June 9, 2020

COVID Consortium Meeting #15

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COVID Consortium Agenda: 6/9/20

Sneak Peek for Next Week:Trach and PEG UpdatesECMO UpdatePPE SurveyMonkey Results & Respiratory Support Guidance DocumentCardiopulmonary Re-emergence Update

Agenda Item PresenterI. Reflection: Words of Mandala Guy Dugan

I. In Memoriam: Dr. James McCrearyA Story of Hope

Karen HawkRaj Desai

I. Announcements / Updates- CME: https://www.surveymonkey.com/r/COVIDCONSORTIUM- Slides & Recording

Guy Dugan

I. Graphs and Analysis: From COVID to Chaos – A Mathematical Journey Guy Dugan

I. Pregnancy and COVID Christine Kovac

I. Playbook Updates- Pulmonary Function Testing

Nawaid Shakir

I. Lancet and NEJM: Ethical Concerns for Cowboys and Academics Guy Dugan

I. Critical Drug Task Force Update Sun Lee

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Reflection

• Words of MandalaPresented by Guy Dugan

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In Memoriam: Dr. James McCreary

January 30,2020

Hi Raj, Christine, Carla, and Hans,

I am emailing to ask if anyone has had a request to extend a fellowship by 1-2 months.

Tragically, my fellow, Lauren Ventola's 20 month old choked and sustained a massive aspiration injury requiring ECMO support and is hospitalized. He seems to be improving, but am anticipating at least a month or two of her needing to be off for his recovery.

I am working with my institution to extend her contract by about 6 months to build in some time before leaving for her next job. I think she will only need to make up the time she will be off for mainly case numbers, she is progressing nicely.

Is this something that the AIPPD needs to approve? Do I need to contact the AABIP board credentialing for any reason?

Any help is appreciated.

May 20, 2020

Christopher

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COVID-19 Graph

COVID AND CHAOSDid a sneeze in Wuhan start a pandemic?

Guy Dugan

Chaos Theory

• Chaos Theory-small changes in the initial conditions result in large and unpredictable outcomes

• Butterfly effect- butterfly flapping its wings in China causes a hurricane in America

• Logistic equation

2 Basic Assumptions

• Future growth is proportional to initial conditions

𝑁𝑁𝑑𝑑+1 ∝ 𝑁𝑁𝑑𝑑

𝑑𝑑𝑁𝑁 𝑡𝑡𝑑𝑑𝑡𝑡 = 𝑟𝑟𝑁𝑁(𝑡𝑡)

∫dN(t)N(𝑡𝑡) = ∫ rdt

𝑁𝑁 𝑡𝑡 = 𝐶𝐶𝑒𝑒𝑟𝑟𝑟𝑟

2 Basic Assumptions

• 2. Growth can’t continue forever. There are limitations- food supply, space, people to infect, etc.

(1 −𝑁𝑁 𝑡𝑡𝑘𝑘 )

𝑑𝑑𝑑𝑑 𝑟𝑟𝑑𝑑𝑟𝑟

= 𝑟𝑟𝑁𝑁 𝑡𝑡 (1 − 𝑑𝑑 𝑟𝑟𝑘𝑘

)

Logistic Curve to Inverted Parabola

• Express 𝑑𝑑𝑑𝑑 𝑟𝑟𝑑𝑑𝑟𝑟

= 𝑟𝑟𝑁𝑁 𝑡𝑡 (1 − 𝑑𝑑 𝑟𝑟𝑘𝑘

) in functional notation

𝑓𝑓 𝑥𝑥 = 𝑟𝑟𝑥𝑥 1 − 𝑥𝑥Complete the square

𝑓𝑓 𝑥𝑥 = −𝑟𝑟 𝑥𝑥 − 𝑥𝑥 +12

2

+ 𝑟𝑟/4

𝑓𝑓 𝑥𝑥 = −𝑟𝑟(𝑥𝑥 − 1/2)2 + 𝑟𝑟/4

Inverted parabola (−𝑥𝑥) with vertex at (12

, 𝑟𝑟4)

Exponential to Parabola

𝑑𝑑𝑁𝑁 𝑡𝑡𝑑𝑑𝑡𝑡

= 𝑟𝑟𝑁𝑁 𝑡𝑡 (1 −𝑁𝑁 𝑡𝑡𝑘𝑘

) 𝑓𝑓 𝑥𝑥 = −𝑟𝑟(𝑥𝑥 − 1/2)2 + 𝑟𝑟/4

Mandelbrot Set

𝑍𝑍𝑛𝑛+1=𝑍𝑍𝑛𝑛2 + 𝐶𝐶

C=1C=-1

1 = 0 + 1,2 = 12 + 1,5 = 22 + 1,26 = 52 + 1

−1 = 0 + −1−1 = 02 + −10 = −12 + −1−1 = 02 + (−1)

VIDEO

Biological and Physical Applications

Retinal cone response to light flashing

Pukinje fibers contributing to arhythmias

Faucets period doubling, and then chotic behavior-constant pressure and fixed aperture

Any “single hump” function- Universality

Ratio of each bifurcatoin interval to the next between doubling periods is called Feigenbaum’sconstant~4.669

Same constant for any “single hump” function

Summary of Pandemic Graph

• Pandemics• Populaiton growth• Mandelbrot Set• Chemical reactions• Change in gene frequency with time• Change in commodity pricing• Interest rates• Radioactive decay• Theories of learning• Heat transfer• Spread of rumors• Dripping faucets

What you have in the future is related to what you have now.

You can’t have everything

References

• https://github.com/jonnyhyman

• https://github.com/jonnyhyman/Chaos/blob/master/logistic_interactive.py

• https://www.stsci.edu/~lbradley/seminar/index.html

• https://www.projectrhea.org/rhea/index.php/Logistic_Models

• https://www.youtube.com/watch?v=ovJcsL7vyrk

• Low dimensional chaos in cardiac tissue Nature volume 343, pages653–657(1990)

• Nature vol 261, 261, June 10, 1976

• https://www.youtube.com/watch?v=ETrYE4MdoLQ

Covid 19 and the Pregnant Patient

Christine Kovac, MDMFM

Maternal physiologic adaptations to pregnancy

Many changes in maternal physiology to improve oxygenation to the fetus. Cardiovascular: blood volume increases

by 50% Cardiac output increases by up to 50 Increased heart rate and decreased SVR Past 20 weeks gravid uterus can compress

vena cava, impede return of blood to heart and decrease CO when supine.

Maternal physiologic adaptations to pregnancy

Respiratory: Increased minute ventilation (30-40%) related

increased tidal volume, RR stays unchanged Diaphragm elevated resulting in decrease

residual volume (20%), functional residual capacity and total lung volume (5%) Results in compensated respiratory alkalosis PCO2 27-32, bicarbonate 18-31, PaO2 106 to 108

Pulse-ox should be maintained >95% in pregnancy

Maternal physiologic adaptations to pregnancy

Hematologic changes: Marked increase in plasma volume, red cell

volume, and coagulation factors Physiologic (dilutional) anemia Hypercoagulable state:

Clotting factors: Fibrinogen (factor I), fibrin split products, factors VII, VIII, IX, and X increase by 50%

Prothrombin (factor II) and factors V and XII remain unchanged.

Activated protein C, protein S decrease* (inhibitors of coagulation)

Maternal physiologic adaptations to pregnancy

Renal, GI, and endocrine changes also present. Alk Phos normally increased in pregnancy

due to fetal production. Hypoxia in pregnancy can have effects on

the fetus, can cause preterm contractions. When treating pregnant patient, Mom

comes first.

Covid and Pregnancy

Pregnant women are considered special population because pregnancy is an immunocompromised state. This was especially so with H1N1 and SARS

pandemics (25% mortality for SARS in preg) 1918 flu: 2.6% mortality, 37% in pregnancy

Fortunately, Covid-19 has not affected pregnant women more severely than other patients with similar age and comorbidities Data on vertical transmission very rare

Covid and pregnancy

Comorbid conditions to look out for: Diabetes Obesity Uncontrolled hypertension Chronic renal disease Chronic cardiopulmonary disease Immunosuppresive state

Covid and Pregnancy Prevalence in asymptomatic patients: 13.7% positive in asymptomatic women in NY 3.9% in southern CT Suggests social distancing and precautions

are working. Study of 116 cases in Wuhan: (77%

presented with symptoms pneumonia) 6.9% in ICU 21% with preterm birth None died

Covid and Pregnancy Recent data shows placental injury in patients

affected with moderate and severe symptoms. 16 placentas showed significant difference in

affected placentas to controls in maternal vascular malperfusion including villous infarction, villous agglutination, atherosis, fibrinoid deposition Fetal changes did not reach statistical

significance Suggest patients that recover should continue

to be followed closely

Covid and Pregnancy

Available data from multiple small series and case reports: pregnancy and childbirth do not increase the

risk for acquiring SARS-CoV-2 infection do not worsen the clinical course of COVID-

19 compared with nonpregnant individuals of the same age most (>90 percent) infected mothers recover

without undergoing delivery

Covid and Pregnancy

In pregnant women who develop COVID-19 pneumonia: Approximately the same rate of intensive care

unit (ICU) admissions as in the nonpregnantpopulation Increased risk of preterm and cesarean

delivery. Some of which may be iatrogenic.

Covid and Pregnancy

During pregnancy, SpO2 should be maintained at ≥95 percent, which is in excess of the oxygen delivery needs of the mother. If SpO2 falls below 95 percent, an arterial blood gas is obtained to measure the PaO2: Maternal PaO2 greater than 70 mmHg is desirable to maintain a favorable oxygen diffusion gradient from the maternal to the fetal side of the placenta.

Covid and Pregnancy VTE prophylaxis in the hospital prior to or

following delivery. LMW heparin is appropriate if delivery is

not expected within 24 hours and after delivery Dosing may be increased based on severity

of disease Unfractionated heparin is used if faster

discontinuation is needed (expect delivery, >36 weeks pregnant)

Covid and Pregnancy

Remdesevir with limited data without adverse fetal outcomes Hydroxychloroquine used in pregnancy for

other indications without adverse fetal outcomes.

Covid and Pregnancy

Betamethasone used for fetal lung maturation if concern for PTB Glucocorticoids with potential increased

mortality in Covid pneumonia Clear benefit to fetus, should still be used if 24

-33 6/7 weeks and anticipate delivery Dexamethason? – crosses placenta

Avoid NSAID’s: use nifedipine instead of indocin for tocolysi. Recs for low-dose aspirin not as clear

Covid and Pregnancy

Some lab abnormalities can overlap with preeclampsia/HELLP syndrome Elevated LFT’s Elevated LDH Low platelets

Covid in Pregnancy

Fetal monitoring Daily if maintain O2 >95 More frequent if <95%

Consider delivery if need intubation Intubation alone is not an indication for

delivery Prone positioning appropriate in

pregnancy Consider cushioning

Covid and Pregnancy

Delivery considerations: Mild disease and recover not indicated Intubated and critically ill, may improve

ventilation regardless of gestational age Severe disease, not yet intubated, and > 32-

34 weeks, may improve respiratory status Positive covid and >36 weeks, controversial

OB care in Covid Pandemic

Pregnancy does not stop for Covid Many pregnancy complications are

unpredictable Many early visits able to be done through

telemedicine Ultrasounds, and third trimester visits

more critical. Consolidate where possible

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PLAYBOOK UPDATES

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Pulmonary Function Testing Playbook

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Pulmonary Function Testing Playbook

• Full draft document can be accessed by clicking on the icon below:

HOW DO WE KNOW WHAT WE KNOW?COWBOYS, THE IVORY TOWER, AND

EPISTEMOLOGY IN THE ERA OF COVID

Guy Dugan

CHLOROQUINE AND ITS ANALOGUE HYDROXYCHLOROQUINE

• Antiviral properties as well as immunomodulatory effects in the laboratory

• On March 28, 2020, the FDA issued an emergency use authorization for these drugs in patients if clinical trial access was unavailable.

• Ancient history

HYDROXYCHLOROQUINE OR CHLOROQUINE WITH OR WITHOUT A MACROLIDE FOR TREATMENT OF COVID-19: A

MULTINATIONAL REGISTRY ANALYSISMANDEEP R MEHRA, SAPAN S DESAI , FRANK RUSCHITZKA, AMIT N PATEL

MAY 22, 2020

• Evaluate the use of chloroquine or hydroxychloroquine alone or in combination with a macrolide for treatment of COVID-19 using a large multinational registry- Surgisphere

• 96, 032 pts were included from 671 hospitals, 6 continents from 12/20/19-4/14/20

• Chloroquine or hydroxychloroquine alone or in combination with a macrolide was associated with an increased hazard for clinically significant occurrence of ventricular arrhythmias and increased risk of in-hospital death with COVID-19.

MULTINATIONAL REGISTRYSURGISPHERE

• The Surgical Outcomes Collaborative -Surgisphere Corporation, Chicago, IL, USA

• Founder and CEO, Dr. Sapan Desai, vascular surgeon at Northwest Community Hospital in Arlington Heights

• De-identified data from inpatient and outpatient electronic health records, supply chain databases, and financial records.

• A manual data entry process is used for quality assurance and validation to ensure that key missing values are kept to a minimum.

• Data for 2 international studies- Lancet, NEJM

• Fewer than 12 employees

• Registry largely unknown,

• Research community surprised such a database existed, or the work could be completed so quickly

MANDEEP R. MEHRA, M.D

• Medical director of the Brigham and Women’s Hospital (BWH) Heart and Vascular Center advanced heart failure and cardiac transplantation

• 200 peer reviewed publications

• Lead author on both the Lance and NEJM study

• Editor-in-chief of The Journal of Heart and Lung Transplantation.

GLOBAL RESPONSE TO STUDY

• The New York Times “Malaria Drug Taken by Trump Is Tied to Increased Risk of Heart Problems and Death in New Study.”

• Washington Post headline: “Antimalarial drug touted by President Trump is linked to increased risk of death in coronavirus patients, study says.”

• CNN- you can imagine

• The WHO stopped recruitment in hydroxychloroquine arm in SOLIDARITY trial

• The UK stopped recruitment into all hydroxychloroquine trials in the UK (treatment and prevention),

• France has changed its national recommendation for the use of hydroxychloroquine in COVID-19 treatment and also halted trials.

• AMITA Critical Drug Task Force stopped hydroxychloroquine use

THERE WAS ANOTHER RESPONSE

• When the data was requested, Professor Mehra has replied;

• “Our data sharing agreements with the various governments, countries and hospitals do not allow us to

share data unfortunately.”

• Oh, the data is a secret.

WTF

• Where’s the form?

SURGISPHERE

Open letter to MR Mehra, SS Desai, F Ruschitzka, and AN Patel, authors of “Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis”. Lancet. 2020 May 22:S0140-6736(20)31180-6. doi:

10.1016/S0140-6736(20)31180-6. PMID: 32450107

and to Richard Horton (editor of The Lancet).

Concerns regarding the statistical analysis and data integrity

Dr James Watson (Statistician, Mahidol Oxford Tropical Medicine Research Unit, Thailand) plus 146 signatories

May 28, 2020

INTERNATIONAL CONCERNS-LETTER TO LANCET

1.Inadequate adjustment for known and measured confounders (disease severity, temporal effects, site effects, dose used).

2.The authors have not adhered to standard practice. They have not released their code or data.

3.There was no ethics review.

4.There was no mention of the countries or hospitals that contributed to the data source and no acknowledgments to their contributions. A request to the authors for information on the contributing centres was denied.

5.Data from Australia are not compatible with government reports (too many cases for just five hospitals, more in-hospital deaths than had occurred in the entire country during the study period). Surgisphere (the data company) have since stated this was an error of classification of one hospital from Asia. This indicates the need for further error checking throughout the database.

INTERNATIONAL CONCERNS-LETTER TO LANCET

• 6.Data from Africa indicate that nearly 25% of all COVID-19 cases and 40% of all deaths in the continent occurred in Surgisphere-associated hospitals which had sophisticated electronic patient data recording, and patient monitoring able to detect and record “nonsustained [at least 6 secs] or sustained ventricular tachycardia or ventricular fibrillation”. Both the numbers of cases and deaths, and the detailed data collection, seem unlikely.

• 7. Unusually small reported variances in baseline variables, interventions and outcomes between continents (Table S3).

• 8. Mean daily doses of hydroxychloroquine that are 100 mg higher than FDA recommendations, whereas 66% of the data are from North American hospitals.

• 9.Implausible ratios of chloroquine to hydroxychloroquine use in some continents • 10. The tight 95% confidence intervals reported for the hazard ratios are unlikely. For

instance, for the Australian data this would need about double the numbers of recorded deaths as were reported in the paper.

RETRACTION—HYDROXYCHLOROQUINE OR CHLOROQUINE WITH OR WITHOUT A MACROLIDE FOR TREATMENT OF COVID-

19: A MULTINATIONAL REGISTRY ANALYSISMANDEEP R MEHRA

FRANK RUSCHITZKAAMIT N PATELJUNE 5TH, 2020

• Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis as such transfer would violate client agreements and confidentiality requirements. As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peer-review process.

• . Today, three of the authors of the paper, “Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis”, have retracted their study.

CARDIOVASCULAR DISEASE, DRUG THERAPY, AND MORTALITY IN COVID-19R. MEHRA, M.D., SAPAN S. DESAI, M.D., PH.D., SREYRAM KUY, M.D., M.H.S. ,

TIMOTHY D. HENRY, M.D., AND AMIT N. PATEL, M.D.NEJM MAY 1, 2020

• NEJM article retracted 1 hour later

LANCET MEA CULPAS

• Richard Horton, editor of the Lancet, “Lessons not consequences I hope.”

• Professor Mehra "I did not do enough to ensure that the data source was appropriate for this use. For that, and for all the disruptions – both directly and indirectly – I am truly sorry.”

INTERNATIONAL REACTIONS

• "When you have reputable journals that put this kind of work out and are retracted 10 days later, it just increases mistrust, it just adds fuel to the fire of this controversy around hydroxychloroquine ... It's the last thing we needed with this particular drug.”

Dr. Walid Gellad, Professor at University of Pittsburgh's medical school.

INTERNATIONAL REACTIONS

• “It is right that these articles were retracted. However, the failure to resolve such basic concerns about the data during the course of normal peer review raises serious questions about the standard of editing at the Lancet and NEJM — ostensibly two of the world’s most prestigious medical journals. If these journals take issues of reproducibility and scientific integrity as seriously as they claim, then they should forthwith submit themselves and their internal review processes to an independent inquiry.”

Prof Chris Chambers, School of Psychology, Cardiff University Brain Research Imaging Centre, (Chair of the Registered Reports Committee, Center for Open Science and Member of the UK Reproducibility Network Steering Group)

CONVERGES TO ONGOING DIALOGUE IN THE CONSORTIUM

• How do we know what we know and how do we act with imperfect or missing data when this repeatedly got though the reviewers and editors of the world’s most prestigious journals.

• What is the role of experience, clinical judgement?

• Levels of evidence to act- drug therapy, ventilation strategies, oxygen delivery, PPE

FIRST DO NO HARMPRIMUM NON NOCEREHIPPOCRATES 400 BCE

• “I will follow that system of regimen which, according to my ability and judgment, I consider for the benefit of my patients, and abstain from whatever is deleterious and mischievous.”

• Yes, the pledge commits to avoiding harm, but there’s nothing about making it a top priority. Meanwhile, Of the Epidemics says

• “The physician must be able to tell the antecedents, know the present, and foretell the future — must mediate these things, and have two special objects in view with regard to disease, namely, to do good or to do no harm.”

COWBOYS AND ACADEMICSJOSH FARKAS, UNIV VERMONT. PULMCRIT

• Nearly all hospitals lack access to randomized controlled trials. So, while it sounds nice to recommend that treatments be provided within randomized controlled trials, this is unrealistic.

• Patients are doing poorly with basic supportive care only.

• Based on indirect evidence, it’s sensible to use some interventions which haven’t been proven to be effective in COVID-19

• Any treatment which hasn’t been proven in a double-blind, randomized controlled trial among COVID-19 patients is experimental.

• Experimental treatments should be restricted to randomized controlled trials.

• Outside of a randomized controlled trial, patients should be treated with basic supportive care only.

Cowboys Academics

COVID19: FIRST DO NO HARM

• Unproven therapies are dangerous and unjustified which may increase mortality

• Clinicians must not succumb to the impulse to “do something else” but instead stick to evidence-based therapies and, if possible, enroll their patients into adaptive clinical trials

• Grant W. Waterer, M.B. B.S., Ph.D. Northwestern University Jordi Rello, M.D., Ph.D. Centro de Investigacio ́ n Biomedica Madrid, Espan ̃aVall d’Hebron Institute of Research (VHIR) Barcelona, SpainandCHU Nˆımes Universite ́ Montpellier-Nˆımes Nˆımes, France Richard G. Wunderink, M.D. Northwestern University

FIRST DO NO HARMWHAT DOES THAT MEAN?IS THAT EVEN POSSIBLE?

• Choosing not to do something is as active as choosing to do something

• All interventions and treatments have risk. Doing nothing has risk.

• What level of evidence is acceptable to initiate an action?

FIRST DO NO HARMWHO DECIDES?

• SCCM guidelines recommended using steroid for intubated COVID patients with ARDS. Meanwhile, the IDSA guidelines recommend that steroid is experimental therapy which should be provided only within an RCT.

• Disagreement on HFNC, NIV

• ASH recommendations on anticoagulation

• Infectious Disease Society of America guidelines for COVID-19. These guidelines recommend against any unproven therapies for COVID-19. However, at least one co-author of these guidelines works at a hospital which was publicly recommending hydroxychloroquine (at the time that the IDSA guidelines were published)

COVID19- FIRST DO NO HARM

• Concerns that results from conventional trials can take yearsis proving false with hundreds of patients enrolled within 6 weeks in at least two SARS-CoV-2–specific clinical trials. Adaptive multicenter trials with interim analyses have the ability to determine if an intervention is superior to placebo and adjust the standard of care and move on to test new therapies in rapid succession.

RESEARCH INFRASTRUCTURE FAILUREJOSH FARKAS, UNIV VERMONT. PULMCRIT

• Instead, relatively few patients were included in randomized controlled trials. The dust is settling now and different hospitals are publishing their experiences with COVID-19 – which are generally ambiguous. A few industry-funded studies will likely emerge soon.

• Fifty years ago we put a man on the moon, but today it seems like an insurmountable challenge to organize an open-label randomized trial of prednisone.

• Overall, this represents a tragically missed opportunity. As we re-tool for the next wave of COVID-19, we remain in a weak position.

• Why did we allow this opportunity to slip through our fingers? Several reasons, but one main one is the delay required for any trial to gain approval of institutional review boards (IRBs). By the time RCTs gained IRB approval, the surge had already passed by. The difficulty of obtaining IRB approval alone may have deterred investigators who were busy managing patients. IRBs are designed to protect patients, but in a time of pandemic they prevented us from properly investigating this disease – thereby placing the remaining populace at risk.

LESSONS TO LEARN

• Science must always be interpreted but we must guard against politicizing it

• But, it is always political: pandemics, environmental science, space exploration, stem cells, etc., etc.

• Science has fads just like everything else

LESSONS TO LEARNCONFIRMATION BIAS IS DEADLY

• What you think of the universe is how you perceive it

• Controls the questions you ask

• The methods and instruments you use

• What you take as reliable evidence

• How you interpret the data from experiments

• Our answers are framed by the way the ask the question and our bias to the answer we are looking

• We must guard against fooling ourselves, and we are the easiest ones to fool

• We all live in glass houses

• A spoonful of humility helps the medicine go down

REFERENCES

•

• https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31180-6.pdf

• https://www.nejm.org/doi/full/10.1056/NEJMoa2007621

• https://zenodo.org/record/3862789#.Xt1pMJ5KiRv open letter

• https://emcrit.org/pulmcrit/pulmcrit-american-research-infrastructure-is-killing-us-the-misbegotten-battle-between-the-ivory-tower-academics-and-the-rogue-cowboys/

• https://www.atsjournals.org/doi/pdf/10.1164/rccm.202004-1153ED

• https://www.thelancet.com/lancet/article/s0140673620313246

• https://www.nejm.org/doi/full/10.1056/NEJMc2021225

REFERENCES

• https://www.nejm.org/doi/full/10.1056/NEJMoa2012410?query=featured_home

• https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31324-6/fulltext

• https://www.health.harvard.edu/blog/first-do-no-harm-201510138421#:~:text=As%20an%20important%20step%20in,translation%20from%20the%20original%20Greek.

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Sun Lee-Such, PharmD, BCPS, FACHESystem Vice President, Pharmacy ServicesJun 9, 2020

Critical Drug Task Force Update

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Critical Drug Task ForceCOVID-19 Treatment Guideline Updates

•Tocilizumab

•https://www.amitahealth.org/covid-19-amita/

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Critical Drug Task ForceCOVID-19 Treatment Guideline Updates

•Remdesivir

•Tocilizumab

•https://www.amitahealth.org/covid-19-amita/

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COVID-19 Treatment Guideline Update:Remdesivir

Restrict use to ID providers• Hospitalized patient

• Positive SARS-CoV-2

• At least ONE of the following respiratory criteria:

- Rapidly worsening gas exchange requiring doubling of oxygen requirements in 12 hours OR

- Requiring supplemental oxygen to maintain SpO2 > 90% OR

- Respiratory failure on mechanical ventilation for less 72 hours

•

Inclusion Criteria

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Remdesivir Inventory & UtilizationMay 13 – Jun 8

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Remdesivir Daily UtilizationMay 13 – Jun 8

New COVID-19 (+) Inpatient – avg 24/day

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Tocilizumab (Actemra)Key Comments/Notable Events

COVID-19 Treatment

History

• Feb-March 2020: Reports from China that tocilizumab was part of clinical treatment protocols, especially in severe and critical patients

• April 2020: Small studies from China and Italy showing improved clinical outcomes as an effective treatment to reduce mortality; severity and progression of inflammatory response seen in COVID-19 made tocilizumab an attractive option in critical COVID-19 cases

Recent Clinical

Evidence

Unclear Benefit

• Retrospective study in severe COVID-19 non-ICU patients with hyper-inflammatory features with 28 day follow-up

• Review of 65 patients: 32 received tocilizumab vs. 33 who did not• No statistically difference in clinical improvement and mortality:

• Clinical improvement reached in 22 (69%) of tocilizumab group vs. 20 (61%) in control group

• 5 (16%) of toclizumab group died vs. 11 (33%) of control group

• Authors’ conclusion: At day 28, clinical improvement and mortality were not statistically different when given tocilizumab vs. standard care

Corrado Campochiaro, et al., Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Int Med. doi: https://doi.org/10.1016/j.ejim.2020.05.021.

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Tocilizumab (Actemra)

Key Comments/Notable Events

Recent Clinical

Evidence

Increased Risk

• Observational study at U of Chicago/Rush in COVID-19 ICU patients• Review of 60 patients: 28 received tocilizumab vs. 32 who did not• Tocilizumab was associated with higher incidence of secondary

bacterial infections including hospital-acquired pneumonia & ventilator-associated pneumonia (64.3% vs. 31.3% p=0.010).

• 2 tocilizumab patients with fungal infections (mucor PNA and sinusitis) vs. none in control group

• No evidence of benefit was seen

• Authors’ conclusion:• While there may be a subset of patients who may potentially

benefit from tocilizumab, current evidence does not support its routine use for COVID-19.

• Findings raise concerns about the use of tocilizumab in the presence of an infection to attenuate cytokine release syndrome

Kimmig LM, Wu D, Gold M, et al. IL6 Inhibition in critically ill COVID-19 patients is associated with increased secondary infections. Prepublication. https://www.medrxiv.org/content/10.1101/2020.05.15.20103531v1.

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Tocilizumab (Actemra)Key Comments/Notable Events

AMITA Historical Use

• Mid-March to early-April: 47 doses (avg 3 doses daily) dispensed daily

• Mid-April to mid-May: 276 doses (avg 9 doses daily) dispensed daily

• Past 10 days: avg 1 dose dispensed daily

National Guideline

Statements

• NIH: Insufficient clinical data to recommend either for or against use

• WHO: Should not be administered as treatment or prophylaxis outside of the context of clinical trials

• IDSA: Should only be used in the context of a clinical trial

AMITA COVID-19 Treatment

Recommendationfrom CDTF

• AVOID USE – Risks outweigh benefit

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THANK YOU

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Meeting Materials & Recording

• Slides and the link to the meeting recording will be distributed following the meeting.

• This information will also be posted on the AMITA Health COVID-19 site (top of page under same section as physician townhall recordings).

CME Information• For CME credit, please complete the form available at the

following link:https://www.surveymonkey.com/r/COVIDCONSORTIUM

Reminders