Characteristics,Comorbidities, and Outcomes of Hospitalized COVID 19 PatientsDavid Steiger MD,

Chief Pulmonary/Critical Care

Mount Sinai Beth Israel

Mount Sinai West

May 1, 2020

COVID-19 . Needs of Patients

Outcomes

Anticoagulation

Steroids

Post acute settingPost ICU SyndromePost ICU ClinicLTAC

Outcomes from COVID-19 Respiratory Failure

Mortality Rate patients admitted to ICU, determined by presence of severe ARDS

Range of mortality rate 16% to 78%

Risk factors for death:Increased ageSevere ARDS and need for mechanical ventilationComorbidities – HTN, DM, chronic cardiopulmonary disease, CKD

Markers of inflammation:Ddimer > 1 mcg/ml, elevated PTLymphopenia

United StatesArentz et al JAMA. (Published online March 19, 2020. doi:10.1001/jama.2020.4326)21 critically ill- Washington StateMortality 67%Large number older residents from SNF

1591 consecutive patients admitted to ICU – Lombardy58% still in ICU - thus true mortality rate may be underestimated16% discharged from ICU26% died

Yang X. Lancet Resp Med 2000

52 patients admitted to ICUMortality rate 62%

67% ARDS29% kidney injury23% cardiac injury29% liver dysfunction

Prothrombotic State in COVID-19

Haemostatic changes in COVID-19, secondary toCOVID-19 “cytokine storm” observed in other viral illnessesliver dysfunctionantiphospholipid antibodies

Lab abnormalitiesMild thrombocytopenia, Elevated D dimer and Prothrombin time– associated with increased risk mechanical ventilation, and death(Lippi Throm Haemost – in press 2020, Tang J Thromb Haemost 2020)

Investigational agents:Bevacizumab – binds VEGF, increased risk MI, CVA, VTEHydroxychloroquine – anti thrombotic properties versus antiphospholipid antibodies

Risk of VTE secondary to:Critical illness, Immobility, paralysisSystemic inflammation, Central lines

Public health Considerations Relating to Management Thrombotic DiseaseCOVID-19

Home quarantine – predisposing to relative immobility, increased risk VTE

particularly elderly, higher risk patients

Decreased access to food/change in diet – effect VKA metabolism

Socioeconomic consequences of loss of income/health insurance, Inability to cover costs of medication

COVID-19 and Thrombotic or Thromboembolic Disease:Implications for prevention and Antithrombotic Therapy and Follow-up

JACC 15 April, In press

VTE ProphylaxisEstablished practice: Acute medically ill – LMWH NEJM 1999, 341:793Older, acute medical patient - fonadaparinux BMJ 2006,332:325

CHEST 2012 141;195S Grade 1 B

LMWH > UFH – pharmacokinetic advantages, less use PPE

Post Discharge VTE ProphylaxisNo data specific to COVID-19 patientsLMWH, DOAC’sRisk stratify thrombotic and bleeding risk

Duration: ≤ 45 days in highest risk (poor mobility, cancer, Ddimer > x 2 normal))

COVID-19 and Thrombotic or Thromboembolic Disease:Implications for prevention and Antithrombotic Therapy and Follow-up

JACC 15 April, In press

Empiric Therapeutic AnticoagulationOptimal dose unknown - empirical full dose/intermediate dose

Prevention microvascular thrombosis

Tang J Thromb Haemost 2020;18:1094

Anticoagulation (LMWH) Vs no anticoagulationAssociated with lower 28 day mortality:

SIC ≥ 4, Ddimer > x 6 normal

Single center, retrospective, many confounders

Incident VTEPrevalence unknownStudies reporting incident VTE, under reporting/underutilization prophylaxis

184 patients, severe COVID-19, 31% incident VTE, significant underdosing prophylaxisKlok Thrombosis Research 2020

All admitted patients should be assessed for VTE risk factors and signs or symptoms of DVT and PE.

Patients without evidence of severe respiratory compromise should receive aggressive VTE prophylaxis:

BMI <40CrCl >30: Enoxaparin 30 mg SQ Q12HCrCl ≤30: Enoxaparin 30 mg SQ daily; Alternative - heparin 5,000 units SQ Q8hrs

BMI ≥40CrCl >30: Enoxaparin 40 mg SQ Q12HCrCl ≤30: Enoxaparin 40 mg SQ daily; Alternative - heparin 7,500 units SQ Q8hrs

Mount Sinai health System Recommendation Anticoagulation COVID-19

Medicine Wards, severe respiratory compromise or worsening respiratory status, low bleeding risk:

Intermediate-dose anticoagulation: Enoxaparin 1mg/kg SC q 24hrAssessment of severity:Increased oxygen requirement (e.g., ≥6L O2 NC), and Elevated biomarkers (e.g., D-dimers >1.5 or increasing).

CKDCrCl <30 and not on Renal Replacement Therapy (RRT: HD, PD, CVVH) – No dose change recommended.

RRT – Avoid treatment dose enoxaparin. Apixaban 2.5mg PO BID.

Empiric Full dose AnticoagulationHigh clinical suspicion, unable to perform diagnostic studies

Mount Sinai health System Recommendation Anticoagulation COVID-19

ICU, low bleeding risk:Empiric treatment dose : Enoxaparin 1mg/kg SC q 12hr.CKD with CrCl <30 - IV heparin

Confirmed VTE, based on positive diagnostic test Treatment dose anticoagulation

Apixaban or rivaroxaban avoids need to transition from UFH/LMWH to oral agent.Apixaban dose: 10mg PO BID for 7 days then 5mg PO BID.Rivaroxaban dose: 15mg PO BID for 21 days then 20mg daily.

CrCl <30, including RRT: No adjustment to apixban is needed. Avoid rivaroxaban if CrCl <30. IV heparin and warfarin alternative to DOAC

Duration – Minimum of 3 months. Total duration should be determined based on an individualized assessment of the patient’s risk of recurrent VTE and bleeding.

Post-discharge ProphylaxisDOAC – apixaban 5 mg po q 12h, rivaroxaban 10 mg po qd – duration?

Mount Sinai health System Recommendation Anticoagulation COVID-19

Interplay between Inflammation and CoagulationPublished OnlineLancet Resp Med April 27, 2020

Overproduction early response pro inflammatory cytokines TNF alpha, IL6, IL Beta

Immune response activates coagulation pathways – increasing cytokine production

Thrombinconverts fibrinogen to fibrin, activates plateletsaugments inflammation via PARs receptor (proteinase activated receptor)

Anticoagulants control thrombin activityanti-thrombin 111, tissue factor pathway inhibitor, activated protein Cimpaired activity in inflammation – consumption, decreased production

Impaired coagulant/anticoagulant balance:microthrombosis, DIC, MSOF

Coagulation-Inflammation Cross-TalkThorax 2014;69:190-192

European Heart Journal 2019 00,1-61ESC Guidelines

Potential Role for Steroids in COVID-19 Pneumonia/ARDS

Steroids in non-COVID-19 ARDS

Steroids for ARDS secondary to viral infectionSARS, MERS, influenza pneumoniaCOVID-19

Acute Respiratory Distress Syndrome

Acute, inflammatory, diffuse lung injury, associated with a variety etiologies10% ICU admissions23% mechanically ventilated patients in an ICUMortality > 40% in severe ARDS

Pathology:DAD – diffuse alveolar damageAtelectasis, alveolar hemorrhage and edemaLater – hyaline membrane formationType 2 cell hyperplasiaInterstitial edema

40 candidate genes associated with development of ARDSACE2 receptor protein for SARS, COVID-19

ARDS

Standard of careLung protective strategy 4-8 ml/Kg predicted body weight, Plateau pressure < 30 cm H20 N Engl J Med 2000; 342: 1301–08.

Prior trialsNO, NSAID, ketoconazole, heparin, activated protein C

Steroids have been evaluated for ARDS since 1980’sNo evidence supporting their benefit to until 2020, based on RCT

Society of CCMConditional recommendation use of steroids ARDS – 9 RCT Crit Care Med 2017; 45: 2078–88.

Clinical characteristics and outcomes of 201 consecutive patients who had COVID-19 pneumoniaand ARDS, or died

Retrospective study

Treatment:Antibiotics 97%Antiviral 84% tamiflu, gangcyclovir, lopincivir/ritonavirAntioxidants 52% NAC, glutathioneMethylprednisolone 30.8%

71% discharged

N Engl J Med 2006;354:1671-84 180 patients with ARDS > 7 days – RCTmethyprednisolone 2mg/Kg x1, then 0.5 mg/Kg q 6h x 7 days, then0.5 mg/kg q 12h x 7 days, then taper over 4 days

Results: 60 day MR 28.6% placebo, 29.2% treatment groupHigher mortality in treatment group if patient enrolled > 14 days ARDSMethyprednisolone increased vent free days, decreased use pressors, improved oxygenation –first 28 daysNo increase infectious complications

Role for steroids in early ARDS?Previous studies did not implement lung protective strategy

Dexamethasone5 x more potent than prednisone, minimal mineralocorticoid propertiesNot previously evaluated in ARDS studies

Lancet Resp Medicine 2020,8:267-276

Lancet Respiratory Medicine March 2020, 8: 267

Method:17 sites, Spain, new onset ARDS, moderate to severe ARDS within 1 week of insultPaO2: FiO2 ≤ 200 mmHg, PEEP ≥ 5

Treatment arm (unblinded)Dexamethasone 20 mg IV qd x 5 days, then 10 mg IV qd x 5 days Lung protective strategy both arms of study

Primary OutcomeVentilator free days – if survived > 28 days, and remained extubated > 48 hours, 60 day mortality

Lancet Resp Medicine 2020,8:267-276

Lancet Resp Medicine 2020,8:267-276

Lancet Respiratory Medicine 2020. Published online Feb 17 2020

Pathology resembles lung damage secondary to MERS, SARS

Potential Role for Steroids for 2019-nCOV Lung Injury

WHO advised against use of steroids for 2019-nCOV “unless indicated for another reason” Jan 20 2020

Steroids suppress inflammation, but inhibit immune responses and pathogen clearance

MERS – use of steroids associated with increase use pressors, MV, RRTNo change 90 day mortalityEffect of confounding variables?

SARS – use of steroids associated with increase viraemia Vs patients given IV N SalineJ Clin Virology 2004, 31;304

Influenza – meta-analysis 10 observational studies:Steroids associated with increased mortality, increased LOS, increase fungal and bacterial infection

Most studies describing use of steroids in MERS/SARS/viral pneumonia – observationalSelection bias and confounders may have contributed to adverse outcomes

Systematic review and meta-analysis of use of steroids in severe CAP:Systemic steroids associated with:Reduction mortality 3%Reduction need for MV 5%Reduction LOS 1 day

Ann Int. Med 2015, Oct 6; 163, 7:519-528

Chinese Thoracic Society Consensus StatementZhonghua Jie He He Hu Xi Za Zhi 2020; 43: E007.

Weigh potential benefits and harm of use of steroids

Use steroids prudently on COVID-19 pneumonia

Dosage should be low to moderate≤ 0.5 -1 mg/Kg methylprednisoolne qd

Duration of steroids < 7 days

Prior meta analyses demonstrated improvement mortality in subgroup of patients with severe CAP treated with steroidsSevere pneumonia associated with increased levels IL 6, IL 8, IL 10

Method:Multicenter RCT, severe CAP, CRP > 150 mg/lIV 0.5 mg/kg per 12 hours Vs placebo for 5 days

Results:Decreased treatment failure* in steroid group 13% Vs 31%*Development shockNeed for MV, mortality within 72 hLate treatment failure – radiographic progression, mortality

Use of concomitant corticosteroids is a contraindication to the use of tocilizumabdue to the risk of lower gastrointestinal perforation.

CRITERIA:1. COVID-19 confirmed2. Less than 7 days since onset of ARDS, as defined by the Berlin criteria 2012 with an imputedPaO2/FiO2 (using a SpO2/FiO2) or measured PaO2/FiO2 of <300, bilateral infiltrates, without aprimary cardiac pulmonary edema3. Increased oxygen requirements, with one of the following:a. Invasive mechanical ventilation with PEEP > 5b. High-flow nasal cannula to maintain O2 sat > 92%c. BIPAP with FiO2 100% to maintain O2 sat > 92%d. Non-rebreather at 15L/min4. Suggestion of systemic inflammation, with one or more of the following:a. CRP > 150 mg/Lb. D-dimer > 2.5

MSHS Corticosteroid Recommendations COVID-19

DOSING:1. Methylprednisolone 1mg/kg/daily, divided up into Q12h dosing for 5 days.2. Taper over the next 5 days:a. Methylprednisolone 0.5mg/kg/daily, divided into Q12h dosing x 3 daysb. Methylprednisolone 0.5mg/kg/daily x 2 days3. Optional: switch to oral dosing during taper

OTHER CONDITIONS:1. Septic shock – rising norepinephrine requirements or 2+ vasopressors: Hydrocortisone 50mg Q6h +/- fludrocortisone 0.1 mg/day2. Steroid-responsive obstructive lung disease:

MSHS Corticosteroid Recommendations COVID-19

Lung pathology

ARDS - DAD patternZhe Xu Lancet Resp Med 2000

AFOP – Acute Fibrinous and Organizing Pneumonia

Correlation with hypothesized “H type” lung physiology Gattioni

Treatment Implications

Outcomes Post ARDS

Survivors of ARDS

1. Outcomes 3, 6, 12 months (N Engl J Med 2003;348:683)Reduced diffusing capacityReduced 6 MWT

2. Outcomes 5 years (N Engl J Med 2011;364: 1293)Reduced 6 MWTNear normal PFT’sPersistent physical and psychological impairment in patients and care givers

3. ARDS (SARS) (Eur Respir J 2004;24:436)PFT abnormalities in 50%Mostly mildDecreased aerobic capacity

Retrospective, observational study214 consecutive patients hospitalized with COVID-19 pneumonia41% severe infection

36 % “neurological manifestations”CVA 5.7%Impaired consciousness 14%

Manji. J Neurol Neurosurg Psychiatry 2020

MeningoencephalitisMyelitisGuillan Barre

PICS – Post Intensive Care Syndrome

Long term complications in patients surviving critical illness

Impact of Post Intensive Care Syndrome

I33% survivors do not return to work

33% do not return to pre-ICU job/salary

Financial constraints Decreased ability to pay for medication, Travel to OPPay for home PT

High risk for readmission to hospital / ICU

25% require assistance ADL’s

50% families required to make major adjustmentsmove to less expensive home, less money for health care, education

Psychological problems for family members

Post Intensive Care Syndrome - Prevention

Prevention

ABCDEF bundle (CCM 2018,46:e825)evidence based guide to decrease cognitive impairment, delirium and physical decline in ICU

Emphasis on prevention and treatment of delirium determinant of mortality/cognitive impairment

Daily awakening trials, - shorten duration MV

Non-benzodiazepine sedation

Early mobilization – decreases delirium

Post ICU Management

Post ICU Clinics:Multidisciplinary approach, first started 1985 U.K.

Evaluation health impairment (6 MWT, PFT’s)

Symptom management

Medicine reconciliation

Implementation physical, cognitive, psychological rehabilitation

How to predict which patients will benefit from post ICU clinic?

Improvement in health related quality of life Versus standard of care

Post ICU rehabilitationPhysical rehab 6-12 weeks – in-house/telehealth guidedCognitive rehabPsychological rehab – telehealth – efficient, practical

ERS 2019 June, Vol 15, No 2

COVID 19 Center of Excellence:

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Multidisciplinary TeamA collaborative team based approach to multidisciplinary care including primary care, specialty care, lab diagnostics

and imaging

Longitudinal Care Patients will be followed over time to treat and evaluate

the short and long term impact of Covid -19

Clinical Research , Epidemiology, Biomedical

Research and Health PolicyUnique opportunity to provide comprehensive clinical care

alongside research and clinical trials to define new standards of care

The Mount Sinai Health System’s COVID 19 Center of Excellence will be a destination for post-COVID patients; providing multidisciplinary and collaborative care,

psychosocial resources, research and clinical trials.

COVID 19 Center of Excellence

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Providing comprehensive care and a personalized treatment plan ______________________________

Medical Specialties & Support Services

• Primary Care• Pulmonary Medicine• Cardiology• Infectious Diseases• Nephrology• Physiatry• Physical & Occupational Therapy• Radiology• Neuropsychiatry• Behavioral Health• Social Work• Pharmacy

Personalized Treatment Plan

• Individualized care utilizing state-of-the-art diagnostic tools and innovative treatment protocols

Patient Flyer

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� Patient Flyer

• Provides an overview of next steps

for patients discharged to home

• Flyers are available in English

Operational Infrastructure Guidelines in an Ambulatory Setting

Aims:To reduce the likelihood of the spread of infection To ensure the provision of safe care

Guidelines & RecommendationsScheduling Template

staggered scheduled

Tier 3:High acuity treatment or service, lack of in-person treatment or service would result in patient harm.

Tier 2: Intermediate acuity treatment or service, not providing the service has the potential for increasing morbidity or mortality.

medical complications, patient harm, or near-term reduction in quality of life.

Tier 1:Low acuity: Telehealth visits

Hour of OperationExpanded hour of operationsBlock time for elderly or pediatrics

StaffConsiderations for work to be done remotely (non-patient facing tasks)Stagger staff schedules on site to promote social distancing on public transportation and in the office during various times of the dayDaily employee symptom monitoring

Visitor PolicyNo visitors except if assistance is needed

Patient Outreach/ EducationProactively reach out to patients to educate on telehealth, MyChartIdentify high-risk/chronically ill patients who require follow up

 

Operational Infrastructure Guidelines in an Ambulatory Setting

COVID-19 Registry

Multispecialty clinicProvide follow up, evaluate long term complicationsSupport biomedical research – bench, translational, epidemiological

Establish registry of patients discharged from urgent care, ER, hospital

Sociodemographic dataPMHDetails of hospitalization/severity of illness/labs

Pulmonary symptomsMRC dyspnea score, St George Questionnaire, 6 MWT, Cognition, depression, PTSDFunctional statusLabs, inflammatory markers

CXR. Chest CTClinical trials

Aim:Liberation from mechanical ventilation in a clinical environment that supports ongoing medical, rehabilitative, nutritional and cognitive needs. ADMISSION CRITERIA: POSITIVE COVID testing (PCR or antibody) good potential for liberation from MV RESPIRATORY:Tracheostomy in place for a minimum of 24HFIO2 < 0.6, PEEP < 8 cmH2O, PaO2>60, SaO2 >88%Relative Stability of ventilatory needs x 48hNo significant increase in SOFA score x 48hNo need for paralytics (intermittent or continuous) x 48hChest Thoracotomy Tube CARDIOVASCULAR:No Vasopressor requirement

Long Term Acute Care Hospital - COVID-19

RENAL:Intermittent hemodialysis

INFECTIOUS DISEASE:Candida auris SEDATION:Intermittent IV sedation medication administration PAIN CONTROL:Continuous infusions (fentanyl, Morphine etc.)Intermittent enteral and parental therapy NUTRITION:Percutaneous Enteral Gastrostomy (Jejunostomy or Gastro-jejunostomy) tube in place X 24H

Long Term Acute Care Hospital - COVID-19