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TUFTS MEDICAL CENTER COVID-19 TREATMENT AND CRITICAL CARE PROTOCOLS
MARY HOPKINS, MDANTHONY J FAUGNO, MD
AUGUST 28, 2020
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White Coats for Black LivesWhite Coats for Black LivesGeorge Floyd Breonna TaylorAhmaud ArberyElijah McClainJacob Blake
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CME credit is only available for the live version of this activity and only for participants who have a Tufts faculty appointment/staff appointment at Tufts Medical Center or are affiliated with Wellforce or NEQCA. There is no CME credit offered for viewing the archived online recording of this activity.
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OBJECTIVES
• DESCRIBE TUFTS MEDICAL CENTER TREATMENT PROTOCOLS FOR SARS-COV-2 AND COVID-19
• RECOGNIZE TUFTS MEDICAL CENTER CRITICAL CARE PROTOCOLS FOR COVID-19
• DEFINE TUFTS MEDICAL CENTER PRONING PROTOCOLS FOR COVID-19
Treatment Protocols of COVID-19 PatientsMary Hopkins, M.D.
Associate Fellowship Director for Infectious DiseasesDivision of Geographic Medicine and Infectious DiseaseTufts Medical Center
August 28th, 2020
Patient Presentation
57 yo man w/ pmhx of hypertension, hyperlipidemia, and obesity, presenting with shortness of breath, and cough
In August, one week prior to presentation the patient was at a party and in contact with 2 people who tested positive for SARS CoV-2. Over 2 days prior to presentation he had progressive shortness of breath, dry cough, fever, fatigue, mild diarrhea.
VS: T 104F, HR 115, BP 92/60, RR 28, Satting 91% on RA
Labs
• WBC 4.0, Absolute Lymphocytic count of 450• Plt 180, Hg/Hct nml• Renal function and Liver function are normal• LDH, ferritin, crp, d-dimer were all elevated• SARS CoV-2 PCR nasopharyngeal swab positive
What do you do?
• Call a friend
Supportive Care
• Supplemental oxygen, ventilation • Fluids for hypotension and dehydration• Acetaminophen for fever• DVT prophylaxis
Objectives• Anti-viral management
• Remdesivir• Convalescent Plasma
• Anti-inflammatory management • Corticosteroids• Infliximab• Sarilumab and Tocilizumab
• Other trials and considerations• Monoclonal antibody• Vaccine trials
Antiviral TherapyAntibodies – to “neutralize” the virus• Directed against the SARS CoV-2
spike protein• Convalescent plasma• Monoclonal antibodies
Antiviral medication• Remdesivir• Stops ability of virus to
multiply by interfering with RNA polymerase
https://www.nytimes.com/interactive/2020/03/11/science/how-coronavirus-hijacks-your-cells.html
Gordon CJ, et al. J Biol Chem April 13, 2020.https://www.jbc.org/cgi/doi/10.1074/jbc.RA120.013679
Remdesivir
• Effective when there is still active viral replication• Limited supply, needs ID approval• Give it to patients satting <94% on RA or requiring supplemental 02• Avoid if patients have CrCl <30• Avoid in liver failure (need to stop the medication if ALT >5X ULN)
• FDA Emergency Use Authorization • Pediatrics and the Pregnant patients - Compassionate Use Program
Remdesivir
• How to dose:
• 200 mg IV loading dose on day one, and then 100 mg IV daily after• 5 days for most patients on supplemental oxygen• 10 days for critically ill patients who are vented
• Monitor daily Creatinine and LFTs• Report adverse events
Remdesivir
• The ACTT-1 trial
• Placebo-controlled double blind randomized trial of 10 days of remdesivir for hospitalized adults with COVID-19
• 60 sites, 10 countries, just over a 1000 patients• Shortened time to recovery on Remdesivir (11 days vs. 15)• Trended towards improved 14 day mortality (8% vs. 11% p value 0.059)
• The Simple Trial • Phase three trial where patients were randomized to 5 days of Remdesivir or 10• 55 sites, 8 countries, almost 400 patients• For non vented patients, no organ failure there was no statistical difference in clinical
improvement between the 5 and 10 day treatment groups
Beigel JH et al. N Engl J Med 2020 epub May 22; Goldman JD et al. N Engl J Med 2020 epub May 27
Convalescent Plasma• 8/23/20 was given emergency use authorization status by FDA• Use in severe or life threatening COVID 19 • Use in patients judged by the treating provider to be at high risk of
progression to severe or life threatening disease• Informed consent
https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma
US experience with convalescent plasma
• Pre-print article on the Mayo convalescent plasma study• Three month description in 2807 Hospitals across the US, over 35,000
patients, more than half in ICUs
• Mortality was improved if you gave it early • If IgG titers were drawn, mortality was improved if patients received
units with higher IgG titers
http://medrxiv.org/content/10.1101/2020.08.12.20169359v1
Our Patient
57 yo man w/ pmhx of hypertension, hld, and obesity, presented at day 2 of symptoms w/ hypoxic respiratory failure.
He is on IV Remdesivir and he had received a unit of convalescent plasma. This is his 7th day of symptoms.
He is still febrile, now requiring 8 L n/c, his inflammatory markers continue to rise
Objectives• Anti-viral management
• Remdesivir• Convalescent Plasma
• Anti-inflammatory management • Corticosteroids• Infliximab• Sarilumab, Tocilizumab
• Other trials and considerations• Monoclonal antibody• Vaccine trials
Corticosteroids
• O2 saturation ≤94% on ambient air or requiring O2 supplementation without absolute or relative contraindications for corticosteroids.
• Studies show most benefit of corticosteroids in those with symptom duration of 7 days or longer and in those intubated.
• Use dexamethasone 6 mg IV or PO daily for up to 10 days or until discharge
Corticosteroids
Recovery Trial• Randomized open label trial in 175 hospitals in the UK• Total of 2104 patients were assigned to receive dexamethasone and
4321 to receive usual care. • Mortality at 28 days was 22.9% in the dexamethasone group and
25.7% in the usual care group (P<0.001)• Mortality at 28 days for those vented showed a larger difference
29.3% vs. 41.4%
The RECOVERY Collaborative Group. N Engl J Med 2020 epub July 17
Our Patient
• Patient received convalescent plasma, he going to received 10 days of IV Remdesivir, and we have started dexamethasone 6 mg IV daily
• Patient is now day 12 days into his symptoms and his hypoxia is worsening, he gets intubated
• Labs show rising LDH, ferritin, fibrinogen, CPK, CRP, and d-dimer
Hospital Course: Cytokine Release SyndromeExcessive release of cytokines in response to a trigger (here SARS CoV-2):- Activation of monocytes, macrophages,
dendritic cells- TNF, Interleukin-6 and other inflammatory
mediators- Downstream “cytokine storm” with release of
other mediators causing tissue damage- Vascular endothelial (blood vessel lining)
injury, cell permeability and leakage- Inflammatory marker elevation- Hypotension, pulmonary dysfunction
Moore JB, June CH, Science 368:473, 2020
Infliximab Trial
• TNF blocker• At Tufts through the Hematology-Oncology Division, PI Paul Matthew• Prospective, single center, phase 2 trial to assess the efficacy of
infliximab in hospitalized adult patients with severe or critical COVID-19.
• Observations from this study will inform the conduct of prospective randomized controlled studies to follow.
Sarilumab Tocilizumab• Phase 2/3 clinical trial of an IL6
receptor antagonist• Double-blind, placebo-controlled
trial to evaluate the efficacy and safety of sarilumab in hospitalized adults w/ severe or critical COVID-19.
• Trial Closed, awaiting results
• Anti IL6• Off label use• Patients or health care
proxy are informed this is off label use
Objectives• Anti-viral management
• Remdesivir• Convalescent Plasma
• Anti-inflammatory management • Corticosteroids• Sarilumab and Tocilizumab
• Other trials and considerations• Monoclonal antibody• Vaccine trials
Monoclonal Antibodies
• Combination of monoclonal antibodies targeted against the spike protein
• Inpatients may be approached for treatment
• Covid 19 positive outpatients will identify household contacts and monoclonal antibody will be given for either prophylaxis or preemptive treatment.
Vaccine Trials
• AZD1222, the Oxford University adenovirus vector vaccine• In July Lancet, reported study at 5 UK sites, over 1000 patients• 95% of patients get 4-fold increase in antibodies to the SARS-CoV-2
virus spike protein in 95% of participants one month after injection.• If it is effective, safe, goal is to have vaccine available early 2021• 300 million doses by July 2021
Folegatti PM et al. Lancet 2020;396:467-8 epub July 20
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ANTHONY J FAUGNO, MDPULMONARY & CRITICAL CARE MEDICINE
CARDIOVASCULAR CRITICAL CARE
ASSISTANT PROFESSOR AT TUFTS UNIVERSITY SCHOOL OF MEDICINE
TUFTS MEDICAL CENTER, BOSTON, MA
08/09/2020
UPDATES IN COVID-19 CRITICAL CARE
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IS COVID-19 RELATED ARDS DIFFERENT THAN TYPICAL ARDS?
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TRADITIONAL ARDS
Thompson N Engl J Med. 2017;377(6):562-572J Clin Pathol. 2009 May; 62(5): 387–401.
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TRADITIONAL ARDS
Thompson N Engl J Med. 2017;377(6):562-572J Clin Pathol. 2009 May; 62(5): 387–401.
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BERLIN DEFINITION
Ranieri, V. M. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012
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EMERGING PATHOBIOLOGY OF COVID-19 LUNG INJURY
• COMPARISON OF COVID-19 AND H1N1 RESPIRATORY FAILURE WITH NORMAL LUNGS— Diffuse Alveolar Damage— COVID-19 lungs have more
endothelial injury, 9 times more microthrombi
— COVID-19 lungs have more 2.7 times more neovascularization
Ackermann . N Engl J Med. 2020;383(2):120-128
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SILENT HYPOXIA
• THE RESPIRATORY CENTER IS PRIMARILY SENSITIVE TO CO2— Small changes (+ 10 mmHg) general a high degree of
patient discomfort• OXYGEN TENSIONS GENERATE LESS
RESPIRATORY DRIVE— Stable over 90 to 60 mm Hg O2, below 60 the
increase in drive is exponential• This is blunted by
— Hypocapnea (<39 mm Hg)— Age— Diabetes — 50% of patients don’t experience dyspnea below
this threshold— Wide individual variation
Tobin MJ Am J Respir Crit Care Med. 2020;202(3):356-360
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WHEN TO INTUBATE
• MANY EARLY PROTOCOLS CALLED FOR EARLY INTUBATION TO CONTROL AEROSOLS— Treated eventual intubation as high likelihood
• RISK IS ENHANCED AEROSOL PRODUCTION DURING INTUBATION— Biggest risk factor for HCP infection in SARS was being in the room during intubation
• IN TRADITIONAL ARDS, CHALLENGING DECISION, LIKELY NO “SAFE” POSITIVE PRESSURE
• IMPORTANT TO TAKE INTO ACCOUNT PATIENT WORK OF BREATHING— Should you intubate silent hypoxia?
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CURRENT THEORY: PATIENT SELF INFLICTED LUNG INJURY
• INJURED LUNGS HAVE HETEROGENOUS VENTILATION— High regional strain propagates lung
injury— Already injured lungs may be prone to
more inflammation— Animal models show that high
respiratory drive without underlying injury can induce ARDS pathology when drive is sustained
Retamal J Critical Care Medicine. 2018;46(6):e591-e599Brochard L Am J Respir Crit Care Med. 2017;195(4):438-442
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John J. Marini & Luciano Gattinoni . JAMA Published online April 24, 2020
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HIGH FLOW NASAL CANNULA IN ARDS
• COMPARISON HFNC V NIV V NRB— Acute Hypoxemic Respiratory Failure
• RR >25 • PaO2/FiO2 <300 mmHg on 10 L NRB
— Excluded• Hypercapnea• Heart Failure• Hemodynamic Instability
• BILATERAL PNEUMONIA 79%• PAO2/FIO2 RATIO <200 77%• REDUCED MORTALITY AND INTUBATION
RATE IN HFNC
Frat J-P N Engl J Med. 2015;372(23):2185-2196. doi:10.1056/NEJMoa1503326
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HIGH FLOW NASAL CANNULA IN COVID-19 RESPIRATORY FAILURE
• RETROSPECTIVE STUDY OF 379 CRITICALLY ILL PATIENTS FEB 21 TO APRIL 24 IN FRENCH ICUS— Propensity Score matched analysis based on immunosuppression, ICU admission within 7
days of onset, vasopressors and AKI— 379 patients (39% HFNC n=146)
• Similar PaO2/FiO2 ratios (126 vs 130)• Less AKI and Pressors in HFNC group
— No Mortality Difference After Matching (21% vs 22% HR 1.35 95% CI [0.56-3.26])— Not a great study
• Doesn’t report rate of DNI patients • Doesn’t combine the outcome of death and intubation, less intubations because the died?
Demoule A Am J Respir Crit Care Med. Published online August 6, 2020:rccm.202005-2007LE.
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NON INVASIVE VENTILATION IN ARDS
Bellani G Am J Respir Crit Care Med. 2017;195(1):67-77.
PaO2/FiO2 <300 PaO2/FiO2 <150 PaO2/FiO2 >150
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NON INVASIVE VENTILATION IN COVID
• RETROSPECTIVE STUDY OF ITALIAN RESPIRATORY UNIT FROM MAR 1ST-MAY 10TH
— First line therapy CPAP with helmet interface— Compared HFNC v CPAP v NIV (BiPAP)— 607 patients
• 42 STAFF MEMBERS (12%) DEVELOPED COVID DURING CARE OF PATIENTS— How do you know this isn’t community spread
• NO DIFFERENCE IN HFNC, CPAP AND NIV MORTALITY AT 30 DAYS— HFNC probably applied in less sick patients
• DID NOT STANDARDIZE INCLUSION CRITERIA— Only ~26.6% of patients went on to require intubation— 30 day mortality 26.9%
Bellani G Am J Respir Crit Care Med. 2017;195(1):67-77.
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TMC GUIDELINES
• RECOMMEND AGAINST UNIFORM EARLY INTUBATION— Do recommend vigilance, communication and early planning as it takes a while to set up
intubation team with PPE
• RECOMMEND FOR A TIME LIMITED TRIAL OF HFNC— Frequently Reassess for patient stability need for intubation
• RECOMMEND AGAINST NIV UNLESS: CHF, COPD OR DNI
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ARDSnet Strategy
Respiratory Therapy Ideal PEEP Protocol
Ventilator Dyssynchrony?
Excessive Patient Effort?
P/F Ratio Remains < 150
Or
Plateau Pressure >30, Driving Pressure >16
Optimize sedation to assure synchrony
Failing that initiate Paralytics
Prone Mechanical Ventilation
P/F Ratio <80
Or
Plateau Pressure >30, Driving Pressure >16
Consult to ECMO team for Multidisciplinary Evaluation
BEST AVAILABLE THERAPY: MOST PROTECTIVE VENTILATION
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ARDSNET MECHANICAL VENTILATION
• MINIMIZE TRANSPULMONARY PRESSURE USING PLATEAU PRESSURE AS SURROGATE— Trans pulmonary pressure is the
pressure delivered to the lung independently from the effects of the chest wall and the abdomen and is computed as the difference between airway pressure and pleural pressure.
— Plateau pressure addresses global lung strain
— Start at 6-8 cc/kg Ideal Body Weight, and down titrate to get plateau pressures <30 cm H20
The Acute Respiratory Distress Syndrome Network. New England Journal of Medicine. 2000;342(18):1301-1308.
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IS COVID RESPIRATORY FAILURE PATHOPHYSIOLOGY DIFFERENT?
• TRADITIONAL ARDS IS ASSOCIATED WITH STIFFER LUNGS (LOWER COMPLIANCE)— Compliance = Change in Volume/Change in Pressure
• Associated with higher lung weights (more edema)• There is potential to recruit this lung by applying increasing pressures, and improve ventilation of
inflamed alveoli
• COVID RESPIRATORY FAILURE PHYSIOLOGIC PHENOTYPES BASED ON ELASTANCE— Elastance = 1/Compliance
• Type L (Low Elastance) has normal Compliance; hypothesized to be related to impact on regulation of pulmonary perfusion
— Recruitment not as effective because less alveolar disease• Type H (High Elastance) lower compliance and more traditional ARDS
Gattinoni L Intensive Care Med. Published online April 14, 2020:1-4.
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Gattinoni L Intensive Care Med. Published online April 14, 2020:1-4.
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Bos LD Annals ATS. Published online May 12, 2020:AnnalsATS.202004-376RL.
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NON COVIDARDS
LUNG SAFE Investigators and the ESICM Trials Group. Am J Respir Crit Care Med. Published online August 17, 2020:rccm.202005-2046OC.
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SELECTING OPTIMAL PEEP
• THIS TOPIC IS GENERALLY DEBATED— How should we set PEEP
• Physiology vs Pre Defined Table?— Should we Favor Higher or Lower PEEP?
• Meta analysis favors higher PEEP with mortality benefit, but obviously no COVID
• THE DEBATE IS WORSE NOW— What is the PEEP for the L Phenotype? — What is the PEEP for the H Phenotype?
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COVID-19 Hypoxic Resp Failure
Low Elasticity Low Recruitability
Low V/Q ratio Limited “PEEP” response *
High Elasticity High Recruitability High R L shunt
High “PEEP” response
L Phenotype H Phenotype
Pulmonary Perfusion Dysregulation and possibly pulmonary micro-thrombotic process
Non-cardiogenic pulmonary edema due to capillary leak
John J. Marini & Luciano Gattinoni . JAMA Published online April 24, 2020
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PARALYTICS FOR VENTILATOR SYNCHRONY
• ARDS PF RATIO < 150, 1006 PATIENTS ASSIGNED TO TWO GROUPS • INTERVENTION GROUP: 48 HOURS OF CISATRACURIUM INFUSION • MORTALITY 42% IN EACH GROUP
• RECOMMENDATION: ONLY USE IT IF NEEDED FOR DYSCHRONY DESPITE SEDATION AND DO NOT USE IT ROUTINELY
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WHY PRONE POSITION?
Scholten EL Chest. 2017;151(1):215-224
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WHY PRONE POSITION?
Scholten EL Chest. 2017;151(1):215-224
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PRONE MECHANICAL VENTILATION
• PROSEVA STUDY ENROLLED PATIENTS WITH PAO2/FIO2 RATIO <150— Proned for 16 hrs daily— Unprone when P/F >150 4 hrs after
supination— Resume Proning When P/F below 150
again
• REDUCED MORTALITY AND TIME ON VENTILATOR
• PATIENTS EXPERIENCE SKIN BREAKDOWN, <2% RISK OF CATHETER OR ETT DISLODGEMENT
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PRONING WHILE AWAKE? TMC DOCUMENT
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JAMA, April 7, 2004—Vol 291, No. 13
INHALED PULMONARY VASODILATORS
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TMC GUIDELINES
• RECOMMEND STRICT ADHERENCE TO LUNG PROTECTIVE VENTILATION
• RECOMMEND UTILIZING PRONE VENTILATION AS SUPPORTED BY PROSEVA— Debate should we prone earlier? Should we prone longer?— Alternative is that it’s very resource intensive, lots of people/PPE.
• RECOMMEND INHALED VASODILATORS ONLY AFTER TRIALING PRONE VENTILATION— Weak recommendation for Nitric over Epoprostenol— Viricidal? Less aerosol with nitric, less respiratory therapy exposure?
• NO RECOMMENDATION MADE ON AWAKE PRONING OF NON INTUBATED PATIENTS
• WE ARE OFFERING ECMO TO COVID PATIENTS ON A CASE BY CASE BASIS— Depends on surge capacity, perceived benefit to the patient and number of available circuits
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ANTICOAGULATION?
• VARIABLE INCIDENCE REPORTED IN LITERATURE— None of this is done systematically
• KLOK ET AL — PE INCIDENCE OF 35% (65/184) 71% WERE SEGMENTAL OR MORE PROXIMAL — Thrombosis Research 191 (2020) 148–150”
• HELMS ET AL — PE INCIDENCE OF 16.7% (25/150) 88% SEGMENTAL OR MORE PROXIMAL — Intensive Care Med (2020) 46:1089–1098”
• AL-SAMKARI ET AL — VTE INCIDENCE OF 7.6% IN 144 CRITICALLY ILL PATIENTS BUT ALSO MAJOR BLEEDING
INCIDENCE OF 5.6%
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MOUNT SINAI RETROSPECTIVE DATA
Nadkarni ET AL, JACC e-pub 8/20/20
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• PROPHYLAXIS IS MUST AND AGREED ON UNLESS CONTRAINDICATION• SUSPECT PE IN NON-EXPLAINED HYPOXEMIA OR OUT OF PROPORATION
HYPOXEMIA OR DEAD SPACE, RV DYSFUNTION, OR TROPONIN ELEVATION • SUSPECT DVT WITH ASYMMETRIC SWELLING • D-DIMER GUIDANCE OF ANTICOAGULATION IS CONTROVERSIAL• THERE ARE REPORTS OF BLEEDING RISK IN COVID-19 PATEINTS TOO
ANTICOAGULATION?
No Medical Grand Rounds next week 9/4/20. Join us on 9/11/20 for The Covid-19 magic 8 ball: Where do we go from here? with TUSM and TGSBS alum Eric Rubin, MD, PhD Editor-in-Chief at the New England Journal of Medicine
