The ACTS Randomized Clinical Trial

Now we  got three decently-sized randomized controlled trials, all in agreement: vitamin C does not reverse organ failure in sepsis," commented critical care physician Robert Dickson, MD, of the University of Michigan School of Medicine in Ann Arbor.

The VITAMINS trial showed no advantage in recovery from septic shock and numerically higher mortality with a vitamin C-hydrocortisone-thiamine combination. The CITRIS-ALI trial showed no impact on SOFA scores from high-dose IV vitamin C.

"If the signal of benefit for vitamin C was anywhere near as strong as was initially suggested, it shouldn't be this hard to detect it in clinical trials," Dickson added.

The researchers noted that vitamin C has also been proposed for treating respiratory failure from COVID-19, as was seen in a recent case report.

However, Dickson said, "the data supporting use of vitamin C in sepsis were already weak. The data supporting its use in COVID-19 are non-existent."

Any excuses Paul Marick after belittling the primary investigator of the Vitamins Trial?

Ref: Kamagurka

Cytokine Storm Nothing but a Tempest in Teapot?

I have often asked myself if I ever saw a patient with cytokine storm syndrome (CSS)  in the COVID-19 population. The "infamous " H-score which has been proposed as a clinical tool to assess post-test probability for CSS, has never been tested in a  COVID-19 population. 

Manifestations of CSS include systemic inflammation including fever, tachycardia, tachypnea and hypotension . How is this different from systemic inflammatory response syndrome (SIRS).

In the attached article we will also see that inflammatory markers, particularly IL-6 are "MUCH, MUCH"  lower on  average compared to  patients with ARDS due to  other etiologies.

Giving tocilizumab for example , directed at the single inflammatory response cytokine, reminds me of the multiple trials we ran years ago, giving  patient's monoclonal antibodies directed against a single inflammatory marker and sepsis. All those trials were acute disappointments.

We have absolutely no data if tocilizumab or sarilumab , beneficially affects mortality. As a matter of fact, these mediators are needed in a complex cascade of immunomodulation. Do we know for sure  that we do not increase risk for secondary infections?  Immunomodulation is a complex mechanism with pleiotropic effects of various modulators.

A simpler concept to understand and we now  have data on is that  SARS CoV-2 with it S-proteins deregulates ( and invades actual cells) endothelial function and is associated with  arterial thrombosis and venous thrombosis, both intra- pulmonary and extrapulmonary. Although we have no outcome studies yet, treating patients with anticoagulation in COVID-19, biologically makes far more sense than chasing CSS.

The attached article questions if CSS is actually a real and separate syndrome in COVID-19.

Please send me some comments after reading the article. I quite frankly do not worry much about CSS. Identifying the need of anticoagulation is far more important, something we totally disregarded in the treatment package early on during the COVID-19 epidemic.  Yet we saw patient receiving tocilizumab all the time, based on zero data. 

From HCQ/AZ, no steroids and  tocilizumab........to  remdesivir ( I have serious doubts on its beneficial effect, Tamiflu 2.0 ), DXM and anticoagulation....

Severe COVID-19 is associated with deep and sustained multifaceted cellular immunosuppression https://t.co/CpbQRnVFAI

— Guy De Gent (@gdegent) July 4, 2020

9/5/2020. Here is  more data from theUniversiteit van Nijmegen in Holland that cytokine storm probably is not part of SARSCov2 infection, as already written earlier in this post, I can't recall ever seen one clinically. As a matter a fact we maybe doing the complete wrong intervention by suppressing the immune system .Tociluzimab is even given from day one by some institutions with Remdesivir, biologically that makes no sense. 

Their Conclusion :

 "In this study, critically ill patients with COVID-19 with ARDS had circulating cytokine levels that were lower compared with patients with bacterial sepsis and similar to other critically ill patients. These findings are in line with lower leukocyte counts observed in patients with COVID-19, and are possibly due to lower overall disease severity, despite the presence of severe pulmonary injury. The findings of this preliminary analysis suggest COVID-19 may not be characterized by cytokine storm. Whether anticytokine therapies will benefit patientswith COVID-19 remains to be determined."

Covid-19 deadlier than acute myocardial infarction

This figure (via @ScottGottliebMD) receiving a lot of attention

And folks rightly point out mortality rates lower for young than for elderly

But thats true for every disease

So as point of reference:

How do these rates compare to mortality for folks with heart attack?

Thread pic.twitter.com/Vw1mtCcXCE

— Ashish K. Jha (@ashishkjha) June 28, 2020

Anticoagulation for COVID-19 (correspondence in the European Heart Journal)

Anticoagulation Management COVID-19

UNC Chapel Hill developed an anticoagulation algorithm (link here) in which COVID-19 patients to use anticoagulants and at what dose-intensities. The algorithm was created through discussions between UNC hematologists, intensivists, and pulmonologists, consideration of published data, and discussions with national hematology-coagulation colleagues. It is neither overly aggressive, nor overly passive; it’s an intermediate anticoagulant approach.

Link to SCCM article on coagulopathy in COVID -19

Click on Images to Enlarge

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up

JACC State-of-the-Art Review

Role of TEG in COVID-19? reference letter in JAMA 

Thromboelastographic Results and Hypercoagulability Syndrome in Patients With Coronavirus Disease 2019 Who Are Critically Ill

• All patients with COVID-19 should undergo coagulation studies at admission, in particular: D-dimer, prothrombin time, and platelet count.
• Because of the possibility of patients to develop coagulopathy later in their hospital course, routine serial measurements of coagulation studies should be undertaken in all COVID-19 patients. The ideal interval has not yet been defined . 
• All patients with COVID-19 should be placed on prophylactic doses of anticoagulation, preferably with LMWH, unless there is a contraindication, such as acute kidney injury (AKI), wherein unfractionated heparin is preferred. 
• Therapeutic anticoagulation should be strongly considered in patients at high-risk for coagulopathy (including CRRT and ECMO), demonstrating signs of microthrombi-induced organ dysfunction, or with documented or strongly suspected macro-thromboembolism. Determination of high-risk patients by laboratory measures of coagulopathy may include: platelet count, prothrombin time, fibrinogen, fibrinogen-degradation products, D-dimer, and TEG. Of note, some centers are therapeutically anticoagulating all patients on admission when no absolute contraindications exist. 
• Given the significant rate of AKI seen in COVID, intravenous contrast for imaging should be used with caution. Duplex ultrasonography, echocardiography, and clinical suspicion can play an increased role in these cases. 
• Some early reports support extended-infusion tPA as a potential approach to refractory cases 
• Aspirin should be considered in cases with elevated troponin and cardiac dysfunction, particularly with elevated maximal amplitude on TEG.

Conclusions  Lancet study on TEG:
COVID-19 patients in the intensive care unit (ICU) demonstrated venous thromboembolism (VTE) in 27%, and arterial thrombosis in 3.7%.
Investigators observed the TEG parameter for lysis at 30 minutes (LY30) was statistically significantly linked to VTE, with an AUROC of 0.742 (P = .021).  The TEG α-angle and D-dimer were significantly associated with new onset need for dialysis (0.771 [P = .035] and 0.779 [P = .005], respectively).
"As a rapid test to demonstrate complete fibinolysis shutdown, an LY30 of 0% in conjunction with D-dimer levers of 2600ng/ml may serve as a sensitive marker for the patients most at risk for VTE and other thrombotic complications," Wright and colleagues concluded.

Money Isn't Everything

How were Kerala, India and Vietnam so successful vs #COVID19?
“Countries that took early, aggressive action, using proven methods, have severely limited the virus. ..if you reduce fast enough, you never reach the point of exponential growth.” @toddmpollack https://t.co/5oWeISdNu7 pic.twitter.com/VJ19ZAkbtA

— Eric Topol (@EricTopol) May 8, 2020

How to Ventilate Patients with COVID-19