS)

  1. Many patients with COVID-19 who require ICU level of care will develop ARDS.
  2. The Berlin definition of ARDS requires the following four criteria:
    1. Acute (onset over 1 week or less)
    2. Bilateral opacities detected on CT or chest radiograph
    3. PF ratio <300mmHg with a minimum of 5 cmH20 PEEP (or CPAP)
    4. Must not be fully explained by cardiac failure or fluid overload
Severity PaO2/FiO2 (on PEEP/CPAP >5) Mortality (all cause, cohort)
Mild 200-300 27%
Moderate 100-200 32%
Severe <100 45%

Time course

  1. Anecdotally, many report that progression of hypoxemic respiratory failure occurs rapidly (within ~12-24 hours).
  2. From onset of symptoms, the median time to:
    1. Development of ARDS: 8-12 days (Wang et al, JAMA, 2020; Zhou et al, Lancet, 2020; Huang et al, Lancet, 2020)
    2. Mechanical ventilation: 10.5-14.5 days (Huang et al, Lancet, 2020; Zhou et al, Lancet, 2020)

Management of Hypoxemia for COVID PUI/ Confirmed Cases

Supplemental Oxygen Escalation

  1. Nasal cannula:
    1. Initial oxygen delivery should be humidified nasal cannula (NC) 1 to 8 LPM for target SpO2 92-96%.
      1. If a patient requires >6L, anesthesia requests early consultation for assessment and preparation. (COVID anesthesia pager p39265)
        1. This does not mean they necessarily need intubation.
  2. Venturi mask:
    1. If a patient requires > 8 LPM NC, initiate dry Venturi mask (non-humidified to reduce aerosolization risk)
      1. Start at 9 LPM and FiO2 28%, and notify the ICU triage pager
      2. Up-titrate FiO2 to goal SpO2 of 92-96% (not exceeding FiO2 35%)
        1. If FiO2 > 35% then increase flow to 12 LPM

Early intubation

  1. For patients maintained on a Venturi mask;
    1. once FiO2 = 60% and SpO2 < 92%, call for intubation (COVID anesthesia pager p39265)
      1. Consider other indications for intubation (tachypnea, work of breathing).
  2. Avoid NIPPV or HFNC to stave off intubation (see discussion below)
    1. For patients already on NIPPV/HFNC, transition to Venturi mask or non-rebreather mask if possible, ideally 45 minutes prior to intubation
  3. Rapid Sequence Induction(RSI) should be performed
    1. by the most experienced airway provider
    2. using a video laryngoscope (SCCM COVID19 Guidelines)(APSF Considerations for Airway Manipulation, 3/20/2020).
    3. For more detailed instructions, see intubation chapter
  4. Intubations outside the ICU should be attended by the Resource RT, who can facilitate early and appropriate ventilator settings

Non-invasive Positive Pressure Ventilation (NIPPV) and High Flow Nasal Cannula (HFNC)

  1. We recommend avoiding high-flow nasal cannula (HFNC) and non-invasive positive pressure ventilation (NIPPV; i.e. CPAP/BiPAP) in most circumstances

    1. There is a paucity of data on the increased aerosol risk of these interventions, and their role in increasing transmission.
      1. General consensus suggests that HFNC and NIPPV increase the risk of viral transmission, but the degree of aerosolization is poorly understood and data on this is lacking. WHO interim guidance (published March 13, 2020) recommends it only in select patients.
      2. A systematic review on SARS found that NIPPV was associated with increased risk of viral transmission to healthcare workers (n=2 studies), but HFNC was not (n=1) (Tran et al, PLoS One, 2012)
      3. Other studies with very limited power exist, such as a post-hoc analysis that found no secondary infections in medical staff from patients with influenza H1N1 treated with HFNC (but n=20) (Rello et al, J Crit Care, 2012);
    2. Given the rapid progression of disease in most patients, we do not anticipate many patients would avoid intubation using NIPPV/HFNC, but this remains unknown.
      1. 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), though there are some patients who may recover on HFNC.
      2. Generally, NIPPV is thought to stave off intubation only in early ARDS and the data is inconsistent (Rochberg et al, ERJ, 2016).
  2. Exceptions to this include:

    1. As a short-term bridge to ventilator availability:
      1. If a patient would otherwise be a candidate for intubation but no ventilator is immediately available, NIPPV/HFNC can be considered as a bridge
    2. For rapidly reversible causes of hypoxemia:
      1. e.g. flash pulmonary edema, mucus plug, or witnessed small aspiration
    3. For Obstructive Sleep Apnea or Tracheobronchomalacia:
      1. Where possible, patients with mild or moderate OSA should be transitioned to nocturnal nasal cannula.
      2. Patients on home nocturnal NIPPV for severe sleep apnea may continue NIPPV, but must use a BWH device with the specifications below. Patients may not use home NIPPV mask or nasal pillow or single-limb machine due to increased aerosol risk.
    1. For select DNI patients or those not eligible for intubation:
      1. this should be used only as a bridge to a short-term aim such as a family member’s arrival or an intervention
  3. If HFNC or NIPPV are used:

    1. For HFNC, patient wears surgical mask and limit flow rate to < 30 L/min
    2. For BiPAP, use BWH NIPPV machine with dual limb with a HEPA filter and BWH mask without anti-asphyxia valve
    3. Use under strict airborne precautions, including N95s, strict isolation, and a negative pressure room.
    4. Ensure masks/devices fit well and there is minimal air leak
      1. Measured exhaled air distances are minimally increased with CPAP pressures up to 20 cm H2O and HFNC up to 60 LPM; importantly device/interface leaks cause significant lateral air travel (Hui et al, Eur Respir J, 2019)

Initial Mechanical Ventilation

Checklist Following intubation

  1. Set the initial ventilator settings:
    1. Initiate ARDS ventilation as described below
    2. Determine PEEP and mechanics as described below
    3. Assure adequate sedation as described below
  2. Obtain STAT portable CXR to confirm endotracheal tube location
    1. Prioritize CXR and vent settings over procedures (such as central venous catheter placement) if possible.
  3. Complete the “Mechanical Ventilation with Sedation” orderset in EPIC
  4. Obtain an ABG (preferred) or a VBG within 30 minutes
    1. Calculate P/F ratio from initial post-intubation ABG. Adjust oxygenation as described below
    2. Goal pH 7.25 to 7.45 adjust ventilation as described below

Initial ARDS Ventilation Settings

  1. Set mode to volume control (AC/VC)
  2. Set Initial tidal volume (Vt):
    1. Vt = 6 ml/kg (based on ideal body weight [IBW] from ARDSnet table, see table below)
      1. IBW men (kg) = 50 + 2.3 (height in inches – 60)
      2. IBW women (kg) = 45.5 + 2.3 (height in inches – 60)

image1

  1. Set Initial respiratory rate 16-24, higher if acidosis present.
  2. Set an Initial PEEP based on BMI:
    1. BMI < 35: PEEP 5
    2. BMI > 35: PEEP 10
  3. Initial FiO2: 100% on intubation then rapidly wean to SpO2 92-96% (Barrot et al, N Engl J Med, 2020)

Determining optimal PEEP, and mechanics

  1. Titrate FiO2 and PEEP for oxygenation
    1. Initiate PEEP based on BMI, per above, and then titrate PEEP and FiO2 to target oxygenation SpO2 92-96% as per the following guidelines:
      1. BMI < 35: titrate PEEP and FiO2 as per the ARDSnet LOW PEEP table
image2
  1. BMI ≥ 35: titrate PEEP and FiO2 as per the ARDSnet HIGH PEEP table
image3
  1. If SpO2 < 92% or > 96% then titrate PEEP and FiO2 according to the ARDSnet table as per BMI
  2. Special consideration: anecdotal reports of COVID-19 patients describe a compliant, highly PEEP dependent phenotype in which PEEP management may not strictly adhere to specified ARDSnet tables
    1. PEEP titration may be appropriate (see section below)
  1. Obtain respiratory mechanics:
    1. Plateau pressure (with goal < 30, management below)
    2. Static compliance

Sedation and Ventilator Synchrony

  1. If paralyzed, target sedation to RASS -2 to -3 (see table below):
    1. Maintain deep sedation immediately post-intubation while paralyzed (assume 60 minutes for Rocuronium, 10 minutes for succinylcholine)
      1. Preferred initial sedation regimen:
        1. Fentanyl/Hydromorphone (boluses +/- infusion) + Propofol: target analgosedation and optimize analgesia first while decreasing sedative requirements
          1. Measure triglycerides and lipase every third day on propofol or earlier if other reasons for hypertriglyceridemia
      2. Adjunct agent: Midazolam
      3. Use dexmedetomidine only when nearing extubation
  2. In unparalyzed, target sedation to ventilator synchrony:
    1. Ventilator-induced lung injury (VILI) is common in patients who are not synchronous with the ventilator and can cause significant lasting damage. After paralytics have worn off, assess patient synchrony with the ventilator (e.g., signs of breath-stacking, double triggering, other ventilator alarms).
      1. Titrate sedatives/analgesics to ventilator synchrony allowing for deeper RASS.
      2. If patient remains dyssynchronous despite deep sedation (RASS -5), initiate continuous paralytics (ensure BIS 40 to 60 prior to initiating and during paralysis).
image4

Ventilator Adjustments and Daily Management

General management of ventilated patients

  1. Consider whether patient requires daily CXR:
    1. CXR clearly indicated for:
      1. Clinical change
      2. Concern for displaced ET tube:
        1. Sudden increase in peak inspiratory pressure or resistance
        2. Decreased, unilateral breath sounds (usually on the right)
        3. RN or RT concern for change in depth of ET tube at teeth
  2. COVID-19 ICU Bundle:
    1. Ventilated patients should all have a daily ICU “Bundle” of best practices. See Addendum 1 for a proposed “COVID-19 ICU Bundle”.
  3. Ventilator consults:
    1. If you need additional assistance managing ventilator choices, you can request a pulmonary phone/in-person consult

Changing ventilation parameters (respiratory rate and tidal volume)

  1. Follow ARDSnet ventilation where possible:
    1. Tidal volumes should be 4-6 cc/kg using IBW (see table above) to minimize volumes (and thus ventilator injury).
  2. Minute ventilation (respiratory rate x tidal volume) typically drives pH and PCO2:
    1. Titrate ventilatory parameters to pH, not PCO2.
      1. To achieve low tidal volumes, we tolerate hypercapnia (functionally no limitation unless clinical sequelae) and acidemia (pH > 7.2).
      2. Because tidal volumes are low, the respiratory rate often has to be high to accommodate; typical RR is 20-35 breaths/minute.
  3. pH goal is normally 7.25-7.45:
    1. If pH > 7.45, decrease respiratory rate
    2. If pH 7.15-7.30, then increase respiratory rate until pH > 7.30, or PaCO2 < 25 (maximum RR= 35 breaths/minute)
    3. If pH < 7.15, then increase respiratory rate to 35 breaths/minute
    4. If pH still < 7.15, then perform the following:
      1. Tidal volume may be increased by 1 mL/kg until pH > 7.15 (until plateau pressure reaches 30 cm H2O or tidal volume reaches 8 cc/kg)
      2. Deep sedation advancing to RASS -5 if needed
      3. If no improvement, initiate continuous paralysis
      4. If still no improvement, initiate prone ventilation (may improve V/Q matching and better ventilation)

Changing oxygenation parameters

  1. Minimize oxygen toxicity: PEEP and Fi02 drive oxygenation
    1. The goal is to deliver a partial pressure of oxygen to perfuse tissues (PaO2 > 75, Sp02 >92%) [1] while limiting lung injury from high distending pressures (Ppl < 30) and hyperoxia (FiO2 < 75, SpO2 < 96%) [2].
      1. Lower limit goals for PaO2 / SpO2 are widely debated; PaO2 > 55 and SpO2 >88% are also commonly used at BWH.
  2. Optimize PEEP:
    1. Initial PEEP should be set as explained above.
    2. This section is under development. PEEP titration will be included soon.
  3. Adjust Fi02:
    1. Adjust Fi02 after optimizing PEEP
    2. Goal FiO2 < 75%; if FiO2 > 75%; patient requires ventilator optimization. If you need assistance, pulmonary consultation is available (pager 11957)
      1. It is reasonable to put a desaturating patient temporarily on 100% Fi02, but remember to wean oxygen as rapidly as possible
  4. Checking plateau pressure:
    1. Check plateau pressure with every change in tidal volume, PEEP, or clinical deterioration (worsening oxygenation) but not as part of routine practice
    2. If plateau pressure is > 30 cm H20, then decrease tidal volume by 1 ml/kg (minimum 4 mL/kg)
    3. If plateau pressure is < 25 H20 and tidal volume < 6 mL/kg, then increase tidal volume by 1 mL/kg until plateau pressure is > 25 cm H2O or tidal volume = 6 mL/kg
    4. If plateau pressure is < 30 cm H20 and patient is breath stacking or dyssynchronous, then increase tidal volume in mL/kg increments to 7 mL/kg or 8 mL/kg so long as plateau pressure is < 30 cm H20

Refractory hypoxemia

  1. Refractory Hypoxemia pathway:
    1. If patient is hypoxic (Pa02 <55) on Vt = 6 ml/kg, ideal PEEP from PV tool (or PEEP determination from ARDSnet table for non-Hamilton G5 ventilators), and Fi02 >75%, perform the following in this order:
      1. Optimize volume status by diuresing or RRT if possible;
        1. if no improvement then:
      2. Deep sedation, advancing to RASS -5 if needed;
        1. if no improvement then:
      3. Initiate continuous paralysis (cisatracurium bolus 0.2mg/kg followed by infusion at 0-5 mcg/kg/min titrated to patient-ventilator synchrony);
        1. if no improvement then:
      4. 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%)
        1. if no improvement then:
      5. Initiate continuous inhaled epoprostenol (see “COVID-19 Therapies and Clinical Trials” chapter), and call the ECMO team
        1. If no improvement then;
      6. Consider ECMO if offered

Proning

  1. Prone early:
    1. 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).
  2. Eligibility criteria for proning:
    1. The only absolute contraindications to proned ventilation are spinal cord injury and open chest; BMI and patient size are not contraindications
    2. Eligibility may vary depending on resources and staffing. Currently we recommend:
      1. Age < 75
      2. No high grade shock (either single agent norepinephrine 20 mcg/min or norepinephrine < 15 mcg/min and vasopressin)
      3. Not on CRRT or at risk of impending renal failure (due to difficulties in maintaining dialysis access while proned)
  3. To initiate prone ventilation outside of MICU and 11C:
    1. Discuss with the PCCM Consultation team assigned to that unit
    2. ICU charge nurse to contact MICU charge nurse for nursing assistance
  4. Managing a proned patient:
    1. Proning protocol is available in the MICU Sharepoint, or an abbreviated version will be made available soon
    2. Maintain deep sedation with target RASS -4 to -5 while proned.
    3. 1 hour post-initiation of prone ventilation:
      1. Adjust oxygen parameters: re-assess lung mechanics (plateau pressure and re-optimize PEEP, see above
      2. Assess tidal volume and adjust ventilation parameters as in section 6
        1. If Vt < 6 ml/kg, may increase to maximum limit of 8 ml/kg while Ppl < 30 (preferred maximum is 6 ml/kg)
    4. If patient demonstrates improvement on proning then recommend:
      1. Discontinuing of continuous neuromuscular blockade and re-assess ventilator dyssynchrony; re-institute if dyssynchronous
      2. Return to supine ventilation when following criteria are met:
        1. Ppl < 25
        2. FiO2 < 50%
        3. pH > 7.3
        4. P:F > 200
    5. Repositioning and skin care while proned:
      1. Currently we recommend continuing proning as per the MICU proning protocol. This may change in the future depending on availability of PPE and staffing.

ECMO consultation

  1. If despite all the above measures the patient meets the following criteria, then consider ECMO consult (pager 35010):
    1. Ppl > 30
    2. FiO2 > 75%
    3. P:F < 80
  2. Candidacy: Final ECMO guidelines for COVID-19 patients remain under development. Examples of common considerations include:
    1. Patient age < 65
    2. Mechanical ventilation duration < 7 days
    3. BMI < 35 and patient body weight < 150 kg
    4. CrCl > 30
    5. No multiorgan failure or high grade shock (can be on single pressor; norepinephrine < 15 mcg/min)
    6. No active solid or liquid malignancy
    7. Absolute neutrophil count > 500
    8. Platelets > 50,000
    9. Able to tolerate anticoagulation on initiation (no active hemorrhage)
    10. No evidence of irreversible neurological injury
    11. Able to perform ADLs at baseline prior to illness

Ventilator Weaning and Extubation

  1. This section is in process

4: Therapeutics and Clinical Trials

Overview

Therapeutics summary

  1. The anti-viral and anti-inflammatory section below is meant to provide a summary of the literature. The BWH Infectious Diseases COVID-19 treatment guidelines and ID consultation service take precedence over the information provided in the literature review below
  2. This table is from the BWH Infectious Diseases COVID-19 treatment guidelines. Partners employees can click here to view the full guideline.

image5

Infectious Diseases Consultation

  1. The inpatient Infectious Diseases (ID) team should be consulted for patients with +COVID-19 PCR as well as patients with both clinical history and any chest imaging suspicious for COVID-19.
  2. Re-consultation should occur if the patient develops ARDS (mechanically-ventilated with P/F ratio < 300) or shock/cytokine activation syndrome.

Clinical Trials

  1. ID teams are enrolling for ongoing clinical trials of antiviral agents. ID and the PETAL network are coordinating to enroll for clinical trials of host-response modifying therapies (see “Systemic Corticosteroids” and “Anti-IL6 agents” sections of this chapter).
  2. Some patients may also arrive at the ICU already enrolled in a COVID-19 clinical trial. In such cases, verify that ICU treatment regimen does not add harmful drug interactions with study agents.

Antibiotics

Choice of agent

  1. 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 is often seen 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 Interim guidance, March 2020).
  2. Antibiotics should reflect IDSA guidelines, presumed source, and MDRO risk.
    1. For empiric coverage for a presumed pulmonary source of infection:
      1. In patients without risk factors for MRSA or Pseudomonas (i.e., living in community, no prior MDROs), start with ceftriaxone + azithromycin.
      2. In patients with risk factors for MRSA or Pseudomonas (i.e., chronic hospitalization, prior MDR infections), start with vancomycin + cefepime and consider ciprofloxacin if high concern for Pseudomonas.
  3. For coverage of potential coinfections:
    1. If concurrent influenza, treat with oseltamivir.
    2. Given prevalence of lymphopenia in clinical presentation of COVID-19, consider Pneumocystis and treat accordingly.
  4. See special dispensations for oncology patients in “Considerations for Oncology Patients” section within “Other Guidance” chapter.

Formulation

  1. Give oral antibiotics (azithromycin, levofloxacin, ciprofloxacin, etc.) when possible to reduce volume load, unless concerns for poor oral absorption.

Discontinuation

  1. Antibiotics should be discontinued as soon as possible (ideally, within 48 hours), given the following criteria are met:
    1. Clinical status is not deteriorating.
    2. Cultures do not reveal pathogens at 48h and/or Procalcitonin and WBC are relatively stable from 0 to 48h
  2. Clinical judgement should prevail over any specific lab value.

Metered-Dose Inhalers (MDIs) vs. Nebulizers

  1. 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 Respir Med, 2020; Guan et al, N Engl J Med, 2020; WHO, COVID-19 Interim guidance, March 2020).

Non-intubated patients

  1. Ask patients / families to bring in their home inhalers if possible.
  2. If COVID-19 is confirmed or suspected:
    1. Use MDI (inhalers), NOT nebulizers, due to the increased aerosol risk associated with nebulization. Because MDI supply is limited, only prescribe when needed.
  3. In patients WITHOUT suspicion for COVID-19 or COVID-19 negative:
    1. Use nebulizers even if on droplet precautions (e.g., influenza) because MDI supply is limited.
  4. If COVID is ruled out (and no patient is longer on COVID precautions per infection control)
    1. Continue patient’s current inhalers until they run out, then switch to nebulizers.

Intubated patients

  1. At BWH, an in-line nebulizer container is part of a closed ventilator circuit, so nebulizers can be used without opening the circuit and increasing aerosol risk.
    1. Other hospitals may need to add this setup or add other options, such as a Heat-Moisture-Exchanger that allows MDI delivery into a closed circuit.

Airway Clearance

Management principles

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

Secretion thinning

  1. Nebulized treatments
    1. Only use in ventilated patients on strict airborne precautions in a negative-pressure room.
    2. Options include:
      1. Normal (0.9%) saline nebulizer BID.
      2. Dornase alfa 2.5mg nebulizer once daily, as part of a clinical trial [3].
        1. Note that this can cause bronchoconstriction and mucosal bleeding.
        2. Pre-treat with albuterol 2.5mg, just prior to delivery.
        3. Avoid in setting of bloody secretions.
      3. Nebulized hypertonic (3-7%) saline once daily is of unclear benefit and may not be worth risk of bronchospasm
        1. If using, start with 3% saline to assess response and bronchoconstriction.
        2. Pre-treat with albuterol 2.5mg just prior to delivery
      4. Avoid N-acetylcysteine due to bronchospasm and frequent dosing requirements

Mechanical airway clearance

  1. Avoid oscillating positive expiratory pressure devices (Aerobika or Acapella) and cough assist (MIE).
  2. Avoid routine use of chest PT, but can continue chest PT vests if patient uses at home (e.g., CF patients) with appropriate isolation precautions. Patients with bronchiectasis may be considered on a case-by-case basis.

Inhaled Pulmonary Vasodilators

Indications

  1. 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).
  2. Given this, inhaled vasodilators should NOT be routinely used, except in two circumstances:
    1. As a rescue strategy in already prone ventilated patients (see “respiratory” chapter).
    2. To reduce RV afterload in hemodynamically-significant RV failure in consultation with Cardiology.

Instructions for use

  1. If inhaled vasodilators are used, their use should be reevaluated at 4 hours.
    1. First, try inhaled epoprostenol (Veletri):
      1. Start continuous nebulization at 0.05 mcg/kg/min based on IBW (MDcalc online calculator).
      2. If no improvement in P/F ratio in 2 hours, wean off by decreasing 0.01mcg/kg/min every hour.
    2. If no response to epoprostenol, strongly consider use of inhaled nitric oxide (iNO) in refractory ARDS:
      1. 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).
      2. Inhaled NO may be included in future trial protocols, such as early initiation in milder disease (non-intubated).
      3. Dosing regimen will be linked here soon

Systemic Corticosteroids

Evidence

  1. Data on corticosteroids for COVID-19 is mixed.
    1. 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 Interim guidance, March 2020; Wu et al, JAMA Int Med, 2020).
    2. However, there is some evidence toward a potential benefit. Specifically, a retrospective cohort trial (201 patients, 42% of whom developed ARDS) demonstrated that among patients with COVID-19 positive ARDS, methylprednisolone decreased risk of death (HR, 0.38; 95% CI, 0.20-0.72) (Wu et al, JAMA Int Med, 2020). An earlier, non-blinded randomized controlled trial of patients with ARDS (not COVID-19) suggested a possible benefit to dexamethasone treatment: more ventilator-free days by day 28, and lower mortality at day 60 (21% vs 36%) (Villar et a, Lancet Resp Med, 2020).

Recommendations

  1. We recommend against using steroids for COVID-19 except as part of a clinical trial or if treating another indication. This is in line with WHO guidance (WHO, COVID-19 Interim guidance, March 2020).
  2. If treating another indication, use corticosteroids at the lowest dose for the shortest duration:
    1. For asthma or COPD exacerbation, treat with 40mg prednisone PO or 30mg methylprednisolone IV, once daily x 3-5 days.
    2. For shock with history of chronic steroid use in excess of 10mg prednisone daily, treat with 50mg hydrocortisone IV Q6H until improvement in shock.
    3. For multipressor shock without history of chronic steroid use, treat with 50mg hydrocortisone IV Q6H until improvement in shock.

Anti-IL6 Agents (Tocilizumab, Siltuximab, Sarilumab)

Pathophysiology

  1. IL-6 activates T cells and macrophages, among other cell types (see “Cytokine Activation Syndrome” section in “Shock” chapter). IL-6 inhibitors are approved for cytokine activation syndrome complications related to Chimeric Antigen Receptor T cell (CAR-T) therapy (Brudno and Kochenderfer, Blood Rev, 2019; Rubin et al, Brain, 2019).
  2. 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.

Recommendations

  1. We do not recommend routine use of anti-IL-6 agents unless part of a clinical trial. There are anecdotal reports of benefit of tocilizumab in COVID-19 patients but no rigorous studies are available (Anecdotal reports from Italy; National Health Commission & State Administration of Traditional Chinese Medicine, Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia [Trial Version 7], March 2020)
  2. For severe cases of COVID-19 with suspicion of cytokine activation syndrome (see “Other Guidance” chapter), consider use in conjunction with Infectious Diseases consultation.
    1. Retrospective reviews in patients with rheumatological disease suggest a possible increase in serious bacterial infection, so use caution if secondary infection is clinically suspected.
      1. Tocilizumab is routinely used at BWH (e.g., CRS in patients after CAR-T cell treatment) without obvious increase in bacterial infection.

Dosing regimens

  1. 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.
    1. Common adverse effects of tocilizumab include:
      1. Transaminitis (AST, ALT), >22%
      2. Infusion reaction, 4-20%
      3. Hypercholesterolemia, 20%
      4. Upper respiratory tract infection, 7%
      5. Neutropenia, 2-7%
  2. Alternative - Siltuximab: 11mg/kg IV x1 (anti-IL6 mAb).
    1. Common adverse effects of siltuximab include:
      1. Edema, >26%
      2. Upper respiratory infection, >26%
      3. Pruritus / skin rash, 28%
      4. Hyperuricemia, 11%
      5. Lower respiratory tract infection, 8%
      6. Thrombocytopenia, 8%
      7. Hypotension, 4%
  3. Sarilumab: New intravenous formulation and dosing, available only as part of a clinical trial.
    1. Common adverse effects of sarilumab include:
      1. Transaminitis (AST, ALT), 28-47%
      2. Neutropenia, 7-10%
      3. Infusion reactions, 7%
      4. Upper respiratory tract infections, 4%
      5. Urinary tract infections, 3%
  4. Tocilizumab and sarilumab both have black box warnings for a risk of serious infections, including tuberculosis and other opportunistic infections. Patients treated with either agent should be tested for latent tuberculosis prior to discharge from the hospital and followed up in the TB clinic if that testing is positive.

Remdesivir

  1. This section is under development

Hydroxychloroquine and Chloroquine

Pathophysiology

  1. Hydroxychloroquine (HCQ) 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 and de Lamballerie, Antivir Res, 2020).
  2. HCQ is thought to act through multiple mechanisms (Devaux et al, Int J Antimicrob Agent, 2020):
    1. Inhibition of viral entry. HCQ 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).
    2. Inhibition of viral release into the host cell. HCQ blocks endosomal acidification, which activates endosomal proteases. These proteases are required to initiate coronavirus/endosome fusion that releases viral particles into the cell (Yang et al, J Virol 2004).
    3. Reduction of viral infectivity. HCQ 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 Acquir Immune Defic Syndr, 2004; Klumperman et al, J Virol, 1994).
    4. Immune modulation. HCQ 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).

Evidence

  1. 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).
  2. Hydroxychloroquine was found to be more potent than chloroquine in inhibiting SARS-CoV-2 in vitro (Yao et al, Clin Infect Dis, 2020).

Recommendations

  1. Consideration should be given for use of hydroxychloroquine in patients who:
    1. Are not candidates for other clinical trials AND
    2. Require supplemental oxygen OR are inpatients not on supplemental oxygen but at high risk for progression to severe disease

Dosing regimens (from published literature)

  1. Hydroxychloroquine: 400mg PO BID on the first day, followed by 200mg q12 (q8h if concerns for absorption) for 5 days.
    1. May extend up to 10 days depending on clinical response.
    2. The half-life of HCQ is over 7 days, so a 5-day treatment course should still yield therapeutic HCQ levels past day 10 (Yao et al, Clin Infect Dis, 2020).
  2. Chloroquine phosphate: 500mg PO BID for 10 days.
    1. Not available at BWH and no plans to start use.

Monitoring and Toxicity

  1. Hydroxychloroquine is contraindicated in epilepsy and porphyria and is is known to cause:
    1. Bone marrow suppression
    2. Cardiomyopathy and retinopathy
      1. 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, Semin Arthritis Rheum, 2004; Yusuf et al, Eye, 2017).
    3. QT-segment prolongation and therefore torsades de pointes, especially if administered in combination with azithromycin.
  2. Given this, the following monitoring is required for patients being treated with hydroxychloroquine:
    1. Obtain baseline ECG, ECG 3.5 hours after first dose, and daily ECG thereafter.
    2. Discontinue all other QT-prolonging agents.
    3. Maintain continuous telemetry while under treatment.
    4. Do not start if QTc > 500 msec (or 550 msec with pacing or BBB).
    5. Discontinue if there is an increase in PVCs or non-sustained polymorphic VT.

Angiotensin Converting Enzyme Inhibitors (ACE-I) and Angiotensin II Receptor Blockers (ARB)

Pathophysiology

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

Recommendations

  1. This remains an area of investigation and it is unclear how these medications affect patients with COVID-19.
    1. For outpatients, we recommend against discontinuing outpatient ACEi/ARBs.
    2. For inpatients, we recommend against routine discontinuation of ACEi/ARBs, unless otherwise indicated (e.g., acute kidney injury, hypotension, shock, etc).
      1. 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).

Non-steroidal anti-inflammatory drugs (NSAIDs)

Pathophysiology

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

Recommendations

  1. Reports from France indicate possible increase in mortality with ibuprofen in COVID-19 infection, but these reports have not been corroborated (Fang et al, Lancet Respir Med, 2020; Day M, BMJ, 2020). WHO clarified on 3/20/20 it does not recommend avoiding NSAIDs as initially stated 3/18/20 (WHO, COVID-19 Interim guidance, March 2020).
    1. Concern has been raised that NSAIDs may worsen COVID-19 disease. This has not been proven clinically to-date, so we cannot make a recommendation for or against their use at this time.

Vitamin C

  1. While this idea has been popular in mainstream media, there is currently no evidence to support low- or high-dose vitamin C in COVID-19 patients. There is a trial currently recruiting for high-dose vitamin C trial in COVID-19 patients in China slated to be complete in the fall of 2020.
    1. The use of Vitamin C as a treatment for sepsis is beyond the scope of this document. A 96-hour infusion of vitamin C did not demonstrate significant improvement of organ dysfunction, vascular injury or alter inflammatory markers in sepsis patients with ARDS, although a reduction in 28-day mortality was exhibited (Difference -0.17, p=0.03). (Fowler, et al. JAMA, 2019). This study does not look at COVID-19 ARDS patients.

Blood Products

Red blood cells

  1. Restrictive transfusion strategy (Hct > 21, Hgb > 7) is recommended.
    1. If hemodynamically stable, transfuse 1 unit at a time and reassess needs.
    2. Transfusion thresholds for pRBCs are recommended as follows:
      1. Acute coronary syndrome: consider transfusion for Hgb < 10.
      2. Oncology patients: transfuse for Hgb < 7.
      3. All others: transfuse for Hgb < 7.
  2. Parsimony is encouraged given:
    1. Limited supply (blood drives are limited by social distancing).
    2. Volume overload is of particular concern in COVID patients.
      1. Randomized controlled trials of ICU patients have shown that a conservative transfusion strategy (Hgb > 7) is associated with less pulmonary edema, fewer cardiac events and no evidence of harm compared to a liberal transfusion strategy (Hébert et al, N Engl J Med, 1999; Holst et al, N Engl J Med, 2014; Gajic et al, Crit Care Med, 2006).
  3. Massive transfusion protocol, as a very limited resource, will need to be activated only by the ICU attending

Other blood products

  1. In general, treat bleeding not numbers.
  2. FFP or 4 factor-PCC (lower volume) should be given for active bleeding in the setting of known or suspected coagulation abnormalities.
  3. For warfarin reversal, use 4 factor-PCC given longer effect and lower volume.
  4. Platelets should be transfused for platelet count < 10K unless actively bleeding. Transfuse 1 unit at a time.

Blood donation

  1. We encourage all staff who are healthy and eligible to donate to make an appointment to donate blood or platelets at the Kraft Family Blood Donor Center at DFCI and BWH, either by phone (617.632.3206) or online.

5: Cardiac Complications

Acute Cardiac Injury

Definition and incidence

  1. Definition: Defined in studies as troponin > 99th percentile, or abnormal ECG or echocardiographic findings (Zhou et al, Lancet, 2020). Non-specific study definition..
  2. 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; Shi et al, JAMA Cardiology, 2020).

Pathophysiology

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

Time course and prognostic implication

  1. Troponin rise and acute cardiac injury may be late manifestations of COVID-19.
    1. Troponin increased rapidly from ~14 days from illness onset, after the onset of respiratory failure (Zhou et al, Lancet, 2020).
    2. 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).
  2. ACI is associated with ICU admission and mortality
    1. ACI is higher in non-survivors (59%, n=32) than survivors (1%, n=1) (Zhou et al, Lancet, 2020).
    2. ACI is higher in ICU patients (22%, n=22) compared to non-ICU patients (2%, n=2) (Wang et al, JAMA, 2020)

Cardiovascular Testing and Consultation

Testing

  1. Troponin:
    1. ICU patients: Check hsTrop daily and ScvO2 daily
    2. Inpatients: Check hsTrop every other day
      1. If hsTrop > 200 ng/L or ScvO2 <60%
        1. Obtain 12-lead ECG
        2. Perform point-of-care US (POCUS) if you are trained to do so
        3. If no new ECG or echocardiographic abnormalities, continue to monitor hsTrop and ScvO2
  2. Telemetry:
    1. Telemetry should be used for all critically-ill patients
    2. At BWH, COVID-19 intermediate-care patients also have telemetry.
    3. For hospitals, with resource-limitations, telemetry is most important for patients who meet AHA criteria (Sandau et al, Circulation, 2017).
  3. ECGs:
    1. Daily ECGs are reasonable for individuals with severe COVID-19.
      1. When possible, print ECGs from the in-room monitor to minimize contamination of equipment
  4. TTE
    1. Do not order routine TTEs on COVID-19 patients.
    2. Cardiology consult or a trained provider should perform POCUS (uploaded to PACS/Centricity) if:
      1. Significant troponin elevation or decline in ScvO2/MvO2
      2. Shock
      3. New heart failure (not pre-existing heart failure)
      4. New persistent arrhythmia
      5. Significant ECG changes
        1. If abnormalities are identified on POCUS (e.g. new reduction in LVEF < 50%), a formal TTE should be obtained and cardiology consulted.
        2. Where possible order limited TTEs instead of full TTEs to conserve resources.
  5. Cardiac Imaging & Stress Testing:
    1. Cardiac imaging, including TEE, cardiac CT, and cardiac MRI will be considered on a case-by-case basis in consultation with cardiology.
    2. Stress testing is likely not indicated in individuals with active COVID unless in discussion with cardiology consultation.
  6. Cardiology Consultation
    1. The following clinical scenarios should prompt cardiology consultation:
      1. Malignant and unstable arrhythmias
      2. A marked rise in cardiac biomarkers
      3. Concern for myocarditis
      4. Concern for ACS, particularly ST-elevation pattern on ECG
      5. New heart failure
      6. Undifferentiated or cardiogenic shock

Arrhythmias

Incidence

  1. 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).
  2. There are anecdotal reports of VT and VF as a late manifestation of COVID-19. No specific published findings were identified.

Workup

  1. Telemetry, 12-lead EKG, cardiac troponin, NT-proBNP, TFT
  2. ScvO2 if central line present
  3. POCUS to assess LV and RV function with uploaded images
  4. Obtain formal TTE and consider cardiology consultation if abnormalities of any of the above

Management

  1. Atrial fibrillation/atrial flutter
    1. Beta blockade if no evidence of heart failure or shock
    2. If significant heart failure or borderline BPs, use amiodarone. There is no known increased concern for amiodarone lung toxicity
    3. If unstable, synchronized DCCV with 200 Joules biphasic
  2. Ventricular tachycardia (VT)
    1. Unstable/pulseless: initiate ACLS
    2. Stable:
      1. Cardiology consult (may represent evolving myocardial involvement)
      2. Amiodarone 150mg IV x 1 or lidocaine 100mg IV x 1

Acute Coronary Syndromes

Incidence

  1. 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.
    1. The incidence of ACS is about 6 times as high within seven days of an influenza diagnosis than during the control interval - incidence ratio 6.05 (95% CI, 3.86 to 9.50) (Kwong et al, NEJM, 2018).

Workup

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

Management

  1. Medical management of ACS should be coordinated with cardiology
    1. 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).
    2. Beta blockers should be used with caution given possible concomitant myocarditis/decompensated heart failure.
  2. As of the time of this writing, the cath lab will take COVID-19 patients, even if ventilated.
    1. 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.

Pericarditis and Myocarditis

Incidence

  1. 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)
  2. However, there is currently no evidence of proven pericarditis or myocarditis, either by biopsy or cMRI.

Workup

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

Management

  1. Supportive for heart failure and direct viral treatments
  2. 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.

6: Shock: Septic, Cardiogenic, and Cytokine

Undifferentiated Shock in COVID

Overview

  1. Definition:
    1. 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
  2. Time course:
    1. Patients rarely present in shock on admission
      1. Natural history seems to favor the development of shock after multiple days of critical illness.
  3. Etiology:
    1. The range of reasons for shock is wide and more variable than for most patients and includes:
      1. Cardiogenic shock
      2. Secondary bacterial infection
      3. Cytokine storm

Workup

  1. Assess for severity of end organ damage:
    1. UOP, mental status, lactate, BUN/creatinine, electrolytes, LFTs
  2. Obtain a FULL infectious/ septic workup, which includes all of the following:
    1. 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
    2. Portable CXR (avoid CT unless absolutely necessary)
    3. Full skin exam
  3. Assess for cardiogenic shock
    1. Assess extremities: warm or cool on exam
    2. Assess patient volume status: JVP, CVP, edema, CXR
    3. 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)
    4. Perform POCUS if trained to do so and upload to PACS/Centricity
      1. For TTE protocols see “Cardiac Complications of COVID-19” chapter.
    5. Labs: Obtain an SCV02 or MV02 if the patient has central access, troponin x2, NT proBNP, A1c, lipid profile, TSH
    6. EKG (and telemetry)
    7. Calculate estimated Fick Cardiac Output
      1. MDcalc online calculators: Fick CO, BSA
    8. Obtain cardiology consultation if any suspicion of cardiogenic shock
  4. Assess for other causes of shock:
    1. Vasoplegia:
      1. Run medication list for recent cardiosuppressive medications, vasodilatory agents, antihypertensives
    2. Adrenal insufficiency:
      1. Unless high pretest probability of adrenal insufficiency, we recommend against routine cortisone stimulation testing
    3. Obstruction:
      1. PE (given the elevated risk of thrombosis)
      2. Tamponade (given elevated risk of pericarditis)
      3. Obstruction from PEEP
    4. Cytokine storm (see “Cytokine Activation Syndrome” section in this chapter below)
    5. Allergic reactions to recent medications
    6. Neurogenic shock is uncommon in this context
    7. Hypovolemia:
      1. Bleeding
      2. Insensible losses from fever
      3. Diarrhea/vomiting

Differentiating Shock

This video is a helpful tutorial.

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Septic Shock and Secondary Infections

Incidence

  1. The reported rates of sepsis and septic shock are not reported consistently in currently available case series
    1. Secondary bacterial infections are reported:
      1. 20% of non-survivors (Zhou et al, Lancet, 2020)
      2. 16% of non-survivors (Ruan et al, Intensive Care Med, 2020)
      3. 12-19% In H1N1 epidemic (MacIntyre et al, BMC Infect Dis, 2018)
    2. Concurrent Pneumocystis pneumonia has been reported in at least one case (possibly due to lymphopenia)

Management

  1. Antibiosis:
    1. Early empiric antibiotics should be initiated within 1 hour (see “Antibiotic Stewardship” section within “COVID-19 Therapies and Clinical Trials” chapter)
  2. Pressors and Fluid Management:
    1. Goal MAP > 65mmHg
      1. While there is emerging data that lower MAP thresholds may be beneficial, we recommend following this threshold for now.
    2. Pressors
      1. Start Norepinephrine while determining the etiology of undifferentiated shock
      2. 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
    3. Conservative fluid management:
      1. Do not give conventional 30cc/kg resuscitation
        1. 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)
        2. Conservative fluid management is also part of the most recent WHO guidelines. WHO, COVID-19 Interim guidance, March 2020).
      2. Instead, give 250-500cc IVF and assess in 15-30 minutes for:
        1. Increase > 2 in CVP
        2. Increase in MAP or decrease in pressor requirement
          1. Use isotonic crystalloids; Lactated Ringer’s solution is preferred where possible. Avoid hypotonic fluids, starches, or colloids
      3. Repeat 250-500cc IVF boluses; Use dynamic measures of fluid responsiveness
        1. Pulse Pressure Variation: can be calculated in mechanically ventilated patients without arrhythmia; PPV >12% is sensitive and specific for volume responsiveness
        2. 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
        3. Ultrasound evaluation of IVC collapsibility should only be undertaken by trained personnel to avoid contamination of ultrasound
        4. For further guidance, Conservative Fluid Management protocols are available from from FACCT Lite trial (Grissom et al, Crit Care Med, 2015).
      4. Corticosteroids
        1. See “Systemic Corticosteroids” section
        2. Stress dose hydrocortisone should still be considered in patients on > 2 pressors.

Cardiogenic Shock

Incidence and clinical course

  1. Etiology: See “Acute Cardiac Injury” section.
    1. Mechanism is unknown, potentially direct viral toxicity, ACS, or inflammatory cardiomyopathy
  2. Incidence:
    1. Heart failure or cardiogenic shock was observed
      1. In 23% (n=44 of 191) of hospitalized patients in one case series (Zhou et al, Lancet, 2020).
        1. There were higher rates in non-survivors (52%, n=28) compared to survivors (12%, n=16),
      2. In 33% of patients admitted to an ICU in Washington State 33% (n=7 of 21) (Arentz et al, JAMA, 2020).
        1. These patients tended to be older with more comorbidities and had a high mortality (11 of the 21 died).
  3. Prognostic implication:
    1. Heart failure or myocardial damage contributed to death
      1. 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).
  4. Time course:
    1. 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)

Workup

  1. Significant concern for cardiogenic shock if any of the following are present with evidence of hypoperfusion (e.g., elevated lactate):
    1. Elevated NT-proBNP, or
    2. CvO2 < 60% (PvO2 < 35 mm Hg), or
    3. Echocardiogram with depressed LV and/or RV function
  2. Rule out ACS and complete the initial work up as described in “Cardiac Complications” chapter.
  3. Ongoing monitoring:
    1. Labs: Trend troponins to peak, SCvO2 (obtained by upper body CVC) or MvO2 q8-12h or with clinical change, Lactate q4-6h, LFTs daily (for hepatic congestion)
    2. Daily EKGs or prn with clinical deterioration
    3. Trend troponin to peak
  4. All cardiogenic shock cases require cardiovascular medicine consult
    1. PA catheters may be placed bedside by experienced providers, with preference for use only in mixed shock or complex cases with cardiology guidance

Management

  1. Close collaboration with the cardiovascular medicine consultation service is recommended.
    1. Goals: MAPs 65-75, CVP 6-14, PCWP 12-18, PAD 20-25, SVR 800-1000, SCvO2 > 60%, CI > 2.2
      1. Note: Achieving MAP goal is first priority, then optimize other parameters
    2. How to achieve goals:
      1. Continue titration of norepinephrine gtt for goal MAP 65-75
      2. Initiate diuretic therapy for CVP > 14, PCWP >18, PAD > 25
      3. Initiate inotropic support:
        1. 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.
      4. Ensure negative inotropes such as beta blockers, calcium channel blockers and antihypertensives are discontinued.

Mechanical Support

  1. Patients who experience the following should prompt an immediate call to the cardiovascular medicine consult service for consideration of mechanical support:
    1. Dobutamine gtt at 5mcg/kg/min (or unable to tolerate dobutamine due to tachyarrhythmias) and ScvO2 < 60% or CI < 2.2
    2. Lactate > 4 after medical therapy
  2. The criteria for ECMO and other mechanical cardiovascular support varies among centers and are difficult to develop even under typical circumstances. The unclear trajectory of the COVID-19 pandemic makes these evaluations even more difficult.
    1. BWH ECMO and Cardiovascular Medicine guidelines are in development and will be linked once available.
    2. For the purposes of general education, a hypothetical set of inclusion criteria for ECMO or MCS could cover:
      1. Younger age
      2. Expected life expectancy >6 months pre-hospitalization
      3. No evidence of solid or liquid malignancy
      4. Able to tolerate anticoagulation
      5. Platelets >50,000
      6. Absence of severe peripheral arterial disease
      7. No evidence of irreversible neurological injury
      8. Able to perform ADLs at baseline prior to illness
      9. 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)

Cytokine Activation Syndrome

Pathophysiology

  1. A subgroup of patients with severe COVID-19 may have cytokine activation syndrome and secondary HLH (Mehta et al, Lancet, 2020).
    1. Patients who had cytokine activation developed rapid progression to ARDS, shock, and multiorgan failure (Chen et al, Lancet, 2020)
  2. Pathophysiology:
    1. 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)
    2. Similar patterns of cytokine storm and ARDS have been seen with SARS, MERS (Kim et al, J Korean Med Sci, 2016)
    3. 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

  1. Suspect if clinical deterioration with shock and multiorgan failure.
    1. 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)
      1. CRP seems to correlate with disease severity and prognosis of COVID-19 (Ruan et al, Intensive Care Med, 2020; Young et al, JAMA, 2020)
      2. An HScore (MDcalc online calculator) may be helpful in estimating the probability of secondary HLH in these patients

Management

  1. 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.

7: Cardiac Arrest

Preparation

Minimizing Healthcare Worker Risk of Exposure

  1. Code Responses to COVID-19 patients are high-risk events for healthcare worker exposure due to the aerosolization that occurs with chest compressions and intubation
    1. Use PPE:
      1. CDC guidelines recommend N95 respirator, face shield, gown and gloves be used by all code responders during code events (CDC Guidelines, 2020) as well as Face Shield, Gown and Gloves).
    2. Minimize personnel:
      1. Use an automated compression device where available to minimize personnel.
    3. Prepare code equipment:
      1. To limit transmission of virus while passing meds/supplies into the patient’s room from the code cart, consider creating Code Bags inside the Code Cart pre-packed with necessary code meds (Epinephrine, Bicarbonate, Calcium etc.) and IV/lab supplies.

Early goals of care conversations

  1. To avoid unnecessary codes in patients with an irreversible underlying condition, patients who are at high-risk for acute decompensation should be identified early and appropriate steps should be taken to confirm code status and initiate early goals of care conversations with the patient and family.

Code Management

  1. Efforts should be made to minimize the total number of Code responders in the room to 7-8.
    1. Code responders inside the patient’s room who should don full PPE prior to entering the patient’s room:
      1. Code Leader (1)
      2. Code RN (1)
      3. Scribe RN (Primary RN or NIC) (1)
      4. Respiratory Therapist (1)
      5. Anesthesiologist (1)
      6. 2 Chest Compressors, resting compressor holds femoral pulse (2)
      7. If needed for surgical procedures, Surgical Responder (1)
    2. Code responders outside the patient’s room should not don PPE unless called upon in the room:
      1. Additional unit nurses (2-3) (supplies, meds from omnicell, code cart)
      2. Code Cart
      3. Pharmacist (1)
      4. Additional medical resident/MDs (2) (Medical resident on computer outside the room placing orders, calling consults, and providing code leader with patient information)
      5. Additional Code Responders (3-4) Surgery and Anesthesia team if not needed in the room
      6. Security
      7. Observer (for PPE observation)
  2. Circulation
    1. Until a definitive airway is obtained, compression-only CPR should be performed. Multiple studies have shown that compression-only CPR is non-inferior to standard CPR (Svensson et al, NEJM, 2010).
    2. If patient has shockable rhythm (VF/VT), defibrillate as soon as possible.
  3. Airway
    1. Initial Airway Management, Prior to Intubation:
      1. Prior to securing a definitive airway, oxygen should be applied via a non-rebreather mask at 15L/min without humidification
      2. Avoid BVM ventilation, high-flow nasal cannula, and non-invasive ventilation (CPAP, BiPAP) to minimize aerosolized virus (Cheung, Lancet Resp Med, 2020; Tran et al, PLoS One, 2012).
      3. If passive oxygen is not available, place a surgical face-mask and a blanket over the patient’s face prior to chest compressions.
      4. If the patient does not have a shockable rhythm, proceed with Rapid Sequence Intubation as early as possible to limit aerosolization
    2. Endotracheal Intubation
      1. Endotracheal intubation is the procedure that subjects the rescuer to the highest risk of infection during resuscitation. To maximize the success rate for intubation, airway interventions should be carried out by experienced individuals and chest compressions should be stopped (Cheung, Lancet Resp Med, 2020). This may deviate from usual cardiac arrest care leading to a pause in chest compressions, however this is acceptable to maintain the safety of code responders. Please see “intubation” chapter for more details.
      2. Chest compressions should resume once the endotracheal tube (ETT) cuff is inflated and the ETT is connected to the ventilator.
      3. If the pause in chest compressions is excessive and endotracheal intubation does not seem likely, consider LMA or other extraglottic airway device.
      4. Code responders should distance themselves from the head of the bed during the intubation procedure (6 ft distance).
      5. Continuous capnography device should be used to monitor ventilation (Cheung, Lancet Resp Med, 2020).
      6. Depending on institutional policies, anesthesia and respiratory therapy may don higher levels of PPE including PAPR hoods for the intubation procedure.
  4. Etiologies to Consider
    1. Data from a retrospective study in Wuhan (Ruan et al, Intensive Care Med, 2020) revealed cause of death to be:
      1. Respiratory failure (53%)
      2. Heart failure with respiratory failure (33%)
      3. Myocardial damage (7%)
      4. Unknown cause (7%)
    2. It is important to attempt to identify and treat reversible causes (5H’s, 5T’s) before stopping the code.
  5. Terminating Resuscitative Efforts
    1. Avoid prolonged resuscitation if there is no easily reversible etiology identified.
    2. No one factor alone, or in combination, is predictive of outcome during cardiac arrest, however it is reasonable to stop resuscitation efforts if return of spontaneous circulation (ROSC) has not been achieved within 30 minutes.
    3. In intubated patients, failure to achieve an ETCO2 of greater than 10 mm Hg by waveform capnography after 20 minutes of CPR should be considered as one component of a multimodal approach to decide when to end resuscitative efforts (Mancini et al, Circulation, 2015)
  6. Post-Resuscitation Care
    1. Dispose of, or clean, all equipment used during CPR. Any work surfaces used for airway/resuscitation equipment will also need to be cleaned.
    2. After the resuscitation has ended adhere to strict doffing procedure to limit exposure.
    3. If ROSC is achieved, provide usual post-resuscitation care consistent with current recommended guidelines including targeted temperature management (Donnino et al, Circulation, 2015).

8: Thrombotic and Coagulation Manifestations

Thrombotic Disease

Incidence

  1. 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

  1. The mechanism for VTE are unknown and likely multifactorial:
    1. Systemic inflammatory response as seen in sepsis
    2. Stasis/critical illness
    3. Possibly direct endothelial damage from viral injury/ACE2 binding
  2. 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.
    1. 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; Lin et al, Emerging Microbes & Infections, 2020).

Management

  1. Initiate prophylactic anticoagulation therapy for all COVID-19 patients unless otherwise contraindicated
    1. If CrCl > 30: Lovenox 40 mg SC daily
    2. If CrCl < 30 or AKI: Heparin 5000 units SC TID
    3. Hold if Platelets <30,000 or bleeding, start TEDs and SCDs
  2. 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).
  3. 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

  1. 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).

Disseminated Intravascular Coagulation (DIC)

Incidence/pathophysiology

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

Time course

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

Workup

  1. Identify and treat underlying condition
  2. ISTH DIC score (MDcalc online calculator): If score < 5, no DIC; recalculate in 1-2 days
  3. Elevated PT/PTT and D-dimer correlate with worse prognosis: trend PT/INR, PTT, D-dimer, fibrinogen every 3 days until discharge or death

Management

  1. If not bleeding, supportive care:
    1. If fibrinogen < 150: FFP, cryoprecipitate or fibrinogen concentrate (RiaSTAP or Fibryga)
    2. RiaSTAP and Fibryga are less volume, but dose must be discussed with HAT/pharmacy
  2. Transfuse platelets if < 30K
    1. Consider holding anticoagulation if the patient requires blood products for supportive care, though clinician should weigh risks and benefits.
  3. If bleeding, give blood products:
    1. For elevated PT/PTT and bleeding, use FFP or 4F-PCC (KCentra is less volume, but must discuss dose with HAT/pharmacy)
    2. Hold anticoagulation for active bleeding.
  4. Start systemic anticoagulation only if:
    1. Overt thromboembolism or organ failure due to clot (i.e., purpura fulminans)
    2. There has been no mortality benefit of therapeutic anticoagulation in DIC (Levi et al, Blood, 2018).

Prognosis

  1. 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).

9: Renal Manifestations

Acute Kidney Injury

Incidence and Pathophysiology

  1. Incidence of AKI in COVID-19 varies widely, but estimates range from 2.1% to 29%.
  2. 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.
    1. 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).

Workup

  1. Monitor Creatinine at least daily
    1. 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)
  2. If evidence of rising BUN and/or creatinine, order urinalysis
    1. Patients may present with proteinuria (44%), hematuria (26.9%)

Management

  1. Consult ICU nephrology early at the first sign of renal injury for all COVID-19 confirmed patients
    1. Do not wait until need for RRT (renal replacement therapy)/dialysis for consultation.
    2. At this time, all confirmed COVID-19 patients are covered by ICU nephrology, not general nephrology
  2. Managing AKI:
    1. Minimize nephrotoxic agents
    2. 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)

  1. Estimates for RRT range from 1 to 5% of hospitalized patients. Among critically ill patients, need for CRRT ranges from 5 to 23%
    1. 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).
  2. Renal will be coordinating RRT continuation and initiation
    1. Indications for dialysis in COVID-19 patients are the same as the indications for all patients.
  3. ICU nephrology will determine the need, timing, and modality of renal replacement on a case-by-case basis.

Prognosis

  1. Increased serum creatine, BUN, AKI, proteinuria, or hematuria are each independent risk factors for in-hospital death (Cheng et al, medRxiv, 2020 preprint)
    1. 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).
    2. 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).
    3. In SARS, 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).

10: Neurologic Manifestations

  1. This section is in process

11: GI Manifestations

Luminal disease

  1. This section is in development

Liver disease

Overview

  1. Incidence:
    1. The incidence of direct hepatic injury is confounded by pre-existing liver disease, drug-induced liver injury, and shock
      1. The only reported post-mortem liver biopsy from a patient with COVID-19 showed only microvesicular steatosis, a common finding in sepsis
    2. Up to 53% of patients have abnormal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [Zhang et al, Lancet Gastroenterol Hepatol, 2020].
      1. Given often elevated CK, this may also represent a myositis similar to that observed in severe influenza infections [Bangash et al, Lancet Gastroenterol Hepatol, 2020].
    3. Bilirubins and alkaline phosphatase tend to be spared
      1. 54% of patients hospitalized for COVID-19 at a single center in China had elevated gamma-glutamyl transferase (GGT).
  2. Clinical course:
    1. In general, liver injury in mild COVID-19 disease is transient and self-resolving. However, liver injury correlates with severity
      1. ALT > 40 is associated with higher odds of in-hospital death (Zhou et al, Lancet, 2020).
      2. 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).
    2. Acute liver failure has not been reported [Ong et al, BMJ, 2020].
  3. Pathophysiology:
    1. Possible mechanisms of liver injury include:
      1. Direct liver injury (viral hepatitis)
        1. In SARS direct liver injury is seen in up to 60% of patients. Liver biopsies from 3 patients with SARS showed mild to moderate lobular inflammation, apoptosis, and prominent mitotic activity of hepatocytes [Chau et al, Hepatology, 2004].
        2. ACE2 receptors are highly expressed within the biliary tree but not in hepatocytes [Chai et al, BioRxiv, 2020].
      2. Drug hepatotoxicity
      3. Hepatic congestion (impaired venous return and elevated RAP associated with high levels of PEEP)
      4. Cytokine/ immune effects
        1. Other respiratory viruses produce similar elevations of LFTs, thought to involve intrahepatic cytotoxic T cells and Kupffer cells.[Bangash et al, Lancet Gastroenterol Hepatol, 2020].
      5. Shock

Workup

  1. Baseline GGT, CK, LDH, LFT’s, INR
  2. If normal LFTs on presentation, monitor LFTs every third day
    1. If on hepatotoxic medications, monitor more frequently in conjunction with pharmacy.
    2. If starting Lopinavir/Ritonavir and hydroxychloroquine, monitor LFTs daily.
  3. Workup for other etiologies of liver injury with RUQUS, doppler ultrasound, hepatitis serologies, etc., as clinically indicated.

Management

  1. Consult GI/Hepatology if concerned for acute liver failure (defined as severe liver injury with elevated bilirubin, INR >1.5, and encephalopathy).
  2. Review medication list for all possible offending agents and discontinue if possible.
  3. N-Acetyl-Cysteine is not recommended at this time due to significant volume load.
    1. Chinese studies refer to giving “liver protective drugs” in case of severe liver injury but we recommend against this for now.
  4. This section is in development

Endoscopy Guidelines

  1. This section is in development

Special considerations for COVID-19 patients with underlying luminal or liver disease

  1. This section is in development

12: Oncology Patients

General Management

  1. Data:
    1. As of March 16, 2020, there are no available published data specific to COVID-19 management in oncologic or immunosuppressed patients.
  2. Oncology Consultation/Coverage:
    1. For established DFCI patients, oncology consultation and guidance is provided by each patient’s primary oncologist (or coverage).
    2. Contact primary oncologist via page, not the general pager.
  3. Prognosis:
    1. Many patients have reasonable or even good prognosis with current therapies. Do not assume a prognosis, involve outpatient attending.
  4. Meds:
    1. Check in Epic medications tab and in “Research: Active” tab.
  5. Workup:
    1. Labs:
      1. Weekly glucan/galactomannan in neutropenic/transplant patients.
      2. Specific patient populations may require additional monitoring (such as CMV, EBV monitoring in transplant patients – ask outpatient team).
  6. Exam:
    1. Examine catheters (port, CVC, others) daily.
    2. Avoid rectal exams in neutropenic patients, but examine the perirectal area if symptoms or persistent fevers.
      1. Do not give per rectum therapies to neutropenic patients.
    3. In patients with Heme Malignancy or SCT: Findings are more subtle or absent in neutropenic and immune suppressed patients. Examine catheters daily. Avoid rectal exam.
  7. Pain management:
    1. Patients with cancer-related pain may have high opiate needs at baseline. Opiates should not be stopped but type may need to be adjusted in the setting of respiratory failure, renal injury, or liver injury.
      1. Consider Pain / Palliative Care consult
  8. Goals of Care:
    1. Involve primary team whenever possible (recognizing that in critical/emergent situations may not be possible).
  9. Anticoagulation:
    1. Patients with solid tumors are at very high risk of thrombosis but at lower risk of infection than most heme malignancy patients.
    2. Thrombosis prophylaxis for all unless contraindicated
      1. Hold pharmacologic prophylaxis if platelet count < 30K, use pneumoboots
      2. Both COVID-19 infection and malignancy increase thrombotic risk, particularly with solid tumors.
      3. See “Thrombotic Disease” section within “Thrombotic and Coagulation Manifestations” chapter for guidelines on both prophylactic and therapeutic anticoagulation.
  10. Transfusions:
    1. Blood bank reviews orders and will release appropriate products (i.e., irradiated, leukoreduced, etc).
    2. See “Blood Transfusions” section for additional details
      1. RBC transfusion if Hgb < 7 or Hct < 21.
      2. Platelet transfusion if Platelets < 10K. Higher transfusion goals if needed for procedures or if active bleeding:
        1. Platelet count > 20K if mild bleeding (i.e., epistaxis, line oozing) or if patient has rigors.
        2. Platelet count > 50K if more serious bleeding; may be higher for CNS bleeding or neurosurgery required.
      3. Cryoprecipitate transfusion if fibrinogen < 100.
      4. FFP transfusion if procedure needed (INR of FFP = ~1.4).

Febrile Neutropenia

  1. Definition:
    1. ANC < 500 cells/mm3 AND T ≥ 101F or T ≥ 100.5 for 1hr
  2. Workup:
    1. Blood cultures from peripheral (ideally two sets), and each lumen of central line (label clearly); UA/sed with urine culture (UA may not be as informative with neutropenia); glucan and galactomannan (if not checked recently), sputum if able; CXR
      1. Continue DAILY blood cultures while febrile.
      2. Monitor serum galactomannan and 1-3-beta glucan once weekly.
      3. Any positive glucan or galactomannan prompts ID consult.
  3. Initial Empiric Antibiotics:
    1. GNRs: Ceftazidime OR Cefepime
      1. Alternatives: Piperacillin-tazobactam (2nd line) or meropenem (3rd line).
    2. GPCs: add Vancomycin if hemodynamically unstable, or if MRSA pneumonia or catheter-associated infection is suspected. Check dosing with pharmacy if able.
  4. Removal of lines:
    1. Catheter removal should be discussed if associated infection is suspected - involve primary oncologist and/or ID team to weigh risks and benefits, given that not all lines require removal.
  5. Persistent Neutropenic Fever:
    1. If fever persists x3 days despite antibiotics
      1. Micafungin 100mg IV daily
      2. Consideration of further imaging even if patient appears stable (discuss with oncology / ID).
  6. Antiinfective course:
    1. Anti-Infectives should be continued until the patient has met all of these criteria:
      1. clinically improved, and
      2. has been afebrile for 48h, and
      3. has been non-neutropenic for 48h.

Immune Checkpoint Inhibitors

  1. Overview
    1. Most common are CTLA-4 inhibitor (ipilimumab) and PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, durvalumab, atezolizumab and avelumab).
    2. Immune Checkpoint Inhibitors (ICIs) do not significantly immune suppress patients when used alone.
  2. Immune toxicity
    1. If patient develops organ dysfunction, it may be due to immune toxicity
      1. consult the service team of the involved organ system and inform primary oncologist.
    2. Common immune toxicities include pneumonitis / respiratory failure (may be difficult to distinguish between COVID19 disease or may be aggravated by COVID19 infection), colitis, endocrine dysfunction (thyroid, pituitary / hypothalamic, adrenal), nephritis. Less common hepatitis, meningitis, dermatitis.
      1. Check TSH, ACTH, cortisol, T-spot, HIV, HBV, HCV serologies if concerned.
    3. Immune toxicities are usually treated with high dose steroids
      1. risks and benefits must be weighed immediately with primary oncologist and ID consult teams if immune toxicity is suspected concurrent with COVID19 infection.
    4. BWH/DFCI iTox guidelines can be found here on BWH/DFCI intranet.

13: The Role of Palliative Care

Anxiety

  1. Non-pharmacologic:
    1. Counseling (Spiritual, Psychocological, SW), Reiki
  2. Pharmacologic
    1. Benzodiazepines (if patient is not delirious; can use in either intubated or non-intubated pts)
      1. Lorazepam (longer half-life) 0.5-2 mg PO/SL q4-6h PRN; 0.5-2 mg IV q2h PRN
      2. Midazolam (shorter half-life) 0.2-0.5 mg IV slowly q 15 min PRN or 0.1-0.3 mg/hr IV infusion
    2. SSRI/SNRI: Continue home dose if possible. If NPO, replace with prn benzodiazepine

Dyspnea & Acute Pain

Non-opioid management

  1. Non-Pharmacologic for Dyspnea:
    1. Positioning: sitting patient up in bed, if possible. See also Anxiety above.
  2. Pharmacologic:
    1. Please see “Therapeutics” for discussion about NSAID use vs acetaminophen. No recommendation is made at this time
    2. Ativan (as above) can be used to ease the anxiety associated with dyspnea, but would avoid in patients who have had a previous paradoxical reaction (i.e. worsened agitation).
    3. Opioids can be used for both dyspnea and acute pain (see below)

Opioid management

  1. General principles:
    1. Additional information, including algorithm for opioid-induced respiratory depression is available at: DFCI Pink Book
    2. ALWAYS use PRN boluses to address acute, uncontrolled symptoms. PRN bolus dosing should be 10-20% of the 24-hour opioid dose
  2. For opioid naive patients:
    Renal function  
    Normal Abnormal (GFR<50)
COPD No
  • Morphine
    5-10mg PO q3h PRN (use the 20mg/ml concentrate)
  • Morphine
    2-4mg IV q2h PRN
  • Hydromorphone
    1-2mg PO q3h PRN
  • Hydromorphone
    0.1-0.2mg IV q2h PRN
  Yes
  • Morphine
    2-5mg PO q4h PRN (use the 20 mg/ml concentrate)
  • Morphine 1-2
    mg IV q2h PRN
  • Hydromorphone
    2-4mg PO q4h PRN
  • Hydromorphone
    0.2-0.4mg IV q2h PRN
  1. If patient is not well managed with the above, add opioid infusion:
    1. Consider drip If > 3 bolus doses in 8 hours
    2. Calculate initial dose with total mg used/8 hours
      1. e.g. 1+2+2+2= 7 mg; begin drip at 7mg/8 hr = 1 mg/h
      2. Depending on symptoms and goals of care, consider reducing hourly rate by 30-50%. If patient is at end of life, would use 100% of hourly rate.
    3. Continue PRN dosing at current dose (if effective) or titrate as per above.
  1. For Opioid tolerant patients:
    1. If able to take PO:
      1. Continue current long-acting doses if renal and hepatic function tolerate
      2. Continue current oral PRN dose if effective q4h prn
        1. If ineffective, increase dose by 50% and order range of up to 3 x basal dose
          1. e.g. 5 mg PO MS q3h prn; increase to 7.5 mg; 7.5-22 mg PO q3h PRN
    2. If unable to take PO, severe or rapidly escalating symptoms:
      1. Convert as-needed PO doses to IV pushes as needed
        1. Use the IV Conversion chart (see chart below, or DFCI Pink Book)
        2. Decrease PRN dose by ⅓ for incomplete cross-tolerance when switching between opioid classes
          1. e.g. to convert 20 mg of oxycodone to IV hydromorphone: 20 mg oxy = 1.5 mg IV hydromorphone; 1.5 mg x ⅔ =1 mg IV
      2. Convert PO long-acting/ sustained release opioids to an infusion:
        1. Calculate 24-hour dose of PO sustained release (SR) morphine
          1. Divide by 3 for the total 24h mg IV (Morphine PO/IV = 3:1)
        2. Divide the 24h mg IV total by 24h for the hourly drip rate (mg)
          1. e.g. 30 mg SR PO morphine q8 hr= 90 mg PO in 24 h; 90 mg /3 = 30 mg IV dose; 30 mg / 24 h~ 1 mg/hr IV morphine infusion
        3. Continue PRN dosing. PRN dose should be 100-200% of opioid drip rate
          1. e.g. 1 mg/hr IV morphine infusion; PRN dose is 1-2 mg IV q2h

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

Opioid Equianalgesic Doses    
Drug PO/PR (mg) Subcut/IV (mg)
Morphine 30 10
Oxycodone 20 n/a
Hydromorphone 7.5 1.5

Fentanyl

(See table below for transdermal conversions)

n/a 0.1 (100 mcg)

Delirium

  1. Diagnosis:
    1. Confusion Assessment Method (CAM) method
  2. Treatment:
    1. Non-pharmacologic:
      1. Daytime lights, nighttime dark. Frequent reorientation. Reverse contributing medical conditions as able.
      2. Consult Psychiatry; for terminal delirium, consult Palliative Care
    2. Pharmacologic
      1. Additional information available at: Guidelines for Acute Hospital Acquired Delirium (Partners login required)
      2. Alter existing medications and treat comorbid symptoms.
      3. QTc prolonging agents <65 yo or DNR/I +LLST Comfort Measures
        1. Haloperidol, Mild agitation:0.5-1.0 mg IV or 1 to 2 mg PO q6h and 1-2 mg q2h PRN.; Moderate agitation: 2-4 mg IV; Severe agitation: 4-10 mg Maximum dose: 20 mg / 24 hours
        2. If refractory, olanzapine, 2.5 to 5 mg (PO, SL, or IV) q12 hr and 2.5 mg q4h PRN; Maximum dose: 30mg / 24 hours
      4. QTc prolonging agents ≥ 65 yo or frail
        1. Haloperidol, Mild agitation 0.25 -0.5 mg IV or 1 to 2 mg PO q6h and 1 mg q2h PRN; Moderate agitation: 1-2 mg IV; Severe agitation: 2 mg IV Maximum dose: 20 mg / 24 hours
      5. Non-QTc prolonging agents
        1. Aripiprazole (Abilify), 5 mg PO daily; maximum dose 30 mg daily
        2. Valproic Acid 125-250mg IV q8h PRN.

Nausea and Vomiting

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

Constipation

  1. If able to take oral agents, start:
    1. Senna 2 tabs PO qhs, can increase up to 2 tabs PO TID if needed
    2. Polyethylene Glycol 17gm packet PO QD-BID prn
    3. Avoid Docusate given lack of data demonstrating benefit
  2. If unable to take oral agents, suggest Bisacodyl suppository PR daily prn signs of abdominal discomfort/distention likely due to constipation.
  3. For more information, see DFCI Pink Book

Care of the imminently dying patient

  1. Signs and symptoms of imminent death
    1. Somnolence
    2. Warmth, and later cooling and mottling of extremities
    3. Change in respiratory pattern, intermittent apnea, Cheyne-Stokes pattern
    4. Gurgling sounds from oropharynx (often more distressing to family than patient)
  2. Symptom management
    1. Should follow the guidelines provided in sections above
    2. Intensive Comfort Measures Guidelines (BWH Policy 5.5.5)
  3. Communication
    1. Table 1: Common questions from families

Excessive Salivary Secretions at the End of Life

  1. For secretions with significant mucous, evaluate benefit/burden of repositioning and deep suctioning
  2. Communicate with families to expect sounds:
    1. Reassure them that although the “rattling” sound is distressing to hear, the patient is not experiencing difficulty breathing or having to clear phlegm from his or her throat. The rattling sound comes from the movement of air over secretions pooled in the throat and airways.
  3. Pharmacologic management (not to be used with secretions with significant mucous)
    1. Glycopyrrolate 0.2 – 0.4mg IV q2hrs prn secretions, rattling sound
    2. Hyoscyamine 0.125-0.25mg PO q4hrs prn secretions, rattling sound
    3. Scopolamine 1.5mg TD q72hrs if patient not awake and no apparent delirium or history of delirium. NB The patch will take ~ 12 hours to take effect
    4. Avoid using > 2 of these at the same time; if more than one is required, monitor for development of anticholinergic crisis

Communication Skills

  1. Skills for COVID-19 Scenarios
    1. Experts at VitalTalk have created a COVID-19 Communication Guide. See also: Table 2: Suggested Language for COVID-19 scenarios
  2. Important Skills for All Conversations
    1. Respond to emotion with empathy
      1. Key Skill: NURSE Statements (Back et al. CA Cancer J Clin 2005)
        1. Name, Understand, Respect, Support, Explore
        2. Nurse Skills for Responding to Emotion
    2. Assess Understanding & Delivering Information
      1. Key Skill: Table 4: ASK-TELL-ASK (Back et al. CA Cancer J Clin 2005)
      2. For COVID, it is important to make patients and families aware that patients with significant comorbid illnesses or who have poor baseline functional or health status may decompensate rapidly and have very high mortality due to COVID-19 (see “Non-ICU Management, Triage, Transfers” chapter).
    3. Discussing Goals of Care
      1. Key Skill: REMAP mnemonic (Childers et al. J Oncol Pract 2017)
        1. Reframe, Expect Emotion, Map Values, Align, Propose Plan
        2. Table 5: The REMAP Framework
    4. Managing Uncertainty
      1. Key Skill: Pairing hope and worry (Jackson et al, JPM 2013)
        1. “I hope you will improve AND I am also worried because your oxygen level is getting worse.”

Documenting Important Conversations

  1. The Advance Care Planning (ACP) Module in Epic is the single BEST place to document serious illness conversations for patients with COVID-19 and their families. Where to find and how to use the ACP Module in Epic.
  2. In conscious patients, review or sign Health Care Proxy form.

14: Ethical Considerations and Resource Allocation

Overview

  1. Further details about the BWH and Partners HealthCare model will be linked here when available.
  2. Below are general considerations and references about resource allocation in the setting of scarcity. For a comprehensive framework for resource allocation, please see the model developed Douglas White and colleagues at the University of Pittsburgh.

Triage

Crisis Standards of Care

  1. A “crisis standard of care” is a set of principles to help guide triage when there are insufficient resources (including ICU beds, ventilators, dialysis machines, etc.) to meet medical needs (Institute of Medicine 2012).
  2. It is triggered by “a substantial change in usual healthcare operations and the level of care it is possible to deliver, which is made necessary by a pervasive (e.g. pandemic influenza) or catastrophic (e.g. earthquake, hurricane) disaster” (Institute of Medicine 2012)
    1. It must be formally declared by regional/state authorities and hospital leadership.
    2. It typically involves contingencies for different stages of a crisis
  3. It allows transparency. Transparency in decision making, particularly when resources are scarce and cannot be allocated to all who are in need, is essential (Biddison et al. 2014)

Stages of crisis

image7

(Christian et al. 2014)

Triage principles

  1. The goal of triage is to maximize population benefit while treating individuals fairly.
    1. This is different from the usual goal in medicine of promoting the wellbeing of individuals.
  2. The most widely endorsed strategies are to maximize lives saved or life-years saved:
    1. Lives saved (no explicit preference given based on age)
    2. Life-years saved (some explicit preference given to younger patients all else being equal)
  3. Several other strategies have been proposed to allocate scarce resources, but have been criticized for failing to maximize benefit (NY State Task Force 2015). These include:
    1. first-come first served
    2. lottery
    3. preferential allocation (e.g. for healthcare workers)
  4. Consensus statement policies (Biddison et al. 2014) suggest no ethical difference between withholding and withdrawing care.

Structure of triage teams

  1. Consensus guidelines suggest that all decisions about triage are made by a Triage Officer, not the bedside clinicians caring for patients (Christian 2014).
  2. The Triage Officer should be a physician with critical care training.
  3. Decisions about triage should be made based on protocols established by the hospital. These protocols should be evidence based and nondiscriminatory (Gostin & Hanfling 2009)
  4. Bedside clinicians, patients, and families should have mechanisms for appealing triage decisions.
  5. An oversight committee should be established to review decisions made by Triage Officers to ensure consistent application of the triage protocol and to adjudicate appeals.

Duties of Health Care Workers

  1. Regardless of scarcity, clinicians have a duty to care for all patients—including by providing compassionate comfort-oriented to those who will benefit from it.
    1. The duty to care requires that clinicians accept a reasonable level of risk in the provision of care, founded in the principles of fidelity, respect for persons, and non-abandonment.
    2. There is a corollary obligation of organizations to ensure risk is minimized to clinicians as much as possible through, for example, the provision of personal protective equipment (Veterans Health Administration 2010).

15: Intubation

  1. This section is in process

ADDENDUM: COVID ICU Bundle Checklist

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

🗆 Spontaneous Awakening Trial (SAT)

= turn off sedation

🗆 Spontaneous Breathing Trial (SBT)

= Place patient on Pressure Support 5/5

  • Perform SAT & SBT concurrently if able
  • 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

Pressure Ulcers

🗆 Ask: Are pressure ulcers present? Is a wound care consult needed?

🗆 Discuss whether any changes are needed to ulcer management plan

DVT prophylaxis

🗆 Review patient’s current DVT prophylaxis orders and adjust if needed

  • Contraindications to LMWH DVT ppx include AKI (switch to UFH TID),

clinically significant bleeding (hold pharmacologic), platelet count < 30K (hold pharmacologic)

  • Add sequential compression boots if holding pharmacologic prophylaxis

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

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

Disposition

🗆 Discuss anticipated dispo, barriers to dispo

Code Status

🗆 Review current code status, discuss if goals of care are realistic with prognosis - if not, discuss with patient / family

Abbreviations:

SAT = Spontaneous Awakening Trial

SBT = Spontaneous Breathing Trial

CAM = Confusion Assessment Method

RASS = Richmond Agitation and Sedation Scale

[1]

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).
[2]

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.
[3]Anecdotal reports of efficacy in COVID-19; however data for management of secretions in non-CF patients are limited. Dornase is relatively costly.